title: Evaluation of the Genetic Basis of Familial Aggregation of Pacemaker Implantation by a Large Next Generation Sequencing Panel.
abstract: BACKGROUND
  The etiology of conduction disturbances necessitating permanent pacemaker (PPM) implantation is often unknown, although familial aggregation of PPM (faPPM) suggests a possible genetic basis. We developed a pan-cardiovascular next generation sequencing (NGS) panel to genetically characterize a selected cohort of faPPM.
  
  
  METHODS
  We designed and validated a custom NGS panel targeting the coding and splicing regions of 246 genes with involvement in cardiac pathogenicity. We enrolled 112 PPM patients and selected nine (8%) with faPPM to be analyzed by NGS.
  
  
  RESULTS
  Our NGS panel covers 95% of the intended target with an average of 229x read depth at a minimum of 15-fold depth, reaching a SNP true positive rate of 98%. The faPPM patients presented with isolated cardiac conduction disease (ICCD) or sick sinus syndrome (SSS) without overt structural heart disease or identifiable secondary etiology. Three patients (33.3%) had heterozygous deleterious variants previously reported in autosomal dominant cardiac diseases including CCD: LDB3 (p.D117N) and TRPM4 (p.G844D) variants in patient 4; TRPM4 (p.G844D) and ABCC9 (p.V734I) variants in patient 6; and SCN5A (p.T220I) and APOB (p.R3527Q) variants in patient 7.
  
  
  CONCLUSIONS
  FaPPM occurred in 8% of our PPM clinic population. The employment of massive parallel sequencing for a large selected panel of cardiovascular genes identified a high percentage (33.3%) of the faPPM patients with deleterious variants previously reported in autosomal dominant cardiac diseases, suggesting that genetic variants may play a role in faPPM.
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Patrícia B S
authors.initials: PB
authors.lastname: Celestino-Soper
authors.affiliation: Krannert Institute of Cardiology, Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Anisiia
authors.initials: A
authors.lastname: Doytchinova
authors.affiliation: Krannert Institute of Cardiology, Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America.|Baruch Padeh Medical Center, Poriya MP Lower Galilee, Israel.|Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel.
authors.forename: Hillel A
authors.initials: HA
authors.lastname: Steiner
authors.affiliation: Krannert Institute of Cardiology, Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Andrea
authors.initials: A
authors.lastname: Uradu
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Ty C
authors.initials: TC
authors.lastname: Lynnes
authors.affiliation: Krannert Institute of Cardiology, Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: William J
authors.initials: WJ
authors.lastname: Groh
authors.affiliation: Krannert Institute of Cardiology, Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: John M
authors.initials: JM
authors.lastname: Miller
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States of America.|Center for Computational Biology and Bioinformatics, Indiana University Purdue University Indianapolis, Indianapolis, IN, United States of America.
authors.forename: Hai
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Gao
authors.affiliation: Center for Computational Biology and Bioinformatics, Indiana University Purdue University Indianapolis, Indianapolis, IN, United States of America.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States of America.|Center for Computational Biology and Bioinformatics, Indiana University Purdue University Indianapolis, Indianapolis, IN, United States of America.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Krannert Institute of Cardiology, Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States of America.|Krannert Institute of Cardiology, Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Matteo
authors.initials: M
authors.lastname: Vatta
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053840:Brugada Syndrome / Q000235:genetics* / Q000628:therapy; D000075224:Cardiac Conduction System Disease; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010138:Pacemaker, Artificial; D017422:Sequence Analysis, DNA / Q000379:methods*; D012804:Sick Sinus Syndrome / Q000235:genetics* / Q000628:therapy