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

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2015 Dec 5

PMID 26636822

Citations 8

Authors

Patricia 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

Affiliations

Soon will be listed here.

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.

Citing Articles

The impact of common and rare genetic variants on bradyarrhythmia development.

Weng L, Ramo J, Jurgens S, Khurshid S, Chaffin M, Hall A Nat Genet. 2025; 57(1):53-64.

PMID: 39747593 PMC: 11735381. DOI: 10.1038/s41588-024-01978-2.

The Role of Gene Mutations in Causing Familial Progressive Cardiac Conduction Disease: A Further Contribution.

Palladino A, Papa A, Petillo R, Scutifero M, Morra S, Passamano L Genes (Basel). 2022; 13(2).

PMID: 35205305 PMC: 8871839. DOI: 10.3390/genes13020258.

Reevaluating the Mutation Classification in Genetic Studies of Bradycardia Using ACMG/AMP Variant Classification Framework.

Cheng L, Li X, Zhao L, Wang Z, Zhang J, Liang Z Int J Genomics. 2020; 2020:2415850.

PMID: 32211440 PMC: 7061116. DOI: 10.1155/2020/2415850.

Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases.

Hayashi K, Teramoto R, Nomura A, Asano Y, Beerens M, Kurata Y Cardiovasc Res. 2020; 116(13):2116-2130.

PMID: 31977013 PMC: 8453299. DOI: 10.1093/cvr/cvaa010.

Genetic Discovery of ATP-Sensitive K Channels in Cardiovascular Diseases.

Huang Y, Hu D, Huang C, Nichols C Circ Arrhythm Electrophysiol. 2019; 12(5):e007322.

PMID: 31030551 PMC: 6494091. DOI: 10.1161/CIRCEP.119.007322.

References

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5):405-24. PMC: 4544753. DOI: 10.1038/gim.2015.30. View

Tan H, Bezzina C, Viswanathan P, van Tintelen P, van den Berg M, Wilde A . A sodium-channel mutation causes isolated cardiac conduction disease. Nature. 2001; 409(6823):1043-7. DOI: 10.1038/35059090. View

Xu X, Moebius F, Gill D, Montell C . Regulation of melastatin, a TRP-related protein, through interaction with a cytoplasmic isoform. Proc Natl Acad Sci U S A. 2001; 98(19):10692-7. PMC: 58528. DOI: 10.1073/pnas.191360198. View

Frey N, Olson E . Calsarcin-3, a novel skeletal muscle-specific member of the calsarcin family, interacts with multiple Z-disc proteins. J Biol Chem. 2002; 277(16):13998-4004. DOI: 10.1074/jbc.M200712200. View

Balmer C, Fasnacht M, Rahn M, Molinari L, Bauersfeld U . Long-term follow up of children with congenital complete atrioventricular block and the impact of pacemaker therapy. Europace. 2002; 4(4):345-9. DOI: 10.1053/eupc.2002.0266. View

Benson D, Wang D, Dyment M, Knilans T, Fish F, Strieper M . Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A). J Clin Invest. 2003; 112(7):1019-28. PMC: 198523. DOI: 10.1172/JCI18062. View

Vatta M, Mohapatra B, Jimenez S, Sanchez X, Faulkner G, Perles Z . Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction. J Am Coll Cardiol. 2003; 42(11):2014-27. DOI: 10.1016/j.jacc.2003.10.021. View

Senges J, Weihe E, Brachmann J, Pelzer D, Nimmrich H, Kubler W . Effects of hypercholesterolaemia without ischemia on some electrophysiological and ultrastructural properties of the rabbit heart. J Mol Cell Cardiol. 1981; 13(3):253-64. DOI: 10.1016/0022-2828(81)90314-x. View

Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson J . SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell. 1995; 80(5):805-11. DOI: 10.1016/0092-8674(95)90359-3. View

10.

MICHAELSSON M, Jonzon A, Riesenfeld T . Isolated congenital complete atrioventricular block in adult life. A prospective study. Circulation. 1995; 92(3):442-9. DOI: 10.1161/01.cir.92.3.442. View

11.

Chen Q, Kirsch G, Zhang D, Brugada R, Brugada J, Brugada P . Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature. 1998; 392(6673):293-6. DOI: 10.1038/32675. View

12.

Schott J, Alshinawi C, Kyndt F, Probst V, Hoorntje T, Hulsbeek M . Cardiac conduction defects associate with mutations in SCN5A. Nat Genet. 1999; 23(1):20-1. DOI: 10.1038/12618. View

13.

Olson T, Michels V, Ballew J, Reyna S, Karst M, Herron K . Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. JAMA. 2005; 293(4):447-54. PMC: 2039897. DOI: 10.1001/jama.293.4.447. View

14.

Smits J, Veldkamp M, Wilde A . Mechanisms of inherited cardiac conduction disease. Europace. 2005; 7(2):122-37. DOI: 10.1016/j.eupc.2004.11.004. View

15.

Minoretti P, Falcone C, Aldeghi A, Olivieri V, Mori F, Emanuele E . A novel Val734Ile variant in the ABCC9 gene associated with myocardial infarction. Clin Chim Acta. 2006; 370(1-2):124-8. DOI: 10.1016/j.cca.2006.02.007. View

16.

Dobrzynski H, Boyett M, Anderson R . New insights into pacemaker activity: promoting understanding of sick sinus syndrome. Circulation. 2007; 115(14):1921-32. DOI: 10.1161/CIRCULATIONAHA.106.616011. View

17.

Tan B, Iturralde-Torres P, Medeiros-Domingo A, Nava S, Tester D, Valdivia C . A novel C-terminal truncation SCN5A mutation from a patient with sick sinus syndrome, conduction disorder and ventricular tachycardia. Cardiovasc Res. 2007; 76(3):409-17. PMC: 2100438. DOI: 10.1016/j.cardiores.2007.08.006. View

18.

Harris P, Taylor R, Thielke R, Payne J, Gonzalez N, Conde J . Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2008; 42(2):377-81. PMC: 2700030. DOI: 10.1016/j.jbi.2008.08.010. View

19.

Gui J, Wang T, Jones R, Trump D, Zimmer T, Lei M . Multiple loss-of-function mechanisms contribute to SCN5A-related familial sick sinus syndrome. PLoS One. 2010; 5(6):e10985. PMC: 2881866. DOI: 10.1371/journal.pone.0010985. View

20.

Liu H, El Zein L, Kruse M, Guinamard R, Beckmann A, Bozio A . Gain-of-function mutations in TRPM4 cause autosomal dominant isolated cardiac conduction disease. Circ Cardiovasc Genet. 2010; 3(4):374-85. DOI: 10.1161/CIRCGENETICS.109.930867. View