MST1R Gene Variants Predispose Individuals to Tetralogy of Fallot.

IF 3.7 Q2 GENETICS & HEREDITY

Phenomics (Cham, Switzerland) Pub Date : 2025-01-21 eCollection Date: 2024-12-01 DOI:10.1007/s43657-024-00175-9

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

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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.

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MST1R基因变异使个体易患法洛四联症。

法洛四联症（TOF）是最常见的青紫型先天性心脏畸形。虽然已经确定了一些TOF的易感基因，但对TOF遗传基础的研究还很有限。巨噬细胞刺激1受体（MST1R）基因编码具有酪氨酸磷酸酶活性的巨噬细胞刺激蛋白受体，参与免疫防御。在本研究中，我们对10个TOF家族和50例散发性TOF患者进行了全外显子组测序（WES），在同一个家族的两个TOF后代中发现了MST1R基因c.T2009G: p.V670G的隐性纯合错义突变。基因组聚集数据库2 （gnomADv2_EAS）的MST1R基因靶向测序显示，与东亚人相比，417例TOF患者的罕见变异丰富。缺乏mst1r的人诱导多能干细胞（hiPSCs）维持正常的多能性，但分化为无功能心肌细胞（CMs）。综上所述，我们的研究结果表明，MST1R可能在心脏分化中发挥关键作用，MST1R的遗传变异可能与TOF的发病机制有关。补充资料：在线版本包含补充资料，下载地址：10.1007/s43657-024-00175-9。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Phenomics (Cham, Switzerland)

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