A gene mutation is a permanent alteration in the DNA sequence that makes up a gene, such that the sequence differs from what is found in most people. Mutations range in size; they can affect anywhere from a single DNA building block (base pair) to a large segment of a chromosome that includes multiple genes.

Gene mutations can be classified in two major ways:

• Hereditary mutations are inherited from a parent and are present throughout a person's life in virtually every cell in the body. These mutations are also called germline mutations because they are present in the parent's egg or sperm cells, which are also called germ cells. When an egg and a sperm cell unite, the resulting fertilized egg cell receives DNA from both parents. If this DNA has a mutation, the child that grows from the fertilized egg will have the mutation in each of his or her cells.

• Acquired (or somatic) mutations occur at some time during a person's life and are present only in certain cells, not in every cell in the body. These changes can be caused by environmental factors such as ultraviolet radiation from the sun, or can occur if an error is made as DNA copies itself during cell division. Acquired mutations in somatic cells (cells other than sperm and egg cells) cannot be passed to the next generation.

Genetic changes that are described as de novo (new) mutations can be either hereditary or somatic. In some cases, the mutation occurs in a person's egg or sperm cell but is not present in any of the person's other cells. In other cases, the mutation occurs in the fertilized egg shortly after the egg and sperm cells unite. (It is often impossible to tell exactly when a de novo mutation happened.) As the fertilized egg divides, each resulting cell in the growing embryo will have the mutation. De novo mutations may explain genetic disorders in which an affected child has a mutation in every cell in the body but the parents do not, and there is no family history of the disorder.

Somatic mutations that happen in a single cell early in embryonic development can lead to a situation called mosaicism. These genetic changes are not present in a parent's egg or sperm cells, or in the fertilized egg, but happen a bit later when the embryo includes several cells. As all the cells divide during growth and development, cells that arise from the cell with the altered gene will have the mutation, while other cells will not. Depending on the mutation and how many cells are affected, mosaicism may or may not cause health problems.

Most disease-causing gene mutations are uncommon in the general population. However, other genetic changes occur more frequently. Genetic alterations that occur in more than 1 percent of the population are called polymorphisms. They are common enough to be considered a normal variation in the DNA. Polymorphisms are responsible for many of the normal differences between people such as eye color, hair color, and blood type. Although many polymorphisms have no negative effects on a person's health, some of these variations may influence the risk of developing certain disorders.

To function correctly, each cell depends on thousands of proteins to do their jobs in the right places at the right times. Sometimes, gene mutations prevent one or more of these proteins from working properly. By changing a gene's instructions for making a protein, a mutation can cause the protein to malfunction or to be missing entirely. When a mutation alters a protein that plays a critical role in the body, it can disrupt normal development or cause a medical condition. A condition caused by mutations in one or more genes is called a genetic disorder.

In some cases, gene mutations are so severe that they prevent an embryo from surviving until birth. These changes occur in genes that are essential for development, and often disrupt the development of an embryo in its earliest stages. Because these mutations have very serious effects, they are incompatible with life.

It is important to note that genes themselves do not cause disease—genetic disorders are caused by mutations that make a gene function improperly. For example, when people say that someone has “the cystic fibrosis gene,” they are usually referring to a mutated version of the CFTR gene, which causes the disease. All people, including those without cystic fibrosis, have a version of the CFTR gene.

No; only a small percentage of mutations cause genetic disorders—most have no impact on health or development. For example, some mutations alter a gene's DNA sequence but do not change the function of the protein made by the gene.

Often, gene mutations that could cause a genetic disorder are repaired by certain enzymes before the gene is expressed and an altered protein is produced. Each cell has a number of pathways through which enzymes recognize and repair errors in DNA. Because DNA can be damaged or mutated in many ways, DNA repair is an important process by which the body protects itself from disease.

A very small percentage of all mutations actually have a positive effect. These mutations lead to new versions of proteins that help an individual better adapt to changes in his or her environment. For example, a beneficial mutation could result in a protein that protects an individual and future generations from a new strain of bacteria.

