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Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes.
Walsh, Roddy; Buchan, Rachel; Wilk, Alicja; John, Shibu; Felkin, Leanne E; Thomson, Kate L; Chiaw, Tang Hak; Loong, Calvin Chin Woon; Pua, Chee Jian; Raphael, Claire; Prasad, Sanjay; Barton, Paul J; Funke, Birgit; Watkins, Hugh; Ware, James S; Cook, Stuart A.
  • Walsh R; NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, Sydney Street, London SW3 6NP, UK.
  • Buchan R; Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK.
  • Wilk A; NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, Sydney Street, London SW3 6NP, UK.
  • John S; Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK.
  • Felkin LE; NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, Sydney Street, London SW3 6NP, UK.
  • Thomson KL; Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK.
  • Chiaw TH; NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, Sydney Street, London SW3 6NP, UK.
  • Loong CCW; Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK.
  • Pua CJ; NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, Sydney Street, London SW3 6NP, UK.
  • Raphael C; Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK.
  • Prasad S; Oxford Medical Genetics Laboratory, Oxford University Hospitals NHS Foundation Trust, The Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK.
  • Barton PJ; Radcliffe Department of Medicine, Level 6, West Wing, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK.
  • Funke B; National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, 169609 Singapore, Singapore.
  • Watkins H; National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, 169609 Singapore, Singapore.
  • Ware JS; National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, 169609 Singapore, Singapore.
  • Cook SA; NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK.
Eur Heart J ; 38(46): 3461-3468, 2017 Dec 07.
Article en En | MEDLINE | ID: mdl-28082330
ABSTRACT

AIM:

Hypertrophic cardiomyopathy (HCM) exhibits genetic heterogeneity that is dominated by variation in eight sarcomeric genes. Genetic variation in a large number of non-sarcomeric genes has also been implicated in HCM but not formally assessed. Here we used very large case and control cohorts to determine the extent to which variation in non-sarcomeric genes contributes to HCM. METHODS AND

RESULTS:

We sequenced known and putative HCM genes in a new large prospective HCM cohort (n = 804) and analysed data alongside the largest published series of clinically genotyped HCM patients (n = 6179), previously published HCM cohorts and reference population samples from the exome aggregation consortium (ExAC, n = 60 706) to assess variation in 31 genes implicated in HCM. We found no significant excess of rare (minor allele frequency < 110 000 in ExAC) protein-altering variants over controls for most genes tested and conclude that novel variants in these genes are rarely interpretable, even for genes with previous evidence of co-segregation (e.g. ACTN2). To provide an aid for variant interpretation, we integrated HCM gene sequence data with aggregated pedigree and functional data and suggest a means of assessing gene pathogenicity in HCM using this evidence.

CONCLUSION:

We show that genetic variation in the majority of non-sarcomeric genes implicated in HCM is not associated with the condition, reinforce the fact that the sarcomeric gene variation is the primary cause of HCM known to date and underscore that the aetiology of HCM is unknown in the majority of patients.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Sarcómeros / Cardiomiopatía Hipertrófica / Genes Tipo de estudio: Observational_studies / Risk_factors_studies Límite: Female / Humans / Male Idioma: En Año: 2017 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Sarcómeros / Cardiomiopatía Hipertrófica / Genes Tipo de estudio: Observational_studies / Risk_factors_studies Límite: Female / Humans / Male Idioma: En Año: 2017 Tipo del documento: Article