부산대학교 도서관

Introduction: Pediatric cardiomyopathy (CM) is a genetically heterogeneous high-risk condition, with a large proportion of cases labeled as idiopathic.Hypothesis: A comprehensive sequencing approach will demonstrate additional rare variants, implicating sarcomeric and non-sarcomeric protein mutations, in presumed idiopathic pediatric CM.Methods: Exome sequencing was performed in 528 unrelated pediatric CM probands recruited from12 centers. Positive (pathogenic/likely pathogenic) findings were identified by manual interpretation of 36 CM genes. After testing against this manual annotation, a support vector machine (SVM) learning approach was applied for classification of all exome rare variants.Results: Clinical phenotypes were: 53% dilated CM, 30% hypertrophic CM, 11% LV noncompaction/mixed CM and 6% restrictive CM. Average age at diagnosis was 4.5 years (IQR: 0.5-13.2). Only 42% had prior clinical genetic testing, mainly in HCM. Exome sequencing identified 793,725 variants of which 139,386 (264/subject) were rare variants (MAF < 0.01) predicted to impact protein function. Clinical-grade manual interpretation of rare variants in 36 CM genes was positive in 15% of DCM, 44% of HCM, 50% of RCM, and 31% of LVNC/mixed patients. Sarcomeric gene mutation frequency was similar to that reported in adult CM. SVM variant classification identified possible disease-causing variants in 46.6% of this cohort compared with 7.4% reported in the 1000 Genomes cohort. Strikingly, ≥ 2 potentially disease-causing variants per individual were identified in 14.6% of our cohort vs. only 0.96% in 1000 Genomes (p < 0.0001).Conclusions: Clinical genetic testing is underutilized in pediatric CM. Sarcomeric mutations occur at rates similar or greater than in adults. Individuals with multiple candidate causal alleles are not uncommon, suggesting that the interaction effects from several alleles may be clinically relevant in pediatric CM.