{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T13:42:20Z","timestamp":1790170940247,"version":"4.1.0"},"reference-count":57,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2016,5,16]],"date-time":"2016-05-16T00:00:00Z","timestamp":1463356800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["1R01HL129008-01"],"award-info":[{"award-number":["1R01HL129008-01"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"DOI":"10.1371\/journal.pone.0155421","type":"journal-article","created":{"date-parts":[[2016,5,16]],"date-time":"2016-05-16T17:38:57Z","timestamp":1463420337000},"page":"e0155421","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":29,"title":["Exome Sequencing Identifies a Novel LMNA Splice-Site Mutation and Multigenic Heterozygosity of Potential Modifiers in a Family with Sick Sinus Syndrome, Dilated Cardiomyopathy, and Sudden Cardiac Death"],"prefix":"10.1371","volume":"11","author":[{"given":"Michael V.","family":"Zaragoza","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianna","family":"Fung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ember","family":"Jensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances","family":"Oh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Cung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda A.","family":"McCarthy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine K.","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Van","family":"Hoang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simin A.","family":"Hakim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Grosberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2016,5,16]]},"reference":[{"key":"ref1","first-page":"1725","article-title":"Diagnosis and treatment of sick sinus syndrome","volume":"67","author":"V Adan","year":"2003","journal-title":"Am Fam Physician"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1161\/01.CIR.47.3.635","article-title":"The sick sinus syndrome","volume":"47","author":"MI Ferrer","year":"1973","journal-title":"Circulation"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1161\/01.CIR.22.5.887","article-title":"Congenital familial nodal rhythm","volume":"22","author":"JM Bacos","year":"1960","journal-title":"Circulation"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1172\/JCI200318062","article-title":"Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A)","volume":"112","author":"DW Benson","year":"2003","journal-title":"J Clin Invest"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1056\/NEJMoa052475","article-title":"Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel","volume":"354","author":"R Milanesi","year":"2006","journal-title":"N Engl J Med"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1038\/nrg3031","article-title":"Exome sequencing as a tool for Mendelian disease gene discovery","volume":"12","author":"MJ Bamshad","year":"2011","journal-title":"Nature Reviews Genetics"},{"key":"ref7","first-page":"93","article-title":"Guidelines for the study of familial dilated cardiomyopathies. Collaborative Research Group of the European Human and Capital Mobility Project on Familial Dilated Cardiomyopathy","volume":"20","author":"L Mestroni","year":"1999","journal-title":"Eur Heart J"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1161\/01.CIR.103.2.196","article-title":"Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia","volume":"103","author":"SG Priori","year":"2001","journal-title":"Circulation"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1093\/nar\/10.2.459","article-title":"A catalogue of splice junction sequences","volume":"10","author":"SM Mount","year":"1982","journal-title":"Nucleic Acids Res"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1056\/NEJM199912023412302","article-title":"Missense mutations in the rod domain of the lamin A\/C gene as causes of dilated cardiomyopathy and conduction-system disease","volume":"341","author":"D Fatkin","year":"1999","journal-title":"N Engl J Med"},{"key":"ref11","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gks596","article-title":"Primer3-new capabilities and interfaces","volume":"40","author":"A Untergasser","year":"2012","journal-title":"Nucleic Acids Research"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1186\/1471-2105-13-134","article-title":"Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction","volume":"13","author":"J Ye","year":"2012","journal-title":"BMC Bioinformatics"},{"key":"ref13","first-page":"66","article-title":"Involvement of the Kir2 gene family in catecholaminergic polymorphic ventricular tachycardia; analysis for mutation and identification of numerous pseudogenes","volume":"25","author":"A Postma","year":"2004","journal-title":"Eur Heart J"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1097\/HCO.0b013e32835fb728","article-title":"Genetic testing in cardiovascular medicine: current landscape and future horizons","volume":"28","author":"AC Sturm","year":"2013","journal-title":"Curr Opin Cardiol"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1097\/HCO.0b013e328352207e","article-title":"Next-generation sequencing to identify genetic causes of cardiomyopathies","volume":"27","author":"N Norton","year":"2012","journal-title":"Curr Opin Cardiol"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1093\/cvr\/cvt106","article-title":"Nuclear accumulation of androgen receptor in gender difference of dilated cardiomyopathy due to lamin A\/C mutations","volume":"99","author":"T Arimura","year":"2013","journal-title":"Cardiovasc Res"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1038\/ejhg.2013.16","article-title":"Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy","volume":"21","author":"R