Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project

Abstract

Cascade testing using DNA-mutation information is now recommended in the UK for patients with familial hypercholesterolaemia (FH). We compared the detection rate and mutation spectrum in FH patients with a clinical diagnosis of definite (DFH) and possible (PFH) FH. Six hundred and thirty-five probands from six UK centres were tested for 18 low-density lipoprotein receptor gene (LDLR) mutations, APOB p.Arg3527Gln and PCSK9 p.Asp374Tyr using a commercial amplification refractory mutation system (ARMS) kit. Samples with no mutation detected were screened in all exons by single strand conformation polymorphism analysis (SSCP)/denaturing high performance liquid chromatography electrophoresis (dHPLC)/direct-sequencing, followed by multiplex ligation-dependent probe amplification (MLPA) to detect deletions and duplications in LDLR.The detection rate was significantly higher in the 190 DFH patients compared to the 394 PFH patients (56.3% and 28.4%, p > 0.00001). Fifty-one patients had inadequate information to determine PFH/DFH status, and in this group the detection rate was similar to the PFH group (25.5%, p = 0.63 vs PFH). Overall, 232 patients had detected mutations (107 different; 6.9% not previously reported). The ARMS kit detected 100 (44%) and the MLPA kit 11 (4.7%). Twenty-eight (12%) of the patients had the APOB p.Arg3527Gln and four (1.7%) had the PCSK9 p.Asp374Tyr mutation. Of the 296 relatives tested from 100 families, a mutation was identified in 56.1%. In 31 patients of Indian/Asian origin 10 mutations (two previously unreported) were identified. The utility of the ARMS kit was confirmed, but sequencing is still required in a comprehensive diagnostic service for FH. Even in subjects with a low clinical suspicion of FH, and in those of Indian origin, mutation testing has an acceptable detection rate.

Characteristics and Vascular Complications of Familial Hypercholesterolemia in Korea

“…It is well known that only some patients with clinically diagnosed FH have pathogenic mutations in LDLR, APOB, or PCSK9 10,12,17) . In the KSLA-supported study, the largest Korean FH study to date, putative mutations in these 3 genes were found in 32% of the enrolled patients.…”

Coronary heart disease mortality in treated Familial Hypercholesterolaemia: Update of the UK Simon Broome FH Register

“…Overall, CHD risk was independently related to age, sex, smoking, previous CHD and total cholesterol, but after adjustment for these variables the higher CHD risk in DFH compared to PFH patients was no longer statistically significant. Since we know that up to 80% of those with clinical DFH will carry an FH-causing mutation [13,14] while probably 80% of those with clinical PFH have a polygenic aetiology of their hyperlipidaemia [15,16], this confirms reports that carriage of an FH mutation is associated with greater CHD risk [4]. This higher risk is supported by the observation that, even though LDL-C levels were similar, compared to those with polygenic hypercholesterolaemia, those with an FH-causing mutation have greater carotid intimalmedial thickening and coronary calcification [24].…”

“…While in DFH patients an FH-causing mutation can be identified in about 80% of subjects, this falls to only 20e30% in PFH patients [13]. In the majority of patients with a clinical diagnosis of FH but with no detectable mutation in any of the three common genes [14], it is now widely accepted that there is a polygenic cause for their raised LDL-C level [15,16].…”

Angeborene Störungen im Lipoproteinstoffwechsel

“…Bei 93 % der Betroffenen liegen die verantwortlichen Mutationen im Gen des LDL-Rezeptors (LDL-R; [27, 52, 54]), bei 5 % findet man Mutationen der rezeptorbindenden Domäne des Apolipoproteins B-100 (APOB-100; [45,47]) und bei 2 % "Gain-of-function"-Mutationen von PCSK9 ("proprotein convertase subtilisin/kexin type 9"; [1,36,68,[71][72][73]). PCSK9 ist eine Protease, die am zellulären Abbau von LDLR beteiligt ist.…”