From the Guidelines
Significance of Being Heterozygous for the C282Y Mutation
Being heterozygous for the C282Y mutation in Hereditary Hemochromatosis does not significantly increase the risk of developing iron overload or related diseases.
Details of the Mutation
- The C282Y mutation is a G to A missense mutation leading to the substitution of tyrosine for cysteine at the 282 amino acid position of the protein product of the HFE gene located on the short arm of chromosome 6 (6p) 1.
- Most patients with Hereditary Hemochromatosis are homozygous for the C282Y mutation, and mutation transmission is autosomal recessive 1.
- Compound heterozygotes (C282Y/H63D) can develop iron overload, but this is less common than in homozygotes 1.
Risk of Disease
- Clinically recognized Hereditary Hemochromatosis is primarily associated with the HFE mutation C282Y, but even among individuals with this mutation, only a small subset will develop symptoms of hemochromatosis 1.
- The frequency of homozygosity is 4.4 per 1000 among white persons, with much lower frequencies among other racial and ethnic groups 1.
- Being heterozygous for the C282Y mutation does not significantly increase the risk of developing iron overload or related diseases, as the majority of individuals with this mutation do not develop symptoms 1.
Screening and Diagnosis
- Genotyping primarily focuses on the identification of the C282Y mutation on HFE, while other mutations exist, C282Y homozygosity is most commonly associated with clinical manifestations 1.
- Identifying an individual with the genotypic predisposition does not accurately predict the future risk of developing iron overload or related diseases 1.
- Screening of family members of probands identifies the highest prevalence of undetected C282Y homozygotes, particularly among siblings 1.
From the Research
Significance of Being Heterozygous for the C282Y Mutation
The significance of being heterozygous for the C282Y mutation in Hereditary Hemochromatosis (HH) can be understood through various studies.
- Heterozygosity for the C282Y mutation does not typically lead to severe iron overload by itself, but when combined with other genetic mutations, such as beta-thalassemia or the H63D mutation, it may increase the risk of iron overload 2, 3.
- Studies have shown that C282Y heterozygotes have a lower risk of developing clinical evidence of iron overload compared to C282Y homozygotes, with an estimated 40-70% of C282Y homozygotes developing clinical evidence of iron overload 4.
- Informing C282Y heterozygotes of their genotype does not appear to increase anxiety or reduce health perception, and may lead to cascade testing in a minority of families 5.
- The clinical significance of the C282Y mutation in combination with other mutations, such as the S65C mutation, is still being studied, but it appears that compound heterozygotes may have a higher risk of iron overload or genetic hemochromatosis than single heterozygotes for the C282Y mutation 6, 3.
Key Findings
- C282Y heterozygosity is relatively common in European populations, with a frequency of 9.2% 4.
- The penetrance of the C282Y mutation is not well understood, but it is estimated that 40-70% of C282Y homozygotes will develop clinical evidence of iron overload 4.
- Compound heterozygotes for the C282Y and H63D mutations may have a higher risk of iron overload or genetic hemochromatosis than single heterozygotes for the C282Y mutation 3.