ArticleGenome research2013
The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome.
Article in Genome research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers, 2 of them syntheses that pooled it.
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Who cites it
45 citing papers in PubMed, 2 syntheses or guidelines pooled it, 82 citations in OpenAlex.
- Gender differences in the prevalence of congenital heart disease in Down's syndrome: a brief meta-analysis.BMC medical genetics · 2017Pooled it
- Systematic reanalysis of partial trisomy 21 cases with or without Down syndrome suggests a small region on 21q22.13 as critical to the phenotype.Human molecular genetics · 2016Pooled it
- First- and Second-Trimester Cardiovascular Anomalies in Trisomy 21 Fetuses: Anatomy, Embryology, Genetics and Imaging.Journal of personalized medicine · 2026Review
- Article
- Genome-Wide Association Studies of Down Syndrome Associated Congenital Heart Defects Suggests a Genetically Heterogeneous Risk for CHD in DS.Genetic epidemiology · 2025Article
- Whole-Exome Sequencing Identifies Novel GATA5/6 Variants in Right-Sided Congenital Heart Defects.International journal of molecular sciences · 2025Article
- Article
- ZBTB21 suppresses CRE-mediated transcription to impair synaptic function in Down syndrome.Science advances · 2024Article
- Increased dosage of DYRK1A leads to congenital heart defects in a mouse model of Down syndrome.Science translational medicine · 2024Article
- Epigenomic signature of major congenital heart defects in newborns with Down syndrome.Human genomics · 2023Article
- Multiomic analysis of cohesin reveals that ZBTB transcription factors contribute to chromatin interactions.Nucleic acids research · 2023Article
- Epigenomic signature of major congenital heart defects in newborns with Down syndrome.medRxiv : the preprint server for health sciences · 2023Article
- Genetics and Molecular Basis of Congenital Heart Defects in Down Syndrome: Role of Extracellular Matrix Regulation.International journal of molecular sciences · 2023Review
- Rare copy number variation analysis identifies disease-related variants in atrioventricular septal defect patients.Frontiers in genetics · 2023Article
- A comparative analysis on risk of pulmonary hypertension in children with Atrio-ventricular (AV) canal defect: a multi-centre study.African health sciences · 2022Article
- Review
- A Reassessment of Copy Number Variations in Congenital Heart Defects: Picturing the Whole Genome.Genes · 2021Article
- Importance of determining variations in the number of copies in newborns with autosomal aneuploidiesBiomedica : revista del Instituto Nacional de Salud · 2021Article
- New Molecular and Organelle Alterations Linked to Down Syndrome Heart Disease.Frontiers in genetics · 2021Review
- Congenital heart defects among Down's syndrome cases: an updated review from basic research to an emerging diagnostics technology and genetic counselling.Journal of genetics · 2021Review
Corrections and comments
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Authors and funding
30 authors at 13 institutions in 8 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Congenital heart defect (CHD) occurs in 40% of Down syndrome (DS) cases. While carrying three copies of chromosome 21 increases the risk for CHD, trisomy 21 itself is not sufficient to cause CHD. Thus, additional genetic variation and/or environmental factors could contribute to the CHD risk. Here we report genomic variations that in concert with trisomy 21, determine the risk for CHD in DS. This case-control GWAS includes 187 DS with CHD (AVSD = 69, ASD = 53, VSD = 65) as cases, and 151 DS without CHD as controls. Chromosome 21-specific association studies revealed rs2832616 and rs1943950 as CHD risk alleles (adjusted genotypic P-values <0.05). These signals were confirmed in a replication cohort of 92 DS-CHD cases and 80 DS-without CHD (nominal P-value 0.0022). Furthermore, CNV analyses using a customized chromosome 21 aCGH of 135K probes in 55 DS-AVSD and 53 DS-without CHD revealed three CNV regions associated with AVSD risk (FDR ≤ 0.05). Two of these regions that are located within the previously identified CHD region on chromosome 21 were further confirmed in a replication study of 49 DS-AVSD and 45 DS- without CHD (FDR ≤ 0.05). One of these CNVs maps near the RIPK4 gene, and the second includes the ZBTB21 (previously ZNF295) gene, highlighting the potential role of these genes in the pathogenesis of CHD in DS. We propose that the genetic architecture of the CHD risk of DS is complex and includes trisomy 21, and SNP and CNV variations in chromosome 21. In addition, a yet-unidentified genetic variation in the rest of the genome may contribute to this complex genetic architecture.
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