Megan Thomas

Background: Down syndrome (DS), caused by trisomy 21, is strongly associated with congenital heart defects (CHDs), especially atrioventricular septal defects (AVSDs). AVSD develops from abnormal formation of the endocardial cushions and atrioventricular canal during embryonic heart development, leading to improper septation and valve defects. However, not all individuals with trisomy 21 develop AVSD, suggesting that trisomy 21 alone is not enough to explain disease development and that additional modifier genes and disrupted signaling pathways also contribute.^1-5 Recent studies have started to examine how chromosome 21 gene dosage, signaling pathways, and cellular or epigenetic regulation interact during cardiac development. Understanding these mechanisms is important because it may improve risk prediction and eventually support development or more targeted therapies for congenital heart disease in DS.

Objective: This narrative review examined computational, genetic, molecular, and cellular mechanisms that contribute to AVSD development in individuals with DS.

Search Methods: A literature search was performed using the PubMed database to identify primary studies published from 2018 to 2025 related to DS-associated AVSD. Search terms included “Down syndrome,” “atrioventricular septal defect,” “AVSD,” “trisomy 21,” “CRELD1,” “DYRK1A,” “Wnt signaling,” “interferon signaling,” “HMGN1,” and “machine learning.” Studies involving computational genomic analysis, signaling pathway dysregulation, and cellular or epigenetic mechanisms involved in AVSD pathogenesis were selected for review.

Results: Computational genomic studies demonstrated that DS individuals with AVSD exhibit distinct genomic patterns compared to DS individuals without AVSD, supporting a multi-gene disease model rather than a single causative mutation.¹ Machine learning analysis identified candidate loci including PDE9A, DOPEY2, and LCA5L, which are involved in signaling regulation, intracellular trafficking, and ciliary function important for cardiac development.¹ Sequencing studies also identified CRELD1 variants, including the E325K mutation, which decrease protein stability and disrupt calcineurin/NFAT signaling pathways involved in endocardial cushion development and epithelial-to-mesenchymal transition.² One important finding was that increased interferon receptor gene dosage in trisomy 21 activates JAK-STAT signaling and suppresses canonical Wnt/β-catenin signaling, leading to impaired cardiomyocyte differentiation and abnormal atrioventricular canal formation.³ Rescue experiments further showed that restoring Wnt signaling partially improved cardiac differentiation and function in DS cellular models, supporting a causal role for Wnt dysregulation in AVSD pathogenesis.³ Additional studies demonstrated that increased DYRK1A dosage disrupts cardiomyocyte proliferation and mitochondrial oxidative phosphorylation pathways while also reducing NFAT transcriptional activity.⁴ More recent epigenetic studies identified HMGN1 overexpression as a contributor to altered chromatin accessibility and disrupted developmental gene expression in atrioventricular canal cardiomyocytes.⁵ Taken together, these findings help explain how modifier genes, signaling pathway dysregulation, and impaired cellular development interact during AVSD pathogenesis in DS.

Conclusions: AVSD in DS is a multifactorial disorder involving genetic, signaling, cellular, and epigenetic mechanisms that interact during cardiac development. Current computational and mechanistic studies demonstrate that pathways involving NFAT, Wnt/β-catenin signaling, interferon signaling, and chromatin regulation all contribute to abnormal septation and cardiac differentiation. Overall, these findings improve understanding of why only some individuals with DS develop AVSD and many support earlier risk identification and development of future targeted therapies for congenital heart defects.

Works Cited:

1. Pan X, Hu X, Zhang YH, Feng K, Wang SP, Chen L, et al. Identifying patients with atrioventricular septal defect in Down syndrome populations by using self-normalizing neural networks and feature selection. Genes (Basel). 2018;9(4):208. doi:10.3390/genes9040208
2. Asim A, Agarwal S, Panigrahi I, Sarangi AN, Muthuswamy S, Kapoor A. CRELD1 gene variants and atrioventricular septal defects in Down syndrome. Gene. 2018;641:180-185. doi:10.1016/j.gene.2017.10.044
3. Chi C, Knight WE, Riching AS, Zhang Z, Tatavosian R, Zhuang Y, et al. Interferon hyperactivity impairs cardiogenesis in Down syndrome via downregulation of canonical Wnt signaling. iScience. 2023;26(7):107012. doi:10.1016/j.isci.2023.107012
4. Lana-Elola E, Aoidi R, Llorian M, Gibbins D, Buechsenschuetz C, Bussi C, et al. Increased dosage of DYRK1A leads to congenital heart defects in a mouse model of Down syndrome. Sci Transl Med. 2024;16(731):eadd6883. doi:10.1126/scitranslmed.add6883
5. Ranade SS, Li F, Whalen S, et al. Myocardial reprogramming by HMGN1 underlies heart defects in trisomy 21. Nature. 2025;647(8091):979-987. doi:10.1038/s41586-025-09593-9