Whole exome sequencing reveals genetic landscape associated with left ventricular outflow tract obstruction in Chinese Han population

Zilong Geng; Wenjuan Li; Ping Yang; Shasha Zhang; Shuo Wu; Junhao Xiong; Kun Sun; Dan Zhu; Sun Chen; Bing Zhang

doi:10.3389/fgene.2023.1267368

Whole exome sequencing reveals genetic landscape associated with left ventricular outflow tract obstruction in Chinese Han population

Front Genet. 2023 Dec 18:14:1267368. doi: 10.3389/fgene.2023.1267368. eCollection 2023.

Authors

Zilong Geng^#¹, Wenjuan Li^#², Ping Yang^#¹, Shasha Zhang¹, Shuo Wu¹, Junhao Xiong¹, Kun Sun², Dan Zhu³, Sun Chen², Bing Zhang^{1

2}

Affiliations

¹ Key Laboratory of Systems Biomedicine, Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
² Department of Pediatric Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
³ Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.

^# Contributed equally.

Abstract

Left ventricular outflow tract obstruction (LVOTO), a major form of outflow tract malformation, accounts for a substantial portion of congenital heart defects (CHDs). Unlike its prevalence, the genetic architecture of LVOTO remains largely unknown. To unveil the genetic mutations and risk genes potentially associated with LVOTO, we enrolled a cohort of 106 LVOTO patients and 100 healthy controls and performed a whole-exome sequencing (WES). 71,430 rare deleterious mutations were found in LVOTO patients. By using gene-based burden testing, we further found 32 candidate genes enriched in LVOTO patient including known pathological genes such as GATA5 and GATA6. Most variants of 32 risk genes occur simultaneously rather exclusively suggesting polygenic inherence of LVOTO and 14 genes out of 32 risk genes interact with previously discovered CHD genes. Single cell RNA-seq further revealed dynamic expressions of GATA5, GATA6, FOXD3 and MYO6 in endocardium and neural crest lineage indicating the mutations of these genes lead to LVOTO possibly through different lineages. These findings uncover the genetic architecture of LVOTO which advances the current understanding of LVOTO genetics.

Keywords: congenital heart defect; gene-based burden test; left ventricular outflow tract obstruction; outflow tract malformation; whole-exome sequencing.

Grants and funding

The authors declare financial support was received for the research, authorship, and/or publication of this article. This work is supported by the BZ’s grants from National Foundation of Distinguished Young Scholar (82225006), National Key Research and Development Program of China (2020YFA0803800,2020YFA0803802), the Innovation Program of the Shanghai Municipal Education Commission (2021-01-07-00-02-E00088), WLA Program of Shanghai Science and Technology Commission (21dz2210202, 21dz2210200), and SJTU STAR Award (YG2021ZD11, YG2022ZD023).