Genetic Mutation in Hemochromatosis
The C282Y mutation in the HFE gene on chromosome 6 is the primary genetic mutation responsible for hereditary hemochromatosis, present in more than 90% of affected patients, with most being homozygous (C282Y/C282Y) and inheriting the condition in an autosomal recessive pattern. 1, 2
Primary Mutation: C282Y
The C282Y mutation accounts for 85-90% of all hereditary hemochromatosis cases and is found in approximately 0.44-0.5% of individuals of northern European descent as homozygotes 2, 3
Most clinically affected patients are homozygous for C282Y (C282Y/C282Y), meaning they inherited the mutation from both parents 1, 2
The mutation is transmitted in an autosomal recessive pattern, requiring two copies of the mutated gene for full disease expression 1, 2
Secondary Mutations
H63D mutation is the second most common HFE mutation, though its clinical significance is less certain than C282Y 1
Compound heterozygotes (C282Y/H63D) account for only 3-5% of hemochromatosis cases and can develop iron overload, though typically less severe 2
S65C mutation is much rarer with an allelic frequency of approximately 0.5%, with higher prevalence in certain regions like Brittany, France 2
Non-HFE Mutations (10-15% of Cases)
The remaining 10-15% of hereditary hemochromatosis involves mutations in non-HFE genes 4:
HJV gene (chromosome 1q) - most common cause of juvenile hemochromatosis, coding for hemojuvelin 4
HAMP gene - codes for hepcidin (the principal iron-regulatory hormone), causes juvenile hemochromatosis but less common than HJV 4
TFR2 gene - causes adult-onset hemochromatosis similar to HFE-related disease 4
SLC40A1 gene - causes ferroportin disease (type 4 hemochromatosis) with unique autosomal dominant inheritance pattern, unlike the recessive HFE mutations 4
Geographic Distribution
The C282Y mutation shows highest frequencies in Ireland (12.5%) and decreases toward Southern Europe (approaching 0%) 2
HFE mutations predominate in Northern European ancestry populations, while non-HFE related cases are more common in Mediterranean populations 4
Critical Penetrance Caveat
Not all C282Y homozygotes develop clinical disease - fewer than 10% develop full clinical manifestations despite genetic susceptibility 5
Variable penetrance means that having the homozygous C282Y mutation does not guarantee symptomatic disease, though all homozygotes show elevated transferrin saturation 2
This variable expression makes genetic counseling essential when discussing inheritance patterns with families 2
Clinical Implications for Testing
Genetic testing should focus on C282Y and H63D mutations as the primary targets, as these account for the vast majority of cases 1, 4
Testing is indicated for first-degree relatives of confirmed cases and patients with unexplained elevated serum ferritin (>200 µg/mL) and transferrin saturation (>55%) 1, 5
Early diagnosis before development of cirrhosis or diabetes normalizes survival, making genetic identification clinically critical 5