Evaluation of the Genetic Basis of Familial Aggregation of Pacemaker Implantation by a Large Next Generation Sequencing Panel

• Published in: PloS one 2015-12, Vol.10 (12), p.e0143588-e0143588
• Main Authors: Celestino-Soper, Patrícia B S, Doytchinova, Anisiia, Steiner, Hillel A, Uradu, Andrea, Lynnes, Ty C, Groh, William J, Miller, John M, Lin, Hai, Gao, Hongyu, Wang, Zhiping, Liu, Yunlong, Chen, Peng-Sheng, Vatta, Matteo
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Agglomeration; Bioinformatics; Biology; Brugada Syndrome - genetics; Brugada Syndrome - therapy; Cardiac arrhythmia; Cardiac Conduction System Disease; Cardiology; Cardiovascular disease; Cardiovascular diseases; Care and treatment; Conduction; Congenital diseases; Coronary artery disease; DNA sequencing; Epidemiology; Etiology; Female; Gene sequencing; Genes; Genetic aspects; Genetic diversity; Genetic Predisposition to Disease; Genetic variance; Genetic Variation; Genetics; Heart; Heart diseases; Heart failure; High-Throughput Nucleotide Sequencing - methods; Humans; Implantation; Long QT syndrome; Male; Medicine; Middle Aged; Mutation; Pacemaker, Artificial; Pacemakers; Pathogenicity; Pathogens; Patients; Sequence Analysis, DNA - methods; Sick Sinus Syndrome - genetics; Sick Sinus Syndrome - therapy; Single-nucleotide polymorphism; Sinus; Sinuses; Sodium; Splicing; Studies; Transient receptor potential proteins
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0143588

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. 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. 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. 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.