A genetic disorder is a disease caused in whole or in part by a change in the DNA sequence away from the normal sequence. Genetic disorders can be caused by a mutation in one gene (monogenic disorder), by mutations in multiple genes (multifactorial inheritance disorder), by a combination of gene mutations and environmental factors, or by damage to chromosomes (changes in the number or structure of entire chromosomes, the structures that carry genes).

As we unlock the secrets of the human genome (the complete set of human genes), we are learning that nearly all diseases have a genetic component. Some diseases are caused by mutations that are inherited from the parents and are present in an individual at birth, like sickle cell disease. Other diseases are caused by acquired mutations in a gene or group of genes that occur during a person's life. Such mutations are not inherited from a parent, but occur either randomly or due to some environmental exposure (such as cigarette smoke). These include many cancers, as well as some forms of neurofibromatosis.

A particular disorder might be described as “running in a family” if more than one person in the family has the condition. Some disorders that affect multiple family members are caused by gene variants (also known as mutations), which can be inherited (passed down from parent to child). Other conditions that appear to run in families are not caused by variants in single genes. Instead, environmental factors such as dietary habits, pollutants, or a combination of genetic and environmental factors are responsible for these disorders.

It is not always easy to determine whether a condition in a family is inherited. A genetics professional can use a person’s family health history (a record of health information about a person’s immediate and extended family) to help determine whether a disorder has a genetic component. He or she will ask about the health of people from several generations of the family, usually first-, second-, and third-degree relatives.

This condition affects members in each generation of a family.

Credit: U.S. National Library of Medicine

A family health history is a record of health information about a person and his or her close relatives. A complete record includes information from three generations of relatives, including children, brothers and sisters, parents, aunts and uncles, nieces and nephews, grandparents, and cousins.

Families have similar genetic backgrounds, and often similar environments and lifestyles. Together, these factors can give clues to conditions that may run in a family. By noticing patterns of disorders among relatives, healthcare professionals can determine whether an individual, family members, or future generations may be at an increased risk of developing a particular condition.

A family health history can identify people with a higher-than-usual chance of having common disorders, such as heart disease, high blood pressure, stroke, certain cancers, and type 2 diabetes. These complex disorders are influenced by a combination of genetic factors, environmental conditions, and lifestyle choices. A family history also can provide information about the risk of rarer conditions caused by variants (mutations) in a single gene, such as cystic fibrosis and sickle cell disease.

While a family health history provides information about the risk of specific health concerns, having relatives with a condition does not mean that an individual will definitely develop that condition. On the other hand, a person with no family history of a disorder may still be at risk of developing the disorder.

Knowing one’s family health history allows a person to take steps to reduce his or her risk. For people at an increased risk of certain cancers, healthcare professionals may recommend more frequent screening (such as mammography or colonoscopy) starting at an earlier age. Healthcare providers may also encourage regular checkups or testing for people with a condition that runs in their family. Additionally, lifestyle changes such as adopting a healthier diet, getting regular exercise, and quitting smoking help many people lower their chances of developing heart disease and other common illnesses.

The easiest way to get information about family health history is to talk to relatives about their health. Have they had any health problems, and when did they occur? A family gathering could be a good time to discuss these issues. Additionally, obtaining medical records and other documents (such as obituaries and death certificates) can help complete a family health history. It is important to keep this information up-to-date and to share it with a healthcare professional regularly.

Some genetic conditions are caused by mutations in a single gene. These conditions are usually inherited in one of several patterns, depending on the gene involved:

Patterns of inheritance

Many health conditions are caused by the combined effects of multiple genes (described as polygenic) or by interactions between genes and the environment. Such disorders usually do not follow the patterns of inheritance listed above. Examples of conditions caused by multiple genes or gene/environment interactions include heart disease, type 2 diabetes, schizophrenia, and certain types of cancer.

Disorders caused by changes in the number or structure of chromosomes also do not follow the straightforward patterns of inheritance listed above.

