USA Surgery Today

In autosomal recessive (AR) conditions, both genes at a locus are abnormal, which results in the absence of normal protein product. Abnormal genes are inherited from both parents each of whom has one normal and one abnormal gene (called carriers), but show no clinical evidence of the condition themselves. Many AR conditions are due to the absence of an enzyme; carriers often have one-half the normal amount of enzyme, but this amount is sufficient so they demonstrate no signs or symptoms of the condition. Two carriers of an AR condition have a 25% risk of having an affected child with each pregnancy . It has been estimated that each of us carries 6 to 10 recessive genes. Therefore, these conditions occur more frequently among inbred groups and consanguineous matings, because related individuals are more likely to have inherited the same abnormal recessive gene.

The finding that some AR conditions are more frequent in particular ethnic groups has led to population screening for carrier status. Some examples of this strategy include carrier screening of the Ashkenazi Jewish population for Tay-Sachs disease and those of Caucasian European or Ashkenazi Jewish descent for cystic fibrosis (CF)

An example of a condition inherited in an AR manner is CF (MIM 219700). This condition, occurring in approximately 1 in 3,200 live births in Caucasians, (19) is characterized by chronic pulmonary disease, pancreatic insufficiency, and elevated sweat chloride concentrations. Meconium ileus is seen in 10% to 20% of newborns with CF. The condition is due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene located on chromosome 7, which codes for a protein that acts as a cell membrane chloride channel. Therefore, patients with this condition have abnormal chloride conduction across the apical membrane of epithelial cells. The most common mutation in patients with CF (accounting for 68% of mutant alleles worldwide, but ranging from 30% to 90%, depending on the ethnic group) (20) results in deletion of a single amino acid (phenylalanine) from the CFTR protein (termed ΔF508, referring to a deletion of phenylalanine—abbreviated as F—at amino acid no. 508). More than 1,000 other mutations are known, including missense mutations, frameshift mutations (due to addition or deletion of a number of base pairs that is not a multiple of three), nonsense mutations, and mRNA splicing mutations (20).

Evaluations of large numbers of CF patients for the CFTR mutation have allowed study of the correlation between the specific mutation (genotype) and the observed clinical manifestations (phenotype). This correlation has demonstrated that certain CFTR mutations are associated with early onset of pancreatic insufficiency, whereas other mutations have a low frequency of this problem. However, the occurrence of other common complications and the severity and course of pulmonary disease do not appear to be predicted by the CF genotype, but are believed to be due to other genetic and environmental factors (20).