Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing: a population-based study

BMC Medical Genetics

Timothy J Aitman⁵  Generation Scotland³  Andrew D Morris²  David J Porteous⁵  Anna F Dominiczak⁴  Blair H Smith²  Anne K Soutar¹  Laurence Game¹  Jennifer Biggs¹  Shona M Kerr⁵  Archie Campbell⁵  Ellen RA Thomas¹  Jana Vandrovcova¹  Penny J Norsworthy¹ 

[1] MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, UK;Medical Research Institute, University of Dundee, Dundee, UK;Generation Scotland, A Collaboration between the University Medical Schools and NHS in Aberdeen, Dundee, Edinburgh and Glasgow, UK;College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK;Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK

关键词: Generation Scotland;    Primary care;    Next-generation sequencing;    Molecular diagnostic testing;    LDLR;    Total cholesterol;    Familial hypercholesterolaemia;   

Others  :  1091390
DOI  :  10.1186/1471-2350-15-70

 received in 2014-03-04, accepted in 2014-05-28,  发布年份 2014

【 摘 要 】

Background

Familial hypercholesterolaemia (FH) is a common Mendelian condition which, untreated, results in premature coronary heart disease. An estimated 88% of FH cases are undiagnosed in the UK. We previously validated a method for FH mutation detection in a lipid clinic population using next generation sequencing (NGS), but this did not address the challenge of identifying index cases in primary care where most undiagnosed patients receive healthcare. Here, we evaluate the targeted use of NGS as a potential route to diagnosis of FH in a primary care population subset selected for hypercholesterolaemia.

Methods

We used microfluidics-based PCR amplification coupled with NGS and multiplex ligation-dependent probe amplification (MLPA) to detect mutations in LDLR, APOB and PCSK9 in three phenotypic groups within the Generation Scotland: Scottish Family Health Study including 193 individuals with high total cholesterol, 232 with moderately high total cholesterol despite cholesterol-lowering therapy, and 192 normocholesterolaemic controls.

Results

Pathogenic mutations were found in 2.1% of hypercholesterolaemic individuals, in 2.2% of subjects on cholesterol-lowering therapy and in 42% of their available first-degree relatives. In addition, variants of uncertain clinical significance (VUCS) were detected in 1.4% of the hypercholesterolaemic and cholesterol-lowering therapy groups. No pathogenic variants or VUCS were detected in controls.

Conclusions

We demonstrated that population-based genetic testing using these protocols is able to deliver definitive molecular diagnoses of FH in individuals with high cholesterol or on cholesterol-lowering therapy. The lower cost and labour associated with NGS-based testing may increase the attractiveness of a population-based approach to FH detection compared to genetic testing with conventional sequencing. This could provide one route to increasing the present low percentage of FH cases with a genetic diagnosis.

【 授权许可】

   
2014 Norsworthy et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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