Chromosome abnormalities can be numerical or structural. A numerical abnormality mean an individual is either missing one of the chromosomes from a pair or has more than two chromosomes instead of a pair. A structural abnormality means the chromosome's structure has been altered in one of several ways.

What are chromosomes?

Chromosomes are the structures that hold genes. Genes are the individual instructions that tell our bodies how to develop and function; they govern physical and medical characteristics, such as hair color, blood type and susceptibility to disease.

Many chromosomes have two segments, called "arms," separated by a pinched region known as the centromere. The shorter arm is called the "p" arm. The longer arm is called the "q" arm.

Where are chromosomes found in the body?

The body is made up of individual units called cells. Your body has many different kinds of cells, such as skin cells, liver cells and blood cells. In the center of most cells is a structure called the nucleus. This is where chromosomes are located.

How many chromosomes do humans have?

The typical number of chromosomes in a human cell is 46: 23 pairs, holding an estimated total of 20,000 to 25,000 genes. One set of 23 chromosomes is inherited from the biological mother (from the egg), and the other set is inherited from the biological father (from the sperm).

Of the 23 pairs of chromosomes, the first 22 pairs are called "autosomes." The final pair is called the "sex chromosomes." Sex chromosomes determine an individual's sex: females have two X chromosomes (XX), and males have an X and a Y chromosome (XY). The mother and father each contribute one set of 22 autosomes and one sex chromosome.

How do scientists study chromosomes?

For a century, scientists studied chromosomes by looking at them under a microscope. In order for chromosomes to be seen this way, they need to be stained. Once stained, the chromosomes look like strings with light and dark "bands," and their picture can be taken. A picture, or chromosome map, of all 46 chromosomes is called a karyotype. The karyotype can help identify abnormalities in the structure or the number of chromosomes.

To help identify chromosomes, the pairs have been numbered from 1 to 22, with the 23rd pair labeled "X" and "Y." In addition, the bands that appear after staining are numbered; the higher the number, the farther that area is from the centromere.

In the past decade, newer techniques have been developed that allow scientists and doctors to screen for chromosomal abnormalities without using a microscope. These newer methods compare the patient's DNA to a normal DNA sample. The comparison can be used to find chromosomal abnormalities where the two samples differ.

One such method is called noninvasive prenatal testing. This is a test to screen a pregnancy to determine whether a baby has an increased chance of having specific chromosome disorders. The test examines the baby's DNA in the mother's blood.

What are chromosome abnormalities?

There are many types of chromosome abnormalities. However, they can be organized into two basic groups: numerical abnormalities and structural abnormalities.

• Numerical Abnormalities: When an individual is missing one of the chromosomes from a pair, the condition is called monosomy. When an individual has more than two chromosomes instead of a pair, the condition is called trisomy.

An example of a condition caused by numerical abnormalities is Down syndrome, which is marked by mental disability, learning difficulties, a characteristic facial appearance and poor muscle tone (hypotonia) in infancy. An individual with Down syndrome has three copies of chromosome 21 rather than two; for that reason, the condition is also known as Trisomy 21. An example of monosomy, in which an individual lacks a chromosome, is Turner syndrome. In Turner syndrome, a female is born with only one sex chromosome, an X, and is usually shorter than average and unable to have children, among other difficulties.

• Structural Abnormalities: A chromosome's structure can be altered in several ways.

  • Deletions: A portion of the chromosome is missing or deleted.

  • Duplications: A portion of the chromosome is duplicated, resulting in extra genetic material.

  • Translocations: A portion of one chromosome is transferred to another chromosome. There are two main types of translocation. In a reciprocal translocation, segments from two different chromosomes have been exchanged. In a Robertsonian translocation, an entire chromosome has attached to another at the centromere.

  • Inversions: A portion of the chromosome has broken off, turned upside down, and reattached. As a result, the genetic material is inverted.

  • Rings: A portion of a chromosome has broken off and formed a circle or ring. This can happen with or without loss of genetic material.

Most chromosome abnormalities occur as an accident in the egg or sperm. In these cases, the abnormality is present in every cell of the body. Some abnormalities, however, happen after conception; then some cells have the abnormality and some do not.

Chromosome abnormalities can be inherited from a parent (such as a translocation) or be "de novo" (new to the individual). This is why, when a child is found to have an abnormality, chromosome studies are often performed on the parents.

How do chromosome abnormalities happen?

Chromosome abnormalities usually occur when there is an error in cell division. There are two kinds of cell division, mitosis and meiosis.

• Mitosis results in two cells that are duplicates of the original cell. One cell with 46 chromosomes divides and becomes two cells with 46 chromosomes each. This kind of cell division occurs throughout the body, except in the reproductive organs. This is the way most of the cells that make up our body are made and replaced.

• Meiosis results in cells with half the number of chromosomes, 23, instead of the normal 46. This is the type of cell division that occurs in the reproductive organs, resulting in the eggs and sperm.

In both processes, the correct number of chromosomes is supposed to end up in the resulting cells. However, errors in cell division can result in cells with too few or too many copies of a chromosome. Errors can also occur when the chromosomes are being duplicated.

Other factors that can increase the risk of chromosome abnormalities are:

• Maternal Age: Women are born with all the eggs they will ever have. Some researchers believe that errors can crop up in the eggs' genetic material as they age. Older women are at higher risk of giving birth to babies with chromosome abnormalities than younger women. Because men produce new sperm throughout their lives, paternal age does not increase risk of chromosome abnormalities.

• Environment: Although there is no conclusive evidence that specific environmental factors cause chromosome abnormalities, it is still possible that the environment may play a role in the occurrence of genetic errors.

Human cells normally contain 23 pairs of chromosomes, for a total of 46 chromosomes in each cell. A change in the number of chromosomes can cause problems with growth, development, and function of the body's systems. These changes can occur during the formation of reproductive cells (eggs and sperm), in early fetal development, or in any cell after birth. A gain or loss in the number of chromosomes from the normal 46 is called aneuploidy.

A common form of aneuploidy is trisomy, or the presence of an extra chromosome in cells. "Tri-" is Greek for "three"; people with trisomy have three copies of a particular chromosome in cells instead of the normal two copies. Down syndrome (also known as trisomy 21) is an example of a condition caused by trisomy. People with Down syndrome typically have three copies of chromosome 21 in each cell, for a total of 47 chromosomes per cell.

Monosomy, or the loss of one chromosome in cells, is another kind of aneuploidy. "Mono-" is Greek for "one"; people with monosomy have one copy of a particular chromosome in cells instead of the normal two copies. Turner syndrome (also known as monosomy X) is a condition caused by monosomy. Women with Turner syndrome usually have only one copy of the X chromosome in every cell, for a total of 45 chromosomes per cell.

Rarely, some cells end up with complete extra sets of chromosomes. Cells with one additional set of chromosomes, for a total of 69 chromosomes, are called triploid. Cells with two additional sets of chromosomes, for a total of 92 chromosomes, are called tetraploid. A condition in which every cell in the body has an extra set of chromosomes is not compatible with life.

In some cases, a change in the number of chromosomes occurs only in certain cells. When an individual’s cells differ in their chromosomal makeup, it is known as chromosomal mosaicism. Chromosomal mosaicism occurs from an error in cell division in cells other than eggs and sperm. Most commonly, some cells end up with one extra or missing chromosome (for a total of 45 or 47 chromosomes per cell), while other cells have the usual 46 chromosomes. Mosaic Turner syndrome is one example of chromosomal mosaicism. In females with this condition, some cells have 45 chromosomes because they are missing one copy of the X chromosome, while other cells have the usual number of chromosomes.

Many cancer cells also have changes in their number of chromosomes. These changes are not inherited; they occur in somatic cells (cells other than eggs or sperm) during the formation or progression of a cancerous tumor.

Changes that affect the structure of chromosomes can cause problems with growth, development, and function of the body's systems. These changes can affect many genes along the chromosome and disrupt the proteins made from those genes.

Structural changes can occur during the formation of egg or sperm cells, in early fetal development, or in any cell after birth. Pieces of DNA can be rearranged within one chromosome or transferred between two or more chromosomes. The effects of structural changes depend on their size and location, whether gene function is interrupted, and whether any genetic material is gained or lost. Some changes cause health problems, while others may have no effect on a person's health.

Changes in chromosome structure include the following:

Translocations

A translocation occurs when a piece of one chromosome breaks off and attaches to another chromosome. This type of rearrangement is described as balanced if no genetic material is gained or lost in the cell. If there is a gain or loss of genetic material, the translocation is described as unbalanced.

Deletions

Deletions occur when a chromosome breaks and some genetic material is lost. Deletions can be large or small, and can occur anywhere along a chromosome.

Duplications

Duplications occur when part of a chromosome is abnormally copied (duplicated). This type of chromosomal change results in extra copies of genetic material from the duplicated segment.

Inversions

An inversion occurs when a chromosome breaks in two places; the resulting piece of DNA is reversed and re-inserted into the chromosome. Genetic material may or may not be lost as a result of the chromosome breaks. An inversion that includes the chromosome's constriction point (centromere) is called a pericentric inversion. An inversion that occurs in the long (q) arm or short (p) arm and does not involve the centromere is called a paracentric inversion.

Isochromosomes

An isochromosome is a chromosome with two identical arms. Instead of one q arm and one p arm, an isochromosome has two q arms or two p arms. As a result, these abnormal chromosomes have an extra copy of some genes and are lacking copies of genes on the missing arm.

Dicentric chromosomes

Unlike normal chromosomes, which have one centromere, a dicentric chromosome contains two centromeres. Dicentric chromosomes result from the abnormal fusion of two chromosome pieces, each of which includes a centromere. These structures are unstable and often involve a loss of some genetic material.

Ring chromosomes

Ring chromosomes usually occur when a chromosome breaks in two places, typically at the ends of the p and q arms, and then the arms fuse together to form a circular structure. The ring may or may not include the centromere, depending on where on the chromosome the breaks occur. In many cases, genetic material near the ends of the chromosome is lost.

Many cancer cells also have changes in their chromosome structure. These changes are not inherited; they occur in somatic cells (cells other than eggs or sperm) during the formation or progression of a cancerous tumor.

Although it is possible to inherit some types of chromosomal abnormalities, most chromosomal disorders (such as Down syndrome and Turner syndrome) are not passed from one generation to the next.

Some chromosomal conditions are caused by changes in the number of chromosomes. These changes are not inherited, but occur as random events during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction results in reproductive cells with an abnormal number of chromosomes. For example, a reproductive cell may accidentally gain or lose one copy of a chromosome. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have an extra or missing chromosome in each of the body’s cells.

Changes in chromosome structure can also cause chromosomal disorders. Some changes in chromosome structure can be inherited, while others occur as random accidents during the formation of reproductive cells or in early fetal development. Because the inheritance of these changes can be complex, people concerned about this type of chromosomal abnormality may want to talk with a genetics professional.

Some cancer cells also have changes in the number or structure of their chromosomes. Because these changes occur in somatic cells (cells other than eggs and sperm), they cannot be passed from one generation to the next.

Chromosome 1 is the largest human chromosome, spanning about 249 million DNA building blocks (base pairs) and representing approximately 8 percent of the total DNA in cells. Chromosome 1 likely contains 2,000 to 2,100 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 1.

1p36 deletion syndrome

1p36 deletion syndrome is caused by a deletion of genetic material from a specific region in the short (p) arm of chromosome 1. The signs and symptoms of this disorder, which include intellectual disability, distinctive facial features, and structural abnormalities in several body systems, are probably related to the loss of multiple genes in this region. The size of the deletion varies among affected individuals.

1q21.1 microdeletion

1q21.1 microdeletion is a chromosomal change in which a small piece of the long (q) arm of chromosome 1 is deleted in each cell. Most commonly, affected individuals are missing about 1.35 million DNA building blocks (base pairs), also written as 1.35 megabases (Mb), in the q21.1 region. However, the exact size of the deleted region varies. The loss of multiple genes from this region probably contributes to the various signs and symptoms that can be associated with a 1q21.1 microdeletion. Related features can include delayed development, intellectual disability, physical abnormalities, and neurological and psychiatric problems; however, some individuals with a 1q21.1 microdeletion have no obvious signs or symptoms.

1q21.1 microduplication

A 1q21.1 microduplication is a copied (duplicated) segment of genetic material at position q21.1 on one of the two copies of chromosome 1 in each cell. Some people with a 1q21.1 microduplication have developmental delay, intellectual disability, or features of autism spectrum disorders characterized by impaired communication and socialization skills. Affected individuals may also have psychiatric disorders such as schizophrenia, malformations of the heart, or other neurological or physical features. Other individuals with 1q21.1 microduplications have no identified physical, intellectual, or behavioral problems.

1q21.1 microduplications most often involve the same segment of about 1.35 million base pairs that is missing in 1q21.1 microdeletions (described above). In other cases, individuals have a shorter or longer duplicated segment within the q21.1 region of chromosome 1. Extra copies of genes in the duplicated segment likely contribute to the signs and symptoms that occur in some individuals with 1q21.1 microduplications; researchers are working to determine which specific genes are involved and how they relate to these features. Because some people with a 1q21.1 microduplication have no apparent features of the condition, additional genetic or environmental factors are thought to be involved in the development of signs and symptoms.

Neuroblastoma

Deletions within region 1p36 have also been associated with another condition called neuroblastoma. Neuroblastoma is a type of cancerous tumor composed of immature nerve cells (neuroblasts). These deletions are somatic mutations, which means they occur during a person's lifetime and are present only in the cells that become cancerous. About 25 percent of people with neuroblastoma have a deletion of 1p36.1-1p36.3, which is associated with a more severe form of neuroblastoma. Researchers believe the deleted region could contain a gene that keeps cells from growing and dividing too quickly or in an uncontrolled way, called a tumor suppressor gene. When tumor suppressor genes are deleted, cancer can occur. Researchers have identified several possible tumor suppressor genes in the deleted region of chromosome 1, and more research is needed to understand what role these genes play in neuroblastoma development.

Thrombocytopenia-absent radius syndrome

A deletion in the 1q21.1 region of chromosome 1 is involved in most cases of thrombocytopenia-absent radius (TAR) syndrome. TAR syndrome is characterized by the absence of a bone called the radius in each forearm and a shortage (deficiency) of blood cells involved in clotting (platelets).

The deletion in chromosome 1 involved in TAR syndrome eliminates at least 200,000 DNA building blocks (200 kilobases, or 200 kb) from the long (q) arm of the chromosome, including a gene called RBM8A. Most people with TAR syndrome have the deletion in one copy of chromosome 1, which removes one copy of the RBM8A gene, and a mutation in the other copy of the RBM8A gene in each cell. The RBM8A gene provides instructions for making a protein called RNA-binding motif protein 8A. This protein is believed to be involved in a number of important cellular functions involving the production of other proteins.

RBM8A gene mutations that cause TAR syndrome reduce the amount of RNA-binding motif protein 8A in cells. The deletion on chromosome 1 eliminates one copy of the RBM8A gene in each cell and the RNA-binding motif protein 8A that would have been produced from it. The reduced total amount of RNA-binding motif protein 8A is thought to cause problems in the development of certain tissues, but it is unknown how it causes the specific signs and symptoms of TAR syndrome. No cases have been reported in which individuals have deletions on both copies of chromosome 1 that include both copies of the RBM8A gene; studies indicate that the complete loss of RNA-binding motif protein 8A is not compatible with life.

Researchers sometimes refer to the deletion in chromosome 1 associated with TAR syndrome as the 200-kb deletion to distinguish it from another chromosomal abnormality called a 1q21.1 microdeletion (described above). People with a 1q21.1 microdeletion are missing a different, larger DNA segment in the chromosome 1q21.1 region near the area where the 200-kb deletion occurs. The chromosomal change related to 1q21.1 microdeletion is often called the recurrent distal 1.35-Mb deletion.

Other cancers

Changes in the structure of chromosome 1 are associated with other forms of cancer and conditions related to cancer. These changes are typically somatic, which means they are acquired during a person's lifetime and are present only in tumor cells.

Deletions in the short (p) arm of the chromosome have been identified in tumors of the brain and kidney. Duplications in the long (q) arm of the chromosome have been reported in a disorder called myelodysplastic syndrome, which is a disease of the blood and bone marrow. People with this condition have a low number of red blood cells (anemia) and an increased risk of developing leukemia.

Other chromosomal conditions

Other changes in the number or structure of chromosome 1 can have a variety of effects, including delayed growth and development, distinctive facial features, birth defects, and other health problems. Changes to chromosome 1 may include an extra segment of the short (p) or long (q) arm of the chromosome in each cell (partial trisomy 1p or 1q), a missing segment of the short or long arm of the chromosome in each cell (partial monosomy 1p or 1q), or a circular structure called ring chromosome 1. Ring chromosomes occur when a chromosome breaks in two places and the ends of the chromosome arms fuse together to form a circular structure.

Chromosome 2 is the second largest human chromosome, spanning about 243 million building blocks of DNA (base pairs) and representing almost 8 percent of the total DNA in cells. Chromosome 2 likely contains 1,200 to 1,300 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 2.

2q37 deletion syndrome

2q37 deletion syndrome is caused by a deletion of genetic material near the end of the long (q) arm of chromosome 2, at a location designated 2q37. The signs and symptoms of this condition vary widely, but affected individuals generally have intellectual disability, behavioral problems, obesity, and skeletal abnormalities that often include unusually short fingers and toes (brachydactyly).

Researchers are working to identify all of the genes that contribute to the features of 2q37 deletion syndrome. While the size of the deletion varies among affected individuals, it always contains a certain gene, called HDAC4. The loss of this gene is thought to account for many of the characteristic features of 2q37 deletion syndrome, such as intellectual disability, behavioral problems, and skeletal abnormalities. Researchers are studying what role the other genes on 2q37 play in this disorder.

Cancers

Changes in chromosome 2 have been identified in several types of cancer. These genetic changes are somatic, which means they are acquired during a person's lifetime and are present only in cells that give rise to the cancer. For example, a rearrangement (translocation) of genetic material between chromosomes 2 and 3 has been associated with cancers of a certain type of blood cell originating in the bone marrow (myeloid malignancies).

Trisomy 2, in which cells have three copies of chromosome 2 instead of the usual two copies, has been found in myelodysplastic syndrome. This disease affects the blood and bone marrow. People with myelodysplastic syndrome have a low number of red blood cells (anemia) and an increased risk of developing a form of blood cancer known as acute myeloid leukemia.

MBD5-associated neurodevelopmental disorder

Loss (deletion) or gain (duplication) of a small piece of chromosome 2 at position q23.1 can cause MBD5-associated neurodevelopmental disorder (MAND). MAND is a condition that affects neurological and physical development from birth. Affected individuals often have intellectual disability, developmental delay, impaired speech, sleep problems, distinctive facial features, and mild hand and foot abnormalities. Most people with MAND also have behavior problems similar to autism spectrum disorder, a developmental condition that affects communication and social interaction.

The chromosomal changes that can cause MAND are known as 2q23.1 microdeletions or 2q23.1 microduplications. The deleted or duplicated segment varies in size but always contains the MBD5 gene, and often additional genes. Most features of MAND are due to the loss or gain of one copy of the MBD5 gene. The MBD5 gene provides instructions for a protein that likely regulates the activity (expression) of genes, controlling the production of proteins that are involved in neurological functions such as learning, memory, and behavior.

Chromosome 2 deletions or duplications that cause MAND lead to an abnormal amount of MBD5 protein. Deletions prevent one copy of the MBD5 gene in each cell from producing any functional protein, which reduces the total amount of this protein in cells. Duplications lead to an increase in the amount of MBD5 protein. It is likely that any changes in MBD5 protein levels impair its regulation of gene expression, leading to the uncontrolled production of certain proteins. Proteins that play a role in neurological functions are particularly affected, which helps explain why MAND impacts brain development and behavior. An increase or decrease in MBD5 protein disrupts gene expression that is normally well-controlled by this protein, which is likely why duplications and deletions of this gene lead to the same signs and symptoms. The cause of the skeletal abnormalities and other non-neurological features of MAND is unclear. It is also unknown whether the loss or gain of other genes in chromosome 2 deletions or duplications contribute to the features of MAND.

SATB2-associated syndrome

Genetic changes on the q arm of chromosome 2 have been found to cause SATB2-associated syndrome. Individuals with this condition have intellectual disability and severe speech problems. They may also have an opening in the roof of the mouth (cleft palate), dental abnormalities, or other abnormalities of the head and face (craniofacial anomalies).

Several types of genetic changes are involved in SATB2-associated syndrome, all of which affect a gene on chromosome 2 called SATB2. Some mutations remove genetic material from the long arm of chromosome 2. These deletions occur in regions designated 2q32 and 2q33, and the size of the deletion varies among affected individuals. They may be large, removing several genes from chromosome 2, including SATB2. Or they may be smaller, removing material from within the SATB2 gene. Other mutations, such as those that change single DNA building blocks (nucleotides) in the SATB2 gene, can also cause SATB2-associated syndrome.

