Gene Abnormalities

Abnormalities of one or more genes, particularly recessive genes, are fairly common. Every human being carries an average of six to eight abnormal recessive genes. However, these genes do not cause cells to function abnormally unless two copies of an abnormal recessive gene are present. In the general population, the chance of a person having two copies of an abnormal recessive gene is very small, but in children of close relatives, the chances are higher. Chances are also high among groups that intermarry, such as the Amish or Mennonites.

An abnormal gene may be inherited or may arise spontaneously as a result of a mutation (a sudden change in a gene arising as a result of any one of a number of causes or for no apparent cause at all). Depending on whether the mutation affects the reproductive cells or not, the mutation may be passed on to future generations or may simply die out with the person who has the mutation.

Whether or not a particular gene is "abnormal" can be a matter of interpretation. For example, the sickle cell gene produces disease (sickle cell anemia) but also confers protection against malaria. This so-called abnormal gene may therefore be of significant benefit in certain regions of the world.

See the table Examples of Genetic Disorders.

Gene Expression

The effects of a single-gene abnormality depend on whether the gene is dominant or recessive. For a dominant gene to be expressed, only one copy of the gene is needed. For a recessive gene to be expressed, two copies are necessary. Some genes, dominant or recessive, have only partial penetrance, meaning that even if present, they do not always or do not fully cause a change. Finally, all genes residing on the X chromosome (X-linked) are expressed in males; only dominant ones are expressed in females (unless two copies of a recessive gene are present).

Because each gene directs the production of a particular protein, an abnormal gene produces an abnormal protein or an abnormal amount of protein, which may cause an abnormality in cell function and ultimately in physical appearance or bodily function.

The effect (trait) produced by an abnormal dominant gene may be a deformity, a disease, or a tendency to develop certain diseases.

The following principles generally apply to traits determined by a dominant non-X-linked gene:

People with the trait have at least one parent with the trait, unless it is caused by a new mutation.
Abnormal genetic traits are often caused by new genetic mutations rather than by inheritance from the parents.
When one parent has an abnormal trait and the other does not, each child has a 50% chance of inheriting the abnormal trait. However, if the parent with the abnormal trait has two copies of the abnormal gene--a rare occurrence--all of their children will have the abnormal trait.
A person who does not have the abnormal trait, but whose siblings do have it, does not carry the gene and cannot pass the trait on to his offspring.
Males and females are equally likely to be affected.
The abnormality can, and usually does, appear in every generation.

Dominant genes that cause severe diseases are rare. They tend to disappear because the people who have them are often too ill to have children. However, there are a few exceptions, such as Huntington's disease, which causes severe deterioration in brain function that usually begins after age 35. By the time symptoms occur, the person may already have had children.

The following principles generally apply to traits determined by a recessive non-X-linked gene:

Virtually everyone with the trait has parents who both have the gene, even though neither parent may have the trait (because two copies of the abnormal gene are necessary for the gene to be expressed).
Mutations are highly unlikely to result in expression of the trait (because the mutation would have to have occurred in both parents).
When one parent has the trait and the other has one recessive gene but does not have the trait, half of their children are likely to have the trait; the others will be carriers with one recessive gene. If the parent without the trait does not have the abnormal recessive gene, none of their children will have the trait, but all of their children will inherit an abnormal gene that they can pass on to their offspring.
A person who does not have the abnormal trait but whose siblings do have it is likely to carry one abnormal gene.
Males and females are equally likely to be affected.
The abnormality can appear in every generation but usually does not unless both parents have the trait.

See the animation Inheriting Abnormal Autosomal Recessive Genes.

The following principles generally apply to traits determined by a dominant X-linked gene:

Affected males transmit the abnormality to all of their daughters but to none of their sons. (The sons of the affected male receive his Y chromosome, which does not carry the abnormal gene.)
Affected females with only one abnormal gene transmit the abnormality to, on average, half their children, regardless of sex.
Affected females with both abnormal genes transmit the trait to all of their children.
Twice as many females as males will have the disorder unless it is lethal in males.

