Background For clinical genetic testing of cardiomyopathy (CMP), current guidelines do not address which gene panels to use: targeted panels specific to a CMP phenotype or expanded (panCMP) panels that include genes associated with multiple phenotypic subtypes. Aim Our objective was to assess the clinical utility of targeted versus panCMP panel testing in pediatric CMPs. Methods 151 pediatric patients with primary hypertrophic (n = 66), dilated (n = 64), restrictive (n = 8), or left‐ventricular non‐compaction (n = 13) CMP who underwent clinical genetic panel testing at a single centre were included. PanCMP (n = 47) and targeted panel testing (n = 104) were compared for yield of pathogenic variants and variants of unknown significance (VUS). Results Pathogenic variants were identified in 26% of patients, 42% had indeterminate results (only VUS detected), and 32% had negative results. Yield was lower (15%) in panCMP vs. targeted panel testing (32%) (P = .03) in all CMP subtypes. VUS detection was higher with panCMP (87%) than targeted panel testing (30%) (P <.0001). PanCMP panel testing only identified pathogenic variants in genes that overlapped targeted panels. Conclusion PanCMP testing did not increase diagnostic yield compared to targeted panel testing. Until accuracy of variant interpretation with panCMP panels improves, targeted panels may be suitable for clinical testing in pediatric CMP.

Objectives Adrenergic receptor (ADR) genotypes have been associated with adverse outcomes in heart failure. Our objective was to evaluate the association of ADR genotypes with post-Norwood outcomes in infants with hypoplastic left heart syndrome (HLHS). Methods Infants with HLHS participating in the Pediatric Heart Network Single Ventricle Reconstruction Trial underwent genotyping for four single nucleotide polymorphisms in three ADR genes: ADRB1_231A/G, ADRB1_1165G/C, ADRB2_5318C/G and ADRA2A_2790C/T. The association of genotype with freedom from serious adverse events (SAE) (death, transplant, extra-corporeal membrane oxygenation, cardiopulmonary resuscitation, acute shunt failure, unplanned re-operations, or necrotizing enterocolitis) during 14 months follow-up was assessed using Cox regression and the association with post-Norwood complications was assessed using Poisson regression. Models were adjusted for clinical and surgical factors. Results The study included 351 eligible patients (62% male; 83% White). The mean age at Norwood procedure was 5.6±3.6 days. 152 patients had SAEs during 14-month follow-up including 84 deaths and 10 transplants. ADRA2A_2790CC genotype had lower SAE-free survival compared to CT/TT genotypes during follow-up (Log rank test, p=0.02) and this association was independent of clinical and surgical risk factors (Adjusted Cox regression. HR 1.54 [1.04, 2.30] p=0.033). Post-Norwood complication rate did not differ by genotype. Conclusions Infants with HLHS harboring ADR genotypes that are associated with higher catecholamine release or sensitivity had lower event-free survival after staged palliation. Excess catecholamine activation may adversely affect cardiovascular adaptation after the Norwood procedure. Future studies should explore if targeting adrenergic activation in those harboring risk genotypes can improve outcomes. (ClinicalTrials.gov number, NCT00115934)