Roncarati","year":"2013","journal-title":"Eur J Hum Genet"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"e83322","DOI":"10.1371\/journal.pone.0083322","article-title":"Whole-exome sequencing to identify a novel LMNA gene mutation associated with inherited cardiac conduction disease","volume":"8","author":"CC Lai","year":"2013","journal-title":"PLoS One"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1002\/humu.22033","article-title":"Detecting false-positive signals in exome sequencing","volume":"33","author":"KV Fuentes Fajardo","year":"2012","journal-title":"Hum Mutat"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/gm432","article-title":"Low concordance of multiple variant-calling pipelines: practical implications for exome and genome sequencing","volume":"5","author":"J O'Rawe","year":"2013","journal-title":"Genome Med"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"2426","DOI":"10.1093\/nar\/gkr1073","article-title":"The allele distribution in next-generation sequencing data sets is accurately described as the result of a stochastic branching process","volume":"40","author":"V Heinrich","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1002\/humu.20250","article-title":"Thymopoietin (lamina-associated polypeptide 2) gene mutation associated with dilated cardiomyopathy","volume":"26","author":"MR Taylor","year":"2005","journal-title":"Hum Mutat"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1086\/302623","article-title":"The origins of hypertrophic cardiomyopathy-causing mutations in two South African subpopulations: a unique profile of both independent and founder events","volume":"65","author":"JC Moolman-Smook","year":"1999","journal-title":"Am J Hum Genet"},{"key":"ref24","first-page":"759","article-title":"Mutation of V896M in cardiac myosin binding protein-c gene in two Chinese families with hypertrophic cardiomyopathy","volume":"3","author":"AL Wang","year":"2010","journal-title":"Mol Med Rep"},{"key":"ref25","first-page":"670","article-title":"Acquired Post Patrum Bradycardia: Clinical Features Associated with Mutations in the hyperpolarization-activated nucleotide-gated channel 4 Cardiac Ion Channel","volume":"13","author":"E Nof","year":"2011","journal-title":"Europace"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1161\/01.CIR.0000066323.15244.54","article-title":"Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy","volume":"107","author":"P Richard","year":"2003","journal-title":"Circulation"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1016\/S0735-1097(02)01724-2","article-title":"Autosomal dominant dilated cardiomyopathy with atrioventricular block: A lamin A\/C defect-related disease","volume":"39","author":"E Arbustini","year":"2002","journal-title":"Journal of the American College of Cardiology"},{"key":"ref28","article-title":"GeneReviews(R)","author":"RE Hershberger","year":"1993"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1186\/gb-2011-12-5-222","article-title":"The lamin protein family","volume":"12","author":"TA Dittmer","year":"2011","journal-title":"Genome Biol"},{"key":"ref30","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a000547","article-title":"Nuclear Lamins","volume":"2","author":"T Dechat","year":"2010","journal-title":"Cold Spring Harbor Perspectives in Biology"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.ahj.2008.01.026","article-title":"Lamin A\/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy","volume":"156","author":"SB Parks","year":"2008","journal-title":"American Heart Journal"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"e570","DOI":"10.1016\/j.ejmg.2011.07.005","article-title":"Clinical and mutational spectrum in a cohort of 105 unrelated patients with dilated cardiomyopathy","volume":"54","author":"G Millat","year":"2011","journal-title":"Eur J Med Genet"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"1916","DOI":"10.1016\/j.jacc.2012.05.059","article-title":"Quantitative Expression of the Mutated Lamin A\/C Gene in Patients With Cardiolaminopathy","volume":"60","author":"N Narula","year":"2012","journal-title":"Journal of the American College of Cardiology"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.yexcr.2003.07.002","article-title":"Nuclear envelope alterations in fibroblasts from LGMD1B patients carrying nonsense Y259X heterozygous or homozygous mutation in lamin A\/C gene","volume":"291","author":"A Muchir","year":"2003","journal-title":"Experimental Cell Research"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"3010","DOI":"10.1016\/j.yexcr.2013.08.024","article-title":"The LMNA mutation p.Arg321Ter associated with dilated cardiomyopathy leads to reduced expression and a skewed ratio of lamin A and lamin C proteins","volume":"319","author":"R Al-Saaidi","year":"2013","journal-title":"Exp Cell Res"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/1471-2156-9-83","article-title":"Comparison of nonsense-mediated mRNA decay efficiency in various murine tissues","volume":"9","author":"AB Zetoune","year":"2008","journal-title":"BMC Genet"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1093\/hmg\/ddg054","article-title":"Tissue-specific RNA surveillance? Nonsense-mediated mRNA decay causes collagen X haploinsufficiency in Schmid metaphyseal chondrodysplasia cartilage","volume":"12","author":"JF Bateman","year":"2003","journal-title":"Hum Mol Genet"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1007\/s00109-007-0275-1","article-title":"Incomplete nonsense-mediated decay of mutant lamin A\/C mRNA provokes dilated cardiomyopathy and ventricular tachycardia","volume":"86","author":"SK