Clinical and family studies in genetic hemochromatosis: Microsatellite and HFE studies in five atypical families

Abstract

present in 70% of homozygotes, and an extended ancestral A candidate gene (HFE) has been described for hereditary haplotype including HLA-A3 and other DNA markers on hemochromatosis on chromosome 6. The study of well-dechromosome 6 has been reported. [5][6][7] A candidate gene has fined atypical hemochromatosis families using genetic markbeen described (HFE), 4.5 Mb telomeric to HLA-A. 8 The use ers may increase our understanding of the sensitivity and the of haplotype analysis and the search for recombinations in specificity of genotyping in hemochromatosis. One hundred families are considered to be powerful tools for localizing a and thirteen Canadian families with genetic hemochromatosis gene responsible for a disease. However, in hemochromatowere surveyed to find atypical families as possible examples sis, it had been difficult to prove informative genetic recombiof people with genetic recombinations. All families underwent nations for several reasons: 1) the late presentation of the clinical investigations including iron studies and HLA typing.probands in the fifth or sixth decade often means that parenEach individual was typed at three polymorphic microsatellite tal DNA is not available; 2) ascertainment of the phenotypic loci (D6S105, D6S1260, and D6S299) on chromosome 6. Sixstatus may be difficult and may vary between studies; and teen subjects were studied for the two missense mutations 3) lack of heterogeneity with available DNA markers has described for the candidate gene for hemochromatosis reduced the number of informative family studies. In this (C282Y, H63D). There were eight HLA-identical siblings study, 113 Canadian families with genetic hemochromatosis found in four different families (five men, three women; age were reviewed, and DNA studies are presented in 5 atypical range 30-72) with normal transferrin saturation and ferritin families with potential recombinations. levels. There were two patients identified who were homozy- PATIENTS AND METHODS gous for the C282Y mutation without biochemical evidenceA database of 113 Canadian families that had been investigated of iron overload, and two patients with no evidence of the by family studies was reviewed to search for families with potential mutation with significant iron overload. Our conclusions are genetic recombinations. All families were white with European anas follows: 1) finding HLA-identical siblings without iron overcestry. This study included 4 families in which one or more HLAload does not confirm a genetic recombination, 2) difficulties identical sibling was found without phenotypic expression of the in phenotypic definition of disease and the description of new disease, and 1 family in which two putative homozygotes produced iron overload syndromes that may differ from classical genetic an unaffected son. The diagnosis of hemochromatosis was based HC cause complicated genetic studies, and 3) finding iron-on clinical history, physical examination, and elevated serum ferriloaded patients without a C282Y mutation and patients that tin...

Analysis of HLA-A antigens and C282Y and H63D mutations of the HFE gene in Brazilian patients with hemochromatosis

“…These findings are different from those reported for Northern Europe, where more than 90% of the patients are C282Y homozygotes or C282Y and H63D compound heterozygotes (5,(20)(21)(22)(23)(24)(25), but agree with recent data reported for Italy, where approximately one third of the patients with HH showed neither C282Y or H63D mutations, nor any other mutation in the HFE gene by sequence analysis (26)(27)(28). Similarly, none of these mutations were detected in African Americans with HH or in subjects with African iron overload, another hereditary disorder of iron metabolism that is much more heterogeneous than HH (12,13).…”

Inherited Hfe–Unrelated Hemochromatosis in Italian Families

“…Previous cases of iron loaded patients negative for HFE mutations were sporadic, leaving open the question of a genetic component. 8,9 The single well-characterized non-HFE hemochromatosis is the juvenile form ( JH). 6 The disease is reported more frequently in Italy than elsewhere 10,11 and especially Southern Italy where C282Y HH is uncommon.…”

A Population-Based Study of the Clinical Expression of the Hemochromatosis Gene

“…3,[5][6][7][8][9][10][11][12][13][14] Fifteen to 20 percent of the patient population is heterozygous for the H63D mutation. This mutation may contribute to increased hepatic iron levels but does not result in iron overload in the absence of the C282Y mutation.…”