title: Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.
abstract: The accurate interpretation of variation in Mendelian disease genes has lagged behind data generation as sequencing has become increasingly accessible. Ongoing large sequencing efforts present huge interpretive challenges, but they also provide an invaluable opportunity to characterize the spectrum and importance of rare variation.
  
  
  
  We analyzed sequence data from 7,855 clinical cardiomyopathy cases and 60,706 Exome Aggregation Consortium (ExAC) reference samples to obtain a better understanding of genetic variation in a representative autosomal dominant disorder.
  
  
  
  We found that in some genes previously reported as important causes of a given cardiomyopathy, rare variation is not clinically informative because there is an unacceptably high likelihood of false-positive interpretation. By contrast, in other genes, we find that diagnostic laboratories may be overly conservative when assessing variant pathogenicity.
  
  
  
  We outline improved analytical approaches that evaluate which genes and variant classes are interpretable and propose that these will increase the clinical utility of testing across a range of Mendelian diseases.Genet Med 19 2, 192-203.
authors.affiliation: NIHR Royal Brompton Cardiovascular Biomedical Research Unit, Royal Brompton Hospital and Imperial College London, London, UK.|National Heart and Lung Institute, Imperial College London, UK.
authors.forename: Roddy
authors.identifier: 0000-0001-5092-8825
authors.initials: R
authors.lastname: Walsh
authors.affiliation: Oxford Medical Genetics Laboratory, Oxford University Hospitals NHS Foundation Trust, The Churchill Hospital, Oxford, UK.|Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Kate L
authors.identifier: 0000-0003-2807-3431
authors.initials: KL
authors.lastname: Thomson
authors.affiliation: NIHR Royal Brompton Cardiovascular Biomedical Research Unit, Royal Brompton Hospital and Imperial College London, London, UK.|National Heart and Lung Institute, Imperial College London, UK.|MRC Clinical Sciences Centre, Imperial College London, UK.
authors.forename: James S
authors.identifier: 0000-0002-6110-5880
authors.initials: JS
authors.lastname: Ware
authors.affiliation: Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, Massachusetts, USA.|Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Birgit H
authors.identifier: 0000-0001-6643-3640
authors.initials: BH
authors.lastname: Funke
authors.affiliation: Oxford Medical Genetics Laboratory, Oxford University Hospitals NHS Foundation Trust, The Churchill Hospital, Oxford, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Woodley
authors.affiliation: Oxford Medical Genetics Laboratory, Oxford University Hospitals NHS Foundation Trust, The Churchill Hospital, Oxford, UK.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: McGuire
authors.affiliation: NIHR Royal Brompton Cardiovascular Biomedical Research Unit, Royal Brompton Hospital and Imperial College London, London, UK.|National Heart and Lung Institute, Imperial College London, UK.
authors.forename: Francesco
authors.identifier: 0000-0002-6159-9980
authors.initials: F
authors.lastname: Mazzarotto
authors.affiliation: Department of Clinical Genetics, Oxford University Hospitals NHS Foundation Trust, The Churchill Hospital, Oxford, UK.
authors.forename: Edward
authors.initials: E
authors.lastname: Blair
authors.affiliation: Oxford Medical Genetics Laboratory, Oxford University Hospitals NHS Foundation Trust, The Churchill Hospital, Oxford, UK.
authors.forename: Anneke
authors.initials: A
authors.lastname: Seller
authors.affiliation: Oxford NIHR Biomedical Research Centre, Oxford, UK.|The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Taylor
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA.|Exome Aggregation Consortium (ExAC), Cambridge, Massachusetts, USA.
authors.forename: Eric V
authors.initials: EV
authors.lastname: Minikel
authors.affiliation: Exome Aggregation Consortium (ExAC), Cambridge, Massachusetts, USA.
authors.lastname: Exome Aggregation Consortium
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Exome Aggregation Consortium (ExAC), Cambridge, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: MacArthur
authors.affiliation: Radcliffe Department of Medicine, University of Oxford, Oxford, UK.|The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Martin
authors.identifier: 0000-0003-4564-2165
authors.initials: M
authors.lastname: Farrall
authors.affiliation: National Heart and Lung Institute, Imperial College London, UK.|MRC Clinical Sciences Centre, Imperial College London, UK.|National Heart Centre Singapore, Singapore.|Duke-National University of Singapore, Singapore.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Cook
authors.affiliation: Radcliffe Department of Medicine, University of Oxford, Oxford, UK.|The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Hugh
authors.initials: H
authors.lastname: Watkins
mesh_terms: D009202:Cardiomyopathies / Q000453:epidemiology / Q000235:genetics*; D019295:Computational Biology; D030541:Databases, Genetic; D059472:Exome / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000503:physiopathology; D005820:Genetic Testing; D014644:Genetic Variation; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D000073359:Exome Sequencing