When a genetic disorder is diagnosed in a family, family members often want to know the likelihood that they or their children will develop the condition. This can be difficult to predict in some cases because many factors influence a person's chances of developing a genetic condition. One important factor is how the condition is inherited. For example:

• Autosomal dominant inheritance: A person affected by an autosomal dominant disorder has a 50 percent chance of passing the altered gene to each child. The chance that a child will not inherit the altered gene is also 50 percent. However, in some cases an autosomal dominant disorder results from a new (de novo) variant that occurs during the formation of egg or sperm cells or early in embryonic development. In these cases, the child's parents are unaffected, but the child may pass on the condition to his or her own children.

• Autosomal recessive inheritance: Two unaffected people who each carry one copy of the altered gene for an autosomal recessive disorder (carriers) have a 25 percent chance with each pregnancy of having a child affected by the disorder. The chance with each pregnancy of having an unaffected child who is a carrier of the disorder is 50 percent, and the chance that a child will not have the disorder and will not be a carrier is 25 percent. If only one parent is a carrier of the altered gene and the other parent does not carry the variant, none of their children will develop the condition, and the chance with each pregnancy of having an unaffected child who is a carrier is 50 percent.

• X-linked dominant inheritance: The chance of passing on an X-linked dominant condition differs between men and women because men have one X chromosome and one Y chromosome, while women have two X chromosomes. A man passes on his Y chromosome to all of his sons and his X chromosome to all of his daughters. Therefore, the sons of a man with an X-linked dominant disorder will not be affected, but all of his daughters will inherit the condition. A woman passes on one or the other of her X chromosomes to each child. Therefore, a woman with an X-linked dominant disorder has a 50 percent chance of having an affected daughter or son with each pregnancy.

• X-linked recessive inheritance: Because of the difference in sex chromosomes, the probability of passing on an X-linked recessive disorder also differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected, and his daughters will carry one copy of the altered gene. With each pregnancy, a woman who carries an altered gene for X-linked recessive has a 50 percent chance of having sons who are affected and a 50 percent chance of having daughters who carry one copy of the altered gene. Females with one gene variant associated with an X-linked recessive disorder typically have no or very mild signs or symptoms of the condition.

• X-linked: Because the inheritance pattern of many X-linked disorders is not clearly dominant or recessive, some experts suggest that conditions be considered X-linked rather than X-linked dominant or X-linked recessive. As above, the probability of passing on an X-linked disorder differs between men and women. The sons of a man with an X-linked disorder will not be affected, but all of his daughters will inherit the altered gene and may develop signs and symptoms of the condition. A woman passes on one or the other of her X chromosomes to each child. Therefore, with each pregnancy, a woman with an X-linked disorder has a 50 percent chance of having a child with the altered gene. An affected daughter may have milder signs and symptoms than an affected son.

• Y-linked inheritance: Because only males have a Y chromosome, only males can be affected by and pass on Y-linked disorders. All sons of a man with a Y-linked disorder will inherit the condition from their father.

• Codominant inheritance: In codominant inheritance, each parent contributes a different version of a particular gene, and both versions influence the resulting genetic trait. The chance of developing a genetic condition with codominant inheritance, and the characteristic features of that condition, depend on which versions of the gene are passed from parents to their child.

• Mitochondrial inheritance: Mitochondria, which are the energy-producing centers inside cells, each contain a small amount of DNA. Disorders with mitochondrial inheritance result from variants in mitochondrial DNA. Although these disorders can affect both males and females, only females can pass variants in mitochondrial DNA to their children. A woman with a disorder caused by changes in mitochondrial DNA will pass the variants to all of her daughters and sons, but the children of a man with such a disorder will not inherit the variant.

It is important to note that the chance of passing on a genetic condition applies equally to each pregnancy. For example, if a couple has a child with an autosomal recessive disorder, the chance of having another child with the disorder is still 25 percent (or 1 in 4). Having one child with a disorder does not “protect” future children from inheriting the condition. Conversely, having a child without the condition does not mean that future children will definitely be affected.

Although the chances of inheriting a genetic condition appear straightforward, factors such as a person's family history and the results of genetic testing can sometimes modify those chances. In addition, some people with a disease-causing mutation never develop any health problems or may experience only mild symptoms of the disorder. If a disease that runs in a family does not have a clear-cut inheritance pattern, predicting the likelihood that a person will develop the condition can be particularly difficult.

