Uncovering the Genetic Basis of Congenital Heart Disease: Recent Advancements and Implications for Clinical Management

Congenital heart disease (CHD) is the most prevalent hereditary disorder, affecting approximately 1% of all live births. A reduction in morbidity and mortality has been achieved with advancements in surgical intervention, yet challenges in managing complications, extracardiac abnormalities, and comorbidities still exist. To address these, a more comprehensive understanding of the genetic basis underlying CHD is required to establish how certain variants are associated with the clinical outcomes. This will enable clinicians to provide personalized treatments by predicting the risk and prognosis, which might improve the therapeutic results and the patient’s quality of life. We review how advancements in genome sequencing are changing our understanding of the genetic basis of CHD, discuss experimental approaches to determine the significance of novel variants, and identify barriers to use this knowledge in the clinics. Next-generation sequencing technologies are unravelling the role of oligogenic inheritance, epigenetic modification, genetic mosaicism, and noncoding variants in controlling the expression of candidate CHD-associated genes. However, clinical risk prediction based on these factors remains challenging. Therefore, studies involving human-induced pluripotent stem cells and single-cell sequencing help create preclinical frameworks for determining the significance of novel genetic variants. Clinicians should be aware of the benefits and implications of the responsible use of genomics. To facilitate and accelerate the clinical integration of these novel technologies, clinicians should actively engage in the latest scientific and technical developments to provide better, more personalized management plans for patients.