22q11.2 deletion syndrome (which is also known by several other names, listed below) is a disorder caused by the deletion of a small piece of chromosome 22. The deletion occurs near the middle of the chromosome at a location designated q11.2.

22q11.2 deletion syndrome has many possible signs and symptoms that can affect almost any part of the body. The features of this syndrome vary widely, even among affected members of the same family. People with 22q11.2 deletion syndrome commonly have heart abnormalities that are often present from birth, recurrent infections caused by problems with the immune system, and distinctive facial features. In affected individuals, the muscles that form the roof of the mouth (palate) may not close completely, even though the tissue covering them does, resulting in a condition called submucosal cleft palate. The abnormal palate is often highly arched and there may be a split in the soft flap of tissue that hangs from the back of the mouth (bifid uvula). Submucosal cleft palate can also interfere with normal speech by causing air to come out of the nose during speech, leading to nasal-sounding speech. Affected individuals may also have breathing problems, kidney abnormalities, low levels of calcium in the blood (which can result in seizures), a decrease in blood platelets (thrombocytopenia), significant feeding difficulties, gastrointestinal problems, and hearing loss. Skeletal differences are possible, including mild short stature and, less frequently, abnormalities of the spinal bones.

Many children with 22q11.2 deletion syndrome have developmental delays, including delayed growth and speech development, and some have mild intellectual disability or learning disabilities. Older affected individuals have difficulty reading, performing tasks involving math, and problem solving. Children with this condition often need help changing and adapting their behaviors when responding to situations. Additionally, affected children are more likely than children without 22q11.2 deletion syndrome to have attention-deficit/hyperactivity disorder (ADHD) and developmental conditions such as autism spectrum disorder that affect communication and social interaction.

Because the signs and symptoms of 22q11.2 deletion syndrome are so varied, different groupings of features were once described as separate conditions. Doctors named these conditions DiGeorge syndrome, velocardiofacial syndrome (also called Shprintzen syndrome), and conotruncal anomaly face syndrome. In addition, some children with the 22q11.2 deletion were diagnosed with the autosomal dominant form of Opitz G/BBB syndrome and Cayler cardiofacial syndrome. Once the genetic basis for these disorders was identified, doctors determined that they were all part of a single syndrome with many possible signs and symptoms. To avoid confusion, this condition is usually called 22q11.2 deletion syndrome, a description based on its underlying genetic cause.

22q11.2 deletion syndrome is a disorder that involves many different areas of the body and can vary greatly in severity among people with the condition. Signs and symptoms may include: cleft palate, heart defects, recurrent infections, unique facial characteristics, feeding problems, kidney abnormalities, hypoparathyroidism, thrombocytopenia, scoliosis, hearing loss, developmental delay, and learning disabilities. People with this condition are also more likely to develop certain autoimmune disorders and personality disorders. 22q11.2 deletion syndrome is caused by a deletion of a small part of chromosome 22 near the middle of the chromosome at a location known as q11.2. In most cases, the syndrome occurs for the first time in the affected person; about 10% of cases are inherited from a parent. It is inherited in an autosomal dominant manner. Although there is no specific treatment or cure, there can be ways to manage the symptoms. A team of doctors is often needed to figure out the treatment options based on each person’s symptoms.

DiGeorge syndrome was once thought to be a distinct syndrome, but is now recognized to fall within the disorder spectrum known as 22q11.2 deletion syndrome. Symptoms of what was formerly known as DiGeorge syndrome were variable and the underlying cause (deletions of 22q11.2) is also responsible for related/overlapping syndromes. Terms such as 'complete' and 'partial' DiGeorge syndrome have been used in reference to individual cases which had all the characteristic signs and symptoms (e.g., hypoparathyroidism, absent thymus, and congenital heart disease) verses those with only some of them.

Velocardiofacial syndrome is the most common syndrome associated with a cleft palate.

What is velocardiofacial syndrome?

