Many types of genetic variations lend diversity to the gene pool, however, some genetic variations play a role in disease. Genetic variations that cause genetic disorders, also called mutations, can occur in a number of different ways and may affect varying amounts of genetic material.
- Single gene disorders (monogenic) occur as the result of genetic variations within a single disease-associated gene. The variation may be as small as a single base pair change or as large as the entire gene. Some single gene disorders are caused by having only one faulty copy of the gene (dominant) while others only occur when both copies are faulty (recessive). Some examples of monogenic disorders include sickle cell disease, cystic fibrosis and hemophilia.
- Complex or multifactorial disorders are those that are caused by interactions between multiple genes or by interactions between genes and environmental factors (diet, activity level, exposures, etc.). Although multifactorial disorders have a genetic basis, significant differences in disease severity (even within a family) may occur. Examples include heart disease, diabetes, and obesity.
- Chromosome disorders occur when there are extra, missing, or structurally altered chromosomes. Down syndrome is a chromosome disorder in which there is an extra (third) chromosome 21 (trisomy 21).
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Table of Genetic Variations
Examples of possible genetic changes that can cause genetic disorders include:
|Deletion||Missing genetic material or pieces of chromosomes. Ranging in size from very small (e.g. one nucleotide is missing), to very large (large segments of chromosomes or even whole chromosomes)||The most common cause of Duchenne Muscular Dystrophy is a deletion of part or all of the DMD gene.(For information, see National Organization for Rare Diseases, Duchenne Muscular Dystrophy|
|Insertion||Genetic material is added into the DNA, often inside of a gene.||One of the most common changes in the BRCA1 gene (associated with increased breast and ovarian cancer risk) is an insertion of 2 extra nucleotides into the gene. This extra information causes a shift in the DNA code and the resulting protein is not made correctly.|
|Substitution||A piece of genetic material is replaced by another||An example of this is sickle cell anemia, in which one nucleotide is substituted for another. This results in an altered protein that doesn’t do its job properly and causes red blood cells to form sickle shapes and break apart (lyse), resulting in anemia.|
|Duplication||Extra genetic material is duplicated one or more times somewhere in a person’s genome. This may result in extra protein product or protein products that build up abnormally or don’t function properly.||A duplication of the PMP22 gene causes a disorder that affects peripheral nerves, called Charcot-Marie-Tooth disease type 1. (For more information, go to National Organization for Rare Disorders, Charcot-Marie-Tooth Disease|
|Amplification||When there is more than the normal number of copies of a gene or genes in a cell, as in tumor cells, the gene is said to be amplified.||An example is HER2 amplification in some cancers, especially breast cancer. Too many copies of produce too much of the HER2 protein, which can promote uncontrolled, cancerous growth.|
|Chromosomal Translocation (chromosomal rearrangement or fusion gene)||Pieces of chromosomes break off and reattach to another chromosome. If the pieces are simply swapped from one chromosome to the other, and all of the genetic material is still present (just in the wrong place), it is said to be a “balanced” translocation and is less likely to cause an abnormal phenotype unless the break occurs inside of a gene. If material goes missing or is duplicated during the switch, this is called an “unbalanced” translocation and can lead to a chromosomal disorder.||The BCR-ABL1 gene sequence is one such change that is formed when pieces of chromosome 9 and chromosome 22 break off and switch places. When this occurs, the ABL1 gene on chromosome 9 fuses with the BCR gene on chromosome 22. The new BCR-ABL1 gene encodes an abnormal protein that is responsible for the development of chronic myelogenous leukemia (CML) and a type of acute lymphoblastic leukemia (ALL). See the article on Leukemia|
|Inversion||An inversion can happen when one chromosome experiences two breaks and the middle piece is flipped, or inverted, before being reattached. Just as with translocations, material could be deleted or duplicated during this process as well. Interpreting the effects of these changes requires expertise.||The resulting disorder depends on which chromosomes and genes are involved, and whether the breaks occur within or near genes or the regions that control them (regulatory regions).|
|Repeat expansion||Some regions of DNA normally contain a sequence of nucleotides that repeat a specific number of times. But If the sequence is repeated too many times (referred to as “expanded repeat”), the structure, function, or expression of the gene may be altered.||There are a variety of genetic disorders that are caused by repeat expansions. Examples include Huntington disease and fragile X syndrome. (See the Genetics Home Reference webpage, Fragile X Syndrome.|
|Trisomy||The presence of an extra chromosome, meaning that there are three chromosomes instead of the usual pair.||Conditions associated with trisomies include Down syndrome (a trisomy of chromosome 21), Edwards syndrome (trisomy 18)and Patau syndrome (trisomy 13).|
|Monosomy||The absence of a chromosome, meaning that there is a single chromosome instead of the usual pair.||An example is Turner syndrome (a female with a single X chromosome – X instead of XX).|
Somatic vs. Inherited (germline) variations / mutations
- Inherited mutations, sometimes also called “constitutional” or “germline” mutations, are changes to the DNA that are present from birth in all cells of the body. Such variants are also called germline mutations because they can be passed on to a child. (Our “germ” cells are the cells that create egg and sperm cells, and these cells would contain the changes as well.) See the next section for examples.
