Sequencing of a Chinese tetralogy of Fallot cohort reveals clustering mutations in myogenic heart progenitors.

Wai-Yee Lam,Yujia Yang,Paul Kwong Hang Tam,Peter J Gruber,Mimmi Mononen,Kenneth R Chien,Xuehan Zhuang,Maria-Mercè Garcia-Barcelo,Elif Eroglu,Haifa Hong,Makoto Sahara,Qiongfen Lin,Clara Sze Man Tang,Sheng Chih Jin

doi:10.1172/jci.insight.152198

Abstract

Tetralogy of Fallot (TOF) is the most common cyanotic heart defect, yet the underlying genetic mechanisms remain poorly understood. Here, we performed whole-genome sequencing analysis on 146 nonsyndromic TOF parent-offspring trios of Chinese ethnicity. Comparison of de novo variants and recessive genotypes of this data set with data from a European cohort identified both overlapping and potentially novel gene loci and revealed differential functional enrichment between cohorts. To assess the impact of these mutations on early cardiac development, we integrated single-cell and spatial transcriptomics of early human heart development with our genetic findings. We discovered that the candidate gene expression was enriched in the myogenic progenitors of the cardiac outflow tract. Moreover, subsets of the candidate genes were found in specific gene coexpression modules along the cardiomyocyte differentiation trajectory. These integrative functional analyses help dissect the pathogenesis of TOF, revealing cellular hotspots in early heart development resulting in cardiac malformations.

Highlights

Congenital heart defects (CHD) have an incidence of ~1% at birth, and remain the leading cause of infant mortality worldwide [1]
Common and ultra-rare variant association analysis in known Tetralogy of Fallot (TOF)-associated genes First, we explored the association of candidate TOF genes implicated both from recent genome wide association studies (GWAS)
Except rs7863990 at SMARCA2 originally reported to be associated with TOF from a Chinese GWAS showed marginal association (odds ratio=1.56; 95% confidence interval(CI): 0.97-2.44; p=0.066), no significant association was detected in other TOF-associated loci reported from European-based GWAS (Supplementary Figure 1) [15]

Summary

Introduction

Congenital heart defects (CHD) have an incidence of ~1% at birth, and remain the leading cause of infant mortality worldwide [1]. Tetralogy of Fallot (TOF) is the most common form of cyanotic CHD, accounting for 10% of all CHD, and is characterized by four anatomic features: (i) a ventricular septal defect (VSD), (ii) pulmonary artery stenosis, (iii) overriding aorta, and (iv) right ventricular hypertrophy [2]. Malalignment of the outflow tract is the primary anatomic defect in TOF, from which other features follow [2]. Despite the improving surgical outcomes, patients remain at substantial risk for cardiac arrhythmias, pulmonary regurgitation, right ventricular failure, and neurodevelopmental deficits with increasing age. Even in patients with similar anatomic features and nearly identical surgical procedures, the ability to predict postoperative course is limited, emphasizing the need for a more complete understanding of the pathogenesis of TOF [4]

Methods

Results

Conclusion