Velocardiofacial syndrome (VCFS) is a genetic condition that is sometimes hereditary. VCFS is characterized by a combination of medical problems that vary from child to child. These medical problems include: cleft palate, or an opening in the roof of the mouth, and other differences in the palate; heart defects; problems fighting infection; low calcium levels; differences in the way the kidneys are formed or work; a characteristic facial appearance; learning problems; and speech and feeding problems.

The name velocardiofacial syndrome comes from the Latin words 'velum' meaning palate, "cardia" meaning heart and "facies" having to do with the face. Not all of these identifying features are found in each child who is born with VCFS. The most common features are palatal differences (~75 percent), heart defects (75 percent), problems fighting infection (77 percent), low calcium levels (50 percent), differences in the kidney (35 percent), characteristic facial appearance (numbers vary depending on the individual's ethnic and racial background), learning problems (~90 percent) and speech (~75 percent) and feeding problems (35 percent).

Two genes - COMT and TBX1 - are associated with VCFS. However, not all of the genes that cause VCFS have been identified. Most children who have been diagnosed with this syndrome are missing a small part of chromosome 22. Chromosomes are threadlike structures found in every cell of the body. Each chromosome contains hundreds of genes. A human cell normally contains 46 chromosomes (23 from each parent). The specific location or address of the missing segment in individuals with VCFS is 22q11.2.

VCFS is also called the 22q11.2 deletion syndrome. It also has other clinical names such as DiGeorge syndrome, conotruncal anomaly face syndrome (CTAF), autosomal dominant Opitz G/BBB syndrome or Cayler cardiofacial syndrome. As a result of this deletion, about 30 genes are generally absent from this chromosome.

VCFS affects about 1 in 4,000 newborns. VCFS may affect more individuals, however, because some people who have the 22q11.2 deletion may not be diagnosed as they have very few signs and symptoms.

What are the symptoms of VCFS?

Despite the involvement of a very specific portion of chromosome 22, there is great variation in the symptoms of this syndrome. At least 30 different symptoms have been associated with the 22q11 deletion. Most of these symptoms are not present in all individuals who have VCFS.

Symptoms include: cleft palate, usually of the soft palate (the roof of the mouth nearest the throat which is behind the bony palate); heart problems; similar faces (elongated face, almond-shaped eyes, wide nose, small ears); eye problems; feeding problems that include food coming through the nose (nasal regurgitation) because of the palatal differences; middle-ear infections (otitis media); low calcium due to hypoparathyroidism (low levels of the parathyroid hormone that can result in seizures); immune system problems which make it difficult for the body to fight infections; differences in the way the kidneys are formed or how they work; weak muscles; differences in the spine such as curvature of the spine (scoliosis) or bony abnormalities in the neck or upper back; and tapered fingers. Children are born with these features.

Children who have VCFS also often have learning difficulties and developmental delays. About 65 percent of individuals with the 22q11.2 deletion are found to have a non-verbal learning disability. When tested, their verbal IQ scores are greater than 10 points higher than their performance IQ scores. This combination of test scores brings down the full scale IQ scores but they won't represent the abilities of the individual accurately. As a result of this type of learning disability, students will have relative strengths in reading and rote memorization but will struggle with math and abstract reasoning. These individuals may also have communication and social interaction problems such as autism. As adults, these individuals have an increased risk for developing mental illness such as depression, anxiety and schizophrenia.

How is VCFS diagnosed?

VCFS is suspected as a diagnosis based on clinical examination and the presence of the signs and symptoms of the syndrome.

A special blood test called FISH (fluorescence in situ hybridization) is then done to look for the deletion in chromosome 22q11.2. More than 95 percent of individuals who have VCFS have a deletion in chromosome 22q11.2.

Those individuals who do not have the 22q11.2 deletion by standard FISH testing may have a smaller deletion that may only be found using more sophisticated lab studies such as comparative genomic hybridization, MLPA, additional FISH studies performed in a research laboratory or using specific gene studies to look for mutations in the genes known to be in this region. Again, these studies may only be available through a research lab.

