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

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.