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. 2015 Dec 4;10(12):e0143588.
doi: 10.1371/journal.pone.0143588. eCollection 2015.

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

Patrícia B S Celestino-Soper  1 , Anisiia Doytchinova  2 , Hillel A Steiner  2   3   4 , Andrea Uradu  2 , Ty C Lynnes  1 , William J Groh  2 , John M Miller  2 , Hai Lin  1   5 , Hongyu Gao  1 , Zhiping Wang  5 , Yunlong Liu  1   5 , Peng-Sheng Chen  2 , Matteo Vatta  1   2
Affiliations

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

Patrícia B S Celestino-Soper et al. PLoS One. .

Erratum in

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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Conflict of interest statement

Competing Interests: MV, PCS, and TCL are members of the Indiana University Molecular Diagnostic Laboratory.

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