title: Genetic basis of familial dilated cardiomyopathy patients undergoing heart transplantation.
abstract: Dilated cardiomyopathy (DCM) is the most frequent cause of heart transplantation (HTx). The genetic basis of DCM among patients undergoing HTx has been poorly characterized. We sought to determine the genetic basis of familial DCM HTx and to establish the yield of modern next generation sequencing (NGS) technologies in this setting.
  
  
  
  Fifty-two heart-transplanted patients due to familial DCM underwent NGS genetic evaluation with a panel of 126 genes related to cardiac conditions (59 associated with DCM). Genetic variants were initially classified as pathogenic mutations or as variants of uncertain significance (VUS). Final pathogenicity status was determined by familial cosegregation studies.
  
  
  
  Initially, 24 pathogenic mutations were found in 21 patients (40%); 25 patients (48%) carried 19 VUS and 6 (12%) did not show any genetic variant. Familial evaluation of 220 relatives from 36 of the 46 families with genetic variants confirmed pathogenicity in 14 patients and allowed reclassification of VUS as pathogenic in 17 patients, and as non-pathogenic in 3 cases. At the end of the study, the DCM-causing mutation was identified in 38 patients (73%) and 5 patients (10%) harbored only VUS. No genetic variants were identified in 9 cases (17%).
  
  
  
  The genetic spectrum of familial DCM patients undergoing HTx is heterogeneous and involves multiple genes. NGS technology plus detailed familial studies allow identification of causative mutations in the vast majority of familial DCM cases. Detailed familial studies remain critical to determine the pathogenicity of underlying genetic defects in a substantial number of cases.
authors.affiliation: Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain.
authors.forename: Sofia
authors.initials: S
authors.lastname: Cuenca
authors.affiliation: Heart Failure and Heart Transplantation Unit, Department of Cardiology, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Ruiz-Cano
authors.affiliation: Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain.
authors.forename: Juan Ramón
authors.initials: JR
authors.lastname: Gimeno-Blanes
authors.affiliation: Heart Failure and Heart Transplantation Unit, Department of Cardiology, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Jurado
authors.affiliation: Department of Pathology, Hospital Universitario Puerta de Hierro, Madrid, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Salas
authors.affiliation: Health In Code, A Coruña, Spain.
authors.forename: Iria
authors.initials: I
authors.lastname: Gomez-Diaz
authors.affiliation: Myocardial Biology Programme, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Padron-Barthe
authors.affiliation: Department of Cardiology, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain.
authors.forename: Jose Javier
authors.initials: JJ
authors.lastname: Grillo
authors.affiliation: Department of Immunology, Hospital Universitario Puerta de Hierro, Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Vilches
authors.affiliation: Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Segovia
authors.affiliation: Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain.
authors.forename: Domingo
authors.initials: D
authors.lastname: Pascual-Figal
authors.affiliation: Myocardial Biology Programme, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Lara-Pezzi
authors.affiliation: Health In Code, A Coruña, Spain.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Monserrat
authors.affiliation: Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Alonso-Pulpon
authors.affiliation: Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain; Myocardial Biology Programme, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. Electronic address: pablogpavia@yahoo.es.
authors.forename: Pablo
authors.initials: P
authors.lastname: Garcia-Pavia
mesh_terms: D002311:Cardiomyopathy, Dilated; D016027:Heart Transplantation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation
keywords: familial dilated cardiomyopathy; genetics; heart transplantation; mutation; next generation sequencing