What are the most clinically relevant HFE (Human Ferritin Gene) gene variants associated with hereditary hemochromatosis?

Most Clinically Relevant HFE Gene Variants

The C282Y variant is by far the most clinically relevant HFE mutation, accounting for >80% of clinically recognized hereditary hemochromatosis cases, with C282Y homozygosity (C282Y/C282Y) representing the primary genotype requiring clinical action. 1

Primary Variant: C282Y

C282Y homozygosity is the critical genotype to identify, as it:

• Accounts for 80.6% of all clinically diagnosed hemochromatosis patients of European ancestry 1
• Is found in >90% of patients with clinically overt hemochromatosis 1, 2
• Carries substantial disease risk: 28.4% of male homozygotes and 1.2% of female homozygotes develop iron-overload-related disease (cirrhosis, hepatocellular carcinoma, diabetes, cardiomyopathy, arthropathy) 3
• Has an allelic frequency of approximately 6.2% in European populations, with homozygosity occurring in 0.44-0.5% of individuals 2

The 2022 EASL guidelines explicitly recommend that adult first-degree relatives of C282Y homozygous patients should be tested specifically for the C282Y variant. 1

Secondary Variant: H63D

H63D has limited clinical relevance as a standalone variant but warrants consideration in specific contexts:

• Average allelic frequency of 14% in European populations (much more common than C282Y) 1
• Compound heterozygosity (C282Y/H63D) accounts for only 5.3% of hemochromatosis cases 1
• The 2022 EASL guidelines state that genotyping for H63D can be performed in special clinical situations, but note that compound heterozygosity alone is insufficient to cause hemochromatosis without additional genetic or environmental risk factors 1
• H63D homozygosity is NOT more common in non-C282Y hemochromatosis patients than in the general population 1
• H63D heterozygosity alone does not cause clinically significant iron overload 2

Tertiary Variant: S65C

S65C has minimal clinical relevance:

• Allelic frequency of only 0.5% (highest in Brittany, France) 1
• Can be associated with excess iron only when inherited in trans with C282Y (compound heterozygote) 1
• Rarely tested in routine clinical practice

Clinical Testing Algorithm

For patients with biochemical evidence of iron overload (transferrin saturation >45% and ferritin >200 μg/L in females or >300 μg/L in males):

1. Test for C282Y first - this is the mandatory initial genetic test 1
2. Consider H63D testing only if:
   • C282Y homozygosity is absent AND
   • Iron overload persists with other risk factors (liver disease, alcohol use) 1
3. S65C testing is rarely indicated except in research settings 1

For family screening:

• Test first-degree relatives of confirmed C282Y homozygotes for C282Y variant only 1
• Penetrance is higher in family members than general population screening 1

Critical Pitfall to Avoid

Do not assume that finding H63D variants explains iron overload. When compound heterozygosity (C282Y/H63D) or H63D variants are identified in patients with iron overload, actively search for cofactors such as alcohol use, viral hepatitis, fatty liver disease, or other causes of secondary iron overload. 1 The 2022 EASL guidelines emphasize that the clinical value of H63D testing remains controversial and it should not generally guide treatment decisions. 1