These genetic changes disrupt the SATB2 gene and are thought to reduce the amount of functional protein produced from it. The SATB2 protein directs development of the brain and craniofacial structures, and a reduction in this protein's function impairs their normal development, leading to the features of the condition.

The signs and symptoms of SATB2-associated syndrome are usually similar, regardless of the type of mutation that causes it. However, some individuals with large deletions have uncommon features of the condition, such as problems with the heart, genitals and urinary tract (genitourinary tract), skin, or hair. These features are thought to be related to loss of other genes near SATB2 on the long arm of chromosome 2.

Other chromosomal conditions

Another chromosome 2 abnormality is known as a ring chromosome 2. A ring chromosome is formed when breaks occur at both ends of the chromosome and the broken ends join together to form a circular structure. Individuals with this chromosome abnormality often have developmental delay, small head size (microcephaly), slow growth before and after birth, heart defects, and distinctive facial features. The severity of symptoms typically depends on how many and which types of cells contain the ring chromosome 2.

Other changes involving the number or structure of chromosome 2 include an extra piece of the chromosome in each cell (partial trisomy 2) or a missing segment of the chromosome in each cell (partial monosomy 2). These changes can have a variety of effects on health and development, including intellectual disability, slow growth, characteristic facial features, weak muscle tone (hypotonia), and abnormalities of the fingers and toes.

Chromosome 3 spans about 198 million base pairs (the building blocks of DNA) and represents approximately 6.5 percent of the total DNA in cells. Chromosome 3 likely contains 1,000 to 1,100 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 3.

3p deletion syndrome

3p deletion syndrome is a condition that often results in intellectual disability, developmental delay, and abnormal physical features. 3p deletion syndrome is caused by the deletion of the end of the small (p) arm of chromosome 3. The size of the deletion varies among affected individuals, from approximately 150,000 DNA building blocks (base pairs) to 11 million base pairs and can include 4 to 71 known genes. In some individuals, the deletion involves material near the end of the chromosome but does not include the tip (the telomere).

The signs and symptoms related to 3p deletion syndrome result from the loss of genes in the 3p region; however, it is difficult to determine which genes influence specific features because not all affected individuals are missing the same genes.

3q29 microdeletion syndrome

3q29 microdeletion syndrome is a condition that results from the deletion of a small piece of chromosome 3 in each cell. Features associated with the deletion vary widely but can include delayed development, intellectual disability, behavioral and psychiatric disorders, and physical abnormalities. Some individuals with this chromosomal change have very mild or no related signs and symptoms.

Most people with 3q29 microdeletion syndrome are missing about 1.6 million base pairs, also written as 1.6 megabases (Mb), on the long (q) arm of the chromosome at a position designated q29. It is the same region of chromosome 3 that is abnormally copied (duplicated) in people with 3q29 microduplication syndrome (described below). This chromosome segment is normally surrounded by short, repeated sequences of DNA that make it prone to rearrangement during cell division. The rearrangement can lead to missing or extra copies of DNA at 3q29.

The segment that is most often deleted in people with 3q29 microdeletion syndrome includes about 20 genes. Some of these genes are thought to be involved in brain development. However, it is unknown which specific genes, when abnormally deleted, are related to the signs and symptoms of 3q29 microdeletion syndrome. It is also unclear why some people with a deletion at 3q29 have no associated health problems. It is possible that genetic changes outside the 3q29 region can influence the features of this condition.

3q29 microduplication syndrome

3q29 microduplication syndrome is a condition that results from the duplication of a small piece of chromosome 3 in each cell. Signs and symptoms related to this duplication vary widely. Some individuals with the duplication have no apparent signs or symptoms, or the features are very mild. Other individuals have delayed development and intellectual disability or learning difficulties. Eye abnormalities, heart defects, and an unusually small head (microcephaly) can also occur.

Most people with 3q29 microduplication syndrome have an extra copy of about 1.6 Mb of DNA at position q29 on chromosome 3. It is the same region of chromosome 3 that is deleted in people with 3q29 microdeletion syndrome (described above). This chromosome segment is prone to rearrangement during cell division, which can lead to extra or missing copies of DNA at 3q29.

The duplicated segment of 3q29 includes about 20 genes. Some of these genes are thought to be involved in brain and eye development. However, it is unknown which specific genes, when abnormally copied, are related to the varied signs and symptoms of 3q29 microduplication syndrome. It is also unclear why some people with a duplication at 3q29 have no associated health problems. It is possible that genetic changes outside the 3q29 region can influence the features of this condition.

Other chromosomal conditions

Other changes in the structure of chromosome 3 in each cell can have a variety of effects, including intellectual disability, developmental delay, distinctive facial features, birth defects, and other health problems. Changes to chromosome 3 include extra (duplicated) or deleted segments of the p arm or q arm of the chromosome in each cell. The size of the extra or deleted segments varies; the amount of genetic material involved contributes to the signs and symptoms that develop. Rarely, chromosome 3 can form a circular structure called a ring chromosome, which occurs when a chromosome breaks in two places and the ends of the chromosome arms fuse together. When the ring chromosome forms, genes near the ends of chromosome 3 are deleted, and because of the ring shape, the chromosome cannot copy (replicate) itself normally during cell division, likely contributing to health problems.

Cancers

Changes in chromosome 3 have been identified in a type of kidney cancer called clear cell renal carcinoma. This cancer can develop when one copy of chromosome 3 is missing or when part of the p arm of chromosome 3 is deleted. Additionally, clear cell renal carcinoma can be associated with abnormal exchanges of genetic material, called translocations, between chromosome 3p and another chromosome. Unlike the changes that cause the syndromes described above, the genetic changes associated with clear cell renal carcinoma are somatic, which means they are acquired during a person's lifetime and are present only in certain kidney cells. These genetic changes allow the cells to grow and divide in an uncontrolled way to form a tumor.

Chromosome 4 spans about 191 million DNA building blocks (base pairs) and represents more than 6 percent of the total DNA in cells. Chromosome 4 likely contains 1,000 to 1,100 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 4.

Cancers

Changes in chromosome 4 have been identified in several types of human cancer. These genetic changes are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. For example, rearrangements (translocations) of genetic material between chromosome 4 and several other chromosomes have been associated with leukemias, which are cancers of blood-forming cells.

A specific translocation involving chromosome 4 and chromosome 14 is commonly found in multiple myeloma, which is a cancer that starts in cells of the bone marrow. The translocation, which is written as t(4;14)(p16;q32), abnormally fuses the WHSC1 gene on chromosome 4 with part of another gene on chromosome 14. The fusion of these genes overactivates WHSC1, which appears to promote the uncontrolled growth and division of cancer cells.

Facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy is caused by genetic changes involving the long (q) arm of chromosome 4. This condition is characterized by muscle weakness and wasting (atrophy) that worsens slowly over time. It results from changes in a region of DNA known as D4Z4, located near the end of the chromosome at a position described as 4q35. The D4Z4 region consists of 11 to more than 100 repeated segments, each of which is about 3,300 DNA base pairs (3.3 kb) long. The entire D4Z4 region is normally hypermethylated, which means that it has a large number of methyl groups (consisting of one carbon atom and three hydrogen atoms) attached to the DNA. Facioscapulohumeral muscular dystrophy results when the region is hypomethylated, with too few methyl groups attached. In facioscapulohumeral muscular dystrophy type 1 (FSHD1), hypomethylation occurs because the D4Z4 region is abnormally shortened (contracted), containing between 1 and 10 repeats instead of the usual 11 to 100 repeats. In facioscapulohumeral muscular dystrophy type 2 (FSHD2), hypomethylation most often results from mutations in a gene called SMCHD1, which normally hypermethylates the D4Z4 region.

The segment of the D4Z4 region closest to the end of chromosome 4 contains a gene called DUX4. Hypermethylation of the D4Z4 region normally keeps the DUX4 gene turned off (silenced) in most adult cells and tissues. In people with facioscapulohumeral muscular dystrophy, hypomethylation of the D4Z4 region prevents the DUX4 gene from being silenced in cells and tissues where it is usually turned off. Although little is known about the function of the DUX4 gene when it is turned on (active), researchers believe that it influences the activity of other genes, particularly in muscle cells. It is unknown how abnormal activity of the DUX4 gene damages or destroys these cells, leading to progressive muscle weakness and atrophy.

The DUX4 gene is located next to a regulatory region of DNA known as a pLAM sequence, which is necessary for the production of the DUX4 protein. Some copies of chromosome 4 have a functional pLAM sequence, while others do not. Copies of chromosome 4 with a functional pLAM sequence are described as 4qA or "permissive." Those without a functional pLAM sequence are described as 4qB or "non-permissive." Without a functional pLAM sequence, no DUX4 protein is made. Because there are two copies of chromosome 4 in each cell, individuals may have two "permissive" copies of chromosome 4, two "non-permissive" copies, or one of each. Facioscapulohumeral muscular dystrophy can only occur in people who have at least one "permissive" copy of chromosome 4. Whether an affected individual has a contracted D4Z4 region or a SMCHD1 gene mutation, the disease results only if a functional pLAM sequence is also present to allow DUX4 protein to be produced.

PDGFRA-associated chronic eosinophilic leukemia

PDGFRA-associated chronic eosinophilic leukemia is caused by genetic abnormalities that involve the PDGFRA gene, a gene found on chromosome 4. This condition is a type of blood cell cancer characterized by an increased number of eosinophils, a type of white blood cell involved in allergic reactions.

The PDGFRA gene abnormalities are somatic mutations, which are mutations acquired during a person's lifetime that are present only in certain cells. The most common of these abnormalities is a deletion of genetic material from chromosome 4 that removes approximately 800 DNA building blocks (nucleotides) and brings together parts of two genes, FIP1L1 and PDGFRA, creating the FIP1L1-PDGFRA fusion gene. Occasionally, through mechanisms other than deletion, genes other than FIP1L1 are fused with the PDGFRA gene. Rarely, mutations that change single DNA building blocks in the PDGFRA gene (point mutations) cause this condition.

The protein produced from the FIP1L1-PDGFRA fusion gene (as well as other PDGFRA fusion genes) has the function of the PDGFRA protein, which stimulates signaling pathways inside the cell that control many important cellular processes, such as cell growth and division (proliferation) and cell survival. Unlike the normal PDGFRA protein, however, the fusion protein is constantly turned on (constitutively activated), which means the cells are always receiving signals to proliferate. Similarly, point mutations in the PDGFRA gene can result in a constitutively activated PDGFRA protein. When the FIP1L1-PDGFRA fusion gene or point mutations in the PDGFRA gene occur in blood cell precursors, the growth of eosinophils (and occasionally other blood cells) is poorly controlled, leading to PDGFRA-associated chronic eosinophilic leukemia. It is unclear why eosinophils are preferentially affected by this genetic change.

Wolf-Hirschhorn syndrome

Wolf-Hirschhorn syndrome is caused by a deletion of genetic material near the end of the short (p) arm of chromosome 4 at a position described as 4p16.3. The signs and symptoms of this condition are related to the loss of multiple genes from this part of the chromosome. The size of the deletion varies among affected individuals; studies suggest that larger deletions tend to result in more severe intellectual disability and physical abnormalities than smaller deletions.

The region of chromosome 4 that is deleted most often in people with Wolf-Hirschhorn syndrome is known as Wolf-Hirschhorn syndrome critical region 2 (WHSCR-2). This region contains several genes, some of which are known to play important roles in early development. A loss of these genes leads to developmental delay, a distinctive facial appearance, and other characteristic features of the condition. Scientists are working to identify additional genes at the end of the short arm of chromosome 4 that contribute to the characteristic features of Wolf-Hirschhorn syndrome.

Other chromosomal conditions

Some deletions of genetic material from the short (p) arm of chromosome 4 do not involve the critical region WHSCR-2. These deletions cause signs and symptoms that are distinct from those of Wolf-Hirschhorn syndrome, including mild intellectual disability and, in some cases, rapid (accelerated) growth. People with this type of deletion usually do not have seizures.

Trisomy 4 occurs when cells have three copies of chromosome 4 instead of the usual two copies. Full trisomy 4, which occurs when all of the body's cells contain an extra copy of chromosome 4, is not compatible with life. A similar but somewhat less severe condition called mosaic trisomy 4 occurs when only some of the body's cells have an extra copy of chromosome 4. The signs and symptoms of mosaic trisomy 4 vary widely and can include heart defects, abnormalities of the fingers and toes, and other birth defects. Mosaic trisomy 4 is very rare; only a few cases have been reported.

Other changes in the number or structure of chromosome 4 can have a variety of effects including delayed growth and development, intellectual disability, distinctive facial features, heart defects, and other medical problems. Changes involving chromosome 4 include an extra piece of the chromosome in each cell (partial trisomy 4), a missing segment of the chromosome in each cell (partial monosomy 4), and a circular structure called a ring chromosome 4. Ring chromosomes occur when a chromosome breaks in two places and the ends of the chromosome arms fuse together to form a circular structure.

Cancers

Changes in chromosome 4 have been identified in several types of human cancer. These genetic changes are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. For example, rearrangements (translocations) of genetic material between chromosome 4 and several other chromosomes have been associated with leukemias, which are cancers of blood-forming cells.

A specific translocation involving chromosome 4 and chromosome 14 is commonly found in multiple myeloma, which is a cancer that starts in cells of the bone marrow. The translocation, which is written as t(4;14)(p16;q32), abnormally fuses the WHSC1 gene on chromosome 4 with part of another gene on chromosome 14. The fusion of these genes overactivates WHSC1, which appears to promote the uncontrolled growth and division of cancer cells.

Chromosome 5 spans about 181 million DNA building blocks (base pairs) and represents almost 6 percent of the total DNA in cells. Chromosome 5 likely contains about 900 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 5.

5q minus syndrome

Deletion of a region of DNA from the long (q) arm of chromosome 5 is involved in a condition called 5q minus (5q-) syndrome. This deletion occurs in immature blood cells during a person's lifetime and affects one copy of chromosome 5 in each cell. 5q- syndrome is a type of bone marrow disorder called myelodysplastic syndrome (MDS), in which immature blood cells fail to develop normally. Individuals with 5q- syndrome often have a shortage of red blood cells (anemia) and abnormalities in blood cells called megakaryocytes, which produce platelets, the cells involved in blood clotting. Affected individuals also have an increased risk of developing a fast-growing blood cancer known as acute myeloid leukemia (AML).

Most people with 5q- syndrome are missing a sequence of about 1.5 million DNA base pairs, also written as 1.5 megabases (Mb). This region of DNA contains 40 genes. Research suggests that the loss of one copy of multiple genes in this region contribute to the features of 5q- syndrome. In particular, loss of the RPS14 gene leads to the problems with red blood cell development characteristic of 5q- syndrome, and loss of MIR145 or MIR146A contributes to the megakaryocyte abnormalities. Scientists are still determining how the loss of other genes in the deleted region might be involved in the features of 5q- syndrome and the development of AML.

5q31.3 microdeletion syndrome

5q31.3 microdeletion syndrome is caused by a chromosomal change in which a small piece of chromosome 5 is deleted in each cell. This rare condition is characterized by severely delayed development of speech and walking, weak muscle tone (hypotonia), breathing problems, seizures, and distinctive facial features. The deletion occurs on the long (q) arm of the chromosome at a position designated q31.3. The size of the deletion can range from several thousand to several million DNA building blocks (base pairs). The deleted region typically contains at least three genes. The loss of one of these genes, PURA, is thought to lead to most of the characteristic features of the condition.

The protein produced from the PURA gene, called Pur-alpha (Purα), is especially important for normal brain development. Purα helps direct the growth and division of nerve cells (neurons). It may also be involved in the formation or maturation of myelin, the protective substance that covers nerves and promotes the efficient transmission of nerve impulses. A loss of one copy of the PURA gene is thought to alter normal brain development and impair the function of neurons, leading to developmental delay, hypotonia, seizures, and other neurological problems in people with 5q31.3 microdeletion syndrome.

Some studies suggest that loss of another nearby gene on chromosome 5, called NRG2, increases the severity of the signs and symptoms. It is unclear how the loss of other genes in the deleted region contributes to the development of 5q31.3 microdeletion syndrome.

Cri-du-chat syndrome

Cri-du-chat (cat's cry) syndrome is caused by a deletion of the end of the short (p) arm of chromosome 5. This chromosomal change is written as 5p- (5p minus). The signs and symptoms of cri-du-chat syndrome are probably related to the loss of multiple genes in this region. Researchers are working to determine how the loss of these genes leads to the features of the disorder. They have discovered that in people with cri-du-chat syndrome, larger deletions tend to result in more severe intellectual disability and developmental delays than smaller deletions. Researchers have also defined regions of the short arm of chromosome 5 that are associated with particular features of cri-du-chat syndrome. A specific region designated 5p15.3 is associated with a cat-like cry, and a nearby region called 5p15.2 is associated with intellectual disability, small head size (microcephaly), and distinctive facial features.

PDGFRB-associated chronic eosinophilic leukemia

Translocations involving chromosome 5 are involved in a type of blood cell cancer called PDGFRB-associated chronic eosinophilic leukemia. This condition is characterized by an increased number of eosinophils, a type of white blood cell. The most common translocation that causes this condition fuses part of the PDGFRB gene from chromosome 5 with part of the ETV6 gene from chromosome 12, written as t(5;12)(q31-33;p13). Translocations fusing the PDGFRB gene with one of more than 20 other genes have also been found to cause PDGFRB-associated chronic eosinophilic leukemia, but these other genetic changes are relatively uncommon. These translocations are acquired during a person's lifetime and are present only in cancer cells. This type of genetic change, called a somatic mutation, is not inherited.

The protein produced from the ETV6-PDGFRB fusion gene, called ETV6/PDGFRβ, functions differently than the proteins normally produced from the individual genes. The ETV6 protein normally turns off (represses) gene activity and the PDGFRβ protein plays a role in turning on (activating) signaling pathways. The ETV6/PDGFRβ protein is always turned on, activating signaling pathways and gene activity. When the ETV6-PDGFRB fusion gene mutation occurs in cells that develop into blood cells, the growth of eosinophils (and occasionally other white blood cells, such as neutrophils and mast cells) is poorly controlled, leading to PDGFRB-associated chronic eosinophilic leukemia. It is unclear why eosinophils are preferentially affected by this genetic change.

Periventricular heterotopia

In a few cases, abnormalities in chromosome 5 have been associated with periventricular heterotopia, a disorder characterized by abnormal clumps of neurons around fluid-filled cavities (ventricles) near the center of the brain. In each case, the affected individual had extra genetic material caused by an abnormal duplication of part of this chromosome. It is not known how this duplicated genetic material results in the signs and symptoms of periventricular heterotopia.

Other chromosomal conditions

Other changes in the number or structure of chromosome 5 can have a variety of effects, including delayed growth and development, distinctive facial features, birth defects, and other health problems. Changes to chromosome 5 include an extra segment of the short (p) or long (q) arm of the chromosome in each cell (partial trisomy 5p or 5q), a missing segment of the long arm of the chromosome in each cell (partial monosomy 5q), and a circular structure called ring chromosome 5. Ring chromosomes occur when a chromosome breaks in two places and the ends of the chromosome arms fuse together to form a circular structure.

Other cancers

Deletions in the long (q) arm of chromosome 5 frequently occur in AML and MDS. While deletions in a specific segment of chromosome 5 are associated with a form of MDS called 5q minus syndrome (described above), other deletions are related to other forms of these blood disorders. These changes are typically somatic, which means they are acquired during a person's lifetime and are present only in tumor cells.

Studies suggest that some genes on chromosome 5 play critical roles in the growth and division of cells. When segments of the chromosome are deleted, as in some cases of AML and MDS, these important genes are missing. Without these genes, cells can grow and divide too quickly and in an uncontrolled way. Researchers are working to identify the specific genes on chromosome 5 that are related to AML and MDS.

Chromosome 6 spans about 171 million DNA building blocks (base pairs) and represents between 5.5 and 6 percent of the total DNA in cells. Chromosome 6 likely contains 1,000 to 1,100 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 6.

6q24-related transient neonatal diabetes mellitus

6q24-related transient neonatal diabetes mellitus, a type of diabetes that occurs in infants, is caused by the overactivity (overexpression) of certain genes in a region of the long (q) arm of chromosome 6 called 6q24. People inherit two copies of their genes, one from their mother and one from their father. Usually both copies of each gene are active, or "turned on," in cells. In some cases, however, only one of the two copies is normally turned on. Which copy is active depends on the parent of origin: some genes are normally active only when they are inherited from a person's father; others are active only when inherited from a person's mother. This phenomenon is known as genomic imprinting.

The 6q24 region includes paternally expressed imprinted genes, which means that normally only the copy of each gene that comes from the father is active. The copy of each gene that comes from the mother is inactivated (silenced) by a mechanism called methylation.

