Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy

DOI Web Site 被引用文献6件
  • Francesco Mazzarotto
    National Heart and Lung Institute (F.M., U.T., R.J.B., W.M., A.W., N.W., R.G., E.M., T.J.W.D., L.E.F., M.A., P.I.T., E.E., A.J.B., A.M.R., P.J.R.B., S.K.P., S.A.C., J.S.W.), Imperial College London, United Kingdom.
  • Upasana Tayal
    National Heart and Lung Institute (F.M., U.T., R.J.B., W.M., A.W., N.W., R.G., E.M., T.J.W.D., L.E.F., M.A., P.I.T., E.E., A.J.B., A.M.R., P.J.R.B., S.K.P., S.A.C., J.S.W.), Imperial College London, United Kingdom.
  • Rachel J. Buchan
    National Heart and Lung Institute (F.M., U.T., R.J.B., W.M., A.W., N.W., R.G., E.M., T.J.W.D., L.E.F., M.A., P.I.T., E.E., A.J.B., A.M.R., P.J.R.B., S.K.P., S.A.C., J.S.W.), Imperial College London, United Kingdom.
  • William Midwinter
    National Heart and Lung Institute (F.M., U.T., R.J.B., W.M., A.W., N.W., R.G., E.M., T.J.W.D., L.E.F., M.A., P.I.T., E.E., A.J.B., A.M.R., P.J.R.B., S.K.P., S.A.C., J.S.W.), Imperial College London, United Kingdom.
  • Alicja Wilk
    National Heart and Lung Institute (F.M., U.T., R.J.B., W.M., A.W., N.W., R.G., E.M., T.J.W.D., L.E.F., M.A., P.I.T., E.E., A.J.B., A.M.R., P.J.R.B., S.K.P., S.A.C., J.S.W.), Imperial College London, United Kingdom.
  • Nicola Whiffin
    National Heart and Lung Institute (F.M., U.T., R.J.B., W.M., A.W., N.W., R.G., E.M., T.J.W.D., L.E.F., M.A., P.I.T., E.E., A.J.B., A.M.R., P.J.R.B., S.K.P., S.A.C., J.S.W.), Imperial College London, United Kingdom.
  • Risha Govind
    National Heart and Lung Institute (F.M., U.T., R.J.B., W.M., A.W., N.W., R.G., E.M., T.J.W.D., L.E.F., M.A., P.I.T., E.E., A.J.B., A.M.R., P.J.R.B., S.K.P., S.A.C., J.S.W.), Imperial College London, United Kingdom.
  • Erica Mazaika
    National Heart and Lung Institute (F.M., U.T., R.J.B., W.M., A.W., N.W., R.G., E.M., T.J.W.D., L.E.F., M.A., P.I.T., E.E., A.J.B., A.M.R., P.J.R.B., S.K.P., S.A.C., J.S.W.), Imperial College London, United Kingdom.
  • Antonio de Marvao
    Medical Research Council-London Institute of Medical Sciences (N.W. A.d.M., T.J.W.D., D.P.O., S.A.C., J.S.W.), Imperial College London, United Kingdom.
  • Timothy J.W. Dawes
    National Heart and Lung Institute (F.M., U.T., R.J.B., W.M., A.W., N.W., R.G., E.M., T.J.W.D., L.E.F., M.A., P.I.T., E.E., A.J.B., A.M.R., P.J.R.B., S.K.P., S.A.C., J.S.W.), Imperial College London, United Kingdom.
  • Leanne E. Felkin
    National Heart and Lung Institute (F.M., U.T., R.J.B., W.M., A.W., N.W., R.G., E.M., T.J.W.D., L.E.F., M.A., P.I.T., E.E., A.J.B., A.M.R., P.J.R.B., S.K.P., S.A.C., J.S.W.), Imperial College London, United Kingdom.
  • Mian Ahmad
    National Heart and Lung Institute (F.M., U.T., R.J.B., W.M., A.W., N.W., R.G., E.M., T.J.W.D., L.E.F., M.A., P.I.T., E.E., A.J.B., A.M.R., P.J.R.B., S.K.P., S.A.C., J.S.W.), Imperial College London, United Kingdom.
  • Pantazis I. Theotokis
    National Heart and Lung Institute (F.M., U.T., R.J.B., W.M., A.W., N.W., R.G., E.M., T.J.W.D., L.E.F., M.A., P.I.T., E.E., A.J.B., A.M.R., P.J.R.B., S.K.P., S.A.C., J.S.W.), Imperial College London, United Kingdom.
  • Elizabeth Edwards
    National Heart and Lung Institute (F.M., U.T., R.J.B., W.M., A.W., N.W., R.G., E.M., T.J.W.D., L.E.F., M.A., P.I.T., E.E., A.J.B., A.M.R., P.J.R.B., S.K.P., S.A.C., J.S.W.), Imperial College London, United Kingdom.
  • Alexander Y. Ing
    Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA (A.Y.I.).
  • Kate L. Thomson
    Oxford Medical Genetics Laboratory, Oxford University Hospitals National Health Service Foundation Trust, The Churchill Hospital, United Kingdom (K.L.T.).
  • Laura L.H. Chan
    National Heart Centre Singapore (L.L.H.C., D.S., S.A.C.).
  • David Sim
    National Heart Centre Singapore (L.L.H.C., D.S., S.A.C.).
  • A. John Baksi
    National Heart and Lung Institute (F.M., U.T., R.J.B., W.M., A.W., N.W., R.G., E.M., T.J.W.D., L.E.F., M.A., P.I.T., E.E., A.J.B., A.M.R., P.J.R.B., S.K.P., S.A.C., J.S.W.), Imperial College London, United Kingdom.
  • Antonis Pantazis
    Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, United Kingdom (F.M., U.T., R.J.B., W.M., A.W., N.W., R.G., E.M., L.E.F., M.A., P.I.T., E.E., A.J.B., A.A.P., A.M.R., P.J.R.B., S.K.P., S.A.C., J.S.W.).
  • Angharad M. Roberts
    National Heart and Lung Institute (F.M., U.T., R.J.B., W.M., A.W., N.W., R.G., E.M., T.J.W.D., L.E.F., M.A., P.I.T., E.E., A.J.B., A.M.R., P.J.R.B., S.K.P., S.A.C., J.S.W.), Imperial College London, United Kingdom.
  • Hugh Watkins
    Radcliffe Department of Medicine, University of Oxford, United Kingdom (K.L.T., H.W.).
  • Birgit Funke
    Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston (B.F.).
  • Declan P. O’Regan
    Medical Research Council-London Institute of Medical Sciences (N.W. A.d.M., T.J.W.D., D.P.O., S.A.C., J.S.W.), Imperial College London, United Kingdom.
  • Iacopo Olivotto
    Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy (F.M., I.O.).
  • Paul J.R. Barton
    National Heart and Lung Institute (F.M., U.T., R.J.B., W.M., A.W., N.W., R.G., E.M., T.J.W.D., L.E.F., M.A., P.I.T., E.E., A.J.B., A.M.R., P.J.R.B., S.K.P., S.A.C., J.S.W.), Imperial College London, United Kingdom.
  • Sanjay K. Prasad
    National Heart and Lung Institute (F.M., U.T., R.J.B., W.M., A.W., N.W., R.G., E.M., T.J.W.D., L.E.F., M.A., P.I.T., E.E., A.J.B., A.M.R., P.J.R.B., S.K.P., S.A.C., J.S.W.), Imperial College London, United Kingdom.
  • Stuart A. Cook
    National Heart and Lung Institute (F.M., U.T., R.J.B., W.M., A.W., N.W., R.G., E.M., T.J.W.D., L.E.F., M.A., P.I.T., E.E., A.J.B., A.M.R., P.J.R.B., S.K.P., S.A.C., J.S.W.), Imperial College London, United Kingdom.
  • James S. Ware
    National Heart and Lung Institute (F.M., U.T., R.J.B., W.M., A.W., N.W., R.G., E.M., T.J.W.D., L.E.F., M.A., P.I.T., E.E., A.J.B., A.M.R., P.J.R.B., S.K.P., S.A.C., J.S.W.), Imperial College London, United Kingdom.
  • Roddy Walsh
    Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, Amsterdam Universitair Medische Centra, University of Amsterdam, The Netherlands (R.W.).

