Clinical criteria versus DNA diagnosis in heterozygous familial hypercholesterolemia: Is molecular diagnosis superior to clinical diagnosis?

Abstract

More than half of all deaths in Western society are related to arteriosclerotic cardiovascular diseases. Approximately 5% of coronary artery disease (CAD) before the age of 55 years is attributable to familial hypercholesterolemia (FH), an autosomal-dominant disease.1 In contrast to population hypercholesterolemia, FH typically leads to a twice-normal LDL cholesterol level for age and sex and to heart attacks in early middle age. The frequency of FH is estimated to be 1 in 500, roughly half a million in the United States and >10 million persons worldwide. FH is also a very heterogeneous disease; worldwide, at least 300 mutations involving several genes divide the clinical disease into two major entities, namely, LDL receptor defects and apoB-100 defects (see Day and Humphries at the World Wide Web site http://www.ucl.ac.uk\/fh for up-to-date information). However, the number of mutations within certain populations varies, due to genetic drift, founder effects, and consanguineous marriages. In the apoB gene, the arginine 3500 to glutamine mutation is also common and affects about one in 600 people.2 This mutation seems to be of central European origin and could not be identified in other Europeans, such as Finns and Russian. Traditionally, the diagnosis of FH is based on clinical findings, an autosomal-dominant family history pattern of early CAD, and elevated LDL cholesterol levels. In some cases, cholesterol deposits (“xanthomata”) in the skin and tendons suggest the diagnosis. However, phenotypes overlap and family studies are complicated to perform. A genetic test …