How common is the HFE gene causing classic HHC type I?
Recent screening studies suggest that the HFE gene occurs in up to 5% of whites, giving a carrier (heterozygote) frequency of approximately 1 in 10 and a disease (homozygote) frequency of 1 in 400. There is wide variation in gene frequency. The mutation frequency is highest in individuals of northwestern European descent (1 in 200 homozygous) and less common in southern and eastern Europe populations, and is rarely found in indigenous populations of Africa, the Americas, Asia, and the Pacific Islands. The global prevalence of the gene mutation is 1.9%, making this one of the most commonly inherited metabolic diseases. Given the frequency of HHC in the general population, many physicians recommend screening iron studies in all white men by the age of 40 years.
The frequency of clinically significant disease (i.e., disease penetrance) in patients homozygous for the HFE gene is controversial. According to reports, the odds ratio for developing HHC is as high as 2300 for C282Y HFE homozygotes but only 6 for H63D homozygotes. Disease penetrance is 1% to 28% in individuals homozygous for C282Y, 1.5% for compound heterozygotes, and <1% for H63D homozygotes. This low disease penetrance suggests that additional gene mutations (hepcidin gene, etc.) or environmental factors must be present for a homozygous patient to develop type I HHC.