Estimating the chance of developing or passing on a genetic disorder can be complex. Genetics professionals can help people understand these chances and help them make informed decisions about their health.

Reduced penetrance and variable expressivity are factors that influence the effects of particular genetic changes. These factors usually affect disorders that have an autosomal dominant pattern of inheritance, although they are occasionally seen in disorders with an autosomal recessive inheritance pattern.

Reduced penetrance

Penetrance refers to the proportion of people with a particular genetic change (such as a mutation in a specific gene) who exhibit signs and symptoms of a genetic disorder. If some people with the mutation do not develop features of the disorder, the condition is said to have reduced (or incomplete) penetrance. Reduced penetrance often occurs with familial cancer syndromes. For example, many people with a mutation in the BRCA1 or BRCA2 gene will develop cancer during their lifetime, but some people will not. Doctors cannot predict which people with these mutations will develop cancer or when the tumors will develop.

Reduced penetrance probably results from a combination of genetic, environmental, and lifestyle factors, many of which are unknown. This phenomenon can make it challenging for genetics professionals to interpret a person’s family medical history and predict the risk of passing a genetic condition to future generations.

Variable expressivity

Although some genetic disorders exhibit little variation, most have signs and symptoms that differ among affected individuals. Variable expressivity refers to the range of signs and symptoms that can occur in different people with the same genetic condition. For example, the features of Marfan syndrome vary widely— some people have only mild symptoms (such as being tall and thin with long, slender fingers), while others also experience life-threatening complications involving the heart and blood vessels. Although the features are highly variable, most people with this disorder have a mutation in the same gene (FBN1).

As with reduced penetrance, variable expressivity is probably caused by a combination of genetic, environmental, and lifestyle factors, most of which have not been identified. If a genetic condition has highly variable signs and symptoms, it may be challenging to diagnose.

The signs and symptoms of some genetic conditions tend to become more severe and appear at an earlier age as the disorder is passed from one generation to the next. This phenomenon is called anticipation. Anticipation is most often seen with certain genetic disorders of the nervous system, such as Huntington disease, myotonic dystrophy, and fragile X syndrome.

Anticipation typically occurs with disorders that are caused by an unusual type of mutation called a trinucleotide repeat expansion. A trinucleotide repeat is a sequence of three DNA building blocks (nucleotides) that is repeated a number of times in a row. DNA segments with an abnormal number of these repeats are unstable and prone to errors during cell division. The number of repeats can change as the gene is passed from parent to child. If the number of repeats increases, it is known as a trinucleotide repeat expansion. In some cases, the trinucleotide repeat may expand until the gene stops functioning normally. This expansion causes the features of some disorders to become more severe with each successive generation.

Most genetic disorders have signs and symptoms that differ among affected individuals, including affected people in the same family. Not all of these differences can be explained by anticipation. A combination of genetic, environmental, and lifestyle factors is probably responsible for the variability, although many of these factors have not been identified. Researchers study multiple generations of affected family members and consider the genetic cause of a disorder before determining that it shows anticipation.

Genomic imprinting and uniparental disomy are factors that influence how some genetic conditions are inherited.

Genomic imprinting

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.

In genes that undergo genomic imprinting, the parent of origin is often marked, or “stamped,” on the gene during the formation of egg and sperm cells. This stamping process, called methylation, is a chemical reaction that attaches small molecules called methyl groups to certain segments of DNA. These molecules identify which copy of a gene was inherited from the mother and which was inherited from the father. The addition and removal of methyl groups can be used to control the activity of genes.

Only a small percentage of all human genes undergo genomic imprinting. Researchers are not yet certain why some genes are imprinted and others are not. They do know that imprinted genes tend to cluster together in the same regions of chromosomes. Two major clusters of imprinted genes have been identified in humans, one on the short (p) arm of chromosome 11 (at position 11p15) and another on the long (q) arm of chromosome 15 (in the region 15q11 to 15q13).

Uniparental disomy

Uniparental disomy (UPD) occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent. UPD can occur as a random event during the formation of egg or sperm cells or may happen in early fetal development.

