Abstract
BackgroundCongenital 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.MethodsWe 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.ResultsWe 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.ConclusionsThe study identifies abnormal calcium signaling as a novel pathophysiological mechanism in human CHD and confirms the complex genetic architecture underlying CHD.
Highlights
Congenital heart disease (CHD) occurs in almost 1% of newborn children and is considered a multifactorial disorder
In the majority of familial cases, the unidentified pathogenic variants may be explained by a “burden of genetic variation” model, which hypothesizes that CHD may occur if the developing embryo is exposed to a certain burden of rare and common genetic variants, possibly in combination with epigenetic, environmental, or stochastic effects [4]
Utilizing a systems biology approach, we discovered recurrent mutation of genes involved in calcium signaling
Summary
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. Most patients survive until adulthood, and the number of adults with CHD has increased to above 3 million in Europe and the USA alone [2]. These patients are challenged by serious cardiovascular complications, which require specialized care, and their children have significantly increased CHD risk [3]. The specific cause of CHD is unknown for most patients, genetic factors contribute significantly to the etiology (reviewed in [3, 4]). In the majority of familial cases, the unidentified pathogenic variants may be explained by a “burden of genetic variation” model, which hypothesizes that CHD may occur if the developing embryo is exposed to a certain burden of rare and common genetic variants, possibly in combination with epigenetic, environmental, or stochastic effects [4]
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