Abstract 15559: Genetic Characterization of a Large Pediatric Cardiomyopathy Cohort Reveals Novel Variants in Half of Patients.

Introduction: Cardiomyopathy (CMP) is a heterogeneous disease group affecting heart function and may lead to heart failure. Genetic variants in more than 50 genes have been linked to CMP phenotypes. The understanding of the natural course and the underlying molecular mechanisms of pediatric CMP and heart failure is incomplete. Hypothesis: This study aims to establish the abundance of genetic variants in known CMP disease genes in a large cohort of pediatric CMP patients. Methods: To identify genetic defects in pediatric CMP we investigated a cohort of patients </=18 years with hypertrophic CMP (HCM), dilated CMP (DCM), left ventricular noncompaction CMP (LVNC), restrictive CMP (RCM), and arrhythmogenic right ventricular CMP (ARVC). Screening of index patients and their first-degree relatives was performed with next generation sequencing (NGS) for genetic variants in 174 target genes. The detected genetic variants were bioinformatically filtered with a minor allele frequency (MAF) of <0.001, evaluated with in silico pathogenicity prediction tools, validated with the gnomAD reference data base, and classified according to the guidelines of the American College of Medical Genetics and Genomics (ACMG). Results: The cohort was composed of 80 index-patients with CMP (34 DCM, 23 HCM, 14 LVNC, 7 RCM, and 2 ARVC). Clinical screening was performed in 77% of the families. In 44% of these families, at least one other affected family member with CMP was identified. In the total cohort we identified 24 pathogenic, 33 likely pathogenic, and 69 variants of unknown significance. At least one likely pathogenic or pathogenic variant was identified in 45/80 cases. Variants were most frequently detected in genes encoding for myosin heavy chain 7 (MYH7), myosin binding protein C 3 (MYBPC3) , desmoplakin (DSP) , LIM domain binding 3 (LDB3) , and cardiac troponin I (TNNI3). Half of the detected variants are novel and not annotated in disease databases. Within this cohort, 26 individuals (32%) underwent heart transplantation (HTX) because of underlying DCM (n=17) and RCM (n=5). Variant classification revealed one pathogenic variant in 5 HTX patients and one likely pathogenic variant in 6 HTX patients. Variant interpretation was substantially limited by the lack of functional data for specific CMP genes. Conclusions: Our study reveals novel variants in half of the patients and is successful in identifying the underlying genetic cause (at least one likely pathogenic or pathogenic variant) in 45/80 cases of pediatric CMP. [ABSTRACT FROM AUTHOR]