Genetics of hereditary hemochromatosis

Hereditary hemochromatosis is probably the most common inherited disorder of people of northern European ancestry. Prevalence is estimated at 1 in 200 to 1 in 400, with an even higher rate in Ireland. The vast majority of patients who have hereditary hemochromatosis have mutations of the HFE gene and are C282Y homozygotes. Another HFE mutation, H63D, is not as penetrant as C282Y. Most compound heterozygotes (C282Y/H63D) will not present with clinical hemochromatosis. Non-HFE hemochromatosis is rare but important to be aware of. A number of non-HFE mutations have recently been identified.

Hemochromatosis should be considered in any patient of European ancestry presenting with fatigue, arthritis, liver dysfunction, gonadal failure, diabetes mellitus, skin pigmentation, arrhythmias, or cardiac disorders.


Hereditary hemochromatosis (HHC), an iron overload disorder, is probably the most common inherited disorder of people of northern European ancestry. Once it was thought to be a very rare condition, only occurring in 1 in 20 000 persons.[1] The disorder was noted to occur most commonly in northern European men in their 50s or 60s who often drank a large amount of alcohol. Indeed, the classic presentation of the triad of diabetes mellitus, cirrhosis, and pigmentation likely occurs in 1 in 20 000 people. However, the disorder, with its protean manifestations, is much more common. Hemochromatosis should be considered in any patient of European ancestry presenting with fatigue, liver dysfunction, gonadal failure, arthritis, pigmentation, diabetes, arrhythmias, or cardiac disorders.

HHC is almost invariably an autosomal recessive condition. The prevalence is between 1 in 200 to 1 in 400 in people of northern European ancestry.[2,3] An even higher prevalence likely occurs in Ireland and has been estimated as great as 1 in 64.[4-7] The identification of the HFE gene in 1996 was a major breakthrough in the understanding of HHC. (HFE is a contraction of HLA-H, the region near the gene, and Fe for iron.) The HFE gene encodes for a novel 343 amino acid MHC class 1 molecule. Initially two missense mutations in the HFE gene, which is located on chromosome 6q, were identified.[8] The most important is a single mutation of G to A at nucleotide 845, resulting in the substitution of tyrosine for cysteine at amino acid 282. This is known as the Cys282Tyr or C282Y mutation. The second mutation identified was of C to G at nucleotide 187, resulting in a substitution of aspartate for histidine at amino acid 63. This mutation is known as His63Asp or H63D. The H63D mutation does not, except in very rare instances, occur on the same allele as C282Y.[9] There is a third mutation resulting in a serine to cysteine substitution at amino acid 65. This Ser65Cys or S65C mutation has recently been suggested to result in a mild form of HHC.[10] There are at least another 38 allelic variants of the HFE gene.[11-13] Most do not appear to be clinically significant.

Homozygosity of the major mutation C282Y among persons of northern European descent accounts for 80% to 100% of those with clinical HHC.[2,4,5] Among those of European ancestry (including both northern and southern European) homozygosity of C282Y is associated with 50% to 100% of patients. There are lower rates among Mediterranean and southern European populations.[11,14] Compound heterozygosity of C282Y and H63D does not usually result in development of HHC. Less than 11% of compound heterozygotes develop clinical symptoms of HHC.[2,15,16] The H63D mutation is not as penetrant as the C282Y mutation, but there are rare reported cases of HHC with this homozygous genotype.[17] In northern Europeans H63D homozygosity is not clinically significant in causing iron overload.[18] However, the H63D mutation may lead to iron overload in the setting of another risk factor such as beta-thalassemia trait[19] or hepatitis C.[20] While the C282Y mutation is largely confined to persons of northern European extraction, the H63D mutation is spread worldwide.[21]

Unusual genetic variations of HHC may occur. In Saguenay-Lac-Saint-Jean, a geographically isolated area in Quebec, an unusual distribution of HHC genotypes has been reported. The genotypes include H63D homozygotes, C282Y, H63D, and S65C heterozygotes. There were also a number of patients with no HFE mutations. The researchers assumed either a founder effect or a high number of patients with the not-yet-identified gene for juvenile hemochromatosis.[22]

Hemochromatosis not associated with the characteristic mutations in the HFE gene—called non-HFE hemochromatosis—is much less common than HFE hemochromatosis (see the Table). As non-HFE mutations are being identified, a numbering system is being adopted. HFE2, or juvenile hemochromatosis, is a rare disorder occurring in different racial groups. It is the most common of the non-HFE hemochromatoses. Clinical symptoms present before the age of 30 because of cardiac disease and hypogonadism. The HFE locus maps to chromosome 1q, but the gene remains to be identified.[23]

Recently the molecular basis of another form of non-HFE hemochromatosis (HFE3) has been identified. The HFE3 locus maps to chromosome 7q22. The gene, transferrin receptor 2 (TfR2), encodes a possible transmembrane protein with moderate homology to transferrin receptor (TfR).[23] Multiple mutations have been identified, and recently a TfR2 mutation has been identified in work done in British Columbia.[24] A fourth form of non-HFE hemochromatosis (HFE4) has been found to be autosomal dominant and mapped to chromosome 2. HFE4 is associated with a mutation in the ferroportin gene (SLC11A3).[25] Other forms of iron overload, such as African iron overload, are known to have a genetic basis but remain to be more clearly identified.


Hereditary hemochromatosis is an underdiagnosed iron overload disorder. The most usual form is autosomal recessive and is associated with homozygosity of the C282Y mutation of the HFE gene. Hemochromatosis is a common disorder, and between 1 in 200 to 1 in 400 persons of northern European ancestry is a C282Y homozygote. Among the Irish the rate of C282Y homozygosity is higher than 1 in 100. Other less common forms of hemochromatosis exist. Because of the protean manifestations of hemochromatosis, it should be considered in any patient presenting with fatigue, arthritis, liver dysfunction, gonadal failure, diabetes mellitus, skin pigmentation, arrhythmias, or cardiac disorders.

Competing interests

None declared.

Table. Hemochromatosis variants




HFE (1)


80% cases worldwide
≤11% present phenotypically
often has a potentiator, e.g., hepatitis C
infection, thalassemia trait
very rare
very rare
very rare
very rare

chromosome 6


presents before age 30
very severe
equal sex ratio

chromosome 1



mutation in TfR2
Tyr250 stop mutation
other mutations identified

chromosome 7


autosomal dominant
mutation in ferroportin gene (SLC11A3)

chromosome 2

African iron overload
Iron overload in
Solomon Islanders
Mediterranean allele




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Chris Whittington MB, MBA, CCFP, FACRRM

Dr Whittington is a clinical assistant professor of Family Medicine at the University of British Columbia.

Chris Whittington, MB BS, MBA, FCFP, FACRRM. Genetics of hereditary hemochromatosis. BCMJ, Vol. 44, No. 10, December, 2002, Page(s) 544-546 - Clinical Articles.

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