Importance of genetic evaluation and testing in pediatric cardiomyopathy

Abstract

Pediatric cardiomyopathies are clinically heterogeneous heart muscle disorders that are responsible for significant morbidity and mortality. Phenotypes include hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, left ventricular noncompaction and arrhythmogenic right ventricular cardiomyopathy. There is substantial evidence for a genetic contribution to pediatric cardiomyopathy. To date, more than 100 genes have been implicated in cardiomyopathy, but comprehensive genetic diagnosis has been problematic because of the large number of genes, the private nature of mutations, and difficulties in interpreting novel rare variants. This review will focus on current knowledge on the genetic etiologies of pediatric cardiomyopathy and their diagnostic relevance in clinical settings. Recent developments in sequencing technologies are greatly impacting the pace of gene discovery and clinical diagnosis. Understanding the genetic basis for pediatric cardiomyopathy and establishing genotype-phenotype correlations may help delineate the molecular and cellular events necessary to identify potential novel therapeutic targets for heart muscle dysfunction in children.

Keywords: Pediatric; Mutation; Exome sequencing; Sarcomere

Core tip: Pediatric cardiomyopathy is a clinically and genetically heterogeneous heart muscle disease with five major phenotypes: hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, left ventricular noncompaction cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy. The genetic basis of these cardiomyopathies has been identified using traditional linkage analysis and sequencing. Novel gene discovery has been increased using modern next generation sequencing technologies, however the exact mechanisms of disease development are not fully known. In this review we focus on the current genetic knowledge of cardiomyopathies and their importance in diagnostic settings.