Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project |
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| Authors: | A Taylor D Wang K Patel R Whittall G Wood M Farrer RDG Neely S Fairgrieve D Nair M Barbir JL Jones S Egan R Everdale Y Lolin E Hughes JA Cooper SG Hadfield G Norbury SE Humphries |
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| Institution: | 1. Regional Molecular Genetics Laboratory, Great Ormond Street Hospital for Children, London, UK;2. Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, The Rayne Building, Royal Free and University College London Medical School, London WC1E 6JJ, UK;3. Department of Clinical Chemistry, Royal Free Hospital, London, UK;4. Lipid and Metabolic Clinic, Royal Victoria Infirmary, Newcastle upon Tyne, UK;5. Royal Brompton and Harefield NHS Trust, Middlesex, UK;6. The Royal Bournemouth and Christchurch Hospitals NHS Trust, Castle Lane East, Bournemouth, UK;7. Maidstone and Tunbridge Wells NHS Trust, Kent, UK;8. Sandwell General Hospital, West Bromwich, UK |
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| Abstract: | Taylor A, Wang D, Patel K, Whittall R, Wood G, Farrer M, Neely RDG, Fairgrieve S, Nair D, Barbir M, Jones JL, Egan S, Everdale R, Lolin Y, Hughes E, Cooper JA, Hadfield SG, Norbury G, Humphries SE. 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. |
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| Keywords: | APOB familial hypercholesterolaemia LDLR mutation detection PCSK9 |
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