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 Groh, John Miller, Hai Lin, Hongyu Gao, Zhiping Wang, Yunlong Liu, Peng-Sheng Chen, Matteo Vatta

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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

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Pacemakers
Agglomeration
heart diseases
Heart Diseases
Genes
etiology
Sick Sinus Syndrome
Charge coupled devices
sinuses
Single Nucleotide Polymorphism
Virulence
pathogenicity
genes
Population

ASJC Scopus subject areas

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

Cite this

Celestino-Soper, P. B. S., Doytchinova, A., Steiner, H. A., Uradu, A., Lynnes, T. C., Groh, W., ... 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

Evaluation of the genetic basis of familial aggregation of pacemaker implantation by a large next generation sequencing panel. / Celestino-Soper, Patrícia B S; Doytchinova, Anisiia; Steiner, Hillel A.; Uradu, Andrea; Lynnes, Ty C.; Groh, William; Miller, John; Lin, Hai; Gao, Hongyu; Wang, Zhiping; Liu, Yunlong; Chen, Peng-Sheng; Vatta, Matteo.

In: PLoS One, Vol. 10, No. 12, e0143588, 01.12.2015.

Research output: Contribution to journalArticle

Celestino-Soper, PBS, Doytchinova, A, Steiner, HA, Uradu, A, Lynnes, TC, Groh, W, Miller, J, 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, vol. 10, no. 12, e0143588. https://doi.org/10.1371/journal.pone.0143588
Celestino-Soper, Patrícia B S ; Doytchinova, Anisiia ; Steiner, Hillel A. ; Uradu, Andrea ; Lynnes, Ty C. ; Groh, William ; Miller, John ; Lin, Hai ; Gao, Hongyu ; Wang, Zhiping ; Liu, Yunlong ; Chen, Peng-Sheng ; Vatta, Matteo. / Evaluation of the genetic basis of familial aggregation of pacemaker implantation by a large next generation sequencing panel. In: PLoS One. 2015 ; Vol. 10, No. 12.
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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.",
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AU - Uradu, Andrea

AU - Lynnes, Ty C.

AU - Groh, William

AU - Miller, John

AU - Lin, Hai

AU - Gao, Hongyu

AU - Wang, Zhiping

AU - Liu, Yunlong

AU - Chen, Peng-Sheng

AU - Vatta, Matteo

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