There are three ways that overexpression of paternally expressed imprinted genes in the 6q24 region can occur. About 40 percent of cases of 6q24-related transient neonatal diabetes mellitus are caused by a genetic change known as paternal uniparental disomy (UPD) of chromosome 6. In paternal UPD, people inherit both copies of the affected chromosome from their father instead of one copy from each parent. Paternal UPD causes people to have two active copies of paternally expressed imprinted genes, rather than one active copy from the father and one inactive copy from the mother.

Another 40 percent of cases of 6q24-related transient neonatal diabetes mellitus occur when the copy of chromosome 6 that comes from the father has a duplication of genetic material including the paternally expressed imprinted genes in the 6q24 region.

The third mechanism by which overexpression of genes in the 6q24 region can occur is by impaired silencing of the maternal copy of the genes (maternal hypomethylation). Approximately 20 percent of cases of 6q24-related transient neonatal diabetes mellitus are caused by maternal hypomethylation. Some people with this disorder have a genetic change in the maternal copy of the 6q24 region that prevents genes in that region from being silenced. Other affected individuals have a more generalized impairment of gene silencing involving many imprinted regions, called hypomethylation of imprinted loci (HIL). Because HIL can cause overexpression of many genes, this mechanism may account for the additional health problems that occur in some people with 6q24-related transient neonatal diabetes mellitus.

It is not well understood how overexpression of genes in the 6q24 region causes 6q24-related transient neonatal diabetes mellitus and why the condition improves after infancy. This form of diabetes is characterized by high blood sugar levels (hyperglycemia) resulting from a shortage of the hormone insulin. Insulin controls how much glucose (a type of sugar) is passed from the blood into cells for conversion to energy.

The protein produced from one gene in the 6q24 region may help control insulin secretion by beta cells in the pancreas. In addition, overexpression of this protein has been shown to stop the cycle of cell division and lead to the self-destruction of cells (apoptosis). Researchers suggest that overexpression of this gene may reduce the number of insulin-secreting beta cells or impair their function in affected individuals.

Lack of sufficient insulin results in the signs and symptoms of diabetes mellitus. In individuals with 6q24-related transient neonatal diabetes mellitus, these signs and symptoms are most likely to occur during times of physiologic stress, including the rapid growth of infancy, childhood illnesses, and pregnancy. Because insulin acts as a growth promoter during early development, a shortage of this hormone may account for the slow growth before birth (intrauterine growth retardation) seen in 6q24-related transient neonatal diabetes mellitus.

Cancers

Duplications of genetic material in the short (p) arm of chromosome 6 have been associated with the growth and spread of several types of cancer. These duplications are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. Researchers believe that some of the genes in the duplicated region on chromosome 6p are oncogenes. Oncogenes play roles in several critical cell functions, including cell division, the maturation of cells to carry out specific functions (cell differentiation), and the self-destruction of cells (apoptosis). When mutated, oncogenes have the potential to cause normal cells to become cancerous. The presence of extra copies of the oncogenes may allow cells to grow and divide in an uncontrolled way, leading to the progression and spread of cancer.

Other chromosomal conditions

Other changes in the number or structure of chromosome 6 can have a variety of effects, including delayed growth and development, intellectual disability, distinctive facial features, birth defects, and other health problems. Changes to chromosome 6 may include deletions or duplications of genetic material in the short (p) or long (q) arm of the chromosome in each cell, or a circular structure called ring chromosome 6. Ring chromosomes occur when a chromosome breaks in two places and the ends of the chromosome arms fuse together to form a circular structure.

Chromosome 7 spans about 159 million DNA building blocks (base pairs) and represents more than 5 percent of the total DNA in cells. Chromosome 7 likely contains 900 to 1,000 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 7.

7q11.23 duplication syndrome

7q11.23 duplication syndrome, a condition that can cause a variety of neurological and behavioral problems as well as other abnormalities, results from an extra copy of a region on the long (q) arm of chromosome 7. This region is called the Williams-Beuren syndrome critical region (WBSCR) because its deletion causes a different disorder called Williams syndrome (described below), also known as Williams-Beuren syndrome. The region, which is 1.5 to 1.8 million DNA base pairs (Mb) in length, includes 25 to 27 genes.

Extra copies of several of these genes likely contribute to the characteristic features of 7q11.23 duplication syndrome. Researchers are studying genes whose functions suggest that they might be related to particular features.

FOXP2-related speech and language disorder

Several different changes affecting chromosome 7 can result in FOXP2-related speech and language disorder. These changes involve a region of the long (q) arm of chromosome 7 containing the FOXP2 gene. FOXP2-related speech and language disorder is an uncommon condition that affects the development of speech and language starting in early childhood. In some affected individuals, problems with speech and language are the only features of the condition. Other individuals also have delayed development of motor skills such as walking and tying shoelaces, and autism spectrum disorders, which are conditions characterized by impaired communication and social interaction.

All of the genetic changes that underlie FOXP2-related speech and language disorder disrupt the activity of FOXP2, a critical gene for normal speech and language development. Some individuals with FOXP2-related speech and language disorder have a deletion that removes a small segment of chromosome 7, including the FOXP2 gene and several neighboring genes. Other people with this condition have a variant (also known as a mutation) within the FOXP2 gene itself. Less commonly, FOXP2-related speech and language disorder results from a rearrangement of the structure of chromosome 7 (such as a translocation) or from inheriting two copies of chromosome 7 from the mother instead of one from each parent (a phenomenon called maternal uniparental disomy or maternal UPD, which is described in more detail with Russell-Silver syndrome, below). It remains unclear how having two maternal copies of chromosome 7 affects the activity of the FOXP2 gene.

Additional features that are sometimes associated with FOXP2-related speech and language disorder, including delayed motor development and autism spectrum disorders, likely result from changes to other genes on chromosome 7. For example, in affected individuals with a deletion involving chromosome 7, a loss of FOXP2 is thought to disrupt speech and language development, while the loss of nearby genes accounts for other signs and symptoms. People with maternal UPD for chromosome 7 have FOXP2-related speech and language disorder as part of a larger condition called Russell-Silver syndrome (described below).

Greig cephalopolysyndactyly syndrome

Abnormalities of chromosome 7 are responsible for some cases of Greig cephalopolysyndactyly syndrome, a disorder that affects development of the limbs, head, and face. These chromosomal changes involve a region of the short (p) arm of chromosome 7 that contains the GLI3 gene. This gene plays an important role in the development of many tissues and organs before birth.

In some cases, Greig cephalopolysyndactyly syndrome results from a rearrangement (translocation) of genetic material between chromosome 7 and another chromosome. Other cases are caused by the deletion of several genes, including GLI3, from the short arm of chromosome 7. The loss of multiple genes can cause a more severe form of this disorder called Greig cephalopolysyndactyly contiguous gene deletion syndrome. People with this form of the disorder have characteristic developmental problems involving the limbs, head, and face, along with seizures, developmental delay, and intellectual disability.

Russell-Silver syndrome

Abnormalities involving the inheritance of chromosome 7 can cause Russell-Silver syndrome, a rare condition characterized by slow growth, distinctive facial features, delayed development, speech and language problems, and learning disabilities.

People normally inherit one copy of each chromosome from their mother and one copy from their father. For most genes, both copies are expressed, or "turned on," in cells. For some genes, however, only the copy inherited from a person's father (the paternal copy) is expressed. For other genes, only the copy inherited from a person's mother (the maternal copy) is expressed. These parent-specific differences in gene expression are caused by a phenomenon called genomic imprinting. Chromosome 7 contains a group of genes that normally undergo genomic imprinting; some of these genes are active only on the maternal copy, while others are active only on the paternal copy.

In 7 percent to 10 percent of cases of Russell-Silver syndrome, people inherit both copies of chromosome 7 from their mother (maternal UPD) instead of one copy from each parent. Maternal UPD causes people to have two active copies of some imprinted genes and no active copies of others. An imbalance in active maternal and paternal genes on chromosome 7 underlies the signs and symptoms of the disorder in these cases.

Saethre-Chotzen syndrome

Abnormalities of chromosome 7 cause some cases of Saethre-Chotzen syndrome. This rare condition is characterized by the premature fusion of certain skull bones (craniosynostosis), which prevents the skull from growing normally and affects the shape of the head and face. The chromosomal changes involve a region of the short (p) arm of chromosome 7 that contains the TWIST1 gene. This gene plays an important role in early development of the head, face, and limbs.

The chromosome abnormalities responsible for Saethre-Chotzen syndrome include translocations of genetic material between chromosome 7 and another chromosome, a rearrangement of genetic material within chromosome 7 (an inversion), or the deletion of a segment of chromosome 7. Each of these chromosomal changes alters or deletes the TWIST1 gene and may also affect nearby genes.

When Saethre-Chotzen syndrome is caused by a chromosomal deletion instead of a variant within the TWIST1 gene, affected children are much more likely to have intellectual disability, developmental delay, and learning difficulties. These features are typically not seen in classic cases of Saethre-Chotzen syndrome. Researchers believe that a loss of other genes on the short arm of chromosome 7 may be responsible for these additional features.

Williams syndrome

Williams syndrome is caused by the deletion of genetic material from the Williams-Beuren critical region at 7q11.23 (described above). Researchers believe that the characteristic features of Williams syndrome, which include mild to moderate intellectual disability or learning problems, unique personality characteristics, distinctive facial features, and heart and blood vessel (cardiovascular) problems, are probably related to the loss of several of the genes in this region.

While the genes related to Williams syndrome have been identified, the relationship between most of those genes and the signs and symptoms of Williams syndrome is under investigation or unknown.

Other chromosomal conditions

Other changes in the number or structure of chromosome 7 can cause delayed growth and development, intellectual disability, distinctive facial features, skeletal abnormalities, delayed speech, and other medical problems. Changes in chromosome 7 include an extra copy of some genetic material from this chromosome in each cell (partial trisomy 7) or a missing segment of the chromosome in each cell (partial monosomy 7). In some cases, several DNA building blocks (nucleotides) are abnormally deleted or duplicated in part of chromosome 7. A circular structure called ring chromosome 7 is also possible. Ring chromosomes occur when a chromosome breaks in two places and the ends of the chromosome arms fuse together to form a circular structure.

Cancers

Changes in the number or structure of chromosome 7 occur frequently in human cancers. These changes are typically somatic, which means they are acquired during a person's lifetime and are present only in tumor cells. Many forms of cancer are associated with damage to chromosome 7. In particular, changes in this chromosome have been identified in cancers of blood-forming tissue (leukemias) and cancers of immune system cells (lymphomas). A loss of part or all of one copy of chromosome 7 is common in myelodysplastic syndrome, which is a disease of the blood and bone marrow. People with this disorder have an increased risk of developing leukemia.

Studies suggest that some genes on chromosome 7 may play critical roles in controlling the growth and division of cells. Without these genes, cells could grow and divide too quickly or in an uncontrolled way, resulting in a cancerous tumor. Researchers are working to identify the genes on chromosome 7 that are involved in the development and progression of cancer.

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 8.

8p11 myeloproliferative syndrome

Translocations of genetic material between chromosome 8 and other chromosomes can cause 8p11 myeloproliferative syndrome. This condition is characterized by an increased number of white blood cells (myeloproliferative disorder) and the development of lymphoma, a blood-related cancer that causes tumor formation in the lymph nodes. The myeloproliferative disorder usually develops into another form of blood cancer called acute myeloid leukemia. The most common translocation involved in this condition, written as t(8;13)(p11;q12), fuses part of the FGFR1 gene on chromosome 8 with part of the ZMYM2 gene on chromosome 13. The translocations are found only in cancer cells.

The protein produced from the normal FGFR1 gene can turn on (activate) cellular signaling that helps the cell respond to its environment, for example by stimulating cell growth. The protein produced from the fused gene, regardless of the partner gene involved, leads to constant FGFR1 signaling. The uncontrolled signaling promotes continuous cell growth and division (proliferation), leading to cancer.

Core binding factor acute myeloid leukemia

A type of blood cancer known as core binding factor acute myeloid leukemia (CBF-AML) is associated with a rearrangement (translocation) of genetic material between chromosomes 8 and 21. This rearrangement is associated with approximately 7 percent of acute myeloid leukemia cases in adults. The translocation, written as t(8;21), fuses part of the RUNX1T1 gene (also known as ETO) from chromosome 8 with part of the RUNX1 gene from chromosome 21. This mutation is acquired during a person's lifetime and is present only in certain cells. This type of genetic change, called a somatic mutation, is not inherited.

The fusion protein produced from the t(8;21) translocation, called RUNX1-ETO, retains some function of the two individual proteins. The normal RUNX1 protein, produced from the RUNX1 gene, is part of a protein complex called core binding factor (CBF) that attaches (binds) to DNA and activates genes involved in blood cell development. The normal ETO protein, produced from the RUNX1T1 gene, turns off (represses) gene activity. The fusion protein forms CBF and attaches to DNA, but instead of activating genes that stimulate the development of blood cells, it represses those genes. This change in gene activity blocks the maturation (differentiation) of blood cells and leads to the production of abnormal, immature white blood cells called myeloid blasts. While t(8;21) is important for leukemia development, one or more additional genetic changes are typically needed for the myeloid blasts to develop into cancerous leukemia cells.

Recombinant 8 syndrome

Recombinant 8 syndrome is caused by a rearrangement of genetic material on chromosome 8. This condition is characterized by heart and urinary tract abnormalities, moderate to severe intellectual disability, abnormal muscle tone, and a distinctive facial appearance. The chromosomal rearrangement that causes recombinant 8 syndrome is a deletion of a piece of the short (p) arm and a duplication of a piece of the long (q) arm. This chromosome abnormality is written rec(8)dup(8q)inv(8)(p23.1q22.1). On the recombinant 8 chromosome, there is one copy of each of the genes instead of the usual two on the section of chromosome 8p that is deleted; and there are three copies each of the genes on the section of chromosome 8q that is duplicated. The signs and symptoms of recombinant 8 syndrome are related to the loss and addition of genetic material on these regions of chromosome 8. While the regions affected in recombinant chromosome 8 includes hundreds of genes, researchers are working to determine which genes play a role in the signs and symptoms of this condition.

Trichorhinophalangeal syndrome type II

Trichorhinophalangeal syndrome type II (TRPS II) is caused by a deletion of genetic material on the long (q) arm of chromosome 8. TRPS II is a condition that causes bone and joint malformations; distinctive facial features; intellectual disability; and abnormalities of the skin, hair, teeth, sweat glands, and nails. The signs and symptoms of TRPS II are related to the loss of multiple genes from this part of the chromosome. The size of the deletion varies among affected individuals; studies suggest that larger deletions tend to result in a greater number of features than smaller deletions.

The TRPS1, EXT1, and RAD21 genes are missing in people with TRPS II. Researchers have determined that the loss of the EXT1 gene is responsible for multiple benign (noncancerous) bone tumors called osteochondromas seen in people with TRPS II. Loss of the TRPS1 gene is thought to cause the other bone and facial abnormalities. Deletion of the RAD21 gene may contribute to intellectual disability. The loss of other genes from this region of chromosome 8 likely contributes to the additional features of this condition.

Other chromosomal conditions

Trisomy 8 occurs when cells have three copies of chromosome 8 instead of the usual two copies. Full trisomy 8, which occurs when all of the body's cells contain an extra copy of chromosome 8, is not compatible with life. A similar but less severe condition called mosaic trisomy 8 occurs when only some of the body's cells have an extra copy of chromosome 8. The signs and symptoms of mosaic trisomy 8 vary widely and can include intellectual disability, absence of the tissue connecting the left and right halves of the brain (corpus callosum), skeletal defects, heart problems, kidney and liver malformations, and facial abnormalities. Trisomy 8 mosaicism is also associated with an increased risk of acute myeloid leukemia.

Another chromosomal condition called inversion duplication 8p is caused by a rearrangement of genetic material on the short (p) arm of chromosome 8. This rearrangement results in an abnormal duplication and an inversion of a segment of the chromosome. An inversion involves the breakage of a chromosome in two places; the resulting piece of DNA is reversed and reinserted into the chromosome. People with inversion duplication 8p typically have severe intellectual disability, a thin or absent corpus callosum, weak muscle tone (hypotonia), abnormal curvature of the spine (scoliosis), and minor facial abnormalities. Some individuals with this condition may also have heart defects, underdeveloped kidneys, or eye abnormalities. Older individuals usually develop abnormal muscle stiffness (spasticity). The signs and symptoms of inversion duplication 8p tend to depend on the size and location of the chromosome segment involved. For example, inclusion of chromosome region 8p21 is thought to be associated with more severe symptoms.

Other cancers

Translocations between chromosome 8 and other chromosomes have been associated with other types of cancer. For example, Burkitt lymphoma (a cancer of white blood cells called B cells that occurs most often in children and young adults) can be caused by a translocation between chromosomes 8 and 14. This translocation, written t(8;14)(q24;q32), leads to continuous cell division without control or order, which likely contributes to the development of Burkitt lymphoma. Less frequently, Burkitt lymphoma can be caused by translocations between chromosomes 8 and 2 or chromosomes 8 and 22.

Chromosome 9 is made up of about 141 million DNA building blocks (base pairs) and represents approximately 4.5 percent of the total DNA in cells. Chromosome 9 likely contains 800 to 900 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 9.

9q22.3 microdeletion

9q22.3 microdeletion is a chromosomal change in which a small piece of the long (q) arm of chromosome 9 is deleted in each cell. Affected individuals are missing at least 352,000 base pairs, also written as 352 kilobases (kb), in the q22.3 region of chromosome 9. This 352-kb segment is known as the minimum critical region because it is the smallest deletion that has been found to cause the signs and symptoms related to 9q22.3 microdeletions. These signs and symptoms include delayed development, intellectual disability, certain physical abnormalities, and the characteristic features of a genetic condition called Gorlin syndrome (also known as nevoid basal cell carcinoma syndrome). 9q22.3 microdeletions can also be much larger; the largest reported deletion included 20.5 million base pairs (20.5 Mb).

People with a 9q22.3 microdeletion are missing two to more than 270 genes on chromosome 9. All known 9q22.3 microdeletions include the PTCH1 gene. Researchers believe that many of the features associated with 9q22.3 microdeletions, particularly the signs and symptoms of Gorlin syndrome, result from a loss of the PTCH1 gene. Other signs and symptoms related to 9q22.3 microdeletions probably result from the loss of additional genes in the q22.3 region. Researchers are working to determine which missing genes contribute to the other features associated with the deletion.

Bladder cancer

Deletions of part or all of chromosome 9 are commonly found in bladder cancer. Bladder cancer is a disease in which certain cells in the bladder become abnormal and multiply uncontrollably to form a tumor. Bladder cancer may cause blood in the urine, pain during urination, frequent urination, the feeling of needing to urinate without being able to, or lower back pain.

Bladder cancer is generally divided into two types, non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC), based on where in the bladder the tumor is located. Many cases of NMIBC tumors have a chromosome 9 deletion, which typically occurs early in tumor formation. These chromosomal changes are seen only in cancer cells. Research shows that several genes that control cell growth and division are located on chromosome 9. Many of these genes are tumor suppressors, which means they normally help prevent cells from growing and dividing in an uncontrolled way. It is likely that a loss of one or more of these genes plays a role in the early development and progression of bladder cancer.

Chronic myeloid leukemia

A rearrangement (translocation) of genetic material between chromosomes 9 and 22 causes a type of cancer of blood-forming cells called chronic myeloid leukemia. This slow-growing cancer leads to an overproduction of abnormal white blood cells. Common features of the condition include excessive tiredness (fatigue), fever, weight loss, and an enlarged spleen.

The translocation involved in this condition, written as t(9;22), fuses part of the ABL1 gene from chromosome 9 with part of the BCR gene from chromosome 22, creating an abnormal fusion gene called BCR-ABL1. The abnormal chromosome 22, containing a piece of chromosome 9 and the fusion gene, is commonly called the Philadelphia chromosome. The translocation is acquired during a person's lifetime and is present only in the abnormal blood cells. This type of genetic change, called a somatic mutation, is not inherited.

The protein produced from the BCR-ABL1 gene signals cells to continue dividing abnormally and prevents them from self-destructing, which leads to overproduction of the abnormal cells.

The Philadelphia chromosome also has been found in some cases of rapidly progressing blood cancers known as acute leukemias. It is likely that the form of blood cancer that develops is influenced by the type of blood cell that acquires the mutation and other genetic changes that occur. The presence of the Philadelphia chromosome provides a target for molecular therapies.

Kleefstra syndrome

Most people with Kleefstra syndrome, a disorder with signs and symptoms involving many parts of the body, are missing a sequence of about 1 million DNA building blocks (base pairs) on one copy of chromosome 9 in each cell. The deletion occurs near the end of the long (q) arm of the chromosome at a location designated q34.3, a region containing a gene called EHMT1. Some affected individuals have shorter or longer deletions in the same region.

