C282Y/H63D Compound Heterozygosity Is a Low Penetrance Genotype for Iron Overload-related Disease

Hereditary hemochromatosis (HH) occurs due to mutations in the HFE gene. While the C282Y mutation is the most common genotype reported in HH, other genotypes are found less frequently, indicating variable degrees of penetrance. We studied the penetrance of the C282Y/H63D compound heterozygote genotype in developing clinically significant iron overload.

We have completed a retrospective analysis on every individual within Newfoundland & Labrador who were diagnosed as C282Y/H63D compound heterozygote between 1996 and 2009 through a molecular genetics study. We collected data for up to 10 years following the initial genotyping using electronic health records, including laboratory values, phlebotomy status, radiologic reports and clinic records. Iron overload status was classified based on the HealthIron study.

Between 1996 and 2009, 247 individuals with available health records tested positive for C282Y/H63D compound heterozygosity. Over the 10 years of our study, 5.3% of patients exhibited iron overload-related disease on the background of documented iron overload. Including these individuals, 10.1% of patients had documented iron overload, 23.1% of patients had a provisional iron overload and the remaining 66.8% of patients had no evidence of iron overload. Only 44 patients had documented phlebotomies, likely based on their severe phenotype at baseline. Despite phlebotomy, the prevalence of iron overload was higher among these patients. The penetrance of compound heterozygosity was also significantly higher among men (P < 0.01).

C282Y/H63D compound heterozygosity is a low penetrance genotype in HH. This is the largest reported cohort of C282Y/H63D compound heterozygotes in North America with an extended follow-up.