What is the treatment for VCFS?

Treatment is based on the type of symptoms that are present. For example, heart defects are treated as they would normally be via surgical interventions in the newborn period. Individuals who have low calcium levels are given calcium supplements and frequently vitamin D to help them absorb the calcium. Palate problems are treated by a team of specialists called a cleft palate or craniofacial team and again often require surgical interventions and intensive speech therapy. Infections are generally treated aggressively with antibiotics in infants and children with immune problems.

Early intervention and speech therapies are started when possible at one year of age to assess and treat developmental delays.

Is VCFS inherited?

VCFS is due to a 22q11.2 deletion. Most often neither parent has the deletion and so it is new in the child (93 percent) and the chance for the couple to have another child with VCFS is quite low (close to zero). However, once the deletion is present in a person he or she has a 50 percent chance for having children who also have the deletion. The 22q11 deletion happens as an accident when either the egg or sperm are being formed or early in fetal development.

In less than 10 percent of cases, a person with VCFS inherits the deletion in chromosome 22 from a parent. When VCFS is inherited in families, this means that other family members may be affected as well.

Since some people with the 22q11.2 deletion are very mildly affected, it is suggested that all parents of children with the deletion have testing. Furthermore, some people with the deletion have no symptoms but they have the deletion in some of their cells but not all. This is called mosaicism. Even other people have the deletion only in their egg cells or sperm cells but not in their blood cells. It is recommended that all parents of a child with a 22q11.2 deletion seek genetic counseling before or during a subsequent pregnancy to learn more about their chances of having another child with VCFS.

Most people with 22q11.2 deletion syndrome are missing a sequence of about 3 million DNA building blocks (base pairs) on one copy of chromosome 22 in each cell. This region contains 30 to 40 genes, many of which have not been well characterized. A small percentage of affected individuals have shorter deletions in the same region. This condition is described as a contiguous gene deletion syndrome because it results from the loss of many genes that are close together.

Researchers are working to identify all of the genes that contribute to the features of 22q11.2 deletion syndrome. They have determined that the loss of a particular gene on chromosome 22, TBX1, is probably responsible for many of the syndrome's characteristic signs (such as heart defects, a cleft palate, distinctive facial features, hearing loss, and low calcium levels). Some studies suggest that a deletion of this gene may contribute to behavioral problems as well. The loss of another gene, COMT, in the same region of chromosome 22 may also help explain the increased risk of behavioral problems and mental illness. The loss of additional genes in the deleted region likely contributes to the varied features of 22q11.2 deletion syndrome.

Normal Function

The COMT gene provides instructions for making an enzyme called catechol-O-methyltransferase. Two versions of this enzyme are made from the gene. The longer form, called membrane-bound catechol-O-methyltransferase (MB-COMT), is chiefly produced by nerve cells in the brain. Other tissues, including the liver, kidneys, and blood, produce a shorter form of the enzyme called soluble catechol-O-methyltransferase (S-COMT). This form of the enzyme helps control the levels of certain hormones.

In the brain, catechol-O-methyltransferase helps break down certain chemical messengers called neurotransmitters. These chemicals conduct signals from one nerve cell to another. Catechol-O-methyltransferase is particularly important in an area at the front of the brain called the prefrontal cortex, which organizes and coordinates information from other parts of the brain. This region is involved with personality, planning, inhibition of behaviors, abstract thinking, emotion, and working (short-term) memory. To function efficiently, the prefrontal cortex requires signaling by neurotransmitters such as dopamine and norepinephrine. Catechol-O-methyltransferase helps maintain appropriate levels of these neurotransmitters in this part of the brain.

Health Conditions Related to Genetic Changes

22q11.2 deletion syndrome

The characteristic signs and symptoms of 22q11.2 deletion syndrome result from a deletion of a small piece of chromosome 22. The chromosomal region that is typically deleted contains 30 to 40 genes, including the COMT gene. As a result of the deletion, people with this disorder have only one copy of the COMT gene in each cell instead of the usual two copies.

