Evaluation of the genetic basis of familial aggregation of pacemaker implantation by a large next generation sequencing panel

Patrícia B.S. Celestino-Soper, Anisiia Doytchinova, Hillel A. Steiner, Andrea Uradu, Ty C. Lynnes, William J. Groh, John M. Miller, Hai Lin, Hongyu Gao, Zhiping Wang, Yunlong Liu, Peng Sheng Chen, Matteo Vatta

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6 Scopus citations

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. Materials and 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. Conclusion: 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.

Original languageEnglish (US)
Article numbere0143588
JournalPloS one
Volume10
Issue number12
DOIs
StatePublished - Dec 1 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Celestino-Soper, P. B. S., Doytchinova, A., Steiner, H. A., Uradu, A., Lynnes, T. C., Groh, W. J., Miller, J. M., Lin, H., Gao, H., Wang, Z., Liu, Y., Chen, P. S., & Vatta, M. (2015). Evaluation of the genetic basis of familial aggregation of pacemaker implantation by a large next generation sequencing panel. PloS one, 10(12), [e0143588]. https://doi.org/10.1371/journal.pone.0143588