Geiger","year":"2008","journal-title":"J Mol Med (Berl)"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1161\/01.CIR.74.1.21","article-title":"Evolution of a hereditary cardiac conduction and muscle disorder: a study involving a family with six generations affected","volume":"74","author":"HL Graber","year":"1986","journal-title":"Circulation"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1159\/000328638","article-title":"Heritable cardiac conduction and myocardial disease: from the clinic to the basic science laboratory and back to the clinic","volume":"118","author":"EA Sparks","year":"2011","journal-title":"Cardiology"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1054\/jcaf.2001.26339","article-title":"Novel lamin A\/C mutations in two families with dilated cardiomyopathy and conduction system disease","volume":"7","author":"PM Jakobs","year":"2001","journal-title":"J Card Fail"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1067\/mhj.2002.126737","article-title":"A novel lamin A\/C mutation in a family with dilated cardiomyopathy, prominent conduction system disease, and need for permanent pacemaker implantation","volume":"144","author":"RE Hershberger","year":"2002","journal-title":"Am Heart J"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1016\/S0735-1097(98)00424-0","article-title":"Clinical characteristics of sudden death victims in heritable (chromosome 1p1-1q1) conduction and myocardial disease","volume":"32","author":"SD Nelson","year":"1998","journal-title":"J Am Coll Cardiol"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1161\/CIRCGENETICS.108.836478","article-title":"Multiple mutations in genetic cardiovascular disease: a marker of disease severity?","volume":"2","author":"M Kelly","year":"2009","journal-title":"Circ Cardiovasc Genet"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1006\/mgme.2000.3052","article-title":"Modifier genes convert "simple" Mendelian disorders to complex traits","volume":"71","author":"KM Dipple","year":"2000","journal-title":"Mol Genet Metab"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1007\/s00439-013-1331-2","article-title":"Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease","volume":"132","author":"DN Cooper","year":"2013","journal-title":"Human Genetics"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/S0959-437X(03)00061-3","article-title":"Modifier genes and protective alleles in humans and mice","volume":"13","author":"JH Nadeau","year":"2003","journal-title":"Current Opinion in Genetics and Development"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1007\/s00439-008-0560-2","article-title":"Identifying modifier genes of monogenic disease: strategies and difficulties","volume":"124","author":"E Genin","year":"2008","journal-title":"Human Genetics"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1007\/s00439-013-1286-3","article-title":"Hunting human disease genes: lessons from the past, challenges for the future","volume":"132","author":"LR Brunham","year":"2013","journal-title":"Human Genetics"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1002\/mus.20293","article-title":"Extreme variability of skeletal and cardiac muscle involvement in patients with mutations in exon 11 of the lamin A\/C gene","volume":"31","author":"E Mercuri","year":"2005","journal-title":"Muscle Nerve"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1093\/brain\/awl062","article-title":"Disease severity in dominant Emery Dreifuss is increased by mutations in both emerin and desmin proteins","volume":"129","author":"F Muntoni","year":"2006","journal-title":"Brain"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1016\/j.hrthm.2011.11.006","article-title":"Developmentally regulated SCN5A splice variant potentiates dysfunction of a novel mutation associated with severe fetal arrhythmia","volume":"9","author":"LL Murphy","year":"2012","journal-title":"Heart Rhythm"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.jacc.2009.11.020","article-title":"Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy","volume":"55","author":"T Xu","year":"2010","journal-title":"J Am Coll Cardiol"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nature11632","article-title":"An integrated map of genetic variation from 1,092 human genomes","volume":"491","author":"GR Abecasis","year":"2012","journal-title":"Nature"},{"key":"ref55","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.cell.2011.09.008","article-title":"Clan Genomics and the Complex Architecture of Human Disease","volume":"147","author":"JR Lupski","year":"2011","journal-title":"Cell"},{"key":"ref56","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1161\/CIRCGENETICS.111.000062","article-title":"Exome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathy","volume":"6","author":"N Norton","year":"2013","journal-title":"Circ Cardiovasc Genet"},{"key":"ref57","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1136\/jmedgenet-2012-101270","article-title":"Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing","volume":"50","author":"LR Lopes","year":"2013","journal-title":"J Med Genet"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pone.0155421","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T04:48:40Z","timestamp":1655959720000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0155421"}},"subtitle":[],"editor":[{"given":"Chunhua","family":"Song","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2016,5,16]]},"references-count":57,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2016,5,16]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0155421","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,5,16]]}}}