Abstract
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.
Funder
The Danish National Advanced Technology Foundation
Novo Nordisk Fonden
Aase og Ejnar Danielsens Fond
Børnehjertefonden
The Danish Heart Association
Dagmar Marshalls Fond
Arvid Nilssons Fond
Oda og Hans Svenningsens Fond
Fonden til Lægevidenskabens Fremme
Lundbeckfonden
Villum Fonden
Van de Werf fund for cardiovascular research
clinical research fund of UZ Leuven
FWO
Eva og Henry Frænkels Mindefond
Kong Christian den Tiendes Fond
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics,Molecular Biology,Molecular Medicine
Cited by
13 articles.
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