Hereditary Hemochromatosis, DNA Analysis

Hereditary hemochromatosis (HH) DNA analysis is a molecular genetic test that detects pathogenic variants in the HFE gene, most commonly the C282Y (p.Cys282Tyr) and H63D (p.His63Asp) mutations, which are the predominant causes of HFE-related hereditary hemochromatosis in populations of Northern European descent. This test identifies individuals who are homozygous or compound heterozygous for these variants, conferring significantly elevated risk for progressive iron overload. Non-HFE forms of hereditary hemochromatosis (types 2–4) involve mutations in HJV, HAMP, TFR2, and SLC40A1 genes and may require additional targeted testing. The HFE protein normally interacts with transferrin receptor 1 and modulates hepcidin expression in the liver; pathogenic HFE variants impair this regulatory axis, leading to inappropriately low hepcidin levels and unchecked intestinal iron absorption. Over years to decades, excess iron accumulates in parenchymal cells of the liver, heart, pancreas, joints, and endocrine glands, causing oxidative tissue injury. Penetrance is variable—C282Y homozygosity carries the highest biochemical and clinical risk, while H63D homozygosity and compound heterozygosity (C282Y/H63D) confer intermediate or lower risk.