The loss of the EHMT1 gene from one copy of chromosome 9 in each cell is believed to be responsible for the characteristic features of Kleefstra syndrome in people with the 9q34.3 deletion. However, the loss of other genes in the same region may lead to additional health problems in some affected individuals.

The EHMT1 gene provides instructions for making an enzyme called euchromatic histone methyltransferase 1. Histone methyltransferases are enzymes that modify proteins called histones. Histones are structural proteins that attach (bind) to DNA and give chromosomes their shape. By adding a molecule called a methyl group to histones, histone methyltransferases can turn off (suppress) the activity of certain genes, which is essential for normal development and function. A lack of euchromatic histone methyltransferase 1 enzyme impairs proper control of the activity of certain genes in many of the body's organs and tissues, resulting in the abnormalities of development and function characteristic of Kleefstra syndrome.

Other cancers

Changes in the structure of chromosome 9 have been found in many types of cancer. These changes, which occur only in cells that give rise to cancer, usually involve a loss of part of the chromosome or a rearrangement of chromosomal material. For example, a loss of part of the long (q) arm of chromosome 9 has been identified in some types of brain tumor. In addition, chromosomal rearrangements that fuse the ABL1 gene with genes other than BCR have been found in a small number of acute leukemias. The exact mechanisms by which these genetic changes lead to cancer are not completely understood, although it is likely that the proteins produced from them promote uncontrolled growth of cells.

Other chromosomal conditions

Other changes in the structure or number of copies of chromosome 9 can have a variety of effects. Intellectual disability, delayed development, distinctive facial features, and an unusual head shape are common features. Changes to chromosome 9 include an extra piece of the chromosome in each cell (partial trisomy), a missing segment of the chromosome in each cell (partial monosomy), and a circular structure called a ring chromosome 9. A ring chromosome occurs when both ends of a broken chromosome are reunited. Rearrangements (translocations) of genetic material between chromosome 9 and other chromosomes can also lead to extra or missing chromosome segments.

Chromosome 10 spans more than 133 million DNA building blocks (base pairs) and represents between 4 and 4.5 percent of the total DNA in cells. Chromosome 10 likely contains 700 to 800 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 10.

10q26 deletion syndrome

10q26 deletion syndrome is a condition that results from the loss (deletion) of a small piece of chromosome 10 in each cell. The deletion occurs on the long (q) arm of the chromosome at a position designated 10q26.

The signs and symptoms of 10q26 deletion syndrome vary widely, even among affected members of the same family. Affected individuals may have distinctive facial features, growth problems, mild to moderate intellectual disability, developmental delay, genital abnormalities in males, or skeletal or heart defects.

People with 10q26 deletion syndrome are missing between 3.5 million and 17 million DNA building blocks (base pairs), also written as 3.5 and 17 megabases (Mb), at position q26 on chromosome 10. The exact size of the deletion varies, and it is unclear what exact region needs to be deleted to cause the condition. In many affected individuals, the 10q26 deletions include the tip of the q arm of chromosome 10; however, some smaller deletions occur within the arm of the chromosome.

The signs and symptoms of 10q26 deletion syndrome are probably related to the loss of one or more genes in the deleted region. However, it is unclear which missing genes contribute to the specific features of the disorder.

Cancers

Changes in the number and structure of chromosome 10 are associated with several types of cancer. For example, a loss of all or part of chromosome 10 is often found in brain tumors called gliomas, particularly in aggressive, fast-growing gliomas. The association of cancerous tumors with a loss of chromosome 10 suggests that some genes on this chromosome play critical roles in controlling the growth and division of cells. Without these genes, cells could grow and divide too quickly or in an uncontrolled way, resulting in cancer. Researchers are working to identify the specific genes on chromosome 10 that may be involved in the development and progression of gliomas.

A complex rearrangement (translocation) of genetic material between chromosomes 10 and 11 is associated with several types of blood cancer known as leukemias. This chromosomal abnormality is found only in cancer cells. It fuses part of a specific gene from chromosome 11 (the KMT2A gene) with part of another gene from chromosome 10 (the MLLT10 gene). The abnormal protein produced from this fused gene signals cells to divide without control or order, leading to the development of cancer.

Other chromosomal conditions

Other changes in the number or structure of chromosome 10 can have a variety of effects. Intellectual disability, delayed growth and development, distinctive facial features, and heart defects are common features. Changes to chromosome 10 include an extra piece of the chromosome in each cell (partial trisomy), a missing segment of the chromosome in each cell (partial monosomy), and an abnormal structure called a ring chromosome 10. Ring chromosomes occur when a chromosome breaks in two places and the ends of the chromosome arms fuse together to form a circular structure. Translocations or inversions (breakage of a chromosome in two places) can also lead to extra or missing material from chromosome 10.

Chromosome 11 spans about 135 million DNA building blocks (base pairs) and represents between 4 and 4.5 percent of the total DNA in cells. Chromosome 11 likely contains 1,300 to 1,400 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 11.

Beckwith-Wiedemann syndrome

Beckwith-Wiedemann syndrome results from the abnormal regulation of genes on part of the short (p) arm of chromosome 11. The genes are located close together in a region designated 11p15.5 near one end of the chromosome.

People normally inherit one copy of chromosome 11 from each parent. For most genes on this chromosome, both copies of the gene are expressed, or "turned on," in cells. For some genes in the 11p15.5 region, however, only the copy inherited from a person's father (the paternally inherited copy) is expressed. For other genes, only the copy inherited from a person's mother (the maternally inherited copy) is expressed. These parent-specific differences in gene expression are caused by a phenomenon called genomic imprinting. Researchers have determined that changes in genomic imprinting disrupt the regulation of several genes located at 11p15.5, including CDKN1C, H19, IGF2, and KCNQ1OT1. Because these genes are involved in directing normal growth, problems with their regulation lead to overgrowth and the other characteristic features of Beckwith-Wiedemann syndrome.

About 20 percent of cases of Beckwith-Wiedemann syndrome are caused by a genetic change known as paternal uniparental disomy (UPD). Paternal UPD causes people to have two active copies of paternally inherited genes rather than one active copy from the father and one inactive copy from the mother. People with paternal UPD are also missing genes that are active only on the maternal copy of the chromosome. In Beckwith-Wiedemann syndrome, paternal UPD usually occurs early in embryonic development and affects only some of the body's cells. This phenomenon is called mosaicism. Mosaic paternal UPD leads to an imbalance in active paternal and maternal genes on chromosome 11, which underlies the signs and symptoms of the disorder.

About 1 percent of all people with Beckwith-Wiedemann syndrome have a chromosomal abnormality such as a rearrangement (translocation) involving 11p15.5 or abnormal copying (duplication) or deletion of genetic material in this region. Like the other genetic changes responsible for Beckwith-Wiedemann syndrome, these changes disrupt the normal regulation of genes in this part of chromosome 11.

Emanuel syndrome

Emanuel syndrome is caused by the presence of extra genetic material from chromosome 11 and chromosome 22 in each cell. In addition to the usual 46 chromosomes, people with Emanuel syndrome have an extra (supernumerary) chromosome consisting of a piece of chromosome 22 attached to a piece of chromosome 11. The extra chromosome is known as a derivative 22 or der(22) chromosome.

People with Emanuel syndrome typically inherit the der(22) chromosome from an unaffected parent. The parent carries a chromosomal rearrangement between chromosomes 11 and 22 called a balanced translocation. No genetic material is gained or lost in a balanced translocation, so these chromosomal changes usually do not cause any health problems. As the translocation is passed to the next generation, it can become unbalanced. Individuals with Emanuel syndrome inherit an unbalanced translocation between chromosomes 11 and 22 in the form of a der(22) chromosome. These individuals have two normal copies of chromosome 11, two normal copies of chromosome 22, and extra genetic material from the der(22) chromosome.

As a result of the extra chromosome, people with Emanuel syndrome have three copies of some genes in each cell instead of the usual two copies. The excess genetic material disrupts the normal course of development, leading to intellectual disability and birth defects. Researchers are working to determine which genes are included on the der(22) chromosome and what role these genes play in development.

Ewing sarcoma

A translocation involving chromosome 11 can cause a type of cancerous tumor known as Ewing sarcoma. These tumors develop in bones or soft tissues, such as nerves and cartilage. This translocation, t(11;22), fuses part of the EWSR1 gene from chromosome 22 with part of the FLI1 gene from chromosome 11, creating the EWSR1/FLI1 fusion gene. This mutation is acquired during a person's lifetime and is present only in tumor cells. This type of genetic change, called a somatic mutation, is not inherited.

The protein produced from the EWSR1/FLI1 fusion gene, called EWS/FLI, has functions of the protein products of both genes. The FLI protein, produced from the FLI1 gene, attaches (binds) to DNA and regulates an activity called transcription, which is the first step in the production of proteins from genes. The FLI protein controls the growth and development of some cell types by regulating the transcription of certain genes. The EWS protein, produced from the EWSR1 gene, also regulates transcription. The EWS/FLI protein has the DNA-binding function of the FLI protein as well as the transcription regulation function of the EWS protein. It is thought that the EWS/FLI protein turns the transcription of a variety of genes on and off abnormally. This dysregulation of transcription leads to uncontrolled growth and division (proliferation) and abnormal maturation and survival of cells, causing tumor development.

Jacobsen syndrome

Jacobsen syndrome, which is also known as 11q terminal deletion disorder, is caused by a deletion of genetic material at the end (terminus) of the long (q) arm of chromosome 11. The size of the deletion varies among affected individuals, with most affected people missing from about 5 million to 16 million DNA building blocks (also written as 5 Mb to 16 Mb). In almost all affected people, the deletion includes the tip of chromosome 11. Larger deletions tend to cause more severe signs and symptoms than smaller deletions.

The features of Jacobsen syndrome are likely related to the loss of multiple genes on chromosome 11. Depending on its size, the deleted region can contain from about 170 to more than 340 genes. Many of these genes have not been well characterized. However, genes in this region appear to be critical for the normal development of many parts of the body, including the brain, facial features, and heart. Only a few genes have been studied as possible contributors to the specific features of Jacobsen syndrome; researchers are working to determine which additional genes may be associated with this condition.

Neuroblastoma

About 35 percent of people with neuroblastoma have a deletion of genetic material on the long (q) arm of chromosome 11 at a position designated 11q23. Neuroblastoma is a type of cancerous tumor composed of immature nerve cells (neuroblasts). The 11q23 deletion can occur in the body's cells after conception, which is called a somatic mutation, or it can be inherited from a parent. This deletion is associated with a more severe form of neuroblastoma. Researchers believe the deleted region could contain a gene that keeps cells from growing and dividing too quickly or in an uncontrolled way, called a tumor suppressor gene. When tumor suppressor genes are deleted, cancer can occur. However, no tumor suppressor genes have been identified in the deleted region of chromosome 11. It is unknown how deletion of this region contributes to the formation or progression of neuroblastoma.

Potocki-Shaffer syndrome

Potocki-Shaffer syndrome is caused by the deletion of a segment of the short (p) arm of chromosome 11 at a position described as 11p11.2. This condition is also known as proximal 11p deletion syndrome. The characteristic features of Potocki-Shaffer syndrome include enlarged openings in the two bones that make up much of the top and sides of the skull (enlarged parietal foramina), multiple noncancerous bone tumors called osteochondromas, intellectual disability, delayed development, a distinctive facial appearance, and problems with vision. Occasionally, people with this condition have defects in the heart, kidneys, and urinary tract. The features of Potocki-Shaffer syndrome result from the loss of several genes on the short arm of chromosome 11. In particular, the deletion of a gene called ALX4 causes enlarged parietal foramina in people with this condition, loss of the EXT2 gene underlies the multiple osteochondromas, and deletion of the PHF21A gene is responsible for the intellectual disability and distinctive facial features. Researchers are working to find genes on the short arm of chromosome 11 that are associated with the other features of Potocki-Shaffer syndrome.

Another condition called WAGR syndrome (described below) is caused by a deletion of genetic material from the short arm of chromosome 11 at a position described as 11p13. Occasionally, a deletion is large enough to include the 11p11.2 and 11p13 regions. Individuals with such a deletion have signs and symptoms of both Potocki-Shaffer syndrome and WAGR syndrome.

Russell-Silver syndrome

Like Beckwith-Wiedemann syndrome, Russell-Silver syndrome can result from changes in genes in the 11p15.5 region. Specifically, Russell-Silver syndrome has been associated with changes in genomic imprinting that affect the regulation of the H19 and IGF2 genes on chromosome 11. The changes are different from those seen in Beckwith-Wiedemann syndrome and have the opposite effect on growth. Although both disorders can be caused by abnormal regulation of these genes, the changes that cause Russell-Silver syndrome lead to slow growth and short stature instead of overgrowth.

WAGR syndrome

WAGR syndrome is caused by a deletion of genetic material on the short (p) arm of chromosome 11 at a position described as 11p13. WAGR syndrome is a disorder that affects many body systems and is named for its main features: a childhood kidney cancer known as Wilms tumor, an eye problem called aniridia, genitourinary anomalies, and intellectual disability (formerly referred to as mental retardation). The signs and symptoms of WAGR syndrome are related to the loss of multiple genes from this part of the chromosome. The size of the deletion varies among affected individuals. Researchers have identified genes on the short arm of chromosome 11 that are associated with particular features of WAGR syndrome. A loss of the PAX6 gene disrupts normal eye development, leading to aniridia and other eye problems, and may also affect the development of the brain. Deletion of the WT1 gene is responsible for the genitourinary abnormalities and the increased risk of Wilms tumor in affected individuals. Researchers are working to identify additional genes deleted in people with WAGR syndrome and determine how their loss leads to the other features of the disorder.

Other cancers

Changes in chromosome 11 have been identified in other types of cancer. These chromosomal changes are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. In some cases, translocations of genetic material between chromosome 11 and other chromosomes have been associated with cancers of blood-forming cells (leukemias) and cancers of immune system cells (lymphomas).

Other chromosomal conditions

Other changes in the number or structure of chromosome 11 can have a variety of effects, including intellectual disability, delayed development, slow growth, distinctive facial features, and weak muscle tone (hypotonia). Changes involving chromosome 11 include an extra piece of the chromosome in each cell (partial trisomy 11), a missing segment of the chromosome in each cell (partial monosomy 11), and a circular structure called a ring chromosome 11. Ring chromosomes occur when a chromosome breaks in two places and the ends of the chromosome arms fuse together to form a circular structure.

Chromosome 12 spans almost 134 million DNA building blocks (base pairs) and represents between 4 and 4.5 percent of the total DNA in cells. Chromosome 12 likely contains 1,100 to 1,200 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 12.

Cancers

Changes in chromosome 12 have been identified in several types of cancer. These genetic changes are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. For example, rearrangements (translocations) of genetic material between chromosome 12 and other chromosomes are often found in certain cancers of blood-forming cells (leukemias) and cancers of immune system cells (lymphomas). Additionally, somatic mutations may lead to an extra copy of chromosome 12 (trisomy 12) in cancer cells, specifically a type of leukemia called chronic lymphocytic leukemia.

Translocations involving chromosome 12 have also been found in solid tumors such as lipomas and liposarcomas, which are made up of fatty tissue. In these tumors, the most common chromosome 12 rearrangements involve the long (q) arm in a region designated q13-q15. Abnormalities of chromosome 12 have been identified in at least two other rare tumors, angiomatoid fibrous histiocytomas and clear cell sarcomas. Angiomatoid fibrous histiocytomas occur primarily in adolescents and young adults and are usually found in the arms and legs (extremities). Clear cell sarcomas occur most often in young adults and tend to be associated with tendons and related structures called aponeuroses.

Researchers are working to determine which genes on chromosome 12 are disrupted by translocations, and they are studying how these chromosomal changes could contribute to the uncontrolled growth and division of tumor cells.

Pallister-Killian mosaic syndrome

Pallister-Killian mosaic syndrome is usually caused by the presence of an abnormal extra chromosome called an isochromosome 12p or i(12p). An isochromosome is a chromosome with two identical arms. Normal chromosomes have one long (q) arm and one short (p) arm, but isochromosomes have either two q arms or two p arms. Isochromosome 12p is a version of chromosome 12 made up of two p arms.

Cells normally have two copies of each chromosome, one inherited from each parent. In people with Pallister-Killian mosaic syndrome, cells have the two usual copies of chromosome 12, but some cells also have the isochromosome 12p. These cells have a total of four copies of all the genes on the p arm of chromosome 12. The extra genetic material from the isochromosome disrupts the normal course of development, causing the characteristic features of this disorder.

Although Pallister-Killian mosaic syndrome is usually caused by an isochromosome 12p, other, more complex chromosomal changes involving chromosome 12 are responsible for the disorder in rare cases.

PDGFRB-associated chronic eosinophilic leukemia

Translocations involving chromosome 12 are involved in a type of blood cell cancer called PDGFRB-associated chronic eosinophilic leukemia. This condition is characterized by an increased number of eosinophils, a type of white blood cell. The most common translocation that causes this condition fuses part of the PDGFRB gene from chromosome 5 with part of the ETV6 gene from chromosome 12, written as t(5;12)(q31-33;p13). Translocations that fuse the PDGFRB gene with other genes can also cause PDGFRB-associated chronic eosinophilic leukemia, but these translocations are relatively uncommon. These translocations are acquired during a person's lifetime and are present only in cancer cells. This type of genetic change, called a somatic mutation, is not inherited.

The protein produced from the ETV6-PDGFRB fusion gene, called ETV6/PDGFRβ, functions differently than the proteins normally produced from the individual genes. The ETV6 protein normally turns off (represses) gene activity and the PDGFRβ protein plays a role in turning on (activating) signaling pathways. The ETV6/PDGFRβ protein is always turned on, activating signaling pathways and gene activity. When the ETV6-PDGFRB fusion gene mutation occurs in cells that develop into blood cells, the growth of eosinophils (and occasionally other white blood cells, such as neutrophils and mast cells) is poorly controlled, leading to PDGFRB-associated chronic eosinophilic leukemia. It is unclear why eosinophils are preferentially affected by this genetic change.

Other chromosomal conditions

Other changes in the number or structure of chromosome 12 can have a variety of effects on health and development. These effects include intellectual disability, slow growth, distinctive facial features, weak muscle tone (hypotonia), skeletal abnormalities, and heart defects.

Several different changes involving chromosome 12 have been reported, including an extra piece of the chromosome in each cell (partial trisomy 12), a missing segment of the chromosome in each cell (partial monosomy 12), and a circular structure called a ring chromosome 12. Ring chromosomes occur when a chromosome breaks in two places and the ends of the chromosome arms fuse together to form a circular structure.

Chromosome 13 is made up of about 115 million DNA building blocks (base pairs) and represents between 3.5 and 4 percent of the total DNA in cells. Chromosome 13 likely contains 300 to 400 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 13.

8p11 myeloproliferative syndrome

A rearrangement (translocation) of genetic material involving chromosome 13 has been identified in most people with a rare blood cancer called 8p11 myeloproliferative syndrome. This condition is characterized by an increased number of white blood cells (myeloproliferative disorder) and the development of lymphoma, a blood-related cancer that causes tumor formation in the lymph nodes. The myeloproliferative disorder usually develops into another form of blood cancer called acute myeloid leukemia. 8p11 myeloproliferative syndrome most commonly results from a translocation between chromosome 13 and chromosome 8, written as t(8;13)(p11;q12). This genetic change fuses part of the ZMYM2 gene on chromosome 13 with part of the FGFR1 gene on chromosome 8. The translocation occurs only in cancer cells.

The protein produced from the normal FGFR1 gene can turn on cellular signaling that helps the cell respond to its environment, for example by stimulating cell growth. The protein produced from the fused ZMYM2-FGFR1 gene leads to constant FGFR1 signaling. The uncontrolled signaling promotes continuous cell growth and division, leading to cancer.

Feingold syndrome

Feingold syndrome type 2 is caused by genetic changes that remove (delete) small pieces of DNA from the long (q) arm of chromosome 13. These changes are known as 13q31.3 microdeletions. Feingold syndrome type 2 is characterized by abnormalities of the fingers and toes, particularly shortening of the second and fifth fingers (brachymesophalangy). Other common features include an unusually small head size (microcephaly) and learning disabilities. 13q31.3 microdeletions involved in this condition delete the MIR17HG gene and sometimes part or all of other nearby genes. Loss of the MIR17HG gene is thought to underlie the characteristic features of the disorder, although loss of other genes may play a role in some cases.

The MIR17HG gene provides instructions for making the miR-17~92 microRNA (miRNA) cluster, which includes six different miRNAs. MiRNAs are short pieces of RNA, a chemical cousin of DNA. These molecules control gene activity (expression) by blocking protein production. MiRNAs in the miR-17~92 cluster help regulate signaling pathways that direct several cellular processes involved in growth and development before birth.

Deletion of one copy of the MIR17HG gene reduces the amount of miR-17~92 cluster miRNAs available to control the activity of specific genes during development. While it is likely that the resulting disruption of signaling pathways leads to the problems with growth and development characteristic of Feingold syndrome type 2, it is unclear exactly how a shortage of miR-17~92 cluster miRNAs causes the specific features of the condition.

