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 low-density 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.