Prevalence of HFE Gene Mutations in the Population
The C282Y mutation of the HFE gene has an allelic frequency of approximately 6.2% in populations of European ancestry, with homozygosity occurring in about 0.44-0.5% (1 in 200-260) of individuals of northern European descent. 1, 2
Geographic Distribution of HFE Mutations
- The prevalence of C282Y mutation shows significant geographic variation across Europe, with a decreasing gradient from northwest to southeast 1
- Highest frequencies are found in Ireland (12.5%) and lowest in Southern Europe (approaching 0%) 1
- In the UK, approximately 1 in 147 blood donors were found to be homozygous for C282Y 3
- The allelic frequency of C282Y in upper Northern Italy is about 3.2%, confirming the decreasing north-to-south gradient 4
- On the island of Majorca (Spain), the C282Y mutation frequency was found to be 2.62% 5
- In Greece, the C282Y allele frequency (2.3%) is lower than the European average (4%) but higher than the global average (1%) 6
Prevalence of Different HFE Genotypes
- Homozygosity for C282Y (C282Y/C282Y) occurs in approximately 0.38-0.44% of European populations 1
- The H63D mutation is more common, with an average allelic frequency of 14% in European populations 1
- Compound heterozygosity (C282Y/H63D) occurs in approximately 1 in 42 individuals of European descent 3
- Homozygosity for H63D occurs in approximately 1 in 42 individuals 3
- The S65C mutation is less common with an allelic frequency of about 0.5%, with higher prevalence in certain regions like Brittany, France 1
Clinical Relevance of HFE Mutations
- C282Y homozygosity is found in 80.6% of clinically recognized hemochromatosis patients of European ancestry 1
- Compound heterozygosity (C282Y/H63D) accounts for only 3-5% of hemochromatosis cases 2, 7
- Not all individuals with homozygous C282Y mutations develop clinical disease - penetrance is variable 2
- In population screening studies, approximately 40-70% of C282Y homozygotes will develop clinical evidence of iron overload 7
Common Pitfalls in Understanding HFE Mutation Prevalence
- Assuming uniform distribution of HFE mutations across all populations when there is significant geographic variation 1
- Confusing allele frequency with genotype frequency (homozygosity is much less common than heterozygosity) 1
- Assuming all individuals with the genetic predisposition will develop clinical hemochromatosis, when penetrance is incomplete 2
- Failing to recognize that the frequency of C282Y homozygosity is significantly higher in clinically diagnosed hemochromatosis patients (80.6%) than in the general population (0.4%) 1, 7