If the His63Asp mutation is responsible, this mutation must have a reduced penetrance. Other researchers have not seen a significant increase in the number of compound heterozygotes with the disease in their populations. The clinical significance of His63Asp is unknown, but is thought to contribute to a mild form of the disease. Compound heterozygotes for Cys282Tyr and His63Asp, and homozygotes for the His63Asp, have been described with some individuals showing mild symptoms, although most have no detectable symptoms of hemochromatosis. The allele frequencies and genotype frequencies are listed in Table 100 .
Hereditary hemochromatosis varies in clinical severity.
Features of hereditary hemochromatosis include cirrhosis of the liver, diabetes, hyperpigmentation of the skin, heart failure, and hepatocellular carcinoma. Some authors have advocated widespread screening programs for the early detection of this disorder. Preclinical disease is more difficult to detect by these methods, with results being dependent on age, gender, and diet. Molecular analysis detects individuals at risk for developing hemochromatosis independent of these factors. Mutation detection, however, does not predict severity of disease or age of onset.