Systems genetics analysis identifies calcium-signaling defects as novel cause of congenital heart disease
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RESEARCH
Open Access
Systems genetics analysis identifies calcium-signaling defects as novel cause of congenital heart disease Jose M. G. Izarzugaza1†, Sabrina G. Ellesøe2†, Canan Doganli3†, Natasja Spring Ehlers1, Marlene D. Dalgaard1,4, Enrique Audain5, Gregor Dombrowsky5, Karina Banasik2, Alejandro Sifrim6,7, Anna Wilsdon8, Bernard Thienpont7, Jeroen Breckpot7,9, Marc Gewillig10, Competence Network for Congenital Heart Defects, Germany, J. David Brook8, Marc-Phillip Hitz5,6,11, Lars A. Larsen3* and Søren Brunak2*
Abstract Background: Congenital heart disease (CHD) occurs in almost 1% of newborn children and is considered a multifactorial disorder. CHD may segregate in families due to significant contribution of genetic factors in the disease etiology. The aim of the study was to identify pathophysiological mechanisms in families segregating CHD. Methods: We used whole exome sequencing to identify rare genetic variants in ninety consenting participants from 32 Danish families with recurrent CHD. We applied a systems biology approach to identify developmental mechanisms influenced by accumulation of rare variants. We used an independent cohort of 714 CHD cases and 4922 controls for replication and performed functional investigations using zebrafish as in vivo model. Results: We identified 1785 genes, in which rare alleles were shared between affected individuals within a family. These genes were enriched for known cardiac developmental genes, and 218 of these genes were mutated in more than one family. Our analysis revealed a functional cluster, enriched for proteins with a known participation in calcium signaling. Replication in an independent cohort confirmed increased mutation burden of calcium-signaling genes in CHD patients. Functional investigation of zebrafish orthologues of ITPR1, PLCB2, and ADCY2 verified a role in cardiac development and suggests a combinatorial effect of inactivation of these genes. Conclusions: The study identifies abnormal calcium signaling as a novel pathophysiological mechanism in human CHD and confirms the complex genetic architecture underlying CHD. Keywords: Congenital heart disease, Genetics, Whole exome sequencing, Developmental biology, Systems biology, Calcium signaling
* Correspondence: [email protected]; [email protected] † Jose M. G. Izarzugaza, Sabrina G. Ellesøe and Canan Doganli contributed equally to this work. 3 Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3A, DK-2200 Copenhagen, Denmark 2 Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3A, DK-2200 Copenhagen, Denmark Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide
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