Retinoblastoma

Retinoblastoma, a cancer of the light-sensing tissue at the back of the eye (the retina) that affects mostly children, is caused by abnormalities of a gene called RB1. This gene is located on a region of the q arm of chromosome 13 designated 13q14. Although most retinoblastomas are caused by variants (also known as mutations) within the RB1 gene, a small percentage of retinoblastomas result from a deletion of the 13q14 region.

In addition to retinoblastoma, deletions of the 13q14 region may cause intellectual disability, slow growth, and characteristic facial features such as prominent eyebrows, a broad nasal bridge, a short nose, and ear abnormalities. A loss of several genes is likely responsible for these developmental problems, although researchers have not determined which other genes in the deleted region are involved.

Trisomy 13

Trisomy 13 occurs when each cell in the body has three copies of chromosome 13 instead of the usual two copies. Trisomy 13 can also result from an extra copy of chromosome 13 in only some of the body's cells (mosaic trisomy 13).

In some cases, trisomy 13 occurs when chromosome 13 becomes attached (translocated) to another chromosome during the formation of reproductive cells (eggs and sperm) or very early in embryonic development. Affected individuals have two copies of chromosome 13, plus extra material from chromosome 13 attached to another chromosome. People with this genetic change are said to have translocation trisomy 13. The physical signs of translocation trisomy 13 may be different from those typically seen in trisomy 13 when only part of chromosome 13 is present in three copies.

Researchers believe that extra copies of some genes on chromosome 13 disrupt the course of normal development, causing the characteristic features of trisomy 13 and the increased risk of medical problems associated with this disorder.

Other chromosomal conditions

Partial monosomy and partial trisomy of chromosome 13 occur when a portion of the q arm of this chromosome is deleted or duplicated, respectively. The effect of missing or extra chromosome material varies with the size and location of the chromosome abnormality. Affected individuals may have developmental delay, intellectual disability, low birth weight, skeletal abnormalities, and other physical features.

Other cancers

Changes in chromosome 13 have been associated with several types of cancer. These genetic changes are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. The loss of genetic material from the middle of chromosome 13 is common in cancers of blood-forming cells (leukemias), cancers of immune system cells (lymphomas), and other related cancers.

Chromosome 14 spans more than 107 million DNA building blocks (base pairs) and represents about 3.5 percent of the total DNA in cells. Chromosome 14 likely contains 800 to 900 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 14.

FOXG1 syndrome

A deletion of genetic material from part of the long (q) arm of chromosome 14 can cause FOXG1 syndrome, which is a rare disorder characterized by impaired development and structural brain abnormalities. The region of chromosome 14 that is deleted includes the FOXG1 gene as well as several neighboring genes. Depending on which genes are involved, affected individuals may have additional signs and symptoms, including distinctive facial features and a missing connection between the left and right halves of the brain (a structure called the corpus callosum).

The protein normally produced from the FOXG1 gene plays an important role in brain development before birth, particularly in a region of the embryonic brain known as the telencephalon. The telencephalon ultimately develops into several critical structures, including the largest part of the brain (the cerebrum), which controls most voluntary activity, language, sensory perception, learning, and memory. A loss of the FOXG1 gene disrupts normal brain development starting before birth, which appears to underlie the structural brain abnormalities and severe developmental problems characteristic of FOXG1 syndrome. It is unclear how the loss of additional genes contributes to the signs and symptoms of the condition.

Multiple myeloma

A rearrangement (translocation) that moves genetic material from one of several other chromosomes to a region of chromosome 14 called 14q32 occurs in 20 to 60 percent of cases of multiple myeloma, which is a cancer arising from plasma cells, a type of white blood cell. The translocation is somatic, which means it is acquired during a person's lifetime and is present only in certain cells. The translocation likely affects genes that play a critical role in regulating cell division by preventing cells from dividing too rapidly or in an uncontrolled way. Disruption of these genes may interfere with proper control (regulation) of cell growth and division (proliferation), resulting in the excessive proliferation of plasma cells that characterizes multiple myeloma.

Ring chromosome 14 syndrome

Ring chromosome 14 syndrome is caused by a chromosomal abnormality known as a ring chromosome 14 or r(14). A ring chromosome is a circular structure that occurs when a chromosome breaks in two places and its broken ends fuse together. People with ring chromosome 14 syndrome have one copy of this abnormal chromosome in some or all of their cells.

Researchers believe that several critical genes near the end of the long (q) arm of chromosome 14 are lost when the ring chromosome forms. The loss of these genes is likely responsible for several of the major features of ring chromosome 14 syndrome, including intellectual disability and delayed development. Researchers are still working to determine which missing genes contribute to the signs and symptoms of this disorder.

Epilepsy is a common feature of ring chromosome syndromes, including ring chromosome 14. There may be something about the ring structure itself that causes epilepsy. Seizures may occur because certain genes on the ring chromosome 14 are less active than those on the normal chromosome 14. Alternately, seizures might result from instability of the ring chromosome in some cells.

Other cancers

Translocations of genetic material between chromosome 14 and other chromosomes have been associated with several types of cancer. Studies show that these translocations disrupt genes that are critical for keeping cell growth and division under control. Unregulated cell division can lead to the development of cancer.

Translocations involving chromosome 14 have been found in cancers of blood-forming cells (leukemias), cancers of immune system cells (lymphomas), and several related diseases. For example, Burkitt lymphoma, a cancer of white blood cells that occurs most often in children and young adults, is related to a translocation between chromosomes 8 and 14. Another type of lymphoma, called follicular lymphoma, is often associated with a translocation between chromosomes 14 and 18.

Other chromosomal conditions

A rare condition known as terminal deletion 14 syndrome causes signs and symptoms similar to those of ring chromosome 14 syndrome. Terminal deletion 14 syndrome is caused by the loss of several genes at the end (terminus) of the long (q) arm of chromosome 14. In addition, some people with terminal deletion 14 syndrome have a loss or gain of genetic material from another chromosome. People with this condition may have weak muscle tone (hypotonia), a small head (microcephaly), frequent respiratory infections, developmental delay, and learning difficulties.

Other changes in the number or structure of chromosome 14 can have a variety of effects, including delayed growth and development, distinctive facial features, and other health problems. Several different changes involving chromosome 14 have been reported. These include an extra copy of a segment of chromosome 14 in every cell (partial trisomy 14), an extra copy of the entire chromosome in only some of the body's cells (mosaic trisomy 14), and deletions or duplications of part of chromosome 14. Full trisomy 14, an extra copy of the entire chromosome 14 in all of the body's cells, is not compatible with life.

Health problems can also result from a chromosome abnormality called uniparental disomy (UPD). UPD occurs when people inherit both copies of a chromosome from one parent instead of one copy from each parent. The long arm of chromosome 14 contains some genes that are active only when inherited from the mother, and other genes that are active only when inherited from the father. Therefore, people who have two paternal copies or two maternal copies of chromosome 14 are missing some functional genes and have an extra copy of others.

When both copies of chromosome 14 are inherited from the mother, the phenomenon is known as maternal UPD 14. Maternal UPD 14 is associated with premature birth, slow growth before and after birth, short stature, developmental delay, small hands and feet, and early onset of puberty. When both copies of the chromosome are inherited from the father, the phenomenon is known as paternal UPD 14. Paternal UPD 14 is associated with an excess of amniotic fluid (which surrounds the baby before birth); an opening in the wall of the abdomen; distinctive facial features; a small, bell-shaped chest with short ribs; and developmental delay. Both maternal UPD 14 and paternal UPD 14 appear to be rare.

Chromosome 15 spans more than 102 million DNA building blocks (base pairs) and represents more than 3 percent of the total DNA in cells. Chromosome 15 likely contains 600 to 700 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 15.

15q11-q13 duplication syndrome

Duplication of a region of the long (q) arm of chromosome 15 can result in 15q11-q13 duplication syndrome (dup15q syndrome), a condition whose features can include weak muscle tone (hypotonia), intellectual disability, recurrent seizures (epilepsy), characteristics of autism spectrum disorder affecting communication and social interaction, and other behavioral problems.

Dup15q syndrome is caused by the presence of at least one extra copy of a region of chromosome 15 called 15q11.2-q13.1. This region is also called the Prader-Willi/Angelman critical region (PWACR) because genetic changes in it are also involved in conditions called Prader-Willi syndrome and Angelman syndrome (described below). Dup15q syndrome arises only if the chromosome abnormality occurs on the copy of the chromosome inherited from the mother (the maternal copy). People normally inherit one copy of chromosome 15 from each parent. However, some genes on this chromosome, including some of those in the 15q11.2-q13.1 region, are turned on (active) only on the maternal copy. This parent-specific gene activation results from a phenomenon called genomic imprinting.

The most common chromosome abnormality that leads to 15q11.2-q13.1 duplication, occurring in about 80 percent of people with dup15q syndrome, is called an isodicentric chromosome 15. An isodicentric chromosome contains mirror-image segments of genetic material and has two constriction points (centromeres), rather than one centromere as in normal chromosomes. In people with an isodicentric chromosome 15, cells have the usual two copies of chromosome 15 plus the two duplicated copies of the segment of genetic material in the isodicentric chromosome, for a total of four copies of the duplicated segment.

In about 20 percent of cases of dup15q syndrome, the duplication occurs on the long (q) arm of one of the two copies of chromosome 15 in each cell; this situation is called an interstitial duplication. In these cases, cells have two copies of chromosome 15, one of which has an extra copy of the segment of genetic material, for a total of three copies of the duplicated segment.

In all cases of dup15q syndrome, the duplicated genetic material results in extra copies of certain genes involved in development. This extra genetic material disrupts normal development, causing the characteristic features of this disorder. People with dup15q syndrome resulting from an interstitial duplication often have milder signs and symptoms than those in whom the disorder results from an isodicentric chromosome 15.

15q13.3 microdeletion

15q13.3 microdeletion is a chromosomal change in which a small piece of chromosome 15 is deleted in each cell. The deletion occurs on the q arm of the chromosome at a position designated q13.3. Most people with a 15q13.3 microdeletion are missing a sequence of about 2 million DNA base pairs, also written as 2 megabases (Mb). The exact size of the deleted region varies, but it typically contains at least six genes. It is unclear how a loss of these genes increases the risk of intellectual disability, seizures, behavioral problems, and psychiatric disorders in some individuals with a 15q13.3 microdeletion.

Other people with a 15q13.3 microdeletion have no obvious signs or symptoms related to the chromosomal change. In these individuals, the microdeletion is often detected when they undergo genetic testing because they have an affected relative. It is unknown why 15q13.3 microdeletion causes cognitive and behavioral problems in some individuals but few or no health problems in others. Researchers believe that additional genetic or environmental factors may be involved.

15q24 microdeletion

15q24 microdeletion is a chromosomal change in which a small piece of chromosome 15 is deleted in each cell. Specifically, affected individuals are missing between 1.7 Mb and 6.1 Mb of DNA at position q24 on chromosome 15. The exact size of the deletion varies, but all individuals are missing the same 1.2 Mb region. This region contains several genes that are thought to be important for normal development. It is unclear how a loss of these genes leads to intellectual disability, distinctive facial features, and other abnormalities often seen in people with a 15q24 microdeletion.

Acute promyelocytic leukemia

A type of blood cancer known as acute promyelocytic leukemia is caused by a rearrangement (translocation) of genetic material between chromosomes 15 and 17. This translocation, written as t(15;17), fuses part of the PML gene from chromosome 15 with part of the RARA gene from chromosome 17. This mutation is acquired during a person's lifetime and is present only in certain cells. This type of genetic change, called a somatic mutation, is not inherited. The t(15;17) translocation is called a balanced reciprocal translocation because the pieces of chromosome are exchanged with each other (reciprocal) and no genetic material is gained or lost (balanced). The protein produced from this fused gene is known as PML-RARα.

The PML-RARα protein functions differently than the protein products from the normal PML and RARA genes. The PML gene on chromosome 15 provides instructions for a protein that acts as a tumor suppressor, which means it prevents cells from growing and dividing too rapidly or in an uncontrolled way. The PML protein blocks cell growth and division (proliferation) and induces self-destruction (apoptosis) in combination with other proteins. The RARA gene on chromosome 17 provides instructions for making a transcription factor called the retinoic acid receptor alpha (RARα). A transcription factor is a protein that attaches (binds) to specific regions of DNA and helps control the activity of particular genes. Normally, the RARα protein controls the activity (transcription) of genes important for the maturation (differentiation) of immature white blood cells beyond a particular stage called the promyelocyte. The PML-RARα protein interferes with the normal function of both the PML and the RARα proteins. As a result, blood cells are stuck at the promyelocyte stage, and they proliferate abnormally. Excess promyelocytes accumulate in the bone marrow and normal white blood cells cannot form, leading to acute promyelocytic leukemia.

Angelman syndrome

Angelman syndrome results from a loss of gene activity (expression) in a specific part of chromosome 15 in each cell. This region is located on the q arm of the chromosome and is designated 15q11-q13. This region contains a gene called UBE3A that, when mutated or absent, likely causes the characteristic neurologic features of Angelman syndrome.

People normally inherit one copy of the UBE3A gene from each parent, and both copies of this gene are active in many of the body's tissues. In certain areas of the brain, however, only the copy inherited from a person's mother (the maternal copy) is active. This parent-specific gene activation results from a phenomenon called genomic imprinting. If the maternal copy is lost because of a chromosomal change or a gene mutation, a person will have no working copies of the UBE3A gene in some parts of the brain.

In most cases (about 70 percent), Angelman syndrome results from a deletion in the maternal copy of chromosome 15. This chromosomal change deletes the region of chromosome 15 that includes the UBE3A gene. Because the copy of the UBE3A gene inherited from a person's father (the paternal copy) is normally inactive in certain parts of the brain, a deletion in the maternal chromosome 15 leaves no active copies of the UBE3A gene in these brain regions.

In 3 percent to 7 percent of cases of Angelman syndrome, the condition results when a person inherits two copies of chromosome 15 from his or her father instead of one copy from each parent. This phenomenon is called paternal uniparental disomy (UPD). People with paternal UPD for chromosome 15 have two copies of the UBE3A gene, but they are both inherited from the father and are therefore inactive in the brain.

About 10 percent of cases of Angelman syndrome are caused by a mutation in the UBE3A gene, and another 3 percent results from a defect in the DNA region that controls the activation of the UBE3A gene and other genes on the maternal copy of chromosome 15. In a small percentage of cases, Angelman syndrome is caused by a chromosomal rearrangement (translocation) or by a mutation in a gene other than UBE3A. These genetic changes abnormally inactivate the UBE3A gene.

Prader-Willi syndrome

Prader-Willi syndrome is caused by a loss of active genes in a region of chromosome 15. This region is located on the q arm of the chromosome and is designated 15q11-q13. It is the same part of chromosome 15 that is usually affected in people with Angelman syndrome, although different genes are associated with the two disorders. People can have either Prader-Willi syndrome or Angelman syndrome, but they typically cannot have both.

People normally inherit one copy of chromosome 15 from each parent. Some genes on this chromosome are turned on (active) only on the copy inherited from a person's father (the paternal copy). This parent-specific gene activation results from a phenomenon called genomic imprinting.

In about 70 percent of cases, Prader-Willi syndrome occurs when the 15q11-q13 region of the paternal chromosome 15 is deleted in each cell. A person with this chromosomal change will be missing certain critical genes in this region because the genes on the paternal copy have been deleted, and the genes on the maternal copy are turned off (inactive). Researchers are working to identify which missing genes are associated with the characteristic features of Prader-Willi syndrome.

In about 25 percent of cases, people with Prader-Willi syndrome inherit two copies of chromosome 15 from their mother instead of one copy from each parent. This phenomenon is called maternal UPD. A person with two maternal copies of chromosome 15 will have no active copies of certain genes in the 15q11-q13 region.

In a small percentage of cases, Prader-Willi syndrome is caused by a chromosomal rearrangement called a translocation. Rarely, the condition results from a mutation or other defect that abnormally inactivates genes on the paternal copy of chromosome 15.

Sensorineural deafness and male infertility

Sensorineural deafness and male infertility is caused by a deletion of genetic material on the q arm of chromosome 15. The symptoms of sensorineural deafness and male infertility are related to the loss of multiple genes in this region. The size of the deletion varies among affected individuals. Researchers have determined that the loss of a particular gene on chromosome 15, STRC, is responsible for hearing loss in affected individuals. The loss of another gene, CATSPER2, in the same region of chromosome 15 is responsible for sperm abnormalities, which lead to an inability to father children (infertility) in affected males. Researchers are working to determine how the loss of additional genes in the deleted region affects people with sensorineural deafness and male infertility.

Other chromosomal conditions

Other changes in the number or structure of chromosome 15 can cause intellectual disability, delayed growth and development, hypotonia, and characteristic facial features. These changes include an extra copy of part of chromosome 15 in each cell (partial trisomy 15), a missing segment of the chromosome in each cell (partial monosomy 15), and a circular structure called ring chromosome 15. A ring chromosome occurs when a chromosome breaks in two places and the ends of the chromosome arms fuse together to form a circular structure.

Chromosome 16 spans more than 90 million DNA building blocks (base pairs) and represents almost 3 percent of the total DNA in cells. Chromosome 16 likely contains 800 to 900 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 16.

16p11.2 deletion syndrome

16p11.2 deletion syndrome is caused by a deletion of about 600,000 base pairs, also written as 600 kilobases (kb), at position 11.2 on the short (p) arm of chromosome 16. This deletion affects one of the two copies of chromosome 16 in each cell. The 600 kb region contains more than 25 genes, and in many cases little is known about their function. Researchers are working to determine how the missing genes contribute to the features of 16p11.2 deletion syndrome, which include delayed development; intellectual disability; and autism spectrum disorder, which affects communication and social interaction. Obesity is another common feature of 16p11.2 deletion syndrome; individuals with the deletion also have an increased risk of seizures. Most people with the deletion have some of these signs and symptoms, but others do not. Although some people have this deletion without serious consequences, they can still pass it to their children, who may be more severely affected.

16p11.2 duplication

A 16p11.2 duplication is an extra copy of the same 600 kb segment of chromosome 16 that is missing in 16p11.2 deletion syndrome (described above). A 16p11.2 duplication may result in similar signs and symptoms as the deletion in some affected individuals, including features of autism spectrum disorder; however, being underweight is common in people with the duplication, while obesity often occurs with the deletion.

The 16p11.2 duplication appears to have a milder effect than the deletion, with a higher proportion of individuals with this chromosomal change showing no apparent problems. These individuals can still pass along the duplication to their children, who may have signs and symptoms related to the chromosomal change. Researchers are working to determine how the extra genetic material contributes to the features that occur in some people with a 16p11.2 duplication, and why duplication or deletion of the same chromosomal region can have some similar effects.

16p12.2 microdeletion

A small amount of missing genetic material on the p arm of chromosome 16 causes a condition called 16p12.2 microdeletion, which is associated with physical and developmental abnormalities in some affected individuals. People with this chromosomal abnormality are missing a sequence of about 520,000 base pairs, also written as 520 kb, at position p12.2 on chromosome 16. The deleted region contains seven genes. This deletion affects one of the two copies of chromosome 16 in each cell.

The signs and symptoms that can result from a 16p12.2 microdeletion are generally related to the loss of one or more genes in this region. However, it is unclear which missing genes contribute to specific features that can occur in the disorder. Because some people with a 16p12.2 microdeletion have no obvious signs or symptoms (a situation called incomplete penetrance), researchers believe that other genetic or environmental factors may also be involved. In particular, studies indicate that individuals with a 16p12.2 microdeletion who have neurological or behavioral problems often have an additional, larger deletion or duplication affecting another chromosome. Small duplications of genetic material that occur near the 16p12.2 microdeletion may also contribute to the features associated with this condition.

Alveolar capillary dysplasia with misalignment of pulmonary veins

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a disorder that affects the development of blood vessels in the lungs. It can be caused by a deletion of genetic material on chromosome 16 in a region known as 16q24.1. This region includes several genes, including the FOXF1 gene. The protein produced from the FOXF1 gene is a transcription factor, which means that it attaches (binds) to specific regions of DNA and helps control the activity of many other genes. The FOXF1 protein helps regulate the development of the lungs and the gastrointestinal tract. Genetic changes that result in a nonfunctional FOXF1 protein interfere with the development of pulmonary blood vessels and cause ACD/MPV. Affected infants may also have gastrointestinal abnormalities.

Researchers suggest that deletions resulting in the loss of other genes in this region of chromosome 16 probably cause the additional abnormalities seen in some infants with this disorder. Like FOXF1, these genes also provide instructions for making transcription factors that regulate development of various body systems before birth.

