ArticlePLoS genetics2016
De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects.
Article in PLoS genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers, 2 of them syntheses that pooled it.
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Who cites it
72 citing papers in PubMed, 2 syntheses or guidelines pooled it, 124 citations in OpenAlex.
- Highlighting cardiovascular manifestations of kleefstra syndrome: literature review and clinical insights.BMC cardiovascular disorders · 2025Pooled it
- Meta-analysis of cardiomyopathy-associated variants in troponin genes identifies loci and intragenic hot spots that are associated with worse clinical outcomes.Journal of molecular and cellular cardiology · 2020Pooled it
- Hi-C informed kernel association test for integrating 3D genome structure into variant-set analysis.Briefings in bioinformatics · 2026Article
- The oligogenic inheritance test GCOD detects risk genes and their interactions in congenital heart defects.Genome research · 2026Article
- A machine learning classifier to identify and prioritise genes associated with murine cardiac development.PLoS genetics · 2026Article
- Clinically Actionable Hypertrophic Cardiomyopathy Genes in South Asian Indian Patients.Journal of the American Heart Association · 2025Article
- Hi-C informed kernel association test: integrating 3-dimensional genome structure into variant-set association for whole-genome sequencing data.bioRxiv : the preprint server for biology · 2025Article
- Identifying Pathogenic Variants in Vietnamese Children with Functional Single Ventricle Based on Whole-Exome Sequencing.Diagnostics (Basel, Switzerland) · 2025Article
- A systems genetics approach identifies roles for proteasome factors in heart development and congenital heart defects.PLoS genetics · 2025Article
- Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants.Journal of the American Heart Association · 2025Article
- Identification of candidate cardiomyopathy modifier genes through genome sequencing and RNA profiling.Frontiers in cardiovascular medicine · 2025Article
- Review
- Maternal Blood Group Is a Possible Predictor for Developing Congenital Heart Disease in Turkish Children with Down's Syndrome.Journal of pediatric genetics · 2024Article
- Article
- Beyond genomic studies of congenital heart defects through systematic modelling and phenotyping.Disease models & mechanisms · 2024Article
- ENU-based dominant genetic screen identifies contractile and neuronal gene mutations in congenital heart disease.Genome medicine · 2024Article
- Distinct roles of COMPASS subunits to Drosophila heart development.Biology open · 2024Article
- Arrhythmias including atrial fibrillation and congenital heart disease in Kleefstra syndrome: a possible epigenetic link.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2023Article
- CRISPR-based knockout and base editing confirm the role of MYRF in heart development and congenital heart disease.Disease models & mechanisms · 2023Article
- H3K36 Di-Methylation Marks, Mediated by Ash1 in Complex with Caf1-55 and MRG15, Are Required duringJournal of cardiovascular development and disease · 2023Article
12 more citing papers are in PubMed but not listed here.
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Authors and funding
28 authors at 12 institutions in 3 countries.
Funding
Abstract
Congenital heart disease (CHD) has a complex genetic etiology, and recent studies suggest that high penetrance de novo mutations may account for only a small fraction of disease. In a multi-institutional cohort surveyed by exome sequencing, combining analysis of 987 individuals (discovery cohort of 59 affected trios and 59 control trios, and a replication cohort of 100 affected singletons and 533 unaffected singletons) we observe variation at novel and known loci related to a specific cardiac malformation the atrioventricular septal defect (AVSD). In a primary analysis, by combining developmental coexpression networks with inheritance modeling, we identify a de novo mutation in the DNA binding domain of NR1D2 (p.R175W). We show that p.R175W changes the transcriptional activity of Nr1d2 using an in vitro transactivation model in HUVEC cells. Finally, we demonstrate previously unrecognized cardiovascular malformations in the Nr1d2tm1-Dgen knockout mouse. In secondary analyses we map genetic variation to protein-interaction networks suggesting a role for two collagen genes in AVSD, which we corroborate by burden testing in a second replication cohort of 100 AVSDs and 533 controls (p = 8.37e-08). Finally, we apply a rare-disease inheritance model to identify variation in genes previously associated with CHD (ZFPM2, NSD1, NOTCH1, VCAN, and MYH6), cardiac malformations in mouse models (ADAM17, CHRD, IFT140, PTPRJ, RYR1 and ATE1), and hypomorphic alleles of genes causing syndromic CHD (EHMT1, SRCAP, BBS2, NOTCH2, and KMT2D) in 14 of 59 trios, greatly exceeding variation in control trios without CHD (p = 9.60e-06). In total, 32% of trios carried at least one putatively disease-associated variant across 19 loci,suggesting that inherited and de novo variation across a heterogeneous group of loci may contribute to disease risk.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.