A Path to Implement Precision Child Health Cardiovascular Medicine

Abstract

Congenital heart defects (CHDs) affect approximately 1% of live births and are a major source of childhood morbidity and mortality even in countries with advanced healthcare systems. Along with phenotypic heterogeneity, the underlying etiology of CHDs is multifactorial, involving genetic, epigenetic, and/or environmental contributors. Clear dissection of the underlying mechanism is a powerful step to establish individualized therapies. However, the majority of CHDs are yet to be clearly diagnosed for the underlying genetic and environmental factors, and even less with effective therapies. Although the survival rate for CHDs is steadily improving, there is still a significant unmet need for refining diagnostic precision and establishing targeted therapies to optimize life quality and to minimize future complications. In particular, proper identification of disease associated genetic variants in humans has been challenging, and this greatly impedes our ability to delineate gene-environment interactions that contribute to the pathogenesis of CHDs. Implementing a systematic multileveled approach can establish a continuum from phenotypic characterization in the clinic to molecular dissection using combined next-generation sequencing platforms and validation studies in suitable models at the bench. Key elements necessary to advance the field are: first, proper delineation of the phenotypic spectrum of CHDs; second, defining the molecular genotype/phenotype by combining whole-exome sequencing and transcriptome analysis; third, integration of phenotypic, genotypic, and molecular datasets to identify molecular network contributing to CHDs; fourth, generation of relevant disease models and multileveled experimental investigations. In order to achieve all these goals, access to high-quality biological specimens from well-defined patient cohorts is a crucial step. Therefore, establishing a CHD BioCore is an essential infrastructure and a critical step on the path toward precision child health cardiovascular medicine.

Keywords: RNA-sequencing; bio banking; congenital heart defects; repository; transcriptome; variants; whole-exome sequencing.

Figure 1

The congenital heart defect BioCore (CHD-BioCore) implements precision child health cardiovascular medicine. Illustration of the basic principle of the CHD BioCore to establish an integrated continuum between the bedside and research laboratory with synergized resources and collaborative expertise.

Figure 2

The congenital heart defect BioCore (CHD-BioCore): strategy and frame work. Illustration of the strategic framework for the CHD BioCore: (1) Proper delineation of the phenotypic spectrum of CHDs. (2) Defining the molecular genotype/phenotype by combining whole-exome sequencing (WES) and transcriptome analysis. (3) Integration of phenotypic and molecular datasets to identify distinct molecular function networks associated with CHD phenotypes. (4) Integration of genomic data by mapping the putative variants to the molecular networks for mutation prioritization or pathway identification. (5) Mechanistic validation in relevant disease models and human induced pluripotent stem cells (iPSCs) for translational application.

Figure 3

The congenital heart defect BioCore (CHD-BioCore): organization and network. Illustration of the central components of an impactful CHD BioCore for integrated multisystem approach: (1) The Clinical Registry. (2) The Bio Banking Repository. (3) The Genomic Depository. The key elements and resources for each component as well as the integration among them by implementing systems biology approach were also illustrated.