A molecular genetic service for diagnosing individuals with familial hypercholesterolaemia (FH) in the United Kingdom

Abstract

A genetic diagnostic service for familial hypercholesterolaemia (FH) has been established over the last 4 years in the Clinical Molecular Genetics Laboratory at Great Ormond Street Hospital for Children NHS Trust (GOSH), London. In total there have been 368 referrals; 227 probands and 141 family members, which have come from a number of lipid clinics and from general practitioners. FH is caused by mutations in the lowdensity lipoprotein receptor gene (LDLR) and these are analysed by SSCP, DNA sequencing and direct assays. The clinically indistinguishable disorder, familial defective apolipoprotein B100 (FDB) is caused by one of three mutations in the apolipoprotein B100 gene (APOB) which are analysed by direct assays. Mutations predicted to be pathogenic were found in 76 probands, 67 in LDLR (23 previously undescribed) and nine in APOB. The mutation detection rate was 53% in paediatric probands, 32% in adults with a`definite' FH diagnosis (tendon xanthoma positive) and 14% in adults with a`possible' FH diagnosis (tendon xanthoma negative). The predicted loss of sensitivity that would result from reducing the number of exons tested has been assessed, and a molecular screening strategy suitable for UK patients is proposed. A similar strategy may be useful for other countries where genetic heterogeneity results in a wide mutation spectrum for FH.

A double heterozygote for familial hypercholesterolaemia and familial defective apolipoprotein B-100

“…The probands were reported to have an unusual phenotype of aggravated hypercholesterolaemia that was complicated with premature coronary arterial disease, although remaining responsive to The case we present in this paper is a double heterozygote for the p.Leu479Pro mutation in the LDLR gene and the common p.Arg3527Gln mutation in the APOB gene. The p.Leu479Pro mutation has been reported previously, 5,14,15 and we have found this mutation in 4/414 ( 1%) of our unrelated patients with detected mutations. Although no functional studies have been performed to confirm its pathogenicity, the p.Leu479Pro mutation occurs in the epidermal growth factor spacer domain of the LDLR protein that is required for acid-dependent dissociation of the receptor from its ligand during recycling, and the mutation may interfere with receptor recycling.…”

Cascade testing in familial hypercholesterolaemia: how should family members be contacted?

“…An unequivocal diagnosis can also be made by the carriage of a pathogenic LDLR mutation, identified by a DNA-based test. 7 The utility of DNA testing remains limited however, as a mutation is currently identified in only 30-60% of clinically identified cases. 8 Despite these potential difficulties, a recent modelling exercise and review have suggested that cascade testing based on lipid or genetic testing in the relatives of known FH probands is cost effective in terms of life-years gained.…”

Genetic Basis of Atherosclerosis: Part II

“…It has proven feasible, even for FH, to design rapid screens that detect a significant fraction of FH mutations. 18 Most of the evidence suggests that common genetic variations will explain a significant fraction of the risk of common diseases, including CHD. 19 The value of genetic testing in cardiology will become clear only when it has been implemented on a large scale.…”