The widespread use of the genotype assay that identifies the common C282Y m
utation in the HFE gene has allowed an earlier diagnosis to be made in many
subjects. A significant number of these patients may have no evidence of p
henotypic disease and have a normal serum ferritin level. This phenomenon i
s more common when the genotype assay is used to screen populations rather
than higher-risk groups such as family members of a proband with hereditary
hemochromatosis. Moreover, patients with significant iron overload may be
wild type for the C282Y mutation and have no other demonstrable mutation of
the HFE gene. The HFE genotype assay has recently been found to give a fal
se-positive C282Y homozygous result in half of the subjects in one populati
on screening study due to the presence of a single nucleotide polymorphism
(SNP) that interfered with primer binding in the PCR assay; The problem may
be overcome by using alternate primers. A number of other groups have conf
irmed the finding but in a much smaller number of subjects, whereas others
found that their assays were not affected by the SNP, The use of the HFE ge
notype assay as the sole diagnostic criterion for hereditary hemochromatosi
s is not recommended. The genotype assay should be used as an adjunct to th
e established methods of demonstrating iron overload and be viewed as a pre
dictor of either the presence of iron overload or the subsequent developmen
t of iron overload during an individual's lifetime.