A loss of one copy of the COMT gene in each cell leads to abnormal regulation of catechol-O-methyltransferase levels in the brain. Researchers believe that changes involving this enzyme in the prefrontal cortex may help explain the increased risk of behavioral problems and mental illness associated with 22q11.2 deletion syndrome. Little is known, however, about the relationship between catechol-O-methyltransferase activity and the specific mental and emotional problems characteristic of this condition. People with 22q11.2 deletion syndrome are much more likely than people without the condition to develop schizophrenia, depression, anxiety, and bipolar disorder.

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Variations in the COMT gene also may be associated with mental illness in people without 22q11.2 deletion syndrome. Researchers have looked extensively at the potential connection between changes in the COMT gene and the risk of developing schizophrenia. Most studies have focused on the effects of a particular common variation (polymorphism) in catechol-O-methyltransferase. This variation alters a single protein building block (amino acid) in the enzyme, replacing the amino acid valine with the amino acid methionine. In the longer form of the enzyme, this variation occurs at position 158 (written as Val158Met). In the shorter form of the enzyme, it occurs at position 108 (written as Val108Met). Researchers often shorten this notation to Val108/158Met. The change affects the stability and activity of catechol-O-methyltransferase, which alters the enzyme's ability to break down neurotransmitters in the prefrontal cortex.

Studies of the Val108/158Met polymorphism in people with schizophrenia have had mixed results. While most studies report no evidence of heightened risk with either methionine or valine at this position, some studies have found a slightly increased risk of schizophrenia in people with valine at position 108/158. Having valine at this position is associated with differences in thought processes that are common in people with schizophrenia, including problems with working memory, inhibition of behavior, and attention. Other changes in the COMT gene may also contribute to these differences. Variations in the COMT gene are among many factors under study to help explain the causes of schizophrenia. A large number of genetic and lifestyle factors, most of which remain unknown, likely determine the risk of developing this condition.

The Val108/158Met polymorphism has also been associated with other disorders that affect thought (cognition) and emotion. For example, researchers have studied this variation as a possible risk factor for bipolar disorder, panic disorder, anxiety, obsessive-compulsive disorder (OCD), eating disorders, and attention-deficit/hyperactivity disorder (ADHD). Studies suggest that these conditions may be related to inefficient processing of information in the prefrontal cortex. As with schizophrenia, however, many factors play a part in determining the risk of these complex disorders.

Other Names for This Gene

• Catechol Methyltransferase
• COMT_HUMAN

Genomic Location

Normal Function

The TBX1 gene provides instructions for making a protein called T-box protein 1. Genes in the T-box family play important roles in the formation of tissues and organs during embryonic development. To carry out these roles, proteins produced from these genes bind to specific areas of DNA. The proteins attach to critical regions near genes and help control the activity of those genes. T-box proteins are called transcription factors on the basis of this action.

T-box protein 1 appears to be necessary for the normal development of muscles and bones of the face and neck, large arteries that carry blood out of the heart, structures in the ear, and glands such as the thymus and parathyroid. Although T-box protein 1 acts as a transcription factor, researchers have not determined which genes are regulated by this protein.

Health Conditions Related to Genetic Changes

22q11.2 deletion syndrome

Most cases of 22q11.2 deletion syndrome are caused by a deletion of a small piece of chromosome 22. This region of the chromosome contains 30 to 40 genes, including the TBX1 gene. In a small number of affected individuals without a chromosome 22 deletion, mutations in the TBX1 gene are thought to be responsible for the characteristic signs and symptoms of the syndrome. The identified mutations include changes in single DNA building blocks (base pairs) in the TBX1 gene and deletions of a small amount of genetic material from the gene. Some of these mutations reduce the amount of T-box protein 1 that is produced in cells, while other mutations alter the protein's function. These genetic changes likely affect the ability of T-box protein 1 to bind to DNA and regulate the activity of other genes.