Because a person's genetic code can have a large number of mutations with no effect on health, diagnosing genetic conditions can be difficult. Sometimes, genes thought to be related to a particular genetic condition have mutations, but whether these changes are involved in development of the condition has not been determined; these genetic changes are known as variants of unknown significance (VOUS) or (VUS). Sometimes, no mutations are found in suspected disease-related genes, but mutations are found in other genes whose relationship to a particular genetic condition is unknown. It is difficult to know whether these variants are involved in the disease.

People have two copies of most genes, one copy inherited from each parent. In some cases, however, the number of copies varies—meaning that a person can be born with one, three, or more copies of particular genes. Less commonly, one or more genes may be entirely missing. This type of genetic difference is known as copy number variation (CNV).

Copy number variation results from insertions, deletions, and duplications of large segments of DNA. These segments are big enough to include whole genes. Variation in gene copy number can influence the activity of genes and ultimately affect many body functions.

Researchers were surprised to learn that copy number variation accounts for a significant amount of genetic difference between people. More than 10 percent of human DNA appears to contain these differences in gene copy number. While much of this variation does not affect health or development, some differences likely influence a person's risk of disease and response to certain drugs. Future research will focus on the consequences of copy number variation in different parts of the genome and study the contribution of these variations to many types of disease.

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 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 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 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 has two or more cell populations with a different chromosomal makeup, this situation is called 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.

It is well established that changes in genes can alter a protein's function in the body, potentially causing health problems. It is becoming clear that changes in regions of DNA that do not contain genes (noncoding DNA) can also lead to disease.

Many regions of noncoding DNA play a role in the control of gene activity, determining when and where certain genes are turned on or off. By altering these sequences, a mutation in noncoding DNA can cause a protein to be expressed in the wrong place or at the wrong time or can reduce or eliminate expression of an important protein when it is needed. Not all changes in noncoding DNA have an impact on health, but those that alter the expression pattern of a protein that plays a critical role in the body can disrupt normal development or cause a health problem.

Mutations in noncoding DNA have been linked to developmental disorders such as isolated Pierre Robin sequence, which is caused by changes in enhancer elements that control the activity of the SOX9 gene. Noncoding DNA mutations have also been associated with several types of cancer. In addition to enhancer elements, these mutations can disrupt other regulatory elements including promoters, insulators, and silencers. Mutations in regions that provide instructions for making functional RNA molecules, such as transfer RNAs, microRNAs, or long noncoding RNAs, have also been implicated in disease.

The same types of genetic changes that occur in genes or that alter the structure of chromosomes can affect health and development when they occur in noncoding DNA. These mutations include changes in single DNA building blocks (point mutations), insertions, deletions, duplications, and translocations. Noncoding DNA mutations can be inherited from a parent or acquired during a person's life.

Much is still unknown about how to identify functional regions of noncoding DNA and the role such regions play. As a result, linking genetic changes in noncoding DNA to their effects on certain genes and to health conditions is difficult. The roles of noncoding DNA and the effects of genetic changes in it are growing areas of research.

8.1. Scientific journal articles for further reading

Scacheri CA, Scacheri PC. Mutations in the noncoding genome. Curr Opin Pediatr. 2015 Dec;27(6):659-64. doi: 10.1097/MOP.0000000000000283. Review. PubMed: 26382709; Free full text from PubMed Central: PMC5084913.

Chatterjee S, Ahituv N. Gene Regulatory Elements, Major Drivers of Human Disease. Annu Rev Genomics Hum Genet. 2017 Aug 31;18:45-63. doi: 10.1146/annurev-genom-091416-035537. Epub 2017 Apr 7. Review. PubMed: 28399667.

Gordon CT, Attanasio C, Bhatia S, Benko S, Ansari M, Tan TY, Munnich A, Pennacchio LA, Abadie V, Temple IK, Goldenberg A, van Heyningen V, Amiel J, FitzPatrick D, Kleinjan DA, Visel A, Lyonnet S. Identification of novel craniofacial regulatory domains located far upstream of SOX9 and disrupted in Pierre Robin sequence. Hum Mutat. 2014 Aug;35(8):1011-20. doi: 10.1002/humu.22606. PubMed: 24934569; Free full text from PubMed Central: PMC4389788.

Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA (known as mitochondrial DNA or mtDNA). In some cases, inherited changes in mitochondrial DNA can cause problems with growth, development, and function of the body's systems. These mutations disrupt the mitochondria's ability to generate energy efficiently for the cell.

Conditions caused by mutations in mitochondrial DNA often involve multiple organ systems. The effects of these conditions are most pronounced in organs and tissues that require a lot of energy (such as the heart, brain, and muscles). Although the health consequences of inherited mitochondrial DNA mutations vary widely, frequently observed features include muscle weakness and wasting, problems with movement, diabetes, kidney failure, heart disease, loss of intellectual functions (dementia), hearing loss, and abnormalities involving the eyes and vision.

Mitochondrial DNA is also prone to somatic mutations, which are not inherited. Somatic mutations occur in the DNA of certain cells during a person's lifetime and typically are not passed to future generations. Because mitochondrial DNA has a limited ability to repair itself when it is damaged, these mutations tend to build up over time. A buildup of somatic mutations in mitochondrial DNA has been associated with some forms of cancer and an increased risk of certain age-related disorders such as heart disease, Alzheimer disease, and Parkinson disease. Additionally, research suggests that the progressive accumulation of these mutations over a person's lifetime may play a role in the normal process of aging.

Researchers are learning that nearly all conditions and diseases have a genetic component. Some disorders, such as sickle cell disease and cystic fibrosis, are caused by mutations in a single gene. The causes of many other disorders, however, are much more complex. Common medical problems such as heart disease, type 2 diabetes, and obesity do not have a single genetic cause—they are likely associated with the effects of multiple genes (polygenic) in combination with lifestyle and environmental factors. Conditions caused by many contributing factors are called complex or multifactorial disorders.

Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a person's risk of inheriting or passing on these disorders. Complex disorders are also difficult to study and treat because the specific factors that cause most of these disorders have not yet been identified. Researchers continue to look for major contributing genes for many common complex disorders.

A genetic predisposition (sometimes also called genetic susceptibility) is an increased likelihood of developing a particular disease based on a person's genetic makeup. A genetic predisposition results from specific genetic variations that are often inherited from a parent. These genetic changes contribute to the development of a disease but do not directly cause it. Some people with a predisposing genetic variation will never get the disease while others will, even within the same family.

Genetic variations can have large or small effects on the likelihood of developing a particular disease. For example, certain mutations in the BRCA1 or BRCA2 genes greatly increase a person's risk of developing breast cancer and ovarian cancer. Variations in other genes, such as BARD1 and BRIP1, also increase breast cancer risk, but the contribution of these genetic changes to a person's overall risk appears to be much smaller.

Current research is focused on identifying genetic changes that have a small effect on disease risk but are common in the general population. Although each of these variations only slightly increases a person's risk, having changes in several different genes may combine to increase disease risk significantly. Changes in many genes, each with a small effect, may underlie susceptibility to many common diseases, including cancer, obesity, diabetes, heart disease, and mental illness.

In people with a genetic predisposition, the risk of disease can depend on multiple factors in addition to an identified genetic change. These include other genetic factors (sometimes called modifiers) as well as lifestyle and environmental factors. Diseases that are caused by a combination of factors are described as multifactorial. Although a person's genetic makeup cannot be altered, some lifestyle and environmental modifications (such as having more frequent disease screenings and maintaining a healthy weight) may be able to reduce disease risk in people with a genetic predisposition.

Evolution is the process by which populations of organisms change over generations. Genetic variations underlie these changes. Genetic variations can arise from gene mutations or from genetic recombination (a normal process in which genetic material is rearranged as a cell is getting ready to divide). These variations often alter gene activity or protein function, which can introduce different traits in an organism. If a trait is advantageous and helps the individual survive and reproduce, the genetic variation is more likely to be passed to the next generation (a process known as natural selection). Over time, as generations of individuals with the trait continue to reproduce, the advantageous trait becomes increasingly common in a population, making the population different than an ancestral one. Sometimes the population becomes so different that it is considered a new species.

