Abstract 20673: Mutations in TTN Coexisting With Others in Genes Encoding Functional, Structural and Ion Channels Components of the Cardiomyocytes Cause Severe Dilated Cardiomyopathy in Children

• Published in: Circulation (New York, N.Y.) Vol. 134; no. Suppl_1 Suppl 1; p. A20673
• Main Authors: Balderrabano-Saucedo, Norma, Cano-Hernández, Karla, Hu, Dan, Pfeiffer, Ryan, Sánchez-Boiso, Adriana, Wu, Yuesheng, Carrier, Tabitha, Zamora-Mejía, José Enrique, Erdmenger-Orellana, Julio, Nava, Santiago, Magaña, Keneth G, Albarracín-Ceballos, Ricardo F, Becerra-Becerra, Rosario, Segura-Stanford, Begoña, Tamayo-Espinosa, Tania, Cruz-Miranda, Ana, Suárez-Delgado, Esteban, Barajas Martínez, Héctor
• Format: Journal Article
• Language: English
• Published: by the American College of Cardiology Foundation and the American Heart Association, Inc 11.11.2016
• ISSN: 0009-7322; 1524-4539

IntroductionDilated cardiomyopathy (DCM) is one of the most frequent causes of heart failure (HF). It has been shown rare variations in more than 40 genes related to DCM, most of which encode structural components of the heart. However, there is still substantial proportion of the genetic basis among DCM cases remains unsolved.HypothesisWe sought to determine the genetic basis of severe idiopathic DCM cases in children with wide spectrum of targeted genes, and to establish the yield of modern next generation sequencing (NGS) technologies in this setting.MethodsChildren with idiopathic DCM referred for cardiac transplantation were clinical, echocardiographic and electrocardiographic studied. DNA from a peripheral blood sample was obtained. Direct sequence of all exons and introns borders were screen for functional, structural and ion channels mutations. To uncover the new molecular genetic basis for DCM we used Next Generation Sequence (NGS) for screening and validation of the results were completed by Sanger Sequencing.ResultsThe study cohort is comprised 23 unrelated children. Fourteen girls (60.8%), age9.36 ± 4.6 y/o, LVEDD z-scores6.35 ± 2.56, LVEF 21.99 ± 9.2. QTc465.3 ± 58.83. Ten died (43.47%), 7 were transplanted (30.43%). Genetic evaluation showed 128 mutations in 60 genes (28 not previously associated to DCM) encoding structural (38.33%) or functional/ion channel (61.66%) components of cardiomyocytes. Patients carried 2-9 mutations in 2-9 genes. TTN was the most commonly affected showing 32 mutations in 19 (82.6%) and commonly coexisting with other mutations in several genes such as DSP, TNNT2, MYH7, DSG2, PKP2, SCN5A, RYR2. The vast majority of mutations were inherited. None of the family members carried all the set of mutations found in the affected children.ConclusionsThe genetic spectrum of DCM in children is heterogeneous and involves multiple genes. NGS technology plus detailed clinical studies allow identification of causative mutations in the vast majority of the DCM cases. A severe phenotypic expression of DCM in children is associated to a high mutational load in genes encoding for structural, functional and ion channels components of the cardiomyocytes, such as TTN.