Next-Generation Sequencing Screening Reveals Novel Genetic Variants for Dilated Cardiomyopathy in Pediatric Chinese Patients

Abstract Dilated cardiomyopathy (DCM) is a myocardial disease characterized by bilateral or left ventricular cardiac dilation and systolic dysfunction leading to heart failure and sudden cardiac death in children. Most studies focus on the genetic alterations in DCM-related genes in adult populations; however, it remains enigmatic about the mutational landscape in pediatric DCM patients, especially in the Chinese population. We exploited the next-generation sequencing (NGS) technologies to genetically analyze 46 pediatric patients and to decipher the genotype-phenotype correlation in these patients’ clinical outcomes. Our results indicated DCM-associated pathogenic mutations in 10 genes related to the structure or function of the sarcomere, desmosomal and cytoskeletal proteins. We also identified 6 pathogenic mutations (5 novel) in the titin (TTN) gene leading to the formation of truncated TTN protein variants in 6 (13%) out of 46 patients each. Furthermore, we investigated the correlations between TTN gene mutation and clinical outcomes in these patients. Conclusion: Our data suggest that one-third of cases of pediatric DCM are caused by genetic mutations. The role of TTN variants should not be underestimated in pediatric DCM and age-dependent pathogenic penetrance of these genetic mutations needs to be considered in the case of familial DCM. Thus, NGS analysis can be applied to decode the yet unknown DCM etiological genetic factors in pediatric as well as adult patients.