Deletion size and background genetic variation shape congenital heart disease phenotypes in 3016 individuals with 22q11.2 deletion syndrome

Lin, Jhih-Rong, Miller, Daniella, Luong, Dana, Nelson, Tanner, Crowley, T. B., Tran, Oanh T., van den Bree, Marianne ORCID: https://orcid.org/0000-0002-4426-3254 and Owen, Michael ORCID: https://orcid.org/0000-0003-4798-0862 2026. Deletion size and background genetic variation shape congenital heart disease phenotypes in 3016 individuals with 22q11.2 deletion syndrome. Journal of Medical Genetics 10.1136/jmg-2026-111761

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Abstract

Introduction: Congenital heart disease (CHD) occurs in over half of individuals with 22q11.2 deletion syndrome (22q11.2DS), but lesion type varies widely. Methods: We analysed basic medical features in 3016 unrelated postnatal individuals with 22q11.2DS from specialised centres in the USA, Canada, Europe, South America, Israel and Australia including 1868 with whole-genome sequencing. Results: The typical 3 Mb LCR22 A–D deletion was present in 2788 individuals (92.4%), with smaller A–B (n=172, 5.7%) and A–C (n=56, 1.9%) deletions comprising the remaining cohort. In multivariable mixed-effects logistic regression adjusting for sex, deletion group, genome-wide principal components (PCs) and recruitment site, four non-intercept associations to test relationships met study-wide false discovery rate significance. Compared with the A–B deletion, the A–D deletion was associated with lower odds of persistent truncus arteriosus (OR 0.37, 95% CI 0.18 to 0.75) and higher odds of isolated septal defects (OR 4.68, 95% CI 1.71 to 12.83), although precision was limited by the smaller A–B group. PC2 was associated with lower odds of pulmonary stenosis/atresia with additional lesions (OR 0.73, 95% CI 0.61 to 0.87) and PC4 with higher odds of abnormal origin of the subclavian arteries (ASA; OR 2.59, 95% CI 1.37 to 4.89). The Polygenic Risk Score for proximal pulmonary artery diameter was associated with a lower likelihood of ASA (OR 0.71, 95% CI 0.56 to 0.89, p=3.7E−3). ADMIXTURE-derived continental ancestry proportions did not show independent associations with these two PC-associated outcomes. Conclusion: These lesion-specific findings in the data presented indicate that the deletion interval on 22q11.2 and broader genetic background may contribute to CHD variability in 22q11.2DS.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Additional Information:	Full author list available at DOI
Publisher:	BMJ Publishing Group
ISSN:	0022-2593
Date of Acceptance:	13 September 2026
Last Modified:	27 Oct 2026 11:46
URI:	https://orca.cardiff.ac.uk/id/eprint/190444

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