Deciphering the digenic architecture of congenital heart disease using trio exome sequencing data

Kars, Meltem Ece, Stein, David, Stenson, Peter D., Cooper, David N. ORCID: https://orcid.org/0000-0002-8943-8484, Chung, Wendy K., Gruber, Peter J., Seidman, Christine E., Shen, Yufeng, Tristani-Firouzi, Martin, Gelb, Bruce D. and Itan, Yuval 2025. Deciphering the digenic architecture of congenital heart disease using trio exome sequencing data. American Journal of Human Genetics 112 (3) , pp. 583-598. 10.1016/j.ajhg.2025.01.024 Item availability restricted.

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Abstract

Congenital heart disease (CHD) is the most common congenital anomaly and a leading cause of infant morbidity and mortality. Despite extensive exploration of the monogenic causes of CHD over the last decades, ∼55% of cases still lack a molecular diagnosis. Investigating digenic interactions, the simplest form of oligogenic interactions, using high-throughput sequencing data can elucidate additional genetic factors contributing to the disease. Here, we conducted a comprehensive analysis of digenic interactions in CHD by utilizing a large CHD trio exome sequencing cohort, comprising 3,910 CHD and 3,644 control trios. We extracted pairs of presumably deleterious rare variants observed in CHD-affected and unaffected children but not in a single parent. Burden testing of gene pairs derived from these variant pairs revealed 29 nominally significant gene pairs. These gene pairs showed a significant enrichment for known CHD genes (p < 1.0 × 10 ) and exhibited a shorter average biological distance to known CHD genes than expected by chance (p = 3.0 × 10 ). Utilizing three complementary biological relatedness approaches including network analyses, biological distance calculations, and candidate gene prioritization methods, we prioritized 10 final gene pairs that are likely to underlie CHD. Analysis of bulk RNA-sequencing data showed that these genes are highly expressed in the developing embryonic heart (p < 1 × 10 ). In conclusion, our findings suggest the potential role of digenic interactions in CHD pathogenesis and provide insights into unresolved molecular diagnoses. We suggest that the application of the digenic approach to additional disease cohorts will significantly enhance genetic discovery rates. [Abstract copyright: Copyright © 2025 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.]

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	Cell Press
ISSN:	0002-9297
Date of First Compliant Deposit:	4 April 2025
Date of Acceptance:	29 January 2025
Last Modified:	04 Apr 2025 10:48
URI:	https://orca.cardiff.ac.uk/id/eprint/176692

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