Molecular diagnosis of hereditary hemochromatosis

Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism with a frequency of homozygosity in the Caucasian population of 1 in 200-400. The pathophysiologic hallmark of HH is chronic, increased absorption of dietary iron beyond that required for normal iron homeostasis. The excess absorption leads to progressive iron accumulation in parenchymal cells that can manifest in adulthood as multiple end-organ damage (1). In 1996, the gene responsible for the majority of cases of HH was identified. Designated HFE, the HH gene resides on the short arm of chromosome 6 telomeric of the major histocompatibility complex (MHC) and encodes a 343 amino acid protein (HFE) that shares sequence and structural homology to class I MHC proteins. Approximately 85% of unrelated HH patients are homozygous for a point mutation involving a G to A change at nucleotide 845 in the HFE cDNA sequence (G845A) that converts cysteine, at amino acid position 282, to tyrosine (Cys282Tyr or C282Y) (2).