As with dominant non-X-linked genes, dominant X-linked genes that cause severe diseases are rare. Examples are familial rickets (familial hypophosphatemic rickets (see Section 11, Chapter 146)) and Alport's syndrome (hereditary nephritis) (see Section 11, Chapter 146). Females with hereditary rickets have less bone symptoms than do affected males. Females with hereditary nephritis usually have no symptoms and little abnormality of kidney function, whereas affected males develop kidney failure in early adult life.

The following principles generally apply to traits determined by a recessive X-linked gene:

Nearly everyone affected is male.
All daughters of an affected male will be carriers.
An affected male never transmits the trait to his sons.
Females who carry the gene do not have the trait (unless they have the abnormal gene on both X chromosomes) but transmit the gene to half their sons, who usually have the trait. None of their daughters have the trait, but half are carriers.

See the figure Inheriting Abnormal Recessive X-Linked Genes.

An example of a common X-linked recessive gene trait is red-green color blindness, which affects about 10% of males but is unusual among females. In males, the gene for color blindness comes from a mother who usually has normal vision but is a carrier of the color-blind gene. It never comes from the father, who instead supplies the Y chromosome. Daughters of color-blind fathers are rarely color-blind but are always carriers of the color-blind gene.

See the animation Inheriting Abnormal Recessive X-Linked Genes.

Codominant Genes and Penetrance

Codominant genes are both expressed. An example is sickle cell anemia: If a person has one normal gene and one abnormal gene, both normal and abnormal red blood cell pigment (hemoglobin) is produced. Nonetheless, the disease is less severe (sickle cell trait) than if the person has two abnormal genes (sickle cell disease).

To further complicate matters, even when a gene is dominant or codominant (or recessive but present on both chromosomes), it may not be expressed because of variable penetrance (the degree or frequency with which a gene is expressed). Penetrance may vary from individual to individual.

Abnormal Mitochondrial Genes

Inside every cell are mitochondria. Mitochondria are tiny structures that provide the cell with energy. Each mitochondrion contains a circular chromosome. Several rare diseases are caused by abnormal genes carried by the chromosome inside a mitochondrion. An example is Leber's hereditary optic neuropathy, which causes a variable but often devastating loss of vision in both eyes that typically occurs during the teenage years. Another example is a syndrome characterized by type 2 diabetes and deafness.

When an egg is fertilized, only mitochondria from the egg become part of the developing fetus; all mitochondria from the sperm are discarded. Therefore, diseases caused by abnormal mitochondrial genes are transmitted by the mother. A father with abnormal mitochondrial genes cannot transmit any such diseases to his children.

Unlike the DNA in the nucleus of cells, mitochondrial DNA varies from cell to cell throughout the body. It may even vary among mitochondria within a single cell. Thus an abnormal mitochondrial gene in one body cell does not necessarily mean it will cause disease in another cell. Even when two people appear to have the same mitochondrial gene abnormality, the expression of disease may be very different in the two people. This makes genetic testing and genetic counseling of limited value in making predictions for people with known or suspected mitochondrial gene abnormalities.

Genes That Cause Cancer

Certain genes are partially responsible for the development and reproduction of cancer cells. These genes may alter the quantity or behavior of the proteins encoded by genes that regulate growth and alter cell division. Two major categories of such genes are oncogenes and tumor suppressor genes.

Oncogenes are abnormal forms of the genes that normally regulate cell growth. Usually, oncogenes are inactive. However, if they become active and signal cells to divide--even though these cells should not--cancer may develop. The activation of oncogenes is not entirely understood, but many factors may contribute, including chemical carcinogens (for example, in tobacco smoke) and infectious agents (for example, certain viruses). Additionally, chromosomal rearrangements such as the translocation of a piece of DNA from one chromosome to another may activate oncogenes (for example, in chronic myelocytic leukemia).

Tumor suppressor genes normally suppress the development of cancers by encoding for proteins that suppress cancer initiation and growth. When mutations occur in tumor suppressor genes, appropriate regulation of the cell cycle (reproduction, growth, and death) may stop, allowing affected cells to divide continuously, leading to cancer.