Low Penetrant Hemochromatosis Phenotype in Eight Families: No Evidence of Modifiers in the MHC Region

The gene responsible for hemochromatosis (HFE) has been identified on the short arm of chromosome 6, 4.5 Mb telomeric to HLA-A. A major mutation C282Y is closely correlated with the disease, as it accounts for 68 to 100\% of the cases of hemochromatosis. Nevertheless, some C282Y homozygotes subjects have no clinical or biological expression of the disease. Moreover, in Northern European populations a large discrepancy is observed between the number of C282Y homozygotes and the number of diagnosed hemochromatosis patients, suggesting incomplete penetrance of the mutation. To localize and identify the modifying genes, we investigated eight families including C282Y homozygous relatives showing no clinical signs of the disease, in addition to the hemochromatosis patients. Genomic DNA from 20 C282Y homozygotes (10 patients and 10 siblings presenting no or minor biological abnormalities) were studied. Five polymorphisms from the HFE gene were determined by PCR restriction. Extended haplotypes of the 6p21.3 region were constructed with 10 microsatellite markers. All the C282Y homozygotes shared the same HFE polymorphism. The haplotypes presented no significant difference between the probands and their unaffected relatives. These studies suggest that neither HFE polymorphism nor genes surrounding HFE are able to modulate HFE expression.