TY - JOUR
T1 - Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies
AU - Mazzarotto, Francesco
AU - Hawley, Megan H.
AU - Beltrami, Matteo
AU - Beekman, Leander
AU - de Marvao, Antonio
AU - McGurk, Kathryn A.
AU - Statton, Ben
AU - Boschi, Beatrice
AU - Girolami, Francesca
AU - Roberts, Angharad M.
AU - Lodder, Elisabeth M.
AU - Allouba, Mona
AU - Romeih, Soha
AU - Aguib, Yasmine
AU - Baksi, A. John
AU - Pantazis, Antonis
AU - Prasad, Sanjay K.
AU - Cerbai, Elisabetta
AU - Yacoub, Magdi H.
AU - O’Regan, Declan P.
AU - Cook, Stuart A.
AU - Ware, James S.
AU - Funke, Birgit
AU - Olivotto, Iacopo
AU - Bezzina, Connie R.
AU - Barton, Paul J. R.
AU - Walsh, Roddy
N1 - Funding Information: The authors acknowledge the following support: Amsterdam Cardiovascular Sciences fellowship (R.W.), University of Florence postdoctoral research fellowship (F.M.), Dutch Heart Foundation CVON-2018-30-Predict2 (C.R.B.) and CVON-2017-15-RESCUED (E.M. L.), Netherlands Organization for Scientific Research VICI fellowship 016.150.610 (C.R. B.) and VIDI fellowship 91718361 (E.M.L.), Fondation Leducq 17-CVD-02 (C.R.B.) and 11-CVD-01 (S.A.C.), Italian Ministry of Health RF-2013-02356787 (I.O.), EU Horizon 2020 framework program GA777204-SILICOFCM (I.O.), British Heart Foundation RE/18/4/ 34215 (K.A.M.), SP/10/10/28431 (S.A.C.) and NH/17/1/32725,RG/19/6/34387 (D.P.O.), Wellcome Trust 107469/Z/15/Z (J.S.W.), NIHR Imperial BRC (A.d.M./D.P.O.), Royal Brompton BRU (J.S.W./P.J.R.B./S.A.C.), Medical Research Council (J.S.W./S.A.C./A.d.M./D. P.O.), Academy of Medical Sciences SGL015/1006 (A.d.M.), Mason Medical Research Trust (A.d.M.), Health Innovation Challenge Fund award HICF-R6-373 (Wellcome Trust/ Department of Health, UK) (J.S.W./P.J.R.B./S.A.C.). The views expressed here are those of the author(s) and not necessarily those of the NHS, NIHR, or Department of Health. This research was conducted using the UK Biobank Resource under application number 47602 (J.S.W.). Publisher Copyright: © 2020, The Author(s).
PY - 2021/5
Y1 - 2021/5
N2 - Purpose: To characterize the genetic architecture of left ventricular noncompaction (LVNC) and investigate the extent to which it may represent a distinct pathology or a secondary phenotype associated with other cardiac diseases. Methods: We performed rare variant association analysis with 840 LVNC cases and 125,748 gnomAD population controls, and compared results to similar analyses on dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Results: We observed substantial genetic overlap indicating that LVNC often represents a phenotypic variation of DCM or HCM. In contrast, truncating variants in MYH7, ACTN2, and PRDM16 were uniquely associated with LVNC and may reflect a distinct LVNC etiology. In particular, MYH7 truncating variants (MYH7tv), generally considered nonpathogenic for cardiomyopathies, were 20-fold enriched in LVNC cases over controls. MYH7tv heterozygotes identified in the UK Biobank and healthy volunteer cohorts also displayed significantly greater noncompaction compared with matched controls. RYR2 exon deletions and HCN4 transmembrane variants were also enriched in LVNC, supporting prior reports of association with arrhythmogenic LVNC phenotypes. Conclusion: LVNC is characterized by substantial genetic overlap with DCM/HCM but is also associated with distinct noncompaction and arrhythmia etiologies. These results will enable enhanced application of LVNC genetic testing and help to distinguish pathological from physiological noncompaction.
AB - Purpose: To characterize the genetic architecture of left ventricular noncompaction (LVNC) and investigate the extent to which it may represent a distinct pathology or a secondary phenotype associated with other cardiac diseases. Methods: We performed rare variant association analysis with 840 LVNC cases and 125,748 gnomAD population controls, and compared results to similar analyses on dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Results: We observed substantial genetic overlap indicating that LVNC often represents a phenotypic variation of DCM or HCM. In contrast, truncating variants in MYH7, ACTN2, and PRDM16 were uniquely associated with LVNC and may reflect a distinct LVNC etiology. In particular, MYH7 truncating variants (MYH7tv), generally considered nonpathogenic for cardiomyopathies, were 20-fold enriched in LVNC cases over controls. MYH7tv heterozygotes identified in the UK Biobank and healthy volunteer cohorts also displayed significantly greater noncompaction compared with matched controls. RYR2 exon deletions and HCN4 transmembrane variants were also enriched in LVNC, supporting prior reports of association with arrhythmogenic LVNC phenotypes. Conclusion: LVNC is characterized by substantial genetic overlap with DCM/HCM but is also associated with distinct noncompaction and arrhythmia etiologies. These results will enable enhanced application of LVNC genetic testing and help to distinguish pathological from physiological noncompaction.
UR - http://www.scopus.com/inward/record.url?scp=85099827329&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41436-020-01049-x
DO - https://doi.org/10.1038/s41436-020-01049-x
M3 - Article
C2 - 33500567
SN - 1098-3600
VL - 23
SP - 856
EP - 864
JO - Genetics in medicine
JF - Genetics in medicine
IS - 5
ER -