A monogenic disorder is caused by a mutation or alteration in a single locus or gene in one or both members of a gene pair. Approximately 2 percent of the population will have a monogenic disorder diagnosed during their lifetime. Monogenic disorders are also called mendelian if their transmission follows the laws of inheritance proposed by Gregor Mendel. Modes of mendelian inheritance include autosomal dominant, autosomal recessive, X linked, and Y linked. Other monogenic patterns of inheritance, including mitochondrial inheritance, trinucleotide repeat expansion, uniparental disomy, and imprinting, are discussed in Chapter 7. As of May 2012, the Online Mendelian Inheritance in Man (OMIM) listed more than 13,800 unique genes with known sequence, of which greater than 13,000 are autosomal dominant or recessive and more than 680 are X or Y linked. Some common mendelian disorders affecting adults are listed in Table 6-1. Although transmission patterns of these diseases are consistent with mendelian inheritance, the phenotypes are strongly influenced by modifying genes and environmental factors.
TABLE 6-1. Some Common Single-Gene Disorders
AUTOSOMAL DOMINANT DISORDERS
If only one member of a gene pair determines the phenotype, that gene is considered to be dominant. The carrier of a gene causing an autosomal dominant disease has a 50 percent chance of passing on the affected gene with each conception. Factors that influence the ultimate phenotype of an individual carrying an autosomal dominant disease include penetrance, expressivity, and occasionally, presence of codominant genes.
This term describes whether or not an autosomal dominant gene is expressed at all (yes or no). The degree of penetrance of a gene is the ratio of gene carriers who have any phenotypic characteristics to the total number of gene carriers. For example, a gene that is 80 percent penetrant is expressed in some way in 80 percent of individuals who have that gene. Incomplete or reduced penetrance explains why some autosomal dominant diseases appear to “skip” generations.
This refers to the degree to which the phenotypic features are expressed. If all individuals carrying the affected gene do not have identical phenotypes, the gene has variable expressivity. Expressivity of a gene can range from complete or severe manifestations to only mild features of the disease. An example of a disease with variable expressivity is neurofibromatosis.
If alleles in a gene pair are different from each other, but both are expressed in a phenotype, they are considered to be codominant. A common example is the human major blood groups—because their genes are codominant, both A and B red-cell antigens can be expressed simultaneously in one individual.
AUTOSOMAL RECESSIVE DISORDERS
Autosomal recessive diseases develop only when both gene copies are abnormal. Phenotypic alterations in gene carriers—that is, heterozygotes—usually are undetectable clinically but may be recognized at the biochemical or cellular level. For example, many enzyme deficiency diseases are autosomal recessive. The enzyme level in the carrier will be about half of normal, but this reduction usually does not cause disease. A couple whose child has an autosomal recessive disease has a 25 percent recurrence risk with each conception. The likelihood that a normal sibling of an affected child is a carrier of the gene is two out of three—one-forth of offspring will be homozygous normal, two-forth will be heterozygote carriers, and one-forth will be homozygous abnormal. Because genes leading to rare autosomal recessive conditions have a low prevalence in the general population, the chance that a partner will be a gene carrier is low unless the couple is related a member of an at-risk population. Important examples of autosomal recessive disorders are phenylketonuria and cystic fibrosis.
This term is used when two individuals have at least one recent ancestor in common. First-degree relatives share half their genes, second-degree relatives share one-fourth, and third-degree relatives (cousins) share one-eighth. Consanguineous unions are at increased risk to produce children with otherwise rare autosomal recessive diseases and multifactorial conditions. First-cousin marriages carry a twofold increased risk of abnormal offspring—4 to 6 percent if there is no family history of genetic disease.
X-LINKED AND Y-LINKED DISEASES
Most X-linked diseases are inherited in a recessive fashion. Females carrying an X-linked recessive gene are generally unaffected, unless unfavorable lyonization—inactivation of one X chromosome in every cell—results in the majority of cells expressing the abnormal gene. When a woman carries a gene causing an X-linked recessive condition, each son has a 50 percent risk of being affected and each daughter has a 50 percent chance of being a carrier. Males carrying an X-linked recessive gene are usually affected because they lack a second X chromosome to express the normal dominant gene. When a man has an X-linked disease, all his sons will be unaffected because they cannot receive his affected X chromosome. X-linked dominant disorders affect females predominantly because they tend to be lethal in male offspring.
The Y chromosome carries genes important for sex determination and a variety of cellular functions such as spermatogenesis and bone development. Deletion of genes on the long arm results in severe spermatogenetic defects, whereas genes at the tip of the short arm are critical for chromosomal pairing during meiosis and for fertility.
For further reading in Williams Obstetrics, 23rd ed.,
see Chapter 12, “Genetics.”