SORBS2 is a genetic factor contributing to cardiac malformation of 4q deletion syndrome

Chromosome 4q deletion is one of the most frequently detected genomic imbalance events in congenital heart disease (CHD) patients. However, a portion of CHD-associated 4q deletions do not include known CHD genes. Alignment of those 4q deletions defined a minimal overlapping region including only one gene-. Histological analysis of heart revealed atrial septal hypoplasia/aplasia or double atrial septum. Mechanistically, had a dual role in maintaining sarcomeric integrity of cardiomyocytes and specifying the fate of second heart field (SHF) progenitors through c-ABL/NOTCH/SHH axis. In a targeted sequencing of a panel of known and candidate CHD genes on 300 CHD cases, we found that rare variants were significantly enriched in CHD patients. Our findings indicate that is a regulator of cardiac development and its haploinsufficiency may contribute to cardiac phenotype of 4q deletion syndrome. The presence of double atrial septum in hearts reveals the first molecular etiology of this rare anomaly linked to paradoxical thromboembolism.