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) is a topic of interest in the field of genetics.
- Heterozygosity for the C282Y mutation is associated with a lower risk of developing iron overload-related disease compared to homozygosity for the mutation 2.
- The frequency of C282Y heterozygosity ranges from 9.2% in Europeans to nil in Asian, Indian subcontinent, African/Middle Eastern, and Australasian populations 2.
- Studies have shown that C282Y heterozygotes may have a higher risk of iron overload or genetic hemochromatosis than the general population, but the penetrance of the C282Y mutation is generally lower in heterozygotes than in homozygotes 3.
- The C282Y mutation is associated with disrupted interaction with beta2-microglobulin, retention in the endoplasmic reticulum and middle Golgi compartment, failure to undergo late Golgi processing, and accelerated degradation 4.
Comparison with Other Genotypes
- 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.
- The penetrance of the C282Y/H63D compound heterozygous genotype is estimated to be lower than that of the C282Y homozygous genotype, with approximately 5.3% of patients exhibiting iron overload-related disease over a 10-year period 5.
- The S65C mutation, when combined with the C282Y mutation, is associated with an increased risk of being diagnosed with phenotypic HH 6.
Population Screening and Penetrance
- Population screening for HH is not currently recommended due to uncertainties about optimal screening strategies, optimal care for susceptible persons, laboratory standardization, and the potential for stigmatization or discrimination 2.
- The penetrance of the different HFE genotypes is not well established, but it is estimated that 40-70% of persons with the C282Y homozygous genotype will develop clinical evidence of iron overload 2.