By Amanda Ewart Toland, PhD

Reviewed by Chris Friedich, MD, PhD

Each person has two copies of every gene — one that they inherit from their mother and one that they inherit from their father. In genes that have many different forms (or alleles), a person can inherit two different versions of the same gene, or they can inherit the same allele from each of their parents. In hemachromatosis, there are two well-known alleles of the hemachromatosis (HFE) gene, designated C282Y and H63D, in addition to the normal version of the gene. The disease symptoms and the age of onset varies depending on which combination of alleles a person has inherited.

C282Y/C282Y: Between 60 percent and 90 percent of individuals with hereditary hemochromatosis have the C282Y mutation in both copies of the hemachromatosis (HFE) gene. This mutation is more severe than H63D and almost always results in symptoms and later health complications if not treated. Many individuals will have increased serum-ferritin levels but will not show symptoms for many years. Many factors, including gender and diet, determine how old a person may be when they first experience symptoms. (This mutation is sometimes called 845 G to A.)

C282Y/H63D: Approximately three percent of people with hereditary hemochromatosis have one copy of the HFE gene with the C282Y mutation and the other copy with the H63D mutation. It is estimated that 0.5 percent to 2 percent of people with this combination of mutations will develop symptoms of hemochromatosis.

H63D/H63D: Approximately one percent of people have a change called H63D in both copies of their HFE gene. These people typically have a very mild course of disease resulting from less iron accumulation. In fact, most individuals with the H63D mutation in both copies of their HFE gene never develop symptoms. (This mutation is sometimes called 187 C to G.)

C282Y/Normal: A small percentage of individuals who carry a C282Y mutation in one copy of their HFE gene and have one normal HFE gene may have mildly increased iron levels and a 1.5-fold to 2-fold increased risk for cardiovascular disease. However, the overwhelming majority of people with this genetic test result are healthy carriers of a mutation in just one HFE gene, and have normal iron levels. About one in ten Caucasians in the USA will have this test result.

Unknown/Unknown: Approximately six percent of individual patients have mutations that are not commonly tested for or have not yet been discovered. Other mutations may be included in future genetic testing for hereditary hemochromatosis. The numbers of individuals with these mutations are very small so researchers do not yet fully understand the clinical implications of these changes in the HFE gene. They may have unknown mutations in their HFE genes, or iron overload caused by mutations in a completely different, as yet unknown gene.

top

References

Diez, O. et al. (2000) BRCA2 germ-line mutations in Spanish male breast cancer patients. Ann Oncol. Jan;11(1):81-4.

Csokay, B. et al. (1999) High frequency of germ-line BRCA2 mutations among Hungarian male breast cancer patients without family history. Cancer Res. Mar 1;59(5):995-8

Prechtel, D. et al. (1998) Frequent loss of heterozygosity at chromosome 13q12-13 with BRCA2 markers in sporadic male breast cancer. Diagn Mol Pathol. Feb;7(1):57-62

Reis L.A.G. et al. (2000). SEER Cancer Statistics Review, 1973-1997. National Cancer Institute. Bethesda, MD

Bingham S.A. (1999). High-meat diets and cancer risk. Proc Nutr Soc. May;58(2):243-8.

Zheng W. et al. (1999). N-acetyltransferase 1 genetic polymorphism, cigarette smoking, well-done meat intake, and breast cancer risk. Cancer Epidemiol Biomarkers Prev Mar;8(3):233-9.