ArticleNature genetics2024
Functional dissection of human cardiac enhancers and noncoding de novo variants in congenital heart disease.
Article in Nature genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers, 1 of them a synthesis that pooled it.
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Who cites it
45 citing papers in PubMed, 1 synthesis or guideline pooled it, 44 citations in OpenAlex.
- Linking Iris Cis-Regulatory Variants to Primary Angle-Closure Glaucoma Via Clinical Imaging and Multiomics.Investigative ophthalmology & visual science · 2024Pooled it
- Engineered human induced pluripotent stem cell models reveal altered podocytogenesis in congenital heart disease-associated SMAD2 mutations.Nature biomedical engineering · 2026Article
- Mechanisms underlying disease-causing variants in promoters and enhancers.Nature genetics · 2026Review
- A cardiac-related, promoter-proximal, regulatory element shapes chromatin and JAG1 transcription.Life science alliance · 2026Article
- Unlocking the Regulatory Genome: Interpreting the Clinical Impact of Noncoding Variants in Genetic Cardiomyopathies.Circulation. Genomic and precision medicine · 2026Review
- Cardiac Organoids for Modeling Congenital Heart Disease: From Genetic Discovery to Therapeutic Screening.Current cardiology reports · 2026Review
- Genome-wide annotation of human multi-nucleotide variants reveals widespread functional differences from single nucleotide variants.Nature communications · 2026Article
- Whole-genome sequencing implicates rare, low-frequency and structural non-coding variation at themedRxiv : the preprint server for health sciences · 2026Article
- Functional noncoding variants within the TBX1 enhancer contribute to tetralogy of Fallot.Science China. Life sciences · 2026Article
- Segmentally Duplicated Regulatory Elements Undergo Human-Specific Rewiring.Molecular biology and evolution · 2026Article
- Functional annotation of non-coding variants identifies a novel enhancer with activity in neural crest cell-derived lineages.Research square · 2026Article
- Cardiac epigenome in heart development and disease.Nature reviews. Cardiology · 2026Review
- Article
- Enhancer Dynamics for Gene Regulation in the Cardiovascular System.Arteriosclerosis, thrombosis, and vascular biology · 2026Review
- Chamber-specific chromatin architecture guides functional interpretation of disease-associated Cis-regulatory elements in human cardiomyocytes.Nature communications · 2026Article
- Global Evaluation of Congenital Heart Disease-Associated Non-Coding Variants.Research square · 2026Article
- Gene4Denovo2: an updated platform for human de novo mutations discovery and interpretation.Nucleic acids research · 2026Article
- Comprehensive perturbation of transcription factors in human cardiomyocytes reveals the regulatory architecture of congenital heart disease.bioRxiv : the preprint server for biology · 2026Article
- Elucidating Gene Functions in Congenital Heart Disease.Current treatment options in cardiovascular medicine · 2026Review
- Functional architecture of cardiac TF regulatory landscapes in control of mammalian heart development.bioRxiv : the preprint server for biology · 2025Article
Corrections and comments
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Authors and funding
21 authors at 7 institutions in 2 countries.
Funding
Abstract
Rare coding mutations cause ∼45% of congenital heart disease (CHD). Noncoding mutations that perturb cis-regulatory elements (CREs) likely contribute to the remaining cases, but their identification has been problematic. Using a lentiviral massively parallel reporter assay (lentiMPRA) in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we functionally evaluated 6,590 noncoding de novo variants (ncDNVs) prioritized from the whole-genome sequencing of 750 CHD trios. A total of 403 ncDNVs substantially affected cardiac CRE activity. A majority increased enhancer activity, often at regions with undetectable reference sequence activity. Of ten DNVs tested by introduction into their native genomic context, four altered the expression of neighboring genes and iPSC-CM transcriptional state. To prioritize future DNVs for functional testing, we used the MPRA data to develop a regression model, EpiCard. Analysis of an independent CHD cohort by EpiCard found enrichment of DNVs. Together, we developed a scalable system to measure the effect of ncDNVs on CRE activity and deployed it to systematically assess the contribution of ncDNVs to CHD.
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Registered trials
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.