Cancers

Changes in the structure of chromosome 16 are associated with several types of cancer. These genetic changes are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. In some cases, chromosomal rearrangements called translocations disrupt the region of chromosome 16 that contains the CREBBP gene. The protein produced from this gene normally plays a role in regulating cell growth and division, which helps prevent the development of cancers.

Researchers have found a translocation between chromosome 8 and chromosome 16 that disrupts the CREBBP gene in some people with a cancer of blood-forming cells called acute myeloid leukemia (AML). Another translocation involving the CREBBP gene, which rearranges pieces of chromosomes 11 and 16, has been found in some people who have undergone cancer treatment. This chromosomal change is associated with the later development of AML and two other cancers of blood-forming tissues (chronic myeloid leukemia and myelodysplastic syndrome). These are sometimes described as treatment-related cancers because the translocation between chromosomes 11 and 16 occurs following chemotherapy for other forms of cancer.

Core binding factor acute myeloid leukemia

Another type of blood cancer known as core binding factor acute myeloid leukemia (CBF-AML) is associated with rearrangements of genetic material on chromosome 16. The most common of these rearrangements is an inversion of a region of chromosome 16 (written as inv(16)). An inversion involves breakage of the chromosome in two places; the resulting piece of DNA is reversed and reinserted into the chromosome. Less commonly, a translocation occurs between the two copies of chromosome 16 (written as t(16;16)). Both types of genetic rearrangement result in the fusion of two genes found on chromosome 16, CBFB and MYH11. These genetic changes are associated with 5 to 8 percent of cases of AML in adults. These mutations are acquired during a person's lifetime and are present only in certain cells. This type of genetic change, called a somatic mutation, is not inherited.

The protein produced from the normal CBFB gene interacts with another protein called RUNX1 to form a complex called core binding factor (CBF). This complex attaches to specific areas of DNA and turns on genes that are involved in the development of blood cells. The protein produced from the fusion gene, CBFβ-MYH11, can still bind to RUNX1. However, the function of CBF is impaired. The presence of CBFβ-MYH11 may block binding of CBF to DNA, impairing its ability to control gene activity. Alternatively, the MYH11 portion of the fusion protein may interact with other proteins that prevent the complex from controlling gene activity. The change in gene activity blocks the maturation (differentiation) of blood cells, which leads to the production of abnormal, immature white blood cells called myeloid blasts and to a shortage of normal, mature blood cell types. However, one or more additional genetic changes are typically needed for the myeloid blasts to develop into cancerous leukemia cells.

Rubinstein-Taybi syndrome

Some cases of severe Rubinstein-Taybi syndrome (sometimes known as chromosome 16p13.3 deletion syndrome) have resulted from a deletion of genetic material from the p arm of chromosome 16. When this deletion occurs in all of the body's cells, it can cause serious complications such as a failure to gain weight and grow at the expected rate (failure to thrive) and an increased risk of life-threatening infections. Affected individuals also have many of the typical features of Rubinstein-Taybi syndrome, including intellectual disability, distinctive facial features, and broad thumbs and first toes. Infants born with the severe form of this disorder usually survive only into early childhood.

Several genes are missing as a result of this deletion in the short arm of chromosome 16. The deleted region includes the CREBBP gene, which is often mutated or missing in people with the typical features of Rubinstein-Taybi syndrome. Researchers believe that the loss of additional genes in this region probably accounts for the serious complications associated with severe Rubinstein-Taybi syndrome. However, a few studies indicate that deletions of multiple genes in the p arm of chromosome 16 do not always cause severe signs and symptoms.

Other chromosomal conditions

Trisomy 16 occurs when cells have three copies of chromosome 16 instead of the usual two copies. Full trisomy 16, which occurs when all of the body's cells contain an extra copy of chromosome 16, causes serious health problems. Most affected individuals die before or shortly after birth, although some have lived for weeks or months with intensive medical support. A similar but less severe condition called mosaic trisomy 16 occurs when only some of the body's cells have an extra copy of chromosome 16. The signs and symptoms of mosaic trisomy 16 vary widely and can include slow growth before birth (intrauterine growth retardation), delayed development, and heart defects.

Other changes in the number or structure of chromosome 16 can have a variety of effects. Intellectual disability, delayed growth and development, distinctive facial features, weak muscle tone (hypotonia), heart defects, and other medical problems are common. Frequent changes to chromosome 16 include an extra segment of the short (p) or long (q) arm of the chromosome in each cell (partial trisomy 16p or 16q) and a missing segment of the long arm of the chromosome in each cell (partial monosomy 16q).

For example, a region of DNA on chromosome 16 that includes the CREBBP gene is copied (duplicated) in some people. This genetic change causes a condition called chromosome 16p13.3 duplication syndrome, which is characterized by intellectual disability, distinctive facial features, abnormal thumbs, and rigid joints (arthrogryposis). Some affected individuals also have abnormalities of the heart, genitals, roof of the mouth, or the eyes.

While other genes can be included in the duplicated region, depending on its size, research shows that the CREBBP gene is most likely responsible for the characteristic signs and symptoms of chromosome 16p13.3 duplication syndrome. Researchers suspect that an extra copy of the CREBBP gene leads to the production of excess CREB binding protein and an increase in protein function. The resulting changes in gene transcription and protein production likely alter development of various systems, causing the signs and symptoms of chromosome 16p13.3 duplication syndrome.

Chromosome 17 spans about 83 million DNA building blocks (base pairs) and represents between 2.5 and 3 percent of the total DNA in cells. Chromosome 17 likely contains 1,100 to 1,200 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 17.

17q12 deletion syndrome

17q12 deletion syndrome is a condition that results from the deletion of a small piece of chromosome 17 in each cell. Signs and symptoms of 17q12 deletion syndrome can include abnormalities of the kidneys and urinary system, a form of diabetes called maturity-onset diabetes of the young type 5 (MODY5), delayed development, intellectual disability, and behavioral or psychiatric disorders. Some females with this chromosomal change have Mayer-Rokitansky-Küster-Hauser syndrome, which is characterized by underdevelopment or absence of the vagina and uterus. Features associated with 17q12 deletion syndrome vary widely, even among affected members of the same family.

Most people with 17q12 deletion syndrome are missing about 1.4 million DNA building blocks (base pairs), also written as 1.4 megabases (Mb), on the long (q) arm of the chromosome at a position designated q12. It is the same region of chromosome 17 that is abnormally copied (duplicated) in people with a 17q12 duplication (described below). This chromosome segment is surrounded by short, repeated sequences of DNA that make it prone to rearrangement during cell division. The rearrangement can lead to missing or extra copies of DNA at 17q12.

The segment that is most often deleted in people with 17q12 deletion syndrome includes 15 genes. Some of the features associated with the condition likely result from the loss of two of these genes, HNF1B and LHX1. Studies suggest that a loss of one copy of the HNF1B gene in each cell causes the kidney and urinary tract abnormalities, as well as diabetes. Missing one copy of LHX1 is thought to contribute to intellectual disability, behavioral and psychiatric conditions, and Mayer-Rokitansky-Küster-Hauser syndrome. The loss of other genes in the deleted region may also influence the signs and symptoms that can occur in 17q12 deletion syndrome.

17q12 duplication

17q12 duplication is a chromosomal change in which a small piece of chromosome 17 is copied abnormally in each cell. Signs and symptoms related to this duplication vary significantly, even among members of the same family. Some individuals with the duplication have no apparent signs or symptoms, or the features are very mild. Other individuals can have intellectual disability, delayed development, and a wide range of physical abnormalities.

Most people with 17q12 duplications have an extra copy of about 1.4 Mb of DNA at position q12 on chromosome 17. It is the same region of chromosome 17 that is deleted in people with 17q12 deletion syndrome (described above). This chromosome segment is prone to rearrangement during cell division, which can lead to extra or missing copies of DNA at 17q12.

The duplicated segment of 17q12 includes at least 15 genes. It is unclear which of these genes, when present in more than one copy, contribute to intellectual disability, delayed development, and other features that can be associated with a 17q12 duplication. Because some people with this duplication have no obvious intellectual or physical problems, researchers suspect that additional genetic factors may influence whether a person has signs and symptoms related to the chromosomal change.

Acute promyelocytic leukemia

A type of blood cancer known as acute promyelocytic leukemia is caused by a rearrangement (translocation) of genetic material between chromosomes 15 and 17. This translocation, written as t(15;17), fuses part of the PML gene from chromosome 15 with part of the RARA gene from chromosome 17. This mutation is acquired during a person's lifetime and is present only in certain cells. This type of genetic change, called a somatic mutation, is not inherited. The t(15;17) translocation is called a balanced reciprocal translocation because the pieces of chromosome are exchanged with each other (reciprocal) and no genetic material is gained or lost (balanced). The protein produced from this fused gene is known as PML-RARα.

The PML-RARα protein functions differently than the protein products from the normal PML and RARA genes. The RARA gene on chromosome 17 provides instructions for making a transcription factor called the retinoic acid receptor alpha (RARα). A transcription factor is a protein that attaches (binds) to specific regions of DNA and helps control the activity (transcription) of particular genes. Normally, the RARα protein controls the activity of genes important for the maturation (differentiation) of immature white blood cells beyond a particular stage called the promyelocyte. The PML gene on chromosome 15 provides instructions for a protein that acts as a tumor suppressor, which means it prevents cells from growing and dividing too rapidly or in an uncontrolled way. The PML protein blocks cell growth and division (proliferation) and induces self-destruction (apoptosis) in combination with other proteins. The PML-RARα protein interferes with the normal function of both the PML and the RARα proteins. As a result, blood cells are stuck at the promyelocyte stage, and they proliferate abnormally. Excess promyelocytes accumulate in the bone marrow and normal white blood cells cannot form, leading to acute promyelocytic leukemia.

Charcot-Marie-Tooth disease

Duplication of a small piece of chromosome 17 at position p12 that includes the PMP22 gene causes most cases of a disorder called Charcot-Marie-Tooth disease. When this disorder is caused by changes affecting the PMP22 gene, it is called Charcot-Marie-Tooth disease type 1A, or CMT1A. Charcot-Marie-Tooth disease damages the peripheral nerves, which connect the brain and spinal cord to muscles and to sensory cells that detect sensations such as touch, pain, heat, and sound. Peripheral nerve damage can result in alteration or loss of sensation and wasting (atrophy) of muscles in the feet, legs, and hands.

The protein produced from the PMP22 gene is a component of myelin, a protective substance that covers nerves and promotes the efficient transmission of nerve impulses. Before they become part of myelin, newly produced PMP22 proteins are processed and packaged in specialized cell structures called the endoplasmic reticulum and the Golgi apparatus. Completion of these processing and packaging steps is critical for proper myelin development, maintenance, and function.

The extra copy of the PMP22 gene resulting from the duplication leads to an overproduction of PMP22 protein. Research suggests that excess PMP22 protein may overwhelm cells' ability to process it correctly, leading to a buildup of unprocessed, nonfunctional protein. This buildup may impair the formation of myelin and lead to instability and loss of myelin (demyelination). Shortage and dysfunction of myelin reduce the ability of the peripheral nerves to activate muscles used for movement or to relay information from sensory cells back to the brain, leading to the signs and symptoms of CMT1A.

Dermatofibrosarcoma protuberans

Translocation of genetic material between chromosomes 17 and 22, written as t(17;22), causes a rare type of skin cancer known as dermatofibrosarcoma protuberans. This translocation fuses part of the COL1A1 gene from chromosome 17 with part of the PDGFB gene from chromosome 22. The translocation is found on one or more extra chromosomes that can be either linear or circular. When circular, the extra chromosomes are known as supernumerary ring chromosomes. This mutation is acquired during a person's lifetime and is present only in certain cells. This type of genetic change, called a somatic mutation, is not inherited.

The fused COL1A1-PDGFB gene provides instructions for making a combined (fusion) protein that researchers believe ultimately functions like the active PDGFB protein. In the translocation, the PDGFB gene loses the part of its DNA that limits its activity, and production of the COL1A1-PDGFB fusion protein is controlled by COL1A1 gene sequences. As a result, the gene fusion leads to the production of a larger amount of active PDGFB protein than normal. Active PDGFB protein signals for cell growth and division (proliferation) and maturation (differentiation). Excess PDGFB protein abnormally stimulates cells to proliferate and differentiate, leading to the tumor formation seen in dermatofibrosarcoma protuberans.

Koolen-de Vries syndrome

Deletion of a small amount of genetic material (a microdeletion) on chromosome 17 can cause Koolen-de Vries syndrome. This disorder is characterized by developmental delay, intellectual disability, a cheerful and sociable disposition, and a variety of physical abnormalities.

Most people with Koolen-de Vries syndrome are missing a sequence of about 500,000 base pairs, also written as 500 kilobases (kb), at position q21.31 on chromosome 17. The exact size of the deletion varies among affected individuals, but it contains at least six genes, including KANSL1. This deletion affects one of the two copies of chromosome 17 in each cell.

Because mutations in the KANSL1 gene cause the same signs and symptoms as the deletion, researchers have concluded that the loss of this gene accounts for the features of Koolen-de Vries syndrome. The protein produced from the KANSL1 gene is involved in controlling the activity of other genes and plays an important role in the development and function of many parts of the body. Although the loss of this gene impairs normal development and function, its relationship to the specific features of Koolen-de Vries syndrome is unclear.

While Koolen-de Vries syndrome is usually not inherited, most individuals with the condition caused by a deletion have had at least one parent with a common variant of the q21.31 region of chromosome 17 called the H2 lineage. This variant is found in 20 percent of people of European and Middle Eastern descent, although it is rare in other populations. In the H2 lineage, a 900 kb segment of DNA, which includes the region deleted in most cases of Koolen-de Vries syndrome, has undergone an inversion. An inversion involves two breaks in a chromosome; the resulting piece of DNA is reversed and reinserted into the chromosome.

People with the H2 lineage have no health problems related to the inversion. However, genetic material can be lost or duplicated when the inversion is passed to the next generation. Researchers believe that a parental inversion is probably necessary for a child to have the 17q21.31 microdeletion most often associated with Koolen-de Vries syndrome, but other, unknown factors are also thought to play a role. So while the inversion is very common, only an extremely small percentage of parents with the inversion have a child affected by Koolen-de Vries syndrome.

Miller-Dieker syndrome

Miller-Dieker syndrome is caused by a deletion of genetic material near the end of the short (p) arm of chromosome 17. The signs and symptoms of Miller-Dieker syndrome are related to the loss of multiple genes in this region. The size of the deletion varies among affected individuals. The loss of a particular gene on chromosome 17, called PAFAH1B1, is responsible for the syndrome's characteristic sign of lissencephaly, a problem with brain development in which the surface of the brain is abnormally smooth. This brain abnormality causes severe intellectual disability, developmental delay, seizures, abnormal muscle stiffness (spasticity), weak muscle tone (hypotonia), and feeding difficulties. The loss of another gene, called YWHAE, in the same region of chromosome 17 increases the severity of lissencephaly in people with Miller-Dieker syndrome. Additional genes in the deleted region contribute to the varied features of this disorder.

Potocki-Lupski syndrome

Potocki-Lupski syndrome results from a duplication of a small piece of chromosome 17 in each cell, specifically a region of the short (p) arm designated p11.2. This condition is characterized by delayed development, mild to moderate intellectual disability, behavioral problems including autism spectrum disorder (which affects social interaction and communication), sleep disturbances, and other health problems.

In about two-thirds of affected individuals, the duplicated segment is approximately 3.7 Mb in size. (A missing copy of this segment causes Smith-Magenis syndrome, described below.) In the remaining one-third of cases, the duplication is larger or smaller, ranging from less than 1 Mb to almost 20 Mb. All of these duplications affect one of the two copies of chromosome 17 in each cell.

Although the duplicated region contains multiple genes, researchers believe that having an extra copy of one particular gene, RAI1, underlies many of the characteristic features of Potocki-Lupski syndrome. All of the duplications known to cause the condition contain this gene. The RAI1 gene provides instructions for making a protein that helps regulate the activity (expression) of other genes. Although most of the genes regulated by the RAI1 protein have not been identified, this protein appears to control the expression of several genes involved in daily (circadian) rhythms, such as the sleep-wake cycle. The RAI1 protein also appears to play a role in development of the brain and of bones in the head and face. Studies suggest that the duplication increases the amount of RAI1 protein, which disrupts the expression of genes that influence circadian rhythms. These changes may account for the sleep disturbances that occur with Potocki-Lupski syndrome. Too much RAI1 protein may also disrupt brain development, which could account for delayed development, intellectual disability, behavioral problems, and other neurological features of this condition. Development of the bones in the head and face may also be affected, leading to subtle facial differences in people with Potocki-Lupski syndrome.

Smith-Magenis syndrome

Smith-Magenis syndrome usually results from a deletion of a small piece of chromosome 17 in each cell, specifically a region of the short (p) arm designated p11.2. This developmental disorder affects many parts of the body. The major features of this condition include mild to moderate intellectual disability, delayed speech and language skills, distinctive facial features, sleep disturbances, and behavioral problems.

Most often, the chromosome segment deleted in Smith-Magenis syndrome is the same one that is duplicated in Potocki-Lupski syndrome (described above). Occasionally the deletion is larger or smaller. All of the deletions affect one of the two copies of chromosome 17 in each cell.

Researchers believe that a loss of function of the RAI1 gene accounts for many of the signs and symptoms of Smith-Magenis syndrome. All of the deletions known to cause the condition contain this gene. Studies suggest that the deletion leads to a reduced amount of RAI1 protein in cells, which disrupts the expression of genes involved in circadian rhythms. These changes may account for the sleep disturbances that occur with Smith-Magenis syndrome. It is unclear how a loss of one copy of the RAI1 gene leads to the other physical, mental, and behavioral problems associated with this condition. It is likely that the loss of other genes in the deleted region also influences the signs and symptoms; the role of these genes is under study.

Yuan-Harel-Lupski syndrome

Duplication of a small piece of chromosome 17 in a region designated p12-11.2 can cause Yuan-Harel-Lupski (YUHAL) syndrome, which is characterized by multiple neurological problems similar to those in Potocki-Lupski syndrome (described above) and CMT1A (described above). In YUHAL syndrome, the duplicated segment ranges in size from about 3 Mb to nearly 20 Mb and always contains the RAI1 and PMP22 genes; it may also include additional genes. Certain features of YUHAL syndrome, such as delayed development and behavioral problems, are likely caused by an extra copy of the RAI1 gene. Other features, including muscle weakness and decreased sensitivity to touch, heat, and cold in the lower legs and feet, are likely due to duplication of the PMP22 gene.

Other cancers

Changes in chromosome 17 have been identified in several additional types of cancer. These genetic changes are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. A particular chromosomal abnormality called an isochromosome 17q occurs frequently in some cancers. This abnormal version of chromosome 17 has two long (q) arms instead of one long arm and one short (p) arm. As a result, the chromosome has an extra copy of some genes and is missing copies of other genes.

An isochromosome 17q is commonly found in a cancer of blood-forming tissue called chronic myeloid leukemia (CML). It also has been identified in certain solid tumors, including a type of brain tumor called a medulloblastoma and tumors of the brain and spinal cord known as primitive neuroectodermal tumors. Although an isochromosome 17q probably plays a role in both the development and progression of these cancers, the specific genetic changes related to cancer growth are unknown.

Other chromosomal conditions

Other changes in the number or structure of chromosome 17 can have a variety of effects, including intellectual disability, delayed development, characteristic facial features, weak muscle tone (hypotonia), and short stature. These changes include an extra piece of chromosome 17 in each cell (partial trisomy 17), a missing segment of the chromosome in each cell (partial monosomy 17), and a circular structure called a ring chromosome 17. Ring chromosomes occur when a chromosome breaks in two places and the ends of the chromosome arms fuse together to form a circular structure.

Chromosome 18 spans about 78 million DNA building blocks (base pairs) and represents approximately 2.5 percent of the total DNA in cells. Chromosome 18 likely contains 200 to 300 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 18.

Distal 18q deletion syndrome

Distal 18q deletion syndrome occurs when a piece of the long (q) arm of chromosome 18 is missing. The term "distal" means that the missing piece (deletion) occurs near one end of the chromosome arm. The signs and symptoms of distal 18q deletion syndrome include delayed development and learning disabilities, short stature, weak muscle tone (hypotonia), foot abnormalities, and a wide variety of other features.

The deletion that causes distal 18q deletion syndrome can occur anywhere between a region called 18q21 and the end of the chromosome. The size of the deletion varies among affected individuals. The signs and symptoms of distal 18q deletion syndrome are thought to be related to the loss of multiple genes from this part of the long arm of chromosome 18. Researchers are working to determine how the loss of specific genes in this region contributes to the various features of the disorder.

Proximal 18q deletion syndrome

Like distal 18q deletion syndrome (described above), proximal 18q deletion syndrome is a chromosomal condition that occurs when a piece of the q arm of chromosome 18 is missing. The term "proximal" means that in this disorder the deletion occurs near the center of the chromosome, in an area between regions called 18q11.2 and 18q21.2. The size of the deletion varies among affected individuals. Proximal 18q deletion syndrome can lead to a wide variety of signs and symptoms among affected individuals, including delayed development and intellectual disability, recurrent seizures (epilepsy), behavioral problems, and characteristic facial features. These signs and symptoms are likely caused by the loss of specific genes in the deleted region.

