Numerous studies conducted in the US, France, Australia, and other countries have reported the prevalence of common HFE mutations among persons with a clinical diagnosis of hereditary hemochromatosis (HH). The homozygous C282Y mutation (C282Y/C282Y) is present in 82% to 90% of Caucasian patients diagnosed with iron overload due to HH.9 This suggests a strong link between the genotype and the phenotypic presentation of clinical iron overload.
Much lower percentages of persons diagnosed with HH do not have two C282Y mutations. A small percentage of persons diagnosed with HH are compound heterozygotes for C282Y and H63D (C282Y/H63D), are homozygous for H63D (H63D/H63D), heterozygous for C282Y (C282Y/wild type) or H63D (H63D/wild type), or carry S65C or other HFE mutations.10
It may be that symptomatic heterozygotes are HFE-compound heterozygotes with additional unidentified mutations modifying the expression of the more severe known mutation. More mutations of HFE and elucidation of other gene mutations modifying HFE may be discovered, enabling scientists to explain this disorder's phenotypic heterogeneity better.
The C282Y mutation is most prevalent in the non-Hispanic white population in the US. It is much less common among Hispanics and African Americans.
