Analysis of the frequency and spectrum of mutations recognised to cause familial hypercholesterolaemia in routine clinical practice in a UK specialist hospital lipid clinic

•54 different LDLR mutations found in a cohort of 272 FH probands.•The cohort was found to be genetically heterogeneous with no specific FH mutation.•Mutation detection rate was highly dependent on pre-treatment TC and TG levels.•No difference in specificity/sensitivity between 2 clinical FH diagnosis approaches.•Inadequate LDL-C reduction marks the need for more effective lipid-lowering therapy.

AimTo determine the frequency and spectrum of mutations causing Familial Hypercholesterolaemia (FH) in patients attending a single UK specialist hospital lipid clinic in Oxford and to identify characteristics contributing to a high mutation detection rate.Methods289 patients (272 probands) were screened sequentially over a 2-year period for mutations in LDLR, APOB and PCSK9 using standard molecular genetic techniques. The Simon Broome (SB) clinical diagnostic criteria were used to classify patients and a separate cohort of 409 FH patients was used for replication.ResultsAn FH-causing mutation was found in 101 unrelated patients (LDLR = 54 different mutations, APOB p.(Arg3527Gln) = 10, PCSK9 p.(Asp374Tyr) = 0). In the 60 SB Definite FH patients the mutation detection rate was 73% while in the 142 with Possible FH the rate was significantly lower (27%, p < 0.0001), but similar (14%, p = 0.06) to the 70 in whom there was insufficient data to make a clinical diagnosis. The mutation detection rate varied significantly (p = 9.83 × 10−5) by untreated total cholesterol (TC) levels (25% in those <8.1 mmol/l and 74% in those >10.0 mmol/l), and by triglyceride levels (20% in those >2.16 mmol/l and 60% in those <1.0 mmol/l (p = 0.0005)), with both effects confirmed in the replication sample (p for trend = 0.0001 and p = 1.8 × 10−6 respectively). There was no difference in the specificity or sensitivity of the SB criteria versus the Dutch Lipid Clinic Network score in identifying mutation carriers (AROC respectively 0.73 and 0.72, p = 0.68).ConclusionsIn this genetically heterogeneous cohort of FH patients the mutation detection rate was significantly dependent on pre-treatment TC and triglyceride levels.