CLINICAL AND FAMILY STUDIES IN GENETIC HEMOCHROMATOSIS - MICROSATELLITE AND HFE STUDIES IN 5 ATYPICAL FAMILIES

A candidate gene (HFE) has been described for hereditary hemochromatos is on chromosome 6. The study of well-defined atypical hemochromatosis families using genetic markers may increase our understanding of the sensitivity and the specificity of genotyping in hemochromatosis. One hundred and thirteen Canadian families with genetic hemochromatosis we re surveyed to find atypical families as possible examples of people w ith genetic recombinations, All families underwent clinical investigat ions including iron studies and HLA typing. Each individual was typed at three polymorphic microsatellite loci (D6S105, D6S1260, and D6S299) on chromosome 6. Sixteen subjects were studied for the two missense m utations described for the candidate gene for hemochromatosis (C282Y, H63D). There were eight HLA-identical siblings found in four different families (five men, three women; age range 30-72) with normal transfe rrin saturation and ferritin levels. There were two patients identifie d who were homozygous for the C282Y mutation without biochemical evide nce of iron overload, and two patients with no evidence of the mutatio n with significant iron overload. Our conclusions are as follows: 1) f inding HLA-identical siblings without iron overload does not confirm a genetic recombination, 2) difficulties in phenotypic definition of di sease and the description of new iron overload syndromes that may diff er from classical genetic HC cause complicated genetic studies, and 3) finding iron-loaded patients without a C282Y mutation and patients th at are homozygous for the C282Y mutation without evidence of iron over load may limit the use of genotyping in population screening for hemoc hromatosis.