Tetrasomy 18p

Tetrasomy 18p results from the presence of an abnormal extra chromosome, called an isochromosome 18p, in each cell. An isochromosome is a chromosome with two identical arms. Normal chromosomes have one long (q) arm and one short (p) arm, but isochromosomes have either two q arms or two p arms. Isochromosome 18p is a version of chromosome 18 made up of two p arms.

Cells normally have two copies of each chromosome, one inherited from each parent. In people with tetrasomy 18p, cells have the usual two copies of chromosome 18 plus an isochromosome 18p. As a result, each cell has four copies of the short arm of chromosome 18. (The word "tetrasomy" is derived from "tetra," the Greek word for "four.") The extra genetic material from the isochromosome disrupts the normal course of development, causing intellectual disability, delayed development, and the other characteristic features of this disorder.

Trisomy 18

Trisomy 18 occurs when each cell in the body has three copies of chromosome 18 instead of the usual two copies, causing severe intellectual disability and multiple birth defects that are usually fatal by early childhood. (The word "trisomy" comes from "tri," the Greek word for "three.") In some cases, the extra copy of chromosome 18 is present in only some of the body's cells. This condition is known as mosaic trisomy 18.

Rarely, trisomy 18 is caused by an extra copy of only a piece of chromosome 18. This condition is known as partial trisomy 18. Partial trisomy 18 occurs when part of the q arm of chromosome 18 becomes attached (translocated) to another chromosome during the formation of reproductive cells (eggs and sperm) or very early in embryonic development. Affected individuals have two copies of chromosome 18, plus the extra material from chromosome 18 attached to another chromosome. If only part of the q arm is present in three copies, the physical signs of partial trisomy 18 may be less severe than those typically seen in trisomy 18. If the entire q arm is present in three copies, individuals may be as severely affected as if they had three full copies of chromosome 18.

Researchers believe that extra copies of some genes on chromosome 18 disrupt the course of normal development, causing the characteristic features of trisomy 18 and the health problems associated with this disorder.

Other chromosomal conditions

Other disorders associated with chromosome 18 occur when pieces of the p arm of this chromosome are missing or when extra genetic material from chromosome 18 is present. Researchers are uncertain how missing or extra pieces of chromosome 18 lead to the specific features of these disorders.

Partial monosomy of chromosome 18p (18p-) occurs when a piece of the p arm of this chromosome is deleted. Individuals with this condition often have short stature, a round face, large ears, a shortened space between the nose and mouth (philtrum), droopy eyelids (ptosis), and mild to moderate intellectual disability. About 10 to 15 percent of people with this condition have serious abnormalities of the brain and spinal cord (central nervous system). The lifespan of individuals with partial monosomy of chromosome 18p is typically not reduced, except when severe brain abnormalities are present.

Some people have a chromosome 18 with a circular structure, which is called a ring chromosome 18. This type of chromosome is formed when breaks occur at both ends of the chromosome and the broken ends join together to form a ring. Individuals with this chromosome abnormality often have intellectual disability, an unusually small head (microcephaly), widely spaced eyes (hypertelorism), low-set ears, and speech problems. The signs and symptoms associated with ring chromosome 18 depend on how much genetic material is lost from each arm of the chromosome.

Chromosome 19 spans about 59 million base pairs (the building blocks of DNA) and represents almost 2 percent of the total DNA in cells. Chromosome 19 likely contains about 1,500 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 19.

19p13.13 deletion syndrome

19p13.13 deletion syndrome results from the deletion of a small piece of the short (p) arm of chromosome 19 in each cell. Major features of 19p13.13 deletion syndrome include an unusually large head size (macrocephaly), tall stature, delayed development of speech and motor skills (such as sitting and walking), and intellectual disability that is usually moderate in severity. Seizures, feeding and digestive difficulties, and eye abnormalities are also common.

People with this condition are missing anywhere from about 300,000 DNA building blocks (300 kilobases or 300 Kb) to more than 3 million DNA building blocks (3 megabases or 3 Mb) on the short arm of chromosome 19. The region of the deletion is usually referred to as p13.13, although some publications refer to it as p13.2. The region is the same; only the numbering differs. The exact size of the deletion varies among affected individuals, but it is thought to include at least 16 genes. This deletion affects one of the two copies of chromosome 19 in each cell.

The signs and symptoms of 19p13.13 deletion syndrome result from the loss of multiple genes in the deleted region. Some of these genes are suspected to have important roles in normal growth and development, and the loss of one copy of each of these genes likely underlies the features of this condition. Researchers are working to determine which missing genes contribute to which specific features of the disorder.

Cancers

Changes in chromosome 19 have been identified in several types of cancer. These chromosome abnormalities are somatic, which means they are acquired during a person's lifetime and are present only in the cells that give rise to cancer. Rearrangements of genetic material between chromosome 19 and one of several other chromosomes have been found in some forms of blood cancer (leukemia). These rearrangements, called translocations, appear to be particularly common in a type of leukemia called acute lymphoblastic leukemia (ALL). These translocations likely disrupt genes that are critical for keeping cell growth and division under control. Unregulated cell division can lead to the development of cancer.

Other chromosomal conditions

Other changes in the number or structure of chromosome 19 can have a variety of effects on growth and development. These chromosomal changes can cause delayed development, intellectual disability, feeding difficulties, hearing and vision impairment, heart problems, or other birth defects. The signs and symptoms that occur in a particular individual depend on the specific chromosomal change and which genes are involved.

Among the changes in chromosome 19 that have been reported are microdeletions, which remove a relatively small number of genes. These include 19p13.13 deletions (described above) and small deletions in other regions of the chromosome. Other possible changes include the presence of an extra piece of the chromosome in each cell (partial trisomy 19) or the absence of a larger segment of the chromosome in each cell (partial monosomy 19). Translocations of genetic material between chromosome 19 and another chromosome can also lead to extra or missing material from chromosome 19. Rarely, chromosome 19 forms a structure called a ring chromosome. Ring chromosomes occur when a chromosome breaks in two places and the ends of the chromosome arms fuse together to form a circular structure.

Chromosome 20 spans about 63 million DNA building blocks (base pairs) and represents approximately 2 percent of the total DNA in cells. Chromosome 20 likely contains 500 to 600 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 20.

Alagille syndrome

Approximately 7 percent of individuals with Alagille syndrome have small deletions of genetic material on chromosome 20, in a region known as 20p12. This region includes the JAG1 gene, which is involved in signaling between neighboring cells during embryonic development. This signaling influences how the cells are used to build body structures in the developing embryo. Loss of the JAG1 gene probably disrupts the signaling pathway. As a result, errors may occur during development, especially affecting the heart, bile ducts in the liver, the spinal column, and certain facial features.

Cancers

Changes in chromosome 20 have been identified in several types of cancer. These chromosome abnormalities are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. Deletions involving the long (q) arm of chromosome 20 appear to be common in blood-related cancers such as leukemia and lymphoma. Deletions of this chromosomal region have also been identified in other disorders of the blood and bone marrow, including polycythemia vera (which causes an overproduction of red blood cells) and myelodysplastic syndrome (which leads to a shortage of healthy blood cells).

Researchers are working to determine which genes on chromosome 20 are disrupted in these conditions. Studies suggest that some genes on the long arm of the chromosome may play critical roles in controlling the growth and division of cells.

Ring chromosome 20 syndrome

Ring chromosome 20 syndrome is caused by a chromosomal abnormality known as a ring chromosome 20 or r(20). A ring chromosome is a circular structure that occurs when a chromosome breaks in two places and its broken ends fuse together. People with ring chromosome 20 syndrome have one copy of this abnormal chromosome in some or all of their cells.

It is not well understood how the ring chromosome causes the signs and symptoms of this syndrome. In some affected individuals, genes near the ends of chromosome 20 are deleted when the ring chromosome forms. Researchers suspect that the loss of these genes may be responsible for epilepsy and other health problems. However, other affected individuals do not have gene deletions associated with the ring chromosome. In these people, the ring chromosome may change the activity of certain genes on chromosome 20, or it may be unable to copy (replicate) itself normally during cell division. Researchers are still working to determine the precise relationship between the ring chromosome 20 and the characteristic features of the syndrome.

Other chromosomal conditions

Deletions or duplications of genetic material from chromosome 20 can have a variety of effects, including intellectual disability, delayed development, distinctive facial features, skeletal abnormalities, and heart defects. Several different changes in the structure of chromosome 20 have been reported. These include an extra segment of the short (p) or long (q) arm of the chromosome in each cell (partial trisomy 20p or 20q) or a missing segment of the short or long arm of the chromosome in each cell (partial monosomy 20p or 20q).

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 21.

Core binding factor acute myeloid leukemia

A genetic rearrangement (translocation) involving chromosome 21 is associated with a type of blood cancer known as core binding factor acute myeloid leukemia (CBF-AML). This rearrangement occurs in approximately 7 percent of acute myeloid leukemia cases in adults. The translocation, written as t(8;21), fuses part of the RUNX1 gene from chromosome 21 with part of the RUNX1T1 gene (also known as ETO) from chromosome 8. This mutation is acquired during a person's lifetime and is present only in certain cells. This type of genetic change, called a somatic mutation, is not inherited.

The fusion protein produced from the t(8;21) translocation, called RUNX1-ETO, retains some functions of the two individual proteins. The normal RUNX1 protein, produced from the RUNX1 gene, is part of a protein complex called core binding factor (CBF) that attaches (binds) to DNA and turns on genes involved in blood cell development. The normal ETO protein, produced from the RUNX1T1 gene, turns off gene activity. The RUNX1-ETO fusion protein forms CBF and attaches to DNA, but instead of turning on genes that stimulate the development of blood cells, it turns those genes off. This change in gene activity blocks the maturation (differentiation) of blood cells and leads to the production of abnormal, immature white blood cells called myeloid blasts. While t(8;21) is important for leukemia development, one or more additional genetic changes are typically needed for the myeloid blasts to develop into cancerous leukemia cells.

Down syndrome

Down syndrome is a chromosomal condition that is associated with intellectual disability, a characteristic facial appearance, and weak muscle tone (hypotonia) in infancy. This condition is most often caused by trisomy 21. Trisomy 21 means that each cell in the body has three copies of chromosome 21 instead of the usual two copies.

Less commonly, Down syndrome occurs when part of chromosome 21 becomes attached (translocated) to another chromosome during the formation of reproductive cells (eggs and sperm) or very early in fetal development. Affected people have two copies of chromosome 21 plus extra material from chromosome 21 attached to another chromosome, resulting in three copies of genetic material from chromosome 21. Affected individuals with this genetic change are said to have translocation Down syndrome.

In a very small percentage of cases, Down syndrome results from an extra copy of chromosome 21 in only some of the body's cells. In these people, the condition is called mosaic Down syndrome.

Researchers believe that having extra copies of genes on chromosome 21 disrupts the course of normal development, causing the characteristic features of Down syndrome and the increased risk of health problems associated with this condition.

Other cancers

Translocations of genetic material between chromosome 21 and other chromosomes have been associated with several types of cancer. For example, acute lymphoblastic leukemia (a type of blood cancer most often diagnosed in childhood) has been associated with a translocation between chromosomes 12 and 21.

Other chromosomal conditions

Other changes in the number or structure of chromosome 21 have a variety of effects on health and development. Chromosome 21 abnormalities can cause intellectual disability, delayed development, and characteristic facial features. In some cases, the signs and symptoms are similar to those of Down syndrome.

Changes involving chromosome 21 can include a missing segment of the chromosome in each cell (partial monosomy 21) and a circular structure called ring chromosome 21. A ring chromosome occurs when a chromosome breaks in two places and the ends of the chromosome arms fuse together to form a circular structure.

Chromosome 22 is the second smallest human chromosome, spanning more than 51 million DNA building blocks (base pairs) and representing between 1.5 and 2 percent of the total DNA in cells. In 1999, researchers working on the Human Genome Project announced they had determined the sequence of base pairs that make up this chromosome. Chromosome 22 was the first human chromosome to be fully sequenced. Chromosome 22 likely contains 500 to 600 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 22.

22q11.2 deletion syndrome

22q11.2 deletion syndrome is a disorder involving heart defects, an opening in the roof of the mouth (a cleft palate), distinctive facial features, low calcium levels, and an increased risk of behavioral problems and mental illness such as schizophrenia. Most people with 22q11.2 deletion syndrome are missing about 3 million base pairs on one copy of chromosome 22 in each cell. The deletion occurs near the middle of the chromosome at a location designated as q11.2. This region contains 30 to 40 genes, but many of these genes have not been well characterized. A small percentage of affected individuals have shorter deletions in the same region.

The loss of a particular gene, TBX1, is thought to be responsible for many of the physical features characteristic of 22q11.2 deletion syndrome. Additional genes in the deleted region likely contribute to the varied signs and symptoms of 22q11.2 deletion syndrome.

22q11.2 duplication

22q11.2 duplication is caused by an extra copy of some genetic material at position q11.2 on chromosome 22. In most cases, this extra genetic material consists of a sequence of about 3 million base pairs, also written as 3 megabases (Mb). This sequence is the same one that is missing in 22q11.2 deletion syndrome. A small percentage of affected individuals have a shorter duplication in the same region. The duplication affects one of the two copies of chromosome 22 in each cell. Researchers are working to determine the genes that may contribute to the developmental delay and other problems that affect some people with this duplication.

22q13.3 deletion syndrome

22q13.3 deletion syndrome, which is also commonly known as Phelan-McDermid syndrome, is caused by a deletion near the end of the long (q) arm of chromosome 22. A ring chromosome 22 can also cause 22q13.3 deletion syndrome. A ring chromosome is a circular structure that occurs when a chromosome breaks in two places, the tips of the chromosome are lost, and the broken ends fuse together. People with ring chromosome 22 have one copy of this abnormal chromosome in some or all of their cells. Researchers believe that several critical genes near the end of the q arm of chromosome 22 are lost when the ring chromosome 22 forms. If the break point on the long arm is at chromosome position 22q13.3, people with ring chromosome 22 will experience similar signs and symptoms as those with a simple deletion.

The signs and symptoms of 22q13.3 deletion syndrome are probably related to the loss of multiple genes at the end of chromosome 22. The size of the deletion varies among affected individuals. The loss of a particular gene, SHANK3, is thought to be responsible for many of the characteristic features of 22q13.3 deletion syndrome, such as developmental delay, intellectual disability, and absent or severely delayed speech. Additional genes in the deleted region likely contribute to the signs and symptoms of 22q13.3 deletion syndrome.

Chronic myeloid leukemia

A rearrangement (translocation) of genetic material between chromosomes 9 and 22 causes a type of cancer of blood-forming cells called chronic myeloid leukemia. This slow-growing cancer leads to an overproduction of abnormal white blood cells. Common features of the condition include excessive tiredness (fatigue), fever, weight loss, and an enlarged spleen.

The translocation involved in this condition, written as t(9;22), fuses part of the ABL1 gene from chromosome 9 with part of the BCR gene from chromosome 22, creating an abnormal fusion gene called BCR-ABL1. The abnormal chromosome 22, containing a piece of chromosome 9 and the fusion gene, is commonly called the Philadelphia chromosome. The translocation is acquired during a person's lifetime and is present only in the abnormal blood cells. This type of genetic change, called a somatic mutation, is not inherited.

The protein produced from the BCR-ABL1 gene signals cancer cells to continue dividing abnormally and prevents them from self-destructing, which leads to overproduction of the abnormal cells and a shortage of normal blood cells.

The Philadelphia chromosome also has been found in some cases of rapidly progressing blood cancers known as acute leukemias. It is likely that the form of blood cancer that develops is influenced by the type of blood cell that acquires the mutation and other genetic changes that occur. The presence of the Philadelphia chromosome provides a target for molecular therapies.

Dermatofibrosarcoma protuberans

A rearrangement (translocation) of genetic material between chromosomes 17 and 22, written as t(17;22), causes a rare type of skin cancer known as dermatofibrosarcoma protuberans. This translocation fuses part of the PDGFB gene from chromosome 22 with part of the COL1A1 gene from chromosome 17. The translocation is found on one or more extra chromosomes that can be either linear or circular. When circular, the extra chromosomes are known as supernumerary ring chromosomes. This mutation is acquired during a person's lifetime and is present only in certain cells. This type of genetic change, called a somatic mutation, is not inherited.

The fused COL1A1-PDGFB gene provides instructions for making a combined (fusion) protein that ultimately functions like the active PDGFB protein. In the translocation, the PDGFB gene loses the part of its DNA that limits its activity, and production of the COL1A1-PDGFB fusion protein is controlled by COL1A1 gene sequences. As a result, the gene fusion leads to the production of a larger amount of active PDGFB protein than normal. Active PDGFB protein signals for cell growth and division (proliferation) and maturation (differentiation). Excess PDGFB protein abnormally stimulates cells to proliferate and differentiate, leading to the tumor formation seen in dermatofibrosarcoma protuberans.

Emanuel syndrome

Emanuel syndrome is caused by the presence of extra genetic material from chromosome 11 and chromosome 22 in each cell. In addition to the usual 46 chromosomes, people with Emanuel syndrome have an extra (supernumerary) chromosome consisting of a piece of chromosome 11 attached to a piece of chromosome 22. The extra chromosome is known as a derivative 22 or der(22) chromosome.

People with Emanuel syndrome typically inherit the der(22) chromosome from an unaffected parent. The parent carries a chromosomal rearrangement between chromosomes 11 and 22 called a balanced translocation. No genetic material is gained or lost in a balanced translocation, so these chromosomal changes usually do not cause any health problems. As this translocation is passed to the next generation, it can become unbalanced. Individuals with Emanuel syndrome inherit an unbalanced translocation between chromosomes 11 and 22 in the form of a der(22) chromosome. These individuals have two normal copies of chromosome 11, two normal copies of chromosome 22, and extra genetic material from the der(22) chromosome.

As a result of the extra chromosome, people with Emanuel syndrome have three copies of some genes in each cell instead of the usual two copies. The excess genetic material disrupts the normal course of development, leading to intellectual disability and birth defects. Researchers are working to determine which genes are included on the der(22) chromosome and what role these genes play in development.

Ewing sarcoma

Translocations involving chromosome 22 are also involved in a type of cancerous tumor known as Ewing sarcoma. These tumors develop in the bones or soft tissues, such as cartilage and nerves. The most common translocation, t(11;22), fuses part of the EWSR1 gene from chromosome 22 with part of the FLI1 gene from chromosome 11, creating the EWSR1/FLI1 fusion gene. Translocations that fuse the EWSR1 gene with other genes that are related to the FLI1 gene can also cause Ewing sarcomas, although these alternative translocations are relatively uncommon. The mutations that cause these cancers are acquired during a person's lifetime and are present only in tumor cells. This type of genetic change, called a somatic mutation, is not inherited.

The protein produced from the EWSR1/FLI1 fusion gene, called EWS/FLI, has functions of the protein products of both genes. The FLI protein, produced from the FLI1 gene, attaches (binds) to DNA and regulates an activity called transcription, which is the first step in the production of proteins from genes. The FLI protein controls the growth and development of some cell types by regulating the transcription of certain genes. The EWS protein, produced from the EWSR1 gene, also regulates transcription. The EWS/FLI protein has the DNA-binding function of the FLI protein as well as the transcription regulation function of the EWS protein. It is thought that the EWS/FLI protein turns the transcription of a variety of genes on and off abnormally. This dysregulation of transcription leads to uncontrolled growth and division (proliferation) and abnormal maturation and survival of cells, causing tumor development.

Opitz G/BBB syndrome

A deletion in one copy of chromosome 22 can cause Opitz G/BBB syndrome. This condition causes several abnormalities along the midline of the body, including widely spaced eyes (ocular hypertelorism), difficulty breathing or swallowing, brain malformations, distinct facial features, and genital abnormalities in males. The deletion that causes Opitz G/BBB syndrome is in the same area as the deletion that causes 22q11.2 deletion syndrome (described above), so Opitz G/BBB is often considered part of 22q11.2 deletion syndrome. It is not yet known which deleted genes cause the signs and symptoms of Opitz G/BBB syndrome.

Schizophrenia

A small percentage of individuals with schizophrenia have a small deletion (microdeletion) in a region of chromosome 22 called 22q11. Schizophrenia is a mental health disorder that affects a person's thinking, sense of self, and perceptions. The 22q11 region contains several genes that are thought to affect schizophrenia risk. Loss of one or more of these genes may affect the brain in ways that increase the risk of developing this disorder. However, the relationships between these gene losses and the development of the disorder are not well understood.

In addition to schizophrenia, some people with this deletion have additional signs and symptoms comprising a condition called 22q11.2 deletion syndrome (described above).

