Deleterious Rare Mutations of Dysregulate Sonic Hedgehog Signaling in Human Congenital Heart Disease

The Glioma-associated oncogene (Gli) family members of zinc finger DNA-binding proteins are core effectors of Sonic hedgehog (SHH) signaling pathway. Studies in model organisms have identified that the genes play critical roles during organ development, including the heart, brain, kidneys, . Deleterious mutations in genes have previously been revealed in several human developmental disorders, but few in congenital heart disease (CHD). In this study, the mutations in genes were captured by next generation sequencing in human cohorts composed of 412 individuals with CHD and 213 ethnically matched normal controls. A total of 20 patient-specific nonsynonymous rare mutations in coding regions of human genes were identified. Functional analyses showed that c.820G> T (p.G274C) is a gain-of-function mutation, while c.878G>A (p.R293H) and c.1442T>A (p.L481X) are loss-of-function mutations. Our findings suggested that deleterious rare mutations in gene broke the balance of the SHH signaling pathway regulation and may constitute a great contribution to human CHD, which shed new light on understanding genetic mechanism of embryo cardiogenesis regulated by SHH signaling.