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. 2025 Dec 8.
doi: 10.1111/cge.70118. Online ahead of print.

Prevalence and Spectrum of Congenital Heart Disease in Individuals With Distal Chromosome 22q11.22-23 Deletions

Tanner J Nelson  1 , Daniel E McGinn  2 , T Blaine Crowley  2 , Lydia Rockart  2 , Audrey Green  2 , Victoria Giunta  2 , Oanh Tran  3 , Daniella Miller  1 , Jeroen Breckpot  4 , Ann Swillen  4 , M Cristina Digilio  5 , Marta Unolt  5   6 , Carolina Putotto  6 , Federica Pulvirenti  6 , Bruno Marino  6 , Beverly S Emanuel  3 , Elaine H Zackai  2   3 , Zhengdong D Zhang  1 , Elizabeth Goldmuntz  3   7 , Erik Boot  8   9   10 , Anne S Bassett  10   11   12   13 , Bernice E Morrow  1 , Donna M McDonald-McGinn  2   3
Affiliations

Prevalence and Spectrum of Congenital Heart Disease in Individuals With Distal Chromosome 22q11.22-23 Deletions

Tanner J Nelson et al. Clin Genet. .

Abstract

This study is aimed at determining the spectrum of congenital heart disease associated with distal 22q11.22-23 deletions flanked by low copy repeats, LCR22 D-H. We analyzed cardiology findings in 128 unrelated individuals with distal LCR22 D-H deletions. A total of 62 were newly described and 66 were derived from previous reports. We found that deletions which included LCR22-D as the proximal endpoint were the most prevalent in the cohort (104/128, 81.3%). Clinically relevant congenital heart disease was identified in 48 individuals (37.5%, 95% CI 29%-46%), which is lower than the prevalence reported for typical, proximal LCR22 A-D deletions (p = 3.7E-4), especially for conotruncal defects (13/128, 10.2%; p = 7.1E-13). Mild to moderate CHD predominated, including ventricular septal defects (22/128), bicuspid aortic valve (9/128) and mild cardiomyopathy (3/128). Persistent truncus arteriosus was the most prevalent (n = 8/13) conotruncal heart defect, but other anomalies also occurred in singleton cases. These findings support the need for cardiac evaluation in all individuals with distal 22q11.22-23 deletions, increased use of clinical genetic testing in syndromic individuals with these findings, and molecular studies in model systems. The results demonstrate that reduced gene dosage of distal 22q11.21-23, particularly within the D-E region including MAPK1 and HIC2 convey risk for CHD.

Keywords: 22q11.2 distal deletion; chromosome abnormalities; chromosome deletion; congenital heart disease; heart defects‐congenital.

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