Global Sequencing Approach for Characterizing the Molecular Background of Hereditary Iron Disorders (Molecular Diagnostics and Genetics‪)‬

Hereditary hemochromatosis (HH) [9] is the main cause of inherited iron overload. When present in a homozygous state, the Cys282Tyr mutation in the hemochromatosis (HFE) [10] gene product is the most common genetic background of HH (1). Ten years after the description of this genotype, further investigations of the disease have revealed considerable heterogeneity. First, other HFE genotypes, including the compound heterozygote encoding the Cys282Tyr and His63Asp mutations, have been associated with an HH phenotype, although individuals with such genotypes accumulate less iron than Cys282Tyr homozygotes (1-3). Other rare private HFE mutations responsible for HH have also been reported. Second, Cys282Tyr homozygotes have been demonstrated to lack full penetrance (4), and some individuals homozygous for the Cys282Tyr mutant remain asymptomatic throughout life. Investigators have also described several other genes that present a phenotype similar to that of HFE-related HH, indicating that hemochromatosis is a multigene disorder. Nowadays, HH is considered an autosomal-recessive inherited disorder with 2 clinical forms, adult and juvenile HH (5, 6), defined according to the age of onset. Juvenile hemochromatosis (JH) is due to a mutation in 1 of 2 genes: HFE2 [hemochromatosis type 2 (juvenile); also known as HJV and encoding hemojuvelin] (7) and, more rarely, HAMP (hepcidin antimicrobial peptide) (8). Adult HH is mainly due to mutation in HFE, and TFR2 (transferrin receptor 2) mutations are rarely found (9). Associations between mutations of different genes leading to modified clinical presentations have been described for some patients. Such findings demonstrate that hemochromatosis can be a multigenic or at least a digenic disease. Indeed, HAMP (10), HFE2 (11), or TFR2 (12) mutations that have been associated with HFE genotypes have been described to aggravate the clinical presentation.