The hemochromatosis distribution in Matera province: a new SNP to explain the low genotype-phenotype correlation.

This study aims to investigate the genotype-phenotype correlation of the hereditary hemochromatosis (HH), a genetic disorder of iron metabolism, in Matera province (Basilicata, Italy). Integrating both epidemiological and molecular approaches, we studied: (a) the frequency of the HH main mutations; (b) the association between mutations and HH cases. The majority of patients with HH are homozygous for the C282Y mutation of the HFE gene. A second mutation (H63D) is more widely distributed and its connection with HH isn’t clear, but a low penetrance is attributed to this variant. The population-based study consists of three steps: (1) determination of iron biochemical parameters, (2) genetic test, (3) sequencing of HFE gene and bioinformatics studies. A case report is presented in a 41-year-old male (genotype: H63D/wt) with biochemical and clinical evidences of HH, in absence of secondary iron overload factors. In the cohort of studied patients (150M:62F), there are 18 homozygous patients; H63D/H63D genotype is found in 11 cases. In the heterozygous group, H63D/wt is the predominant genotype (61/68 subjects). All the H63D/wt residents in the same village (Mont.) show altered biochemical parameter levels. In our case study, a substitution localized into the HFE promoter (nt225A>C) is found. Results show that the H63D genotype is responsible for most cases of HH. The peculiar clinical manifestation found in Mont. suggests a founder effect. In our case, the iron overload is related to a presence of an undetected mutation, critical for the transcriptional regulation of the HFE gene.