Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project.
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.
Great Ormond Street Hospital for Children, London, UK.
A
A
Taylor
D
D
Wang
K
K
Patel
R
R
Whittall
G
G
Wood
M
M
Farrer
R D G
RD
Neely
S
S
Fairgrieve
D
D
Nair
M
M
Barbir
J L
JL
Jones
S
S
Egan
R
R
Everdale
Y
Y
Lolin
E
E
Hughes
J A
JA
Cooper
S G
SG
Hadfield
G
G
Norbury
S E
SE
Humphries
D001055:Apolipoproteins B / Q000235:genetics; D005820:Genetic Testing; D006801:Humans; D006937:Hypercholesterolemia / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D010865:Pilot Projects; D011973:Receptors, LDL / Q000235:genetics; D006113:United Kingdom
D001055:Apolipoproteins B; D011973:Receptors, LDL