In many cases, UPD likely has no effect on health or development. Because most genes are not imprinted, it doesn’t matter if a person inherits both copies from one parent instead of one copy from each parent. In some cases, however, it does make a difference whether a gene is inherited from a person’s mother or father. A person with UPD may lack any active copies of essential genes that undergo genomic imprinting. This loss of gene function can lead to delayed development, intellectual disability, or other health problems.

Several genetic disorders can result from UPD or a disruption of normal genomic imprinting. The most well-known conditions include Prader-Willi syndrome, which is characterized by uncontrolled eating and obesity, and Angelman syndrome, which causes intellectual disability and impaired speech. Both of these disorders can be caused by UPD or other errors in imprinting involving genes on the long arm of chromosome 15. Other conditions, such as Beckwith-Wiedemann syndrome (a disorder characterized by accelerated growth and an increased risk of cancerous tumors), are associated with abnormalities of imprinted genes on the short arm of chromosome 11.

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.

Some genetic disorders are more likely to occur among people who trace their ancestry to a particular geographic area. People in an ethnic group often share certain versions of their genes, which have been passed down from common ancestors. If one of these shared genes contains a disease-causing mutation, a particular genetic disorder may be more frequently seen in the group.

Examples of genetic conditions that are more common in particular ethnic groups are sickle cell disease, which is more common in people of African, African American, or Mediterranean heritage; and Tay-Sachs disease, which is more likely to occur among people of Ashkenazi (eastern and central European) Jewish or French Canadian ancestry. It is important to note, however, that these disorders can occur in any ethnic group.

Heritability is a measure of how well differences in people’s genes account for differences in their traits. Traits can include characteristics such as height, eye color, and intelligence, as well as disorders like schizophrenia and autism spectrum disorder. In scientific terms, heritability is a statistical concept (represented as h²) that describes how much of the variation in a given trait can be attributed to genetic variation. An estimate of the heritability of a trait is specific to one population in one environment, and it can change over time as circumstances change.

Heritability estimates range from zero to one. A heritability close to zero indicates that almost all of the variability in a trait among people is due to environmental factors, with very little influence from genetic differences. Characteristics such as religion, language spoken, and political preference have a heritability of zero because they are not under genetic control. A heritability close to one indicates that almost all of the variability in a trait comes from genetic differences, with very little contribution from environmental factors. Many disorders that are caused by mutations in single genes, such as phenylketonuria (PKU), have high heritability. Most complex traits in people, such as intelligence and multifactorial diseases, have a heritability somewhere in the middle, suggesting that their variability is due to a combination of genetic and environmental factors.

Heritability has historically been estimated from studies of twins. Identical twins have almost no differences in their DNA, while fraternal twins share, on average, 50 percent of their DNA. If a trait appears to be more similar in identical twins than in fraternal twins (when they were raised together in the same environment), genetic factors likely play an important role in determining that trait. By comparing a trait in identical twins versus fraternal twins, researchers can calculate an estimate of its heritability.

Heritability can be difficult to understand, so there are many misconceptions about what it can and cannot tell us about a given trait:

• Heritability does not indicate what proportion of a trait is determined by genes and what proportion is determined by environment. So, a heritability of 0.7 does not mean that a trait is 70% caused by genetic factors; it means than 70% of the variability in the trait in a population is due to genetic differences among people.

• Knowing the heritability of a trait does not provide information about which genes or environmental influences are involved, or how important they are in determining the trait.

• Heritable is not the same as familial. A trait is described as familial if it is shared by members of a family. Traits can appear in families for many reasons in addition to genetics, such as similarities in lifestyle and environment. For example, the language that is spoken tends to be shared in families, but it has no genetic contribution and so is not heritable.

• Heritability does not give any information about how easy or difficult it is to change a trait. For example, hair color is a trait with high heritability, but it is very easy to change with dye.

If heritability provides such limited information, why do researchers study it? Heritability is of particular interest in understanding traits that are very complex with many contributing factors. Heritability can give initial clues as to the relative influences of “nature” (genetics) and “nurture” (environment) on complex traits, and it can give researchers a place to start teasing apart the factors that influence these traits.