Not all mutations lead to evolution. Only hereditary mutations, which occur in egg or sperm cells, can be passed to future generations and potentially contribute to evolution. Some mutations occur during a person's lifetime in only some of the body's cells and are not hereditary, so natural selection cannot play a role. Also, many genetic changes have no impact on the function of a gene or protein and are not helpful or harmful. In addition, the environment in which a population of organisms lives is integral to the selection of traits. Some differences introduced by mutations may help an organism survive in one setting but not in another—for example, resistance to a certain bacteria is only advantageous if that bacteria is found in a particular location and harms those who live there.

So why do some harmful traits, like genetic diseases, persist in populations instead of being removed by natural selection? There are several possible explanations, but in many cases, the answer is not clear. For some conditions, such as the neurological condition Huntington disease, signs and symptoms do not occur until after a person has children, so the gene mutation can be passed on despite being harmful. For other harmful traits, a phenomenon called reduced penetrance, in which some individuals with a disease-associated mutation do not show signs and symptoms of the condition, can also allow harmful genetic variations to be passed to future generations. For some conditions, having one mutated copy of a gene in each cell is advantageous, while having two mutated copies causes disease. The best-studied example of this phenomenon is sickle cell disease: Having two mutated copies of the HBB gene in each cell results in the disease, but having only one copy provides some resistance to malaria. This disease resistance helps explain why the mutations that cause sickle cell disease are still found in many populations, especially in areas where malaria is prevalent.

Statistical data can provide general information about how common a condition is, how many people have the condition, or how likely it is that a person will develop the condition. Statistics are not personalized, however—they offer estimates based on groups of people. By taking into account a person's family history, medical history, and other factors, a genetics professional can help interpret what statistics mean for a particular patient.

Some statistical terms are commonly used when describing genetic conditions and other disorders. These terms include:

14.1 Naming genetic conditions

Genetic conditions are not named in one standard way (unlike genes, which are given an official name and symbol by a formal committee). Doctors who treat families with a particular disorder are often the first to propose a name for the condition. Expert working groups may later revise the name to improve its usefulness. Naming is important because it allows accurate and effective communication about particular conditions, which will ultimately help researchers find new approaches to treatment.

Disorder names are often derived from one or a combination of sources:            

• The basic genetic or biochemical defect that causes the condition (for example, alpha-1 antitrypsin deficiency);

• The gene in which the mutation occurs that causes the condition (for example, TUBB4A-related leukodystrophy);

• One or more major signs or symptoms of the disorder (for example, hypermanganesemia with dystonia, polycythemia vera, and cryptogenic cirrhosis);

• The parts of the body affected by the condition (for example, craniofacial-deafness-hand syndrome);

• The name of a physician or researcher, often the first person to describe the disorder (for example, Marfan syndrome, which was named after Dr. Antoine Bernard-Jean Marfan);

• A geographic area (for example, familial Mediterranean fever, which occurs mainly in populations bordering the Mediterranean Sea); or

• The name of a patient or family with the condition (for example, amyotrophic lateral sclerosis, which is also called Lou Gehrig disease after the famous baseball player who had the condition).        

Disorders named after a specific person or place are called eponyms. There is debate as to whether the possessive form (e.g., Alzheimer's disease) or the nonpossessive form (Alzheimer disease) of eponyms is preferred. As a rule, medical geneticists use the nonpossessive form, and this form may become the standard for doctors in all fields of medicine.

14.2. Naming genes

The HUGO Gene Nomenclature Committee (HGNC) designates an official name and symbol (an abbreviation of the name) for each known human gene. Some official gene names include additional information in parentheses, such as related genetic conditions, subtypes of a condition, or inheritance pattern. The HGNC is a non-profit organization funded by the U.K. Medical Research Council and the U.S. National Institutes of Health. The Committee has named more than 13,000 of the estimated 20,000 to 25,000 genes in the human genome

During the research process, genes often acquire several alternate names and symbols. Different researchers investigating the same gene may each give the gene a different name, which can cause confusion. The HGNC assigns a unique name and symbol to each human gene, which allows effective organization of genes in large databanks, aiding the advancement of research. For specific information about how genes are named, refer to the HGNC's Guidelines for Human Gene Nomenclature.