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

doi:10.1007/s43657-024-00175-9

MST1R Gene Variants Predispose Individuals to Tetralogy of Fallot

Phenomics. 2025 Jan 21;4(6):548-561. doi: 10.1007/s43657-024-00175-9. eCollection 2024 Dec.

Authors

Zhiyu Feng^#^{1

2}, Xianghui Huang^#³, Yuan Gao^{1

2}, Han Gao^{1

2}, Weilan Na⁴, Chaozhong Tan^{1

2}, Shaojie Min^{1

2}, Yuquan Lu^{1

2}, Quannan Zhuang^{1

2}, Siyi Lin^{1

2}, Xiaojing Ma^{1

2}, Weicheng Chen^{1

2}, Weili Yan^{1

4}, Wei Sheng^{1

2

3

4}, Guoying Huang^{1

2

3

4}

Affiliations

¹ Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201002 China.
² Shanghai Key Laboratory of Birth Defects, Shanghai, 201002 China.
³ Fujian Key Laboratory of Neonatal Diseases, Xiamen Children's Hospital, Fujian, 361006 China.
⁴ Research Unit of Early Intervention of Genetically Related Childhood Cardiovascular Diseases (2018RU002), Chinese Academy of Medical Sciences, Beijing, 100730 China.

^# Contributed equally.

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.

Supplementary information: The online version contains supplementary material available at 10.1007/s43657-024-00175-9.

Keywords: Congenital Heart Disease; Macrophage Stimulating 1 Receptor; Tetralogy of Fallot; Variants.