Document Type
Article
Publication Date
2-1-2022
Publication Title
Nat Cardiovasc Res
Keywords
JMG
JAX Source
Nat Cardiovasc Res . 2022 Feb;1(2):157-173.
Volume
1
Issue
2
First Page
157
Last Page
173
ISSN
2731-0590
PMID
39195995
Grant
Hands-on mouse IMPC phenotyping has been carried out by a large number of laboratory staff with superb experimental skills and unsurpassed dedication. We profoundly apologize for not being able to name all these individuals due to space limitations. M.H.d.A., V.G.-D. and H.F. thank all past and present GMC technicians and animal caretakers for their outstanding work. J.D.H. thanks the French National Centre for Scientific Research (CNRS), the French National Institute of Health and Medical Research (INSERM), the University of Strasbourg and all members of the Mouse Clinical Institute (MCI-ICS) for their help and helpful discussions during the project. R.E.B., S.A.M., J.K.W. and K.L.S. thank the members of the Jackson Laboratory Research Animal Facility and Laboratory Informatics Team for their outstanding support. This research was made possible through access to the data and findings generated by the 100KGP. PCGC data were generated by the PCGC under the auspices of the National Heart, Lung, and Blood Institute’s Bench to Bassinet Program (http://www.benchtobassinet.org/). The PCGC program is funded by the National Heart, Lung, and Blood Institute, the National Institutes of Health (NIH), US Department of Health and Human Services through grants U01HL098123, U01HL098147, U01HL098153, U01HL098162, U01HL098163 and U01HL098188. This text was not prepared in collaboration with investigators of the PCGC, has not been reviewed and/or approved by the PCGC and does not necessarily reflect the opinions of PCGC investigators or the NHLBI. The IMPC has been supported by NIH grants U54 HG006364, NIH U42 OD011175 and NIH UM1 OD023221 (K.C.K.L. and C. McKerlie); NIH UM1OD023222 (J.M.W., S.M. and R. Braun); MRC grant code MC_A410 and NIH UM1HG006370 (T.F.M., H. Parkinson, P.F., D.S., J.M., V.M.F. and H.M.); MRC funding for the IMPC (reference 53658) (S.M.W.); Genome Canada and Ontario Genomics (OGI-051) (C. McKerlie and S.D.M.B.). The Czech Centre for Phenogenomics is supported by RVO68378050 and projects LM2015040, LM2018126, CZ.1.05/1.1.00/02.0109, CZ.1.05/2.1.00/19.0395, CZ.02.1.01/0.0/0.0/16_01 3/0001789 and CZ.02.1.01/0.0/0.0/18_046/0015861 (R.S.); the French Agence Nationale de la Recherche grants ANR-10-IDEX-0002-02, ANR-10-LABX-0030-INRT and ANR-10-INBS-07 PHENOMIN (Y.H.); European Union Horizon 2020 (IPAD-MD funding 653961); and the German Center for Diabetes Research (DZD) (M.H.d.A.). The Cambridge-Suda Genomic Research Center of the Soochow University was supported by the National Key R&D program of China (2018YFA0801100)(Y.X.).
Abstract
Clinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural and functional cardiac abnormalities, here we identify 705 lines with cardiac arrhythmia, myocardial hypertrophy and/or ventricular dilation. Among these 705 genes, 486 have not been previously associated with cardiac dysfunction in humans, and some of them represent variants of unknown relevance (VUR). Mice with mutations in Casz1, Dnajc18, Pde4dip, Rnf38 or Tmem161b genes show developmental cardiac structural abnormalities, with their human orthologs being categorized as VUR. Using UK Biobank data, we validate the importance of the DNAJC18 gene for cardiac homeostasis by showing that its loss of function is associated with altered left ventricular systolic function. Our results identify hundreds of previously unappreciated genes with potential function in congenital heart disease and suggest causal function of five VUR in congenital heart disease.
Recommended Citation
Spielmann N,
Miller G,
Oprea T,
Hsu C,
Fobo G,
Frishman G,
Montrone C,
Haseli Mashhadi H,
Mason J,
Munoz Fuentes V,
Leuchtenberger S,
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Westphal D,
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Seong J,
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Tocchini-Valentini G,
Beaudet A,
Meehan T,
Parkinson H,
Smedley D,
Mallon A,
Wells S,
Grallert H,
Wurst W,
Marschall S,
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Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy. Nat Cardiovasc Res . 2022 Feb;1(2):157-173.
Comments
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