| Title: | Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy |
| Journal: | Nature Cardiovascular Research |
| Published: | 1 Feb 2022 |
| DOI: | https://doi.org/10.1038/s44161-022-00018-8 |
| URL: | https://www.nature.com/articles/s44161-022-00018-8.pdf |
| Citations: | 30 (24 in last 2 years) as of 8 Aug 2024 |
Publication 12575
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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.</p>
86 Authors
- Nadine Spielmann
- Gregor Miller
- Tudor I. Oprea
- Chih-Wei Hsu
- Gisela Fobo
- Goar Frishman
- Corinna Montrone
- Hamed Haseli Mashhadi
- Jeremy Mason
- Violeta Munoz Fuentes
- Stefanie Leuchtenberger
- Andreas Ruepp
- Matias Wagner
- Dominik S. Westphal
- Cordula Wolf
- Agnes Görlach
- Adrián Sanz-Moreno
- Yi-Li Cho
- Raffaele Teperino
- Stefan Brandmaier
- Sapna Sharma
- Isabella Rikarda Galter
- Manuela A. Östereicher
- Lilly Zapf
- Philipp Mayer-Kuckuk
- Jan Rozman
- Lydia Teboul
- Rosie K. A. Bunton-Stasyshyn
- Heather Cater
- Michelle Stewart
- Skevoulla Christou
- Henrik Westerberg
- Amelia M. Willett
- Janine M. Wotton
- Willson B. Roper
- Audrey E. Christiansen
- Christopher S. Ward
- Jason D. Heaney
- Corey L. Reynolds
- Jan Prochazka
- Lynette Bower
- David Clary
- Mohammed Selloum
- Ghina Bou About
- Olivia Wendling
- Hugues Jacobs
- Sophie Leblanc
- Hamid Meziane
- Tania Sorg
- Enrique Audain
- Arthur Gilly
- Nigel W. Rayner
- Marc-Phillip Hitz
- Eleftheria Zeggini
- Eckhard Wolf
- Radislav Sedlacek
- Steven A. Murray
- Karen L. Svenson
- Robert E. Braun
- Jaqueline K. White
- Lois Kelsey
- Xiang Gao
- Toshihiko Shiroishi
- Ying Xu
- Je Kyung Seong
- Fabio Mammano
- Glauco P. Tocchini-Valentini
- Arthur L. Beaudet
- Terrence F. Meehan
- Helen Parkinson
- Damian Smedley
- Ann-Marie Mallon
- Sara E. Wells
- Harald Grallert
- Wolfgang Wurst
- Susan Marschall
- Helmut Fuchs
- Steve D. M. Brown
- Ann M. Flenniken
- Lauryl M. J. Nutter
- Colin McKerlie
- Yann Herault
- K. C. Kent Lloyd
- Mary E. Dickinson
- Valerie Gailus-Durner
- Martin Hrabe de Angelis
Enabling scientific discoveries that improve human health