ArticleGenome medicine2020
Systems genetics analysis identifies calcium-signaling defects as novel cause of congenital heart disease.
Article in Genome medicine, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 27 citations in OpenAlex.
- TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development.PLoS biology · 2026Article
- Assessing the contribution of rare variants to congenital heart disease through a large-scale case-control exome study.NPJ genomic medicine · 2026Article
- Single-Cell Multi-Omics Reveal Gene Regulatory Mechanisms Underlying Cardiac Embryonic Development.Genes · 2026Review
- The modulation of calcium and chloride channels induces cardiomyocytes from human pluripotent stem cells.International journal of biological sciences · 2025Article
- Variants of unknown significance in fetal heart malformations: distribution and impact on prenatal decision-making.Frontiers in pediatrics · 2025Article
- Rare homozygous cilia gene variants identified in consanguineous congenital heart disease patients.Human genetics · 2024Article
- Human Genetics of Ventricular Septal Defect.Advances in experimental medicine and biology · 2024Article
- Epigenomic signature of major congenital heart defects in newborns with Down syndrome.Human genomics · 2023Article
- A Multicenter Analysis of Abnormal Chromosomal Microarray Findings in Congenital Heart Disease.Journal of the American Heart Association · 2023Article
- Epigenomic signature of major congenital heart defects in newborns with Down syndrome.medRxiv : the preprint server for health sciences · 2023Article
- Systems analysis of de novo mutations in congenital heart diseases identified a protein network in the hypoplastic left heart syndrome.Cell systems · 2022Article
- Physiological roles of mammalian transmembrane adenylyl cyclase isoforms.Physiological reviews · 2022Review
- Article
- SOX7 loss-of-function variation as a cause of familial congenital heart disease.American journal of translational research · 2022Article
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- Review
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Authors and funding
18 authors at 8 institutions in 5 countries.
Funding
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.
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