説明

<jats:sec> <jats:title>Background:</jats:title> <jats:p>Dilated cardiomyopathy (DCM) is genetically heterogeneous, with >100 purported disease genes tested in clinical laboratories. However, many genes were originally identified based on candidate-gene studies that did not adequately account for background population variation. Here we define the frequency of rare variation in 2538 patients with DCM across protein-coding regions of 56 commonly tested genes and compare this to both 912 confirmed healthy controls and a reference population of 60 706 individuals to identify clinically interpretable genes robustly associated with dominant monogenic DCM.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>We used the TruSight Cardio sequencing panel to evaluate the burden of rare variants in 56 putative DCM genes in 1040 patients with DCM and 912 healthy volunteers processed with identical sequencing and bioinformatics pipelines. We further aggregated data from 1498 patients with DCM sequenced in diagnostic laboratories and the Exome Aggregation Consortium database for replication and meta-analysis.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p> Truncating variants in <jats:italic>TTN</jats:italic> and <jats:italic>DSP</jats:italic> were associated with DCM in all comparisons. Variants in <jats:italic>MYH7, LMNA, BAG3, TNNT2, TNNC1, PLN, ACTC1, NEXN, TPM1</jats:italic> , and <jats:italic>VCL</jats:italic> were significantly enriched in specific patient subsets, with the last 2 genes potentially contributing primarily to early-onset forms of DCM. Overall, rare variants in these 12 genes potentially explained 17% of cases in the outpatient clinic cohort representing a broad range of adult patients with DCM and 26% of cases in the diagnostic referral cohort enriched in familial and early-onset DCM. Although the absence of a significant excess in other genes cannot preclude a limited role in disease, such genes have limited diagnostic value because novel variants will be uninterpretable and their diagnostic yield is minimal. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>In the largest sequenced DCM cohort yet described, we observe robust disease association with 12 genes, highlighting their importance in DCM and translating into high interpretability in diagnostic testing. The other genes analyzed here will need to be rigorously evaluated in ongoing curation efforts to determine their validity as Mendelian DCM genes but have limited value in diagnostic testing in DCM at present. This data will contribute to community gene curation efforts and will reduce erroneous and inconclusive findings in diagnostic testing.</jats:p> </jats:sec>

収録刊行物

  • Circulation

    Circulation 141 (5), 387-398, 2020-02-04

    Ovid Technologies (Wolters Kluwer Health)

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