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

Clinical genetics  ·  2025

Tanner J Nelson; Daniel E McGinn; T Blaine Crowley; Lydia Rockart; Audrey Green; Victoria Giunta; Oanh Tran; Daniella Miller; Jeroen Breckpot; Ann Swillen; M Cristina Digilio; Marta Unolt; Carolina Putotto; Federica Pulvirenti; Bruno Marino; Beverly S Emanuel; Elaine H Zackai; Zhengdong D Zhang; Elizabeth Goldmuntz; Erik Boot; Anne S Bassett; Bernice E Morrow; Donna M McDonald-McGinn;

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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.

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