Journal Article
MST1R Gene Variants Predispose Individuals to Tetralogy of Fallot
Zhiyu Feng; Xianghui Huang; Yuan Gao; Han Gao; Weilan Na; Chaozhong Tan; Shaojie Min; Yuquan Lu; Quannan Zhuang; Siyi Lin; Xiaojing Ma; Weicheng Chen; Weili Yan; Wei Sheng; Guoying Huang
Phenomics · Vol. 4, Issue 6 · pp. 548-561 · 2024
Abstract
Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart malformation. While a few susceptibility genes for TOF have been identified, research on the genetic basis of TOF is limited. The Macrophage stimulating 1 receptor ( MST1R ) gene encodes the macrophage-stimulating protein receptor with tyrosine phosphatase activity that is involved in immune defense. In this study, we performed whole-exome sequencing (WES) on 10 TOF families and 50 sporadic TOF patients and identified a recessive homozygous missense mutation in MST1R , c.T2009G: p.V670G, in two offspring with TOF in a single family. Targeted sequencing of the MST1R gene showed enrichment for rare variants in 417 TOF patients compared with East Asians in Genome Aggregation Database Version 2 (gnomADv2_EAS). MST1R -deficient human induced pluripotent stem cells (hiPSCs) maintained normal pluripotency but differentiated into non-functional cardiomyocytes (CMs). Taken together, our findings indicate that MST1R may play a critical role in cardiac differentiation and genetic variations in MST1R may be associated with the pathogenesis of TOF.