Diagnostic yield of exome and genome sequencing for critically ill pediatric cardiac patients

Genetic testing guidelines for children in cardiac intensive care units (CICUs) remain limited despite a high prevalence of genetic diseases among this population. Advances in next-generation sequencing technologies, especially exome sequencing (ES) and genome sequencing (GS), enable more comprehensive genetic evaluations than traditional testing modalities such as chromosomal microarray (CMA). While testing recommendations exist for cardiomyopathies and arrhythmias, broad application of next-generation sequencing, especially ES/GS, across indications for admission to CICU has not been recommended amongst cardiology societies. We aimed to evaluate the diagnostic efficacy of ES/GS in critically ill pediatric patients with cardiac disease.

Retrospective chart review of patients who underwent clinical ES/GS in a quaternary hospital's pediatric CICU between January 2020 and August 2023. Patient demographics and clinical characteristics were collected and analyzed. Results were compared by test type, cardiac phenotype, and extracardiac anomalies status.

Forty-five patients underwent clinical ES/GS, with median age at testing of 33 [7-905] days. Primary cardiac phenotypes included congenital heart disease (CHD), ventricular dysfunction, and arrhythmia. Diagnostic results were found in 20 patients (44.4%) with 18/20 (90%) linked to cardiac phenotypes. Diagnostic yield was not different among cardiac phenotype groups but was higher in patients with extracardiac anomalies. Notably, gene panels would have failed to make 36% of diagnoses made by ES/GS.

ES and GS provided high diagnostic yield in critically ill cardiac patients across various phenotypes. As next-generation sequencing technologies and interpretation capabilities mature, diagnostic abilities in pediatric cardiac disease will continue to advance.