Pediatric Hypertrophic Cardiomyopathy: Exploring the Genotype-Phenotype Association

Abstract

Pediatric hypertrophic cardiomyopathy (HCM) is the most common form of cardiomyopathy in children and a leading cause of sudden cardiac death. Yet, the association between genotype variation, phenotype expression, and adverse events in pediatric HCM has not been fully elucidated. Although the literature on this topic is evolving in adult HCM, the evidence in children is lacking. Solidifying our understanding of this relationship could improve risk stratification as well as improve our comprehension of the underlying pathophysiological characteristics of pediatric HCM. In this state-of-the-art review, we examine the current literature on genetic variations in HCM and their association with outcomes in children, discuss the current approaches to identifying cardiovascular phenotypes in pediatric HCM, and explore possible avenues that could improve sudden cardiac death risk assessment.

Keywords: cardiomyopathy; congenital heart disease; genetics; hypertrophy; imaging.

Figure 1. A potential link between genetic variation, phenotypic expression, and adverse events.

LVH indicates left ventricular hypertrophy.

Figure 2. Sources of genetic variation.

Nonsarcomeric genetic variations can lead to the ventricular hypertrophy phenotype and outcomes associated with hypertrophic cardiomyopathy (HCM). A, Mutations in genetic pathways that are not directly linked to sarcomeric gene mutations, such as those essential in fibrosis or cardiomyocyte differentiation, can lead to pathologic hypertrophy. B, Mutations in proteins that are associated with the sarcomeric unit, especially those that attach the sarcomere to the extracellular membrane, have been linked to HCM. C, Noncoding mutations, such as in the enhancer or promoter regions of DNA transcription of cardiomyopathy genes, have also been implicated in HCM. Created with BioRender.com. Akt indicates protein kinase B; ALPK3, α‐protein kinase 3; FKTN gene (or FCMD): provides instructions for making a protein called fukutin. Mem., membrane; mTORC, mammalian target of rapamycin complex; and TF, transcription factor.