SOX17 loss-of-function variation underlying familial congenital heart disease.

As the most prevalent form of human birth defect, congenital heart disease (CHD) contributes to substantial morbidity, mortality and socioeconomic burden worldwide. Aggregating evidence has convincingly demonstrated that genetic defects exert a pivotal role in the pathogenesis of CHD, and causative mutations in multiple genes have been causally linked to CHD. Nevertheless, CHD is of pronounced genetic heterogeneity, and the genetic components underpinning CHD in the overwhelming majority of patients remain obscure. In this research, a four-generation consanguineous family suffering from CHD transmitted in an autosomal dominant mode was recruited. By whole-exome sequencing and bioinformatics analyses as well as Sanger sequencing analyses of the family members, a new heterozygous SOX17 variation, NM_022454.4: c.553G > T; p.(Glu185*), was identified to co-segregate with CHD in the family, with complete penetrance. The nonsense variation was neither detected in 310 unrelated healthy volunteers used as controls nor retrieved in such population genetics databases as the Exome Aggregation Consortium database, Genome Aggregation Database, and the Single Nucleotide Polymorphism database. Functional assays by utilizing a dual-luciferase reporter assay system unveiled that the Glu185*-mutant SOX17 protein had no transcriptional activity on its two target genes NOTCH1 and GATA4, which have been reported to cause CHD. Furthermore, the mutation abrogated the synergistic transactivation between SOX17 and NKX2.5, another established CHD-causing transcription factor. These findings firstly indicate SOX17 loss-of-function mutation predisposes to familial CHD, which adds novel insight to the molecular mechanism of CHD, implying potential implications for genetic risk appraisal and individualized prophylaxis of the family members affected with CHD.