The biochemical and clinical penetrance of individuals diagnosed with genetic haemochromatosis by predictive genetic testing.

Background: HFE-related genetic haemochromatosis (GH) is the commonest inherited genetic disorder in Caucasian populations with approximately one in 180 of individuals in the west of Scotland homozygous for the common C282Y mutation. The clinical diagnosis of GH, however, remains relatively uncommon - suggesting either under diagnosis or low clinical penetrance.

Aim: We aimed to assess the biochemical and clinical penetrance of GH in first-degree relatives of patients with known GH, who subsequently themselves screened positive for the common GH mutations.

Methods: Individuals were identified from two large teaching hospitals in North Glasgow from July 1997 to July 2005 diagnosed with GH after predictive genetic testing after a relative was found to have GH. Details of patient history, biochemistry and known comorbidity at diagnosis and results of related further investigations were collected.

Results: Sixty-three individuals were identified, 31 (49%) of whom were males. Fifty-five individuals (87%) were C282Y homozygous and the remaining eight were compound heterozygotes for C282Y and H63D. All 31 male patients were found to have evidence of iron overload as opposed to 63% of females. Elevated liver enzyme levels were encountered in 15 patients (24%). All except one had evidence of iron overload. Four individuals underwent a liver biopsy, two of whom had hepatic fibrosis. Four patients were found to be diabetic. A full clinical history was obtained from 54 of 63 individuals, 38 (70%) of whom were entirely asymptomatic. Thirteen individuals complained of joint pains and a further nine complained of fatigue.

Conclusion: This study suggests that although biochemical penetrance of GH is high, the clinical penetrance is low.