Background Information for Hemochromatosis Mutation Detection
Hereditary hemochromatosis is an autosomal recessive genetic disorder that affects iron metabolism. Over 85% of patients with hereditary hemochromatosis have detectable mutations in the HFE gene. The three known mutations in the HFE gene are C282Y, H63D, and S65C. All three mutations can be detected through the hemochromatosis DNA test.
A normal result means that the person has tested negative for all three of the known mutations in the HFE gene and is not at increased risk of developing hereditary hemochromatosis. This person will not pass a defective HFE gene to the next generation.
A carrier is an individual who has inherited one defective HFE gene and one normal wild type HFE gene. Carriers have a 50% chance of passing the defective gene to future generations but usually do not develop the disease themselves. However, carriers may still have higher than average iron absorption. If two carriers have children, there is a 25% chance that their children will be normal, a 50% chance that their children will also be carriers, and a 25% chance that their children will inherit two defective genes and be at risk of developing hemochromatosis.
An affected individual is one who has inherited two copies of the defective HFE gene, one defective gene from each parent. People who have two defective HFE genes are at risk of absorbing too much iron and developing hemochromatosis. Although people with two defective genes have a significant risk of eventually developing some type of iron overload, not everyone with two copies of the defective HFE gene develops the disease. There is a 100% chance that an affected individual with a homozygous genotype will pass the defective HFE gene to their children. The homozygous C282Y genotype (C282Y/C282Y) is found in the vast majority of patients with hereditary hemochromatosis. While the exact penetrance of C282Y is not yet known, it is far more penetrant than H63D and S65C. Compound heterozygote C282Y/H63D has been described in some patients, but this genotype has a reduced penetrance of less than 2%. Compound heterozygote C282Y/S65C also has a very low penetrance and may contribute to a mild form of hemochromatosis. Homozygous H63D genotypes (H63D/H63D) and homozygous S65C genotypes (S65C/S65C) rarely show symptoms of hemochromatosis.
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