Deletion size and background genetic variation shape congenital heart disease phenotypes in 3,016 individuals with 22q11.2 deletion syndrome

Congenital heart disease (CHD) occurs in over half of individuals with 22q11.2 deletion syndrome (22q11.2DS) and the types of lesions range from mild to severe. To determine the basis of variation in cardiac phenotypes we analyzed demographic data from 3,016 unrelated individuals with 22q11.2DS from centers in the Northeast US, Canada, Europe, South America, Israel and Australia. Most individuals in this cohort had a 3 million base pair hemizygous deletion between low copy repeat, LCR22 A-D (87.2%), while some had nested deletions. We performed multivariable mixed-effects logistic regression and uncovered significant differences between CHD phenotypes and basic demographic features. Individuals with the A-D deletion had a lower risk of persistent truncus arteriosus (OR = 0.37, 95% CI 0.18-0.75) but a higher risk of septal defects (OR = 4.7, 95% CI 1.7-12.8) compared to those with the smaller A-B deletion, suggesting distinct developmental pathways sensitive to 22q11.2 gene dosage. In addition, genome-wide genetic principal components (PCs) were associated with specific CHD subtypes, including reduced risk of pulmonary stenosis or atresia with other heart lesions (PC2; OR = 0.73, 95% CI 0.61-0.87) and increased risk of abnormal origin of the subclavian arteries (PC4; OR = 2.6, 95% CI 1.4-4.9), indicating that background genetic variation modifies heart lesion-specific susceptibility. Together, these results suggest that both deletion size and background genetic variation shape the highly variable cardiac phenotypes in 22q11.2DS.

Authors

Institutions

Publication Details

Journal
medRxiv
Published
2026-02-25
DOI
https://doi.org/10.64898/2026.02.23.26346918
Citations
1
Primary Topic
Congenital heart defects research
Type
article
Field-Weighted Citation Impact
22.24

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 3,016 individuals with 22q11.2 deletion syndrome

Jhih-Rong Lin, S. S. Scherer, Bernice E. Morrow, Daniella Miller et al.
1 citations
medRxiv
Congenital heart defects research
22.24
article

Deletion size and background genetic variation shape congenital heart disease phenotypes in 3,016 individuals with 22q11.2 deletion syndrome

Jhih-Rong Lin, S. S. Scherer, Bernice E. Morrow, Daniella Miller, T. van Amelsvoort, Zhengdong Zhang, Michael E. Mitchell, Donna M. McDonald-McGinn, Donna M. McDonald-McGinn, Anne S. Bassett
article en
1 citations

Abstract

Congenital heart disease (CHD) occurs in over half of individuals with 22q11.2 deletion syndrome (22q11.2DS) and the types of lesions range from mild to severe. To determine the basis of variation in cardiac phenotypes we analyzed demographic data from 3,016 unrelated individuals with 22q11.2DS from centers in the Northeast US, Canada, Europe, South America, Israel and Australia. Most individuals in this cohort had a 3 million base pair hemizygous deletion between low copy repeat, LCR22 A-D (87.2%), while some had nested deletions. We performed multivariable mixed-effects logistic regression and uncovered significant differences between CHD phenotypes and basic demographic features. Individuals with the A-D deletion had a lower risk of persistent truncus arteriosus (OR = 0.37, 95% CI 0.18-0.75) but a higher risk of septal defects (OR = 4.7, 95% CI 1.7-12.8) compared to those with the smaller A-B deletion, suggesting distinct developmental pathways sensitive to 22q11.2 gene dosage. In addition, genome-wide genetic principal components (PCs) were associated with specific CHD subtypes, including reduced risk of pulmonary stenosis or atresia with other heart lesions (PC2; OR = 0.73, 95% CI 0.61-0.87) and increased risk of abnormal origin of the subclavian arteries (PC4; OR = 2.6, 95% CI 1.4-4.9), indicating that background genetic variation modifies heart lesion-specific susceptibility. Together, these results suggest that both deletion size and background genetic variation shape the highly variable cardiac phenotypes in 22q11.2DS.

medRxiv
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), Duke University (US), King's College London (GB), University of Toronto (CA), SUNY Upstate Medical University (US), Medical College of Wisconsin (US), Hospital Universitario La Paz (ES), Hospital for Sick Children (CA), Beilstein-Institut (DE), Clínica Alemana (CL), Toronto General Hospital (CA), Maastricht University (NL), Neurobehavioral Systems (US), Bambino Gesù Children's Hospital (IT), Health Research Institute of the Balearic Islands (ES), Polish Mother’s Memorial Hospital Research Institute (PL), Edmond and Lily Safra Children's Hospital (IL), Université de Nîmes (FR), Syracuse University (US), University of Newcastle Australia (AU), Cardiff University (GB), University of California, Davis (US), Sapienza University of Rome (IT), University of Lausanne (CH), KU Leuven (BE)
National Science Foundation, Simons Foundation Autism Research Initiative, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Fonds Wetenschappelijk Onderzoek, University of Toronto, KU Leuven, Hospital for Sick Children, Agencia Nacional de Investigación y Desarrollo, National Institutes of Health, Canadian Institutes of Health Research
Good health and well-being
Openalex Percentile: Top 1%
Congenital heart defects research
22.24
DOIOpen Access PDFOpenAlex
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.