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

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.

Authors

Institutions

Publication Details

Journal
Journal of Medical Genetics
Published
2026-10-14
DOI
https://doi.org/10.1136/jmg-2026-111761
Primary Topic
Genomic variations and chromosomal abnormalities
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Oanh Tran, Elaine H. Zackai, Marta Unolt, Carrie E. Bearden et al.
Journal of Medical Genetics
Genomic variations and chromosomal abnormalities
article

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

Oanh Tran, Elaine H. Zackai, Marta Unolt, Carrie E. Bearden, Paolo Versacci, Kieran C. Murphy, Maria Cristina Digilio, Jeroen Breckpot, Marco Armando, Beverly S. Emanuel, Thérèse van Amelsvoort, Wendy R. Kates, Elizabeth Goldmuntz, Bernice E. Morrow, Maude Schneider, Bhooma Thiruvahindrapuram, Kathleen Angkustsiri, Stéphan Eliez, Donna M. McDonald‐McGinn, Elena Michaelovsky, Jacob A. S. Vorstman, Kelly Schoch, Wanda Hawuła, Daniella Miller, Claudia Vingerhoets, Damián Heine‐Suñer, Stephen W. Scherer, Gabriela M. Repetto, Linda Campbell, Maria Pontillo, Ruben C. Gur, Erik Boot, Carolina Putotto, Srilakshmi M. Raj, Aoy Tomita‐Mitchell, Robert J. Shprintzen, Koenraad Devriendt, Joris Robert Vermeesch, Ann Swillen, Vandana Shashi, Stefano Vicari, Anne S. Bassett, Marianne B. M. van den Bree, Tao Wang, Declan G. Murphy, Luís Fernández, Bruno Marino, Doron Gothelf, Sixto García‐Miñaúr, Dana Luong, Miri Carmel, Michael Owen, Tanner Nelson, Amirhossein Hajianpour, Abraham Weizman, Michael Mitchell, Tiffany Busa, Zhengdong D Zhang, Jhih-Rong Lin, T B Crowley
article en

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.

Journal of Medical Genetics
Università Cattolica del Sacro Cuore (IT), University of Geneva (CH), Albert Einstein College of Medicine (US), University Health Network (CA), Children's Hospital of Philadelphia (US), Universidad del Desarrollo (CL), Centre for Addiction and Mental Health (CA), Royal College of Surgeons in Ireland (IE), University of California, Los Angeles (US), Tel Aviv University (IL), Duke University (US), King's College London (GB), University of Toronto (CA), SUNY Upstate Medical University (US), Medical College of Wisconsin (US), Rega Institute for Medical Research (BE), Sheba Medical Center (IL), Hospital Universitario La Paz (ES), Hospital for Sick Children (CA), Clínica Alemana (CL), Toronto General Hospital (CA), Maastricht University (NL), Centre Hospitalier Universitaire de Nîmes (FR), Bambino Gesù Children's Hospital (IT), Polish Mother’s Memorial Hospital Research Institute (PL), Edmond and Lily Safra Children's Hospital (IL), Hospital Universitario Son Espases (ES), Centre for Applied Genomics (CA), Campbell Family Mental Health Research Institute (CA), University of Newcastle Australia (AU), Cardiff University (GB), University of Pennsylvania (US), Sapienza University of Rome (IT), University of Lausanne (CH), KU Leuven (BE)
KU Leuven
Good health and well-being
Openalex Percentile: Top 15%
Genomic variations and chromosomal abnormalities
DOISourceOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.