Penetrance of 845G→A (C282Y) HFE hereditary haemochromatosis mutation in the USA

Background There has been much interest in screening populations for disease-associated mutations. A favoured candidate has been the HFE gene, mutations of which are the most common cause of haemochromatosis in the European population. About five people in 1000 are homozygotes for the 845G-->A mutation, but little is known of how many have mutation-caused clinical manifestations. Methods We screened 41038 individuals attending a health appraisal clinic in the USA for the 845G-->A and 187C-->G HFE mutations, and analysed laboratory data and data on signs and symptoms of haemochromatosis as elicited by questionnaire. Findings The most common symptoms of haemochromatosis, including poor general health, diabetes, arthropathies, arrhythmias, impotence, and skin pigmentation were no more prevalent among the 152 identified homozygotes than among the controls. The age distribution of homozygotes and compound heterozygotes did not differ significantly from that of controls: there was no measurable loss of such individuals from the population during ageing. However, there was a significantly increased prevalence of a history of hepatitis or "liver trouble" among homozygotes and in the proportion of homozygotes with increased concentrations of serum aspartate aminotransferase and collagen IV; these changes were not related to iron burden or to age. Only one of the 152 homozygotes had signs and symptoms that would suggest a diagnosis of haemochromatosis. Interpretation The normal age distribution of people with the haemochromatosis genotype, and the lack of symptoms in patients of all ages, indicate that the penetrance of hereditary haemochromatosis is much lower than generally thought. The clinical penetrance of a disorder is an essential consideration in screening for genetic disease; disorders with low penetrance are more expensive candidates for screening than disorders with high penetrance. Our best estimate is that less than 1% of homozygotes develop frank clinical haemochromatosis.