Celestino-Soper, Patrícia B. S.Doytchinova, AnisiiaSteiner, Hillel A.Uradu, AndreaLynnes, Ty C.Groh, William J.Miller, John M.Lin, HaiGao, HongyuWang, ZhipingLiu, YunlongChen, Peng-ShengVatta, Matteo2017-01-042017-01-042015Celestino-Soper, P. B. S., Doytchinova, A., Steiner, H. A., Uradu, A., Lynnes, T. C., Groh, W. J., … 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. http://doi.org/10.1371/journal.pone.01435881932-6203https://hdl.handle.net/1805/11761BACKGROUND: 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.en-USAttribution 4.0 InternationalBrugada SyndromegeneticsGenetic VariationHigh-Throughput Nucleotide SequencingmethodsSequence Analysis, DNASick Sinus SyndromeArticle