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Hereditary hemochromatosis is an inherited, autosomal recessive disorder of iron absorption and metabolism. The term autosomal recessive refers to a genetic state in which there are two copies of a gene mutation on a particular chromosome. This, in turn, usually results in a phenotypic expression, or clinical signs, of the disorder or disease.

A major advance in our understanding of the genetics of hereditary hemochromatosis occurred in 1996, when researchers mapped the HFE gene (located on chromosome 6) that is associated with iron absorption. Two mutations (genetic alterations or variants) of the HFE gene, known as C282Y and H63D, were found to be associated with the increased absorption and storage of iron that is characteristic of hereditary hemochromatosis. Because hereditary hemochromatosis is an autosomal recessive disorder, an individual must acquire both copies of either of these mutated genes (one from each parent) in order to develop the disorder or be considered at high risk for developing hereditary hemochromatosis. The term "homozygous" is used to denote people who carry both copies of the C282Y or H63D mutations while the term "heterozygote" refers to people who carry only one copy of the C282Y or H63D mutation. It is important to note, however, that not all individuals who carry two mutated copies of the HFE gene will actually develop clinical signs and symptoms of hemochromatosis.

The risk of a person inheriting two mutated copies of the HFE gene is as follows:

• 100% risk - if both of your parents have been diagnosed with hereditary hemochromatosis
• 50% risk - if one of your parents AND your sister or brother have been diagnosed with hereditary hemochromatosis
• 25% risk - if your sister or brother (but neither of your parents) have been diagnosed with hereditary hemochromatosis
• 5% risk - if only one of your parents (but not your sister or brother) has been diagnosed with hereditary hemochromatosis
• Less than 5% risk - if your uncle, aunt, or a first-cousin has been diagnosed with hereditary hemochromatosis

In North America, the estimated prevalence of homozygosity for the C282Y mutation [having two identical copies of the C282Y mutation (designated as C282Y/C282Y) - one from each parent] is about 80%. In Europe, the estimated prevalence of homozygosity of the C282Y mutation ranges from 52% to 96%, depending upon specific geographic location. Individuals who are homozygous for the C282Y genotype (C282Y/C282Y) are at highest risk for developing hereditary hemochromatosis. It is not clear what percentage of homozygous individuals actually develop hereditary hemochromatosis (originally estimated to be about 85%), however, emerging research is showing that the actual percentage may be much less. It appears that homozygosity for the C282Y mutation is necessary for the development of hereditary hemochromatosis but not sufficient in many cases. It is not known at this time what other factors (e.g., biochemical, environmental, or genetic) may determine which patients will develop hereditary hemochromatosis making it impossible to predict incidence of hereditary hemochromatosis in the presence of homozygous C282Y.

Approximately 2% of patients affected by hereditary hemochromatosis are homozygous for the H63D mutation (H63D/H63D) and another 5% are compound heterozygotes (the presence of two different mutants or variants of a gene on the same chromosome) and exhibit the C282Y/H63D genotype. Individuals with either the homozygous H63D genotype (H63D/H63D) or those with the compound heterozygous genotype (C282Y/H63D) are much less likely to develop hereditary hemochromatosis than individuals who are homozygous for the C282Y genotype (C282Y/C282Y).