Approaches to understanding the genetics of congenital heart disease in Chinese

Abstract

Congenital heart disease (CHD) is a complex disorder, and understanding of the underlying genetic causes is still limited. Although a proportion of CHD is inherited in families, in the majority of patients, no genetic change is identified. In these cases, the risk of CHD recurring in the family can only be given as an estimation of around 3%. Studying the underlying genetics would benefit patients by making a definitive molecular diagnosis based on new genes identified and further improve the care of those affected by CHD.

This dissertation aimed to use the advanced genomic technologies of chromosomal microarray (CMA) and whole exome sequencing (WES) to decipher the underlying genetic component of two types of CHD: conotruncal heart defects (CTDs), and heterotaxy, a type of left-right patterning abnormality.

First, copy number variation (CNV) analysis of CTDs was performed using CMA. The methodology involves utilizing a large control cohort and stringent CNV filtering criteria. In this study, ten large, clinically relevant CNVs were detected in 116 Chinese patients.

Subsequently, WES data of a homogenous cohort of patients with Tetralogy of Fallot (TOF) was analyzed. Two approaches were employed: 1) Clinically actionable variants and 2) Discovery of novel ultra-rare damaging. Clinically actionable variants were found with a diagnostic yield of 2.2%, and important candidate genes and pathways were identified for TOF. Also, variants in the ZFPM2 gene were described in detail they are more commonly found in the Chinese population.

Finally, in a cohort of 26 patients with heterotaxy disorders, the CC2D1A gene was identified as a candidate gene. Results of zebrafish TALEN experiments are presented to demonstrate the benefit of using animal models for functional validation. Summarizing the evidence, CC2D1A is proposed as a novel disease gene for heterotaxy.

This series of work demonstrates the various approaches to studying the genetics of CHD and presents findings that are specific to the Chinese population. The combination of different methods (CMA and WES) also provides insights towards the best diagnostic strategy for this complex disease.