RNA-Sequencing analysis of control and SORBS2 knockdown cardiac progenitor cells derived from human stem cells in vitro

Chromosome 4q deletion syndrome is one of the most frequently detected genomic imbalance events in congenital heart disease (CHD) patients. However, a portion of terminal 4q deletions with CHD do not include known CHD genes. Here in a target sequencing of a panel of known and candidate CHD genes, we showed that the detrimental rare variants of SORBS2 in 4q35.1 are significantly enriched in CHD patients. Examination of Sorbs2-/- mouse hearts revealed two types of atrial septal defects (ASD), atrial hypoplasia/aplasia and double atrial septum. In vitro human cardiogenesis indicated a dual role of SORBS2 in maintaining sarcomeric integrity of cardiomyocytes and specifying the fate of cardiac progenitors. Mechanistically, SORBS2 promotes the commitment of the second heart field (SHF) over the first heart field (FHF) fate through c-ABL/NOTCH/SHH axis. Taken together, our data demonstrate that SORBS2 is a novel CHD gene within deleted 4q interval. The presence of double atrial septum in Sorbs2-/- mouse reveals the first molecular etiology of the rare anomaly linked to paradoxical thromboembolism. Overall design: Examination of mRNA profiles of control and SORBS2 knockdown cardiac progenitor cells