Researchers believe that changes in the TBX1 gene, due to either a mutation in the gene or a deletion of part of chromosome 22, are responsible for many of the features of 22q11.2 deletion syndrome. Specifically, a reduction in the amount of T-box protein 1 or changes in the protein's normal function are associated with heart defects, an opening in the roof of the mouth (a cleft palate), distinctive facial features, hearing loss, and low calcium levels. Some studies suggest that a loss of the TBX1 gene may also be associated with behavioral problems in affected individuals.

Other Names for This Gene

• CAFS
• CTHM
• DGCR
• DGS
• DORV
• TBX1_HUMAN
• TBX1C
• Testis-specific T-box protein
• TGA
• VCFS

Genomic Location

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.

Most cases of 22q11.2 deletion syndrome are not inherited from a parent and are caused by a random error during the formation of egg or sperm cells, or during early fetal development. In about 10% of cases, the deletion is inherited from a parent with the deletion.

When the deletion is inherited, it is inherited in an autosomal dominant pattern. This means that having the deletion in only one copy of chromosome 22 in each cell is enough to cause features of the condition. There is nothing that either parent can do, before or during a pregnancy, to cause a child to have this condition.

When a person with a deletion that causes an autosomal dominant condition has children, each child has a 50% (1 in 2) chance to inherit that deletion.

The signs and symptoms of 22q11.2 deletion syndrome vary greatly from person to person, even among affected people in the same family. The most common symptoms include:

• Heart defects (74% of individuals)
• Abnormalities with the development of the palate (69% of individuals)
• Characteristic facial features (elongated face, almond-shaped eyes, wide nose, and small ears)
• Learning difficulties (70-90% of individuals)
• Immune system problems (77% of individuals)

Additional symptoms may include:

• Low levels of calcium (50% of individuals)
• Significant feeding problems
• Kidney anomalies (31% of individuals)
• Hearing loss
• Issues with the development of the larynx, trachea, and esophagus (laryngotracheoesophageal anomalies)
• Growth hormone deficiency
• Autoimmune disorders (thrombocytopenia, juvenile rheumatoid arthritis, overactive thyroid)
• Seizures
• Skeletal abnormalities (extra fingers, toes, or ribs, wedge-shaped spinal bones, craniosynostosis)
• Psychiatric illness
• Eye abnormalities (ptosis, coloboma, cataract, and strabismus)
• Central nervous system abnormalities

Developmental delay, intellectual disability, and learning differences are also common in individuals with 22q11.2 deletion syndrome. Individuals may also have an autism spectrum disorders. Psychiatric illness, attention deficit disorder, anxiety, repetitive behaviors, and difficulty with social interactions are also common.

We are not aware of published reports suggesting that feeling faint, or fainting (called syncope) is a symptom directly associated with 22q11.2 deletion syndrome; however, syncope may occur as a result of features associated with 22q11.2 deletion syndrome. For example, syncope has been reported in people with hypoparathyroidism and people with low levels of calcium in the blood (hypocalcemia).

People who feel faint should speak with a health care provider to determine the underlying cause and discuss treatment options.

There is a wide range of symptoms and severity among people with 22q11.2 deletion syndrome. The long-term outlook for each person depends on the specific signs and symptoms each individual has.

Factors that may impact the severity of the disease and the likelihood for a shortened lifespan include whether or not a congenital heart defect is present and how severe the defect is, as well as the severity of immune system problems. For instance, individuals with complete absence of the thymus gland and absent T cells may pass away prematurely.

22q11.2 deletion syndrome affects an estimated 1 in 4,000 people. However, the condition may actually be more common than this estimate because doctors and researchers suspect it is underdiagnosed due to its variable features. The condition may not be identified in people with mild signs and symptoms, or it may be mistaken for other disorders with overlapping features.