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bioRxiv · 10.1101/2020.05.12.087452

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

Liang, F.·Zhang, X.·Wang, B.·Geng, J.·You, G.·Fa, J.·Sun, H.·Chen, H.·Fu, Q.·Zhang, Z.
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Abstract

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-SORBS2. Histological analysis of Sorbs2-/- heart revealed atrial septal hypoplasia/aplasia or double atrial septum. Mechanistically, SORBS2 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 SORBS2 variants were significantly enriched in CHD patients. Our findings indicate that SORBS2 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 Sorbs2-/- hearts reveals the first molecular etiology of this rare anomaly linked to paradoxical thromboembolism.

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Liang, F., Zhang, X., Wang, B., Geng, J., You, G., Fa, J., Sun, H., Chen, H., Fu, Q., Zhang, Z.. 2020-05-14. SORBS2 is a genetic factor contributing to cardiac malformation of 4q deletion syndrome. https://doi.org/10.1101/2020.05.12.087452

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