Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project
| Autor: | Devaki Nair, R Everdale, Y. Lolin, K Patel, G. Wood, S.G. Hadfield, R. Whittall, M. Barbir, E Hughes, Sarah J. Egan, J.A. Cooper, D Wang, Gail Norbury, Steve E. Humphries, Andrew M. Taylor, Matthew J. Farrer, S Fairgrieve, R D G Neely, J L Jones |
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| Rok vydání: | 2009 |
| Předmět: |
Genetics
Proband medicine.medical_specialty Apolipoprotein B biology PCSK9 Hypercholesterolemia Pilot Projects Single-strand conformation polymorphism Gastroenterology United Kingdom Denaturing high performance liquid chromatography Receptors LDL Internal medicine Mutation Mutation (genetic algorithm) biology.protein Mutation testing medicine Humans Genetic Testing Multiplex ligation-dependent probe amplification Genetics (clinical) Apolipoproteins B |
| Zdroj: | Clinical Genetics. 77:572-580 |
| ISSN: | 0009-9163 |
| DOI: | 10.1111/j.1399-0004.2009.01356.x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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