Is the HFE (Human Ferritin Gene) gene mutation associated with hereditary hemochromatosis autosomal dominant?

HFE Gene Mutation and Hereditary Hemochromatosis Inheritance Pattern

The HFE gene mutation associated with hereditary hemochromatosis is primarily transmitted in an autosomal recessive pattern, not autosomal dominant. 1

Genetics of HFE Mutations

• The most common mutation in hereditary hemochromatosis is the C282Y mutation in the HFE gene located on chromosome 6p, which is transmitted in an autosomal recessive pattern 1
• Most patients with hereditary hemochromatosis are homozygous for the C282Y mutation (C282Y/C282Y), which is found in more than 90% of patients with hemochromatosis 1
• Compound heterozygosity (C282Y/H63D) accounts for only 3-5% of hemochromatosis cases 1, 2
• The H63D mutation alone may be associated with hemochromatosis, but its clinical effects are less certain compared to C282Y 1, 3

Inheritance Pattern Evidence

• The American College of Physicians guidelines clearly state that "mutation transmission is autosomal recessive" for the C282Y mutation in the HFE gene 1
• Homozygosity for the C282Y mutation (having the mutation on both alleles of chromosome 6) is required for full expression of the classic HFE-related hemochromatosis phenotype 1
• Population studies show that approximately 0.44-0.5% of individuals of northern European descent are homozygous for the C282Y mutation 1, 2

Penetrance and Expression

• Not all individuals with homozygous C282Y mutations develop clinical disease - in one large population study, all C282Y homozygotes had elevated transferrin saturation, but only 58% developed progressive tissue iron overload 1
• The clinical condition evolves in stages, beginning with clinically insignificant iron accumulation (0-20 years of age), progressing to iron overload without disease (20-40 years), and potentially to iron overload with organ damage if left untreated 1

Exceptions to Autosomal Recessive Inheritance

• While classic HFE-related hemochromatosis is autosomal recessive, it's important to note that some rare forms of hereditary hemochromatosis caused by mutations in other genes (such as ferroportin) can follow an autosomal dominant inheritance pattern 4
• These non-HFE forms of hemochromatosis have distinct clinical features and are much less common than the classic HFE-related form 4

Clinical Implications

• Early diagnosis is critical as survival is normal in patients treated before the development of cirrhosis or diabetes 1
• Genetic testing should be discussed with patients who have a positive family history of hereditary hemochromatosis or elevated serum ferritin/transferrin saturation 1
• Physicians should explain the autosomal recessive inheritance pattern when counseling families, as this affects the risk of disease in offspring 1

Common Pitfalls

• Confusing HFE-related hemochromatosis (autosomal recessive) with rarer forms of iron overload disorders that may follow autosomal dominant inheritance 4
• Assuming all individuals with homozygous C282Y mutations will develop clinical disease, when penetrance is variable 1
• Overlooking the possibility of hemochromatosis in patients without the common mutations, as approximately 7% of cases do not have identifiable C282Y or H63D mutations 2