22q11 microdeletions are among many factors under study to help explain the causes of schizophrenia. A large number of genetic and environmental factors, most of which remain unknown, likely contribute to the risk of developing this complex condition.

Other chromosomal conditions

Other changes in the number or structure of chromosome 22 can have a variety of effects. Intellectual disability, delayed development, delayed or absent speech, distinctive facial features, and behavioral problems are common features. Frequent changes to chromosome 22 include an extra piece of the chromosome in each cell (partial trisomy), a missing segment of the chromosome in each cell (partial monosomy), and a ring chromosome 22. Translocations of genetic material between chromosomes can also lead to extra or missing material from chromosome 22. The most common of these translocations involves chromosomes 11 and 22.

Cat-eye syndrome is a rare disorder most often caused by a chromosomal change called an inverted duplicated 22. In people with this condition, each cell has at least one small extra chromosome made up of genetic material from chromosome 22 that has been abnormally duplicated. The extra genetic material causes the characteristic signs and symptoms of cat-eye syndrome, including an eye abnormality called an iris coloboma (a gap or split in the colored part of the eye), small skin tags or pits in front of the ear, unusually formed ears, heart defects, kidney problems, malformations of the anus, and, in some cases, delayed development.

The X chromosome is one of the two sex chromosomes in humans (the other is the Y chromosome). The sex chromosomes form one of the 23 pairs of human chromosomes in each cell. The X chromosome spans about 155 million DNA building blocks (base pairs) and represents approximately 5 percent of the total DNA in cells.

The following chromosomal conditions are associated with changes in the structure or number of copies of x chromosome.

46,XX testicular difference of sex development

46,XX testicular difference of sex development is a condition in which individuals with two X chromosomes in each cell, the pattern typically found in females, have a male appearance. In most individuals with 46,XX testicular difference of sex development, the condition results from an abnormal exchange of genetic material between chromosomes (translocation). This exchange occurs as a random event during the formation of sperm cells in the affected person's father. The translocation affects the gene responsible for development of a fetus into a male (the SRY gene). The SRY gene, which is normally found on the Y chromosome, is misplaced in this condition, almost always onto an X chromosome. A fetus with an X chromosome that carries the SRY gene will develop as a male despite not having a Y chromosome.

48,XXXY syndrome

48,XXXY syndrome is a chromosomal condition that causes intellectual disability, developmental delays, physical differences, and an inability to have biological children (infertility). This condition results from having two extra X chromosomes in each cell. Individuals with 48,XXXY syndrome have the usual single Y chromosome plus three copies of the X chromosome, for a total of 48 chromosomes in each cell.

Having extra copies of multiple genes on the X chromosome affects many aspects of development, including sex development before birth and at puberty. Researchers are working to determine which genes contribute to the specific developmental and physical differences that occur with 48,XXXY syndrome.

48,XXXY syndrome is sometimes described as a variant of Klinefelter syndrome (described below). However, the features of 48,XXXY syndrome tend to be more severe than those of Klinefelter syndrome and affect more parts of the body. As doctors and researchers have learned more about the differences between these sex chromosome disorders, they have started to consider them as separate conditions.

48,XXYY syndrome

48,XXYY syndrome is a chromosomal condition that causes infertility, developmental and behavioral disorders, and other health problems. This condition is caused by the presence of an extra X chromosome and an extra Y chromosome in cells. Extra genetic material from the X chromosome interferes with sex development, though affected individuals are typically assigned male gender at birth. Affected individuals often have small testes that do not function normally and lead to a reduction in the levels of testosterone (a hormone that directs male sexual development). Extra copies of genes from the pseudoautosomal regions of the extra X and Y chromosomes likely contribute to the signs and symptoms of 48,XXYY syndrome.

49,XXXXY syndrome

49,XXXXY syndrome is a chromosomal condition that causes intellectual disability, developmental delays (especially in speech and language), physical differences, and infertility. This condition results from having three extra X chromosomes in each cell. Individuals with 49,XXXXY syndrome have the usual single Y chromosome plus four copies of the X chromosome, for a total of 49 chromosomes in each cell.

Having extra copies of multiple genes on the X chromosome affects many aspects of development, including sex development before birth and at puberty. Researchers are working to determine which genes contribute to the specific developmental and physical differences that occur with 49,XXXXY syndrome.

49,XXXXY syndrome is sometimes described as a variant of Klinefelter syndrome (described below). However, the features of 49,XXXXY syndrome tend to be more severe than those of Klinefelter syndrome and affect more parts of the body. As doctors and researchers have learned more about the differences between these sex chromosome disorders, they have started to consider them as separate conditions.

Intestinal pseudo-obstruction

Intestinal pseudo-obstruction, a condition characterized by impairment of the coordinated waves of muscle contractions that move food through the digestive tract (peristalsis), can be caused by genetic changes involving the X chromosome.

Some individuals with intestinal pseudo-obstruction have duplications or deletions of genetic material on the X chromosome that affect the FLNA gene. The protein produced from this gene, filamin A, helps form the branching network of filaments called the cytoskeleton, which gives structure to cells and allows them to change shape and move.

Researchers believe that the changes in the X chromosome that affect the FLNA gene impair the function of the filamin A protein. Studies suggest that impaired filamin A function affects the shape of cells in the smooth muscles of the gastrointestinal tract during development before birth, causing abnormalities in the layering of these muscles. Smooth muscles line the internal organs; they contract and relax without being consciously controlled. In the digestive tract, abnormal layering of these muscles may interfere with peristalsis.

Deletions or duplications of genetic material that affect the FLNA gene can also include adjacent genes on the X chromosome. Changes in adjacent genes may account for some of the other signs and symptoms, such as neurological abnormalities and unusual facial features, that occur in some affected individuals.

Klinefelter syndrome

Klinefelter syndrome is a chromosomal condition that can affect physical and intellectual development. It is caused by an extra copy of the X chromosome. Individuals with Klinefelter syndrome have the usual single Y chromosome plus two copies of the X chromosome, for a total of 47 chromosomes in each cell (47,XXY).

Having an extra copy of genes on the X chromosome affects many aspects of development, including sex development before birth and at puberty. Researchers are working to determine which genes contribute to the specific developmental and physical differences that can occur with Klinefelter syndrome.

Some people with features of Klinefelter syndrome have an extra X chromosome in only some of their cells; other cells have one X and one Y chromosome. In these individuals, the condition is described as mosaic Klinefelter syndrome (46,XY/47,XXY). People with mosaic Klinefelter syndrome may have milder signs and symptoms than those with the extra X chromosome in all of their cells, depending on what proportion of cells have the additional chromosome.

Several conditions resulting from the presence of more than one extra sex chromosome in each cell are sometimes described as variants of Klinefelter syndrome. These conditions include 48,XXXY syndrome and 49,XXXXY syndrome (both described above). The features of these disorders tend to be more severe than those of Klinefelter syndrome and affect more parts of the body. As doctors and researchers have learned more about the differences between these sex chromosome disorders, they have started to consider them as separate conditions.

Microphthalmia with linear skin defects syndrome

A deletion of genetic material in a region of the X chromosome called Xp22 causes microphthalmia with linear skin defects syndrome. This condition is characterized by small or poorly developed eyes (microphthalmia) and unusual linear skin markings on the head and neck.

The Xp22 region includes a gene called HCCS, which carries instructions for producing an enzyme called holocytochrome c-type synthase. This enzyme helps produce a molecule called cytochrome c. Cytochrome c is involved in a process called oxidative phosphorylation, by which mitochondria generate adenosine triphosphate (ATP), the cell's main energy source. It also plays a role in the self-destruction of cells (apoptosis).

A deletion of genetic material that includes the HCCS gene prevents the production of the holocytochrome c-type synthase enzyme. In females (who have two X chromosomes), some cells produce a normal amount of the enzyme and other cells produce none. The resulting overall reduction in the amount of this enzyme leads to the signs and symptoms of microphthalmia with linear skin defects syndrome.

In males (who have only one X chromosome), a deletion that includes the HCCS gene results in a total loss of the holocytochrome c-type synthase enzyme. A lack of this enzyme appears to be lethal very early in development, so almost no males are born with microphthalmia with linear skin defects syndrome. A few affected individuals with male appearance who have two X chromosomes have been identified.

A reduced amount of the holocytochrome c-type synthase enzyme can damage cells by impairing their ability to generate energy. In addition, without the holocytochrome c-type synthase enzyme, the damaged cells may not be able to undergo apoptosis. These cells may instead die in a process called necrosis that causes inflammation and damages neighboring cells. During early development this spreading cell damage may lead to the eye and skin abnormalities characteristic of microphthalmia with linear skin defects syndrome.

Trisomy X

Trisomy X (also called triple X syndrome or 47,XXX) results from an extra copy of the X chromosome in each cell. People with trisomy X have three X chromosomes, for a total of 47 chromosomes per cell. An extra copy of the X chromosome can be associated with tall stature, developmental delays, learning problems, and other features.

Some individuals with trisomy X have an extra X chromosome in only some of their cells. This phenomenon is called 46,XX/47,XXX mosaicism.

People with more than one extra copy of the X chromosome (48,XXXX or 49,XXXXX) have been identified, but these chromosomal changes are rare. As the number of extra sex chromosomes increases, so does the risk of learning problems, intellectual disability, birth defects, and other health issues.

Turner syndrome

Turner syndrome results when one normal X chromosome is present in cells and the other sex chromosome is missing or structurally altered. The missing genetic material affects development before and after birth, leading to short stature, ovarian malfunction, and other features of Turner syndrome.

About half of individuals with Turner syndrome have monosomy X (45,X), which means each cell in an individual's body has only one copy of the X chromosome instead of the usual two sex chromosomes. Turner syndrome can also occur if one of the sex chromosomes is partially missing or rearranged rather than completely absent.

Some people with Turner syndrome have a chromosomal change in only some of their cells, which is known as mosaicism. Some cells have the usual two sex chromosomes (either two X chromosomes or one X chromosome and one Y chromosome), and other cells have only one copy of the X chromosome. Individuals with Turner syndrome caused by X chromosome mosaicism (45,X/46,XX or 45,X/46,XY) are said to have mosaic Turner syndrome.

Researchers have not determined which genes on the X chromosome are responsible for most of the features of Turner syndrome. They have, however, identified one gene called SHOX that is important for bone development and growth. The SHOX gene is located in the pseudoautosomal regions of the sex chromosomes. Missing one copy of this gene likely causes short stature and skeletal abnormalities in individuals with Turner syndrome.

X-linked acrogigantism

Duplication of a small amount of genetic material on the X chromosome causes X-linked acrogigantism (X-LAG), which is characterized by abnormally fast growth beginning in infancy or early childhood. Affected individuals may have the condition as a result of enlargement (hyperplasia) of the pituitary gland or development of a noncancerous tumor in the gland (called a pituitary adenoma). The pituitary is a small gland at the base of the brain that produces hormones that control many important body functions, including growth hormone, which helps direct growth of the body. The abnormal gland releases more growth hormone than normal, causing rapid growth in individuals with X-LAG.

The duplication, often referred to as an Xq26.3 microduplication, occurs on the long (q) arm of the chromosome at a location designated q26.3. It can include several genes, but only duplication of the GPR101 gene is necessary to cause X-LAG. The GPR101 gene provides instructions for making a protein whose function is unknown, although it is thought to be involved in the growth of cells in the pituitary gland or in the release of growth hormone from the gland.

Duplication of the GPR101 gene leads to an excess of GPR101 protein. It is unclear how extra GPR101 protein results in the development of a pituitary adenoma or hyperplasia or in the release of excess growth hormone.

Other chromosomal conditions

Other chromosomal conditions involving the sex chromosomes can also affect sex development and fertility. The signs and symptoms of these conditions vary widely and range from mild to severe. They can be caused by missing or extra copies of the sex chromosomes or by structural changes in the chromosomes.

The Y chromosome is one of the two sex chromosomes in humans (the other is the X chromosome). The sex chromosomes form one of the 23 pairs of human chromosomes in each cell. The Y chromosome spans more than 59 million building blocks of DNA (base pairs) and represents almost 2 percent of the total DNA in cells.

The following chromosomal conditions are associated with changes in the structure or number of copies of y chromosome.

46,XX testicular difference of sex development

In most individuals with 46,XX testicular difference of sex development, the condition results from an abnormal exchange of genetic material between chromosomes (translocation). This exchange occurs as a random event during the formation of sperm cells in the affected person's father. In the translocation that causes 46,XX testicular difference of sex development, the SRY gene, which is normally found on the Y chromosome, is misplaced, almost always onto an X chromosome. An individual with an X chromosome that carries the SRY gene will develop as a male despite not having a Y chromosome, but will not be able to produce sperm to father biological children.

47,XYY syndrome

Individuals with 47,XYY syndrome have one X chromosome and two Y chromosomes in each cell, for a total of 47 chromosomes. An extra copy of the genes contained in the pseudoautosomal region of the Y chromosome may explain the tall stature and other features that can affect those individuals with this condition.

Some people with 47,XYY syndrome have an extra Y chromosome in only some of their cells. This phenomenon is called 46,XY/47,XYY mosaicism.

48,XXYY syndrome

48,XXYY syndrome, a condition that leads to infertility, developmental and behavioral disorders, and other health problems, is caused by the presence of an extra X chromosome and an extra Y chromosome in cells. Extra genetic material from the X chromosome interferes with sex development, though affected individuals are often assigned male gender at birth. Small testes that do not function normally lead to a reduction in the levels of testosterone (a hormone that directs male sex development). Extra copies of genes from the pseudoautosomal regions of the extra X and Y chromosomes likely contribute to the signs and symptoms of 48,XXYY syndrome.

Y chromosome infertility

Deletions of small amounts of genetic material in certain areas of the Y chromosome lead to a condition called Y chromosome infertility. This condition affects the production of sperm and makes it difficult or impossible for affected individuals to father children. The deletions occur in areas of the Y chromosome called azoospermia factor (AZF) regions. Genes in these regions provide instructions for making proteins thought to be involved in sperm cell development, although the specific functions of these proteins are unknown.

Deletions in the AZF regions remove all or part of several genes, or, in rare cases, a single gene. Loss of this genetic material likely prevents the production of one or more proteins needed for normal sperm cell development. As a result, sperm develop abnormally or do not develop at all, leading to Y chromosome infertility.

Other chromosomal conditions

Other chromosomal conditions involving the sex chromosomes can also often affect sex development and fertility. The signs and symptoms of these conditions vary widely and range from mild to severe. They can be caused by missing or extra copies of the sex chromosomes or by structural changes in these chromosomes.

Rarely, more than one extra copy of the Y chromosome can occur in every cell (polysomy Y). For example, the presence of two extra Y chromosomes is written as 48,XYYY. The extra genetic material in these cases can lead to skeletal abnormalities, decreased IQ, and delayed development, but the features of these conditions are variable.

What are chromosomes?

Chromosomes are organized packages of DNA found inside your body's cells. Your DNA contains genes that tell your body how to develop and function. Humans have 23 pairs of chromosomes (46 in total). You inherit one of each chromosome pair from your mother and the other from your father. Chromosomes vary in size. Each chromosome has a centromere, which divides the chromosome into two uneven sections. The shorter section is called the p arm, and the longer section is called the q arm.

Are there different types of chromosomes?

Yes, there are two different types of chromosomes; sex chromosomes and autosomal chromosomes. The sex chromosomes are the X and Y chromosomes. They determine your gender (male or female). Females have two X chromosomes, XX, one X from their father and one X from their mother. Males have one X chromosome from their mother and one Y chromosome, from their father, XY. Mothers always contribute and X chromosome (to either their son or daughter). Fathers can contribute either an X or a Y, which determines the gender of the child. The remaining chromosomes (pairs 1 through 22) are called autosomal chromosomes. They contain the rest of your genetic information.

What are the different types of chromosome disorders?

Chromosome disorders can be classified into two main types; numerical and structural. Numerical disorders occur when there is a change in the number of chromosomes (more or fewer than 46). Examples of numerical disorders include trisomy, monosomy and triploidy. Probably one of the most well-known numerical disorders is Down syndrome (trisomy 21). Other common types of numerical disorders include trisomy 13, trisomy 18, Klinefelter syndrome and Turner syndrome.

Structural chromosome disorders result from breakages within a chromosome. In these types of disorders there may be more or less than two copies of any gene. This difference in number of copies of genes may lead to clinical differences in affected individuals. Types of structural disorders include the following:

• Chromosomal deletions, sometimes known as partial monosomies, occur when a piece or section of chromosomal material is missing. Deletions can occur in any part of any chromosome. When there is just one break in the chromosome, the deletion is called a terminal deletion because the end (or terminus) of the chromosome is missing. When there are two breaks in the chromosome, the deletion is called an interstitial deletion because a piece of chromosome material is lost from within the chromosome. Deletions that are too small to be detected under a microscope are called microdeletions. A person with a deletion has only one copy of a particular chromosome segment instead of the usual two copies. Some examples of more common chromosome deletion syndromes include cri-du-chat syndrome and 22q11.2 deletion syndrome.


• Chromosomal duplications, sometimes known as partial trisomies, occur when there is an extra copy of a segment of a chromosome. A person with a duplication has three copies of a particular chromosome segment instead of the usual two copies. Like deletions, duplications can happen anywhere along the chromosome. Some examples of duplication syndromes include 22q11.2 duplication syndrome and MECP2 duplication syndrome.


• Balanced translocations occur when a chromosome segment is moved from one chromosome to another. In balanced translocations, there is no detectable net gain or loss of DNA.


• Unbalanced translocations occur when a chromosome segment is moved from one chromosome another. In unbalanced translocations, the overall amount of DNA has been altered (some genetic material has been gained or lost).


• Inversions occur when a chromosome breaks in two places and the resulting piece of DNA is reversed and re-inserted into the chromosome. Inversions that involve the centromere are called pericentric inversions; inversions that do not involve the centromere are called paracentric inversions.


• Isochromosomes are abnormal chromosomes with identical arms - either two short (p) arms or two long (q) arms. Both arms are from the same side of the centromere, are of equal length, and possess identical genes. Pallister-Killian syndrome is an example of a condition resulting from the presence of an isochromosome.


• Dicentric chromosomes result from the abnormal fusion of twp chromosome pieces, each of which includes a centromere.


• Ring chromosomes form when the ends of both arms of the same chromosome are deleted, which causes the remaining broken ends of the chromosome to be "sticky". These sticky ends then join together to make a ring shape. The deletion at the end of both arms of the chromosome results in missing DNA, which may cause a chromosome disorder. An example of a ring condition is ring chromosome 14 syndrome.

What causes chromosome disorders?

The exact cause is unknown, but we know that chromosome abnormalities usually occur when a cell divides in two (a normal process that a cell goes through). Sometimes chromosome abnormalities happen during the development of an egg or sperm cell (called germline), and other times they happen after conception (called somatic). In the process of cell division, the correct number of chromosomes is supposed to end up in the resulting cells. However, errors in cell division, called nondisjunction, can result in cells with too few or too many copies of a whole chromosome or a piece of a chromosome. Some factors, such as when a mother is of advanced maternal age (older then 35 years), can increase the risk for chromosome abnormalities in a pregnancy.

What is mosaicism?

Mosaicism is when a person has a chromosome abnormality in some, but not all, cells. It is often difficult to predict the effects of mosaicism because the signs and symptoms depend on which cells of the body have the chromosome abnormality.

How are chromosome disorders diagnosed?

Chromosome disorders may be suspected in people who have developmental delays, intellectual disabilities and/or physical abnormalities. Several types of genetic tests can identify chromosome disorders:

• Karyotyping
• Microarray (also called array CGH)
• Fluorescence in situ hybridization (FISH)

What signs and symptoms are associated with rare chromosome disorders?

In general, the effects of rare chromosome disorders vary. With a loss or gain of chromosomal material, symptoms might include a combination of physical problems, health problems, learning difficulties and challenging behavior. The symptoms depend on which parts of which chromosomes are involved. The loss of a segment of a chromosome is usually more serious than having an extra copy of the same segment. This is because when you lose a segment of a chromosome, you may be losing one copy of an important gene that your body needs to function.

There are general characteristics of rare chromosomal disorders that occur to varying degrees in most affected people. For instance, some degree of learning disability and/or developmental delay will occur in most people with any loss or gain of material from chromosomes 1 through 22. This is because there are many genes located across all of these chromosomes that provide instructions for normal development and function of the brain. Health providers can examine the chromosome to see where there is a break (a breakpoint). Then they can look at what genes may be involved at the site of the break. Knowing the gene(s) involved can sometimes, but not always, help to predict signs and symptoms.

Can chromosome disorders be inherited?

Although it is possible to inherit some types of chromosomal disorders, many chromosomal disorders are not passed from one generation to the next. Chromosome disorders that are not inherited are called de novo, which means "new". You will need to speak with a genetics professional about how (and if) a specific chromosome disorder might be inherited in your family.