Inherited Haemochromatosis (C282Y, H63D)

Genetic haemochromatosis is an autosomal recessive disorder and the gene involved is called the HFE gene. Two mutations have been described. The commonest mutation is the C282Y mutation. Homozygosity (ie two copies) for this mutation is seen in greater than 90% of all genetic haemochromatosis patients. Approximately 1 in 300 are homozygous for this mutation, while approximately 1 in 10 are carriers. A second mutation called H63D is less common and has a much lower risk of iron overload. However, compound heterozygotes (ie one copy of C282Y together with one copy of H63D) may express iron overload. This is not as severe as C282Y homozygotes but may be clinically significant.

Who to Test?

• Patients with unexplained elevated ferritinlevels ortransferrin saturations.
• Patients with cirrhosis of the liver.
• Family members of individuals diagnosed with hemochromatosis.
• Family members of individuals who are homozygous for the C282Y mutation.
• Family members of individuals who are compound heterozygotes for the HFE gene.

Interpretation

C282Y Homozygote : This genotype is consistent with genetic haemochromatosis. Most, but not all patients accumulate iron and will develop symptomatic haemochromatosis. Testing of other family members is indicated.

C282Y Heterozygote/H63D Heterozygote : This genotype (compound heterozygote) is associated with an increased risk of genetic haemochromatosis. Monitoring of iron status may be required. Testing of other family members is indicated.

C282Y Not found/ H63D Not found: Neither of the common mutations were detected. This does not exclude genetic haemochromatosis, which may rarely occur despite the absence of either mutation.

Cautions

In some patients, environmental and other genetic factors can lead to symptomatic haemochromatosis even in the absence of either mutation, or in the carrier state, when only one abnormal allele is present (ie simple heterozygotes with one copy.

References

1. Powell LW, Bassett ML Haemochromatosis : Diagnosis and management after the cloning of the HFE gene. Aust NZ J Med28: 159-163 (1998).
2. Feder JN, Gnirke A, Thomas W et al . A novel MHC class-I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genetics 13: 399-408 (1996).
3. Bulaj ZJ, Ajoika RS, Phillips JD, et al.Disease related conditions in relatives of patients with hemochromatosis. N Engl J Med 343:1529-35 (2001)
4. Burke W, Imperatore G, McDonnell SM, Baron RC, Khoury MJ. Contribution of different HFE genotypes to iron overload disease: a pooled analysis. Genet Med;2:271-7 (2000).
5. Andrews NC. Disorders of iron metabolism. N Engl J Med 341:1986-95 (1999)