Hereditary Hemochromatosis, DNA Analysis

Follow-up evaluation in individuals with elevated saturated transferrin; detection of affected individuals and carriers of hereditary hemochromatosis

This assay detects only the C282Y, H63D, and S65C mutations in the HFE gene and will help identify those who are at increased risk for hereditary hemochromatosis. Increased risk for hereditary hemochromatosis can be caused by a variety of genetic and nongenetic factors not detected by this assay.

This test was developed, and its performance characteristics determined, by LabCorp. It has not been cleared or approved by the US Food and Drug Administration (FDA).

Hereditary hemochromatosis (HH) (OMIM 235200) is an autosomal recessive disorder of iron metabolism resulting in the accumulation of excess iron in a variety of organs. Populations of Northern European origin show the highest frequency of HH, with 1 in 300 individuals affected. The HFE gene was identified as being responsible for hemochromatosis. The HFE gene encodes an HLA class I-like protein. In association with β-2 microglobulin, HFE, has an expression pattern that is correlated with the localization of iron absorption. HFE seems to play a role in iron uptake by interacting with the transferrin receptor, which leads to a decreased affinity of the transferrin receptor for transferrin.

Eighty-five percent of HH chromosomes have the mutation 845A that results from a G to A mutation at nucleotide 845 of the open reading frame of HFE. This mutation changes a cysteine to a tyrosine at amino acid 282 (C282Y). The second mutation, 187G, results from a C to G mutation at nucleotide 187 of the open reading frame of HFE. It accounts for 40% to 70% of the non-C282Y HH mutations (about 39% of HH). This mutation changes a histidine to an aspartic acid at amino acid 63 (H63D). The third mutation, 193T, results from an A to T mutation at nucleotide 193 of the open reading frame of HFE. This mutation changes a serine to a cysteine at amino acid 65 (S65C). This mutation accounts for 4.7% of the affected HH chromosomes. Of the three mutations, C282Y carries the highest risk for an iron overload pathology, when inherited in the homozygous state. H63D and S65C are mutations of reduced penetrance, and may not cause disease even when detected in the compound heterozygous state with C282Y.

Dooley JS, Walker AP. Genetic hemochromatosis: Detection, management, and population screening. Genet Test. 2000; 4(2):97-101. PubMed 10953946