Category: 1. Variants and Health

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 new, previously unknown disorder are often the first to propose a name for the condition. Later, healthcare professionals, researchers, people affected by the condition, and other interested individuals may come together to revise the name to improve its usefulness. Naming is important because it allows accurate and effective communication about particular conditions, which will ultimately improve care and help researchers find new approaches to treatment.

Condition 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 variant (or mutation) that causes the condition occurs (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, brain-lung-thyroid 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 is often called Lou Gehrig disease after the famous baseball player who was diagnosed with the condition).        

Conditions named after a specific person 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.

Naming genes

The HUGO Gene Nomenclature Committee (HGNC) designates an official name and symbol (an abbreviation of the name) for each known human gene. The HGNC is a nonprofit organization funded by the U.S. National Human Genome Research Institute and the UK’s Wellcome Trust. The Committee has named more than 19,000 of the estimated 20,000 to 25,000 protein-coding genes in the human genome.

During the research process, genes often acquire several alternate names and symbols from researchers investigating the same gene. To resolve this 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.

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, but they do 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 the statistics and explain what they mean for an individual.

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

Statistical term	Description	Examples
Incidence	The incidence of a gene variant (also called a gene mutation) or a genetic disorder is the number of people in a specified group who develop a variant or disorder during a particular time period. Incidence is often written in the form “1 in [a number]” or as a total number of a population.	About 1 in 200,000 people in the United States are diagnosed with syndrome A each year.  An estimated 15,000 people worldwide were diagnosed with syndrome B last year.
Prevalence	The prevalence of a gene variant or a genetic disorder is the total number of people in a specified group at a given time who are living with the variant or disorder. This term includes both newly diagnosed and pre-existing cases in people of any age. Prevalence is often written in the form “1 in [a number]” or as a total number of people who have a condition.	Approximately 1 in 100,000 people in the United States have syndrome A at the present time.  About 100,000 children worldwide currently have syndrome B.
Mortality	Mortality is the number of deaths from a particular disorder occurring in a specified group per year. Mortality is usually expressed as a total number of deaths.	An estimated 12,000 people worldwide died from syndrome C in 2020.
Lifetime risk	Lifetime risk is the average risk of developing a particular disorder at some point during a lifetime. Lifetime risk is often written as a percentage or as “1 in [a number].” It is important to remember that the risk per year or per decade is much lower than the lifetime risk. In addition, other factors may increase or decrease a person’s risk as compared with the average.	Approximately 1 percent of people in the United States develop disorder D during their lifetimes.  The lifetime risk of developing disorder D is 1 in 100.

Evolution is the process by which populations of organisms change over generations. Genetic variations underlie these changes. Genetic variations can arise from gene variants (also called mutations) or from a normal process in which genetic material is rearranged as a cell is getting ready to divide (known as genetic recombination). Genetic variations that alter gene activity or protein function 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 variants influence evolution. Only hereditary variants, which occur in egg or sperm cells, can be passed to future generations and potentially contribute to evolution. Some variants 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 variants 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 occur later in life, typically after a person has children, so the gene variant can be passed on despite being harmful. For other harmful traits, a phenomenon called reduced penetrance, in which some individuals with a disease-associated variant 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 altered copy of a gene in each cell is advantageous, while having two altered copies causes disease. The best-studied example of this phenomenon is sickle cell disease: Having two altered 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 variants that cause sickle cell disease are still found in many populations, especially in areas where malaria is prevalent.

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 variants (also called mutations) in the BRCA1 or BRCA2 genes greatly increase a person’s risk of developing breast cancer and ovarian cancer. Particular 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. Researchers are working to calculate an individual’s estimated risk for developing a common disease based on the combination of variants in many genes across their genome. This measure, known as the polygenic risk score, is expected to help guide healthcare decisions in the future.

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.

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 variants (also known as mutations) in single genes. The causes of many other disorders, however, are much more complex. Common health problems such as heart disease, type 2 diabetes, and obesity do not have a single genetic cause—they are influenced by multiple genes (polygenic) in combination with lifestyle and environmental factors, such as exercise, diet, or pollutant exposures. 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. It may be difficult to identify the role of genetics in these disorders, particularly because families often also share environments and may have similar lifestyles. 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.

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 variants (also known as mutations) disrupt the mitochondria’s ability to generate energy efficiently for cells.

Conditions caused by variants 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 alterations 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 problems involving the eyes and vision.

Genetic changes that are not inherited (which are known as somatic variants) may also occur in mitochondrial DNA. Somatic variants occur in the DNA of certain cells (not sperm or egg cells) during a person’s lifetime and are not passed to future generations. Because mitochondrial DNA has a limited ability to repair errors, these variants tend to build up over time. A buildup of somatic variants 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 variants over a person’s lifetime may play a role in the normal process of aging.

It is well established that changes in genes can alter a protein’s function in the body, potentially causing health problems. Scientists have determined 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, meaning they help determine when and where certain genes are turned on or off. Other regions of noncoding DNA are important for protein assembly. By altering one of these regions, a variant (also known as a mutation) in noncoding DNA can turn on a gene and cause a protein to be produced in the wrong place or at the wrong time. Alternatively, a variant can reduce or eliminate the production of an important protein when it is needed. Not all changes in noncoding DNA have an impact on health, but those that alter the pattern of a critical protein can disrupt normal development or cause a health problem.

Variants in noncoding DNA have been linked to several types of cancer and developmental disorders such as isolated Pierre Robin sequence. This condition is caused by changes in regions of noncoding DNA that act as enhancer elements. Enhancers attach proteins that help turn on particular genes. The enhancers altered in isolated Pierre-Robin sequence control the activity of the SOX9 gene. 

In addition to enhancer elements, variants in noncoding DNA can disrupt other regulatory elements. These other elements include promoters, where proteins that turn on genes attach; insulators, where proteins that help shape the activity of genes in different ways attach; and silencers, where proteins that turn off genes attach. 

Some regions of noncoding DNA provide instructions for making certain kinds of RNA molecules that play roles in regulating gene activity or assembling proteins. Variants that interrupt these 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 alterations include changes in single DNA building blocks (substitution variants), insertions, deletions, duplications, and translocations. Noncoding DNA variants can be inherited from a parent or acquired during a person’s life.

Much is still unknown about how to identify regions of noncoding DNA that have a function in cells and the roles 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 that genetic changes in noncoding DNA have on the body are growing areas of research.

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.

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.

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 have one, three, or more copies of particular genes. Less commonly, both copies of a gene may be missing. These types of genetic difference are known as copy number variations (CNV).

Copy number variation results from insertions, deletions, and duplications of  large segments of DNA that are at least one thousand nucleotides (also called 1 kilobase or 1kb) in length. These segments are often big enough to include whole genes. Variation in gene copy number can influence the activity of genes and the functioning of proteins made from them, which may affect body processes.

Copy number variation accounts for a significant amount of genetic difference between people. More than 10 percent of the human genome appears to contain differences in gene copy number. While much of this variation does not affect health or development, some differences influence a person’s risk of disease, particularly some types of cancer, or response to certain drugs.