Genetic Disorders Health Article

GENETIC DISORDERS

The traditional method used to study an inherited disease is to observe the pattern of its distribution in families through examination of a pedigree, the construction of which begins with the individual first known to have the disease. The pedigree pattern allows one to judge whether or not the distribution conforms to Mendelian principles of segregation and assortment, and thus represents single-factor inheritance. Patterns that do not conform to Mendelian principles may represent polygenic traits, which represent the cumulative effects of a number of different genes. These complex patterns underlie the vast majority of human diseases.

Disorders caused by single mutant genes show one of four simple (Mendelian) patterns of inheritance: (1) autosomal dominant, (2) autosomal recessive, (3) X-linked dominant, or (4) X-linked recessive. A dominant trait is one that is expressed in the heterozygote (as well as in the homozygote or hemizygote). A recessive trait is one that is expressed in a homozygote (or a hemizygote), but silent in the heterozygote. The terms "dominant" and "recessive" refer to the phenotypic expression of a trait, not to the expression of the gene. Thus it is incorrect to speak of a dominant or recessive gene. A gene is either expressed or not expressed. Whether the trait is considered dominant or recessive often depends upon the level of observation. Sickle cell anemia is a recessive trait—it requires a double dose of the abnormal gene for expression at the clinical level. Nevertheless, the sickle gene can be expressed in single dose as well, giving rise to carriers with SA hemoglobin. In a state of reduced oxygen tension, red cells in SA carriers may sickle. Recessive traits may thus be codominant when viewed biochemically at the level of the gene product, or dominant in an altered environment.

AUTOSOMAL DOMINANT TRAITS

By definition, genes that are situated on chromosomes other than the X or Y sex chromosomes are autosomal. Dominant traits are fully evident when only one abnormal gene (mutant allele) is present and the corresponding partner allele on the homologous chromosome is normal (a heterozygous state). The representative initial for the dominant gene is typically capitalized, and the recessive gene is placed in lower case. Thus, if there are two alleles of a given gene that are referred to as "A" and "a," three possible genotypes exist: AA, Aa, and aa. Genotypes AA and aa are homozygotes; Aa is a heterozygote.

Autosomal dominant traits bear the following characteristic features: (1) an affected individual usually bears an equal number of affected and unaffected offspring; (2) unless the condition arose by a new mutation in a germ cell that formed the individual, each affected individual has an affected parent; (3) males and females are affected in equal numbers; (4) each gender can transmit the trait to male and female; (5) normal children of an affected individual have only normal offspring; and (6) when the trait does not impair viability or reproductive capacity, vertical transmission of the trait occurs through successive generations. The best evidence of a dominant trait is three or more generations of male-to-male transmission.

Autosomal dominant disorders often show two additional characteristics that are rarely seen in recessive disorders: (1) marked variability in the severity, or expressivity, of the disorder and (2) delayed age of onset. In heterozygotes the expression of the abnormal gene can be so weak that a generation appears to be skipped because the carrier of the abnormal gene is clinically normal. In such fortunate individuals, the trait is said to be "nonpenetrant." In some diseases, such as Huntington's disease and adult polycystic kidney disease, the disorder may not become manifest clinically until adult life, even though the mutant gene has been present since conception.

In every autosomal dominant disease, some affected persons owe their disorder to a new mutation rather than to an inherited allele. A reasonable estimate of the frequency of mutation is on the order of 5 × 10^-6 mutations per allele per generation. Because a dominant trait requires a mutation in only one of the parental gametes, the expected frequency for a new autosomal dominant disease in any given gene is one in 100,000 newborns.

A classic example of a dominant trait in humans is familial hypercholesterolemia, an autosomal dominant disorder characterized by elevation of serum cholesterol bound to low-density lipoprotein (LDL). Mutations in the LDL receptor (LDLR) gene on chromosome 19 cause the disorder. Heterozygotes develop fatty collections on their tendons, a corneal arc, and, of greatest concern, coronary artery disease, which typically presents in the fourth or fifth decade of life. Homozygotes develop these features at an accelerated rate. In the United States, the frequency of homozygotes is approximately one in a million, and the frequency of heterozygotes is approximately one in five hundred. However, among patients with a history of myocardial infarction (heart attacks), the heterozygote frequency is about one in twenty.