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Identifying genetic factors that contribute to the increased risk of congenital heart defects in infants with Down syndrome

Lookup NU author(s): Professor Heather Cordell, Professor Bernard Keavney



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2020, The Author(s). Atrioventricular septal defects (AVSD) are a severe congenital heart defect present in individuals with Down syndrome (DS) at a > 2000-fold increased prevalence compared to the general population. This study aimed to identify risk-associated genes and pathways and to examine a potential polygenic contribution to AVSD in DS. We analyzed a total cohort of 702 individuals with DS with or without AVSD, with genomic data from whole exome sequencing, whole genome sequencing, and/or array-based imputation. We utilized sequence kernel association testing and polygenic risk score (PRS) methods to examine rare and common variants. Our findings suggest that the Notch pathway, particularly NOTCH4, as well as genes involved in the ciliome including CEP290 may play a role in AVSD in DS. These pathways have also been implicated in DS-associated AVSD in prior studies. A polygenic component for AVSD in DS has not been examined previously. Using weights based on the largest genome-wide association study of congenital heart defects available (2594 cases and 5159 controls; all general population samples), we found PRS to be associated with AVSD with odds ratios ranging from 1.2 to 1.3 per standard deviation increase in PRS and corresponding liability r2 values of approximately 1%, suggesting at least a small polygenic contribution to DS-associated AVSD. Future studies with larger sample sizes will improve identification and quantification of genetic contributions to AVSD in DS.

Publication metadata

Author(s): Trevino CE, Holleman AM, Corbitt H, Maslen CL, Rosser TC, Cutler DJ, Johnston HR, Rambo-Martin BL, Oberoi J, Dooley KJ, Capone GT, Reeves RH, Cordell HJ, Keavney BD, Agopian AJ, Goldmuntz E, Gruber PJ, O'Brien JE, Bittel DC, Wadhwa L, Cua CL, Moskowitz IP, Mulle JG, Epstein MP, Sherman SL, Zwick ME

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2020

Volume: 10

Issue: 1

Print publication date: 01/12/2020

Online publication date: 22/10/2020

Acceptance date: 05/10/2020

Date deposited: 05/11/2020

ISSN (electronic): 2045-2322

Publisher: Nature Publishing Group


DOI: 10.1038/s41598-020-74650-4


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Funder referenceFunder name
and GM117946 (M.P.E.) from NIH/National Institute of General Medical Sciences.
and R01 HL083300 (R.H.R.) from NIH/National Heart, Lung, and Blood Institute;
Te Cordell et al. (2013) GWAS discovery data used for the PRS analyses were generated with support from the British Heart Foundation, Heart Research UK, Wellcome Trust and European Union.
R01 HD38979 (S.L.S.) from NIH/National Institute of Child Health and Human Development
Te DS Heart Project (R.H.R.) was a collaborative project supported through several National Institutes of Health awards: R01 HL092981-01A1 (M.E.Z.)