Genetic Disorders Health Article

AUTOSOMAL RECESSIVE DISORDERS

Autosomal recessive conditions are clinically apparent only in the homozygous state—when both alleles at a particular genetic locus are deleterious. In most autosomal recessive disorders the clinical presentation tends to be more uniform than in dominant diseases, and the onset is often early in life. The following features are characteristic: (1) on average, male and female siblings are affected in equal proportions; (2) the parents are clinically normal; (3) all of the children of the union between an affected individual and a homozygous normal individual are heterozygous carriers, but none will be affected; (4) on average, half of the children are affected when an affected individual mates with a heterozygous carrier (a pseudo-dominant pedigree); (5) all of the children of a union between two individuals homozygous for the same mutant gene will be affected; (6) on average, if both parents are heterozygous at the same genetic locus, one-fourth of their children are homozygous affected, one-fourth are homozygous normal, and half are heterozygous carriers of the same mutant gene; and (7) the less frequent the mutant gene is in the population, the greater the likelihood that the affected individual is the product of consanguineous parents.

Consanguinity increases the likelihood of a child presenting with a recessive disease because the likelihood of inheriting the same rare mutation from a distant common ancestor, or "founder" increases. First cousins share, on the average, one-eighth of their genes. When two first cousins marry, an offspring has, on average, one-sixteenth of the loci homozygous for a gene derived from a common ancestor. In general, offspring of first cousins are slightly more likely to have congenital malformations, as well as mental defects and metabolic diseases, than are children born to unrelated parents.

Increased frequency of consanguinity is not observed if the recessive disease is common. Cystic fibrosis exemplifies an autosomal recessive disorder that is common among individuals of Northern European descent. In the United States, the frequency of individuals heterozygous for a mutation in the cystic fibrosis conductance regulator gene (CFTR) is quoted as one in twenty-five. Inheritance of two malfunctioning genes leads to the disruption of pancreatic exocrine function and chronic bronchitis with emphysema, as well as biliary cirrhosis, meconium ileus, and an enhanced loss of salt through the skin, which is the basis of the "sweat test" used for screening purposes. The frequency of individuals affected with cystic fibrosis is one in 2,500, and typically the parents are unrelated.