- Somatic mutations are changes to the DNA that occur after birth. They arise within one or more cells later in life, which means they are not found in every cell of that person. Most of these mutations do not affect a person’s health. However, an accumulation of certain somatic mutations over time may increase the risk of cancer and other disorders. Some somatic mutations have been shown to be caused by specific environmental conditions, such as UV radiation’s role in skin cancer. Other times there is no known cause of the somatic mutation. An example of a somatic mutation causing a disorder is the JAK2 mutation that is associated with polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF).
Patterns of Inheritance: How single gene disorders (monogenic) and genetic traits are inherited
Autosomal chromosomes are the 22 chromosomes that do not determine the sex of an individual. When a trait or disease is autosomal dominant, it means that a person only needs to inherit one copy of a gene that has a disease-causing variant in the gene from a parent (mother or father) to have the trait or disorder. Individuals with an autosomal dominant trait or disease have a 50% chance of passing the variant gene on to a child with each pregnancy. Examples of autosomal dominant diseases include familial hypercholesterolemia, neurofibromatosis type 1, and Marfan syndrome. Cleft chins are an example of an autosomal dominant trait.
When a trait or disease is recessive, it means that both copies of the gene must have disease-causing variants in order for the disease or trait to be seen. In an autosomal recessive disease, if a person has one disease-causing variant and one working copy of the gene, it is enough to keep an individual from developing the disease. However, that person can pass either the working copy of that gene or the copy with a disease-causing variant on to their children and are therefore considered “carriers”. Recessive disorders most commonly occur when both parents have a disease-causing variant in the same gene, and they both happen to pass this variant on to their child. Examples of autosomal recessive diseases include cystic fibrosis, sickle cell anemia, and hemochromatosis.
Some traits or diseases are inherited through genes located on either the X or Y sex chromosomes. These are referred to as sex-linked patterns of inheritance.
- X-linked recessive—If a girl or woman carries a gene with a disease-causing variant on one of her two X chromosomes, but has one normal working copy of the gene, she is unlikely to be affected (she is a carrier) or may have less severe symptoms than if she were to inherit a variant gene on both of her X chromosomes. Since boys and men have only one X chromosome, a single copy of the variant gene on the only X chromosome (inherited from their mother) is sufficient to cause the disease. Since it is less common for females to inherit two copies of a variant gene on the X chromosome, they are less likely to be affected by X-linked recessive diseases than males. Examples of X-linked recessive disorders include Duchenne muscular dystrophy and hemophilia A.
- X-linked dominant—this is a relatively rare pattern of inheritance. These diseases are caused by having a single copy of the variant gene on the X chromosome, regardless of a person’s sex. However, because females randomly inactivate one of their two copies of the X chromosome in each cell, a female may have less severe symptoms than a male. Examples of an X-linked dominant disorders are Rett syndrome (Genetic Home Reference: Rett syndrome) and some forms of hereditary hypophosphatemic rickets (GHR: hereditary hypophosphatemic rickets.)
- Y-linked—a variant gene is located on the Y chromosome. It can only be passed from fathers to sons. These are very rare. An example is Y-linked hearing loss.
Mitochondrial DNA and Maternal Pattern of Inheritance
Mitochondria (the powerhouses of the cell) contain some DNA that is not in the nucleus of a cell. Almost all the mitochondria are inherited from the mother through the egg cell. This is referred to as maternal inheritance. While genetic conditions associated with mitochondrial DNA can affect both males and females, these genes are usually seen passing from mothers to their children, and not from fathers to their children.
Ultimately, we are learning that quite a few diseases have a genetic component. In many cases, the genetics of those diseases are complex, and researchers are still working to understand them. In others, researchers have identified the gene or genes contributing to disorders. To learn more about how genetic testing can help diagnose, predict, and manage those disorders read the article “Human Genetic Testing Applications”.
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