title: Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes.
abstract: OBJECTIVE
  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.
  
  
  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 < 1:10 000 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, Sydney Street, London SW3 6NP, UK.|Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK.
authors.forename: Roddy
authors.initials: R
authors.lastname: Walsh
authors.affiliation: NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, Sydney Street, London SW3 6NP, UK.|Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Buchan
authors.affiliation: NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, Sydney Street, London SW3 6NP, UK.|Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK.
authors.forename: Alicja
authors.initials: A
authors.lastname: Wilk
authors.affiliation: NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, Sydney Street, London SW3 6NP, UK.|Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK.
authors.forename: Shibu
authors.initials: S
authors.lastname: John
authors.affiliation: NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, Sydney Street, London SW3 6NP, UK.|Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK.
authors.forename: Leanne E
authors.initials: LE
authors.lastname: Felkin
authors.affiliation: Oxford Medical Genetics Laboratory, Oxford University Hospitals NHS Foundation Trust, The Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK.|Radcliffe Department of Medicine, Level 6, West Wing, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Thomson
authors.affiliation: National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, 169609 Singapore, Singapore.
authors.forename: Tang Hak
authors.initials: TH
authors.lastname: Chiaw
authors.affiliation: National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, 169609 Singapore, Singapore.
authors.forename: Calvin Chin Woon
authors.initials: CCW
authors.lastname: Loong
authors.affiliation: National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, 169609 Singapore, Singapore.
authors.forename: Chee Jian
authors.initials: CJ
authors.lastname: Pua
authors.affiliation: NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Raphael
authors.affiliation: NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Prasad
authors.affiliation: NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, Sydney Street, London SW3 6NP, UK.|Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Barton
authors.affiliation: Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, 65 Lansdowne Street, Cambridge, MA 02139, USA.|Department of Pathology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.
authors.forename: Birgit
authors.initials: B
authors.lastname: Funke
authors.affiliation: Radcliffe Department of Medicine, Level 6, West Wing, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK.|The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Hugh
authors.initials: H
authors.lastname: Watkins
authors.affiliation: Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK.|Cardiovascular Magnetic Resonance Imaging and Genetics, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: James S
authors.initials: JS
authors.lastname: Ware
authors.affiliation: Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK.|National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, 169609 Singapore, Singapore.|Cardiovascular Magnetic Resonance Imaging and Genetics, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.|Division of Cardiovascular & Metabolic Disorders, Duke-National University of Singapore, 8 College Road, 169857 Singapore, Singapore.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Cook
mesh_terms: D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005796:Genes / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D011446:Prospective Studies; D012518:Sarcomeres / Q000235:genetics*
keywords: ExAC; HCM genetics; Hypertrophic cardiomyopathy; Mendelian genetics; Rare genetic variation