Abstract
Sudden unexplained nocturnal death syndrome (SUNDS) is a perplexing disorder to both forensic pathologists and clinic physicians. Desmoplakin (DSP) gene was the first desmosomal gene linked to arrhythmogenic right ventricular cardiomyopathy (ARVC) which was associated with sudden death. To identify the genetic variants of the DSP gene in SUNDS in the southern Chinese Han population, we genetically screened the DSP gene in 40 sporadic SUNDS victims, 16 Brugada syndrome (BrS) patients, and 2 early repolarization syndrome (ERS) patients using next generation sequencing (NSG) and direct Sanger sequencing. A total of 10 genetic variants of the DSP gene were detected in 11 cases, comprised of two novel missense mutations (p.I125F and p.D521A) and eight previously reported rare variants. Of eight reported variants, two were previously considered pathogenic (p.Q90R and p.R2639Q), three were predicted in silico to be pathogenic (p.R315C, p.E1357D and p.D2579H), and the rest three were predicted to be benign (p.N1234S, p.R1308Q, and p.T2267S). This is the first report of DSP genetic screening in Chinese SUNDS and Brugada syndrome. Our results imply that DSP mutations contribute to the genetic cause of some SUNDS victims and maybe a new susceptible gene for Brugada syndrome.
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References
Liu C, Zhao Q, Su T, Tang S, Lv G, Liu H et al (2013) Postmortem molecular analysis of KCNQ1, KCNH2, KCNE1 and KCNE2 genes in sudden unexplained nocturnal death syndrome in the Chinese Han population. Forensic Sci Int 231:82–87
Liu C, Tester DJ, Hou Y, Wang W, Lv G, Ackerman MJ et al (2014) Is sudden unexplained nocturnal death syndrome in Southern China a cardiac sodium channel dysfunction disorder? Forensic Sci Int 236:38–45
Huang L, Liu C, Tang S, Su T, Cheng J (2014) Postmortem genetic screening of SNPs in RyR2 gene in sudden unexplained nocturnal death syndrome in the Southern Chinese Han population. Forensic Sci Int 235:14–18
Elger BS, Michaud K, Fellmann F, Mangin P (2010) Sudden death: ethical and legal problems of post-mortem forensic genetic testing for hereditary cardiac diseases. Clin Genet 77:287–292
Sheikh F, Ross RS, Chen J (2009) Cell-cell connection to cardiac disease. Trends Cardiovasc Med 19:182–190
Rampazzo A, Nava A, Malacrida S, Beffagna G, Bauce B, Rossi V et al (2002) Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 71:1200–1206
van der Zwaag PA, Jongbloed JD, van den Berg MP, van der Smagt JJ, Jongbloed R, Bikker H et al (2009) A genetic variants database for arrhythmogenic right ventricular dysplasia/cardiomyopathy. Hum Mutat 30:1278–1283
Zhang Q, Deng C, Rao F, Modi RM, Zhu J, Liu X et al (2013) Silencing of desmoplakin decreases connexin43/Nav1.5 expression and sodium current in HL1 cardiomyocytes. Mol Med Rep 8:780–786
Cheng J, Makielski JC, Yuan P, Shi N, Zhou F, Ye B et al (2011) Sudden unexplained nocturnal death syndrome in Southern China: an epidemiological survey and SCN5A gene screening. Am J Forensic Med Pathol 32:359–363
Illumina Protocol for Whole Genome Sequencing using SBS Technology (2006) BioTechniques protocol guide. Biotechniques, New York
Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25:1754–1760
McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A et al (2010) The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20:1297–1303
DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C et al (2011) A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 43:491–498
Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, Del Angel G, Levy-Moonshine A et al (2013) From FastQ data to high confidence variant calls: the genome analysis toolkit best practices pipeline. Curr Protoc Bioinformatics 11:11.10.1–11.10.33
Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR et al (2008) ACMG recommendations for standards for interpretation and reporting of sequence variations: revisions 2007. Genet Med 10:294–300
Lapouge K, Fontao L, Champliaud MF, Jaunin F, Frias MA, Favre B et al (2006) New insights into the molecular basis of desmoplakin- and desmin-related cardiomyopathies. J Cell Sci 119:4974–4985
Delmar M, McKenna WJ (2010) The cardiac desmosome and arrhythmogenic cardiomyopathies: from gene to disease. Circ Res 107:700–714
Basso C, Bauce B, Corrado D, Thiene G (2012) Pathophysiology of arrhythmogenic cardiomyopathy. Nat Rev Cardiol 9:223–233
Yu CC, Yu CH, Hsueh CH, Yang CT, Juang JM, Hwang JJ et al (2008) Arrhythmogenic right ventricular dysplasia: clinical characteristics and identification of novel desmosome gene mutations. J Formos Med Assoc 107:548–558
Sato T, Nishio H, Suzuki K (2015) Identification of arrhythmogenic right ventricular cardiomyopathy-causing gene mutations in young sudden unexpected death autopsy cases. J Forensic Sci 60:457–461
Yang Z, Bowles NE, Scherer SE, Taylor MD, Kearney DL, Ge S et al (2006) Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Res 99:646–655
Xu T, Yang Z, Vatta M, Rampazzo A, Beffagna G, Pilichou K et al (2010) Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol 55:587–597
Cox MG, van der Zwaag PA, van der Werf C, van der Smagt JJ, Noorman M, Bhuiyan ZA et al (2011) Arrhythmogenic right ventricular dysplasia/cardiomyopathy: pathogenic desmosome mutations in index-patients predict outcome of family screening: Dutch arrhythmogenic right ventricular dysplasia/cardiomyopathy genotype-phenotype follow-up study. Circulation 123:2690–2700
Gomes J, Finlay M, Ahmed AK, Ciaccio EJ, Asimaki A, Saffitz JE et al (2012) Electrophysiological abnormalities precede overt structural changes in arrhythmogenic right ventricular cardiomyopathy due to mutations in desmoplakin-A combined murine and human study. Eur Heart J 33:1942–1953
Lyon RC, Mezzano V, Wright AT, Pfeiffer E, Chuang J, Banares K et al (2014) Connexin defects underlie arrhythmogenic right ventricular cardiomyopathy in a novel mouse model. Hum Mol Genet 23:1134–1150
Gutstein DE, Morley GE, Tamaddon H, Vaidya D, Schneider MD, Chen J et al (2001) Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ Res 88:333–339
Gutstein DE, Morley GE, Vaidya D, Liu F, Chen FL, Stuhlmann H et al (2001) Heterogeneous expression of gap junction channels in the heart leads to conduction defects and ventricular dysfunction. Circulation 104:1194–1199
Patel DM, Dubash AD, Kreitzer G, Green KJ (2014) Disease mutations in desmoplakin inhibit Cx43 membrane targeting mediated by desmoplakin-EB1 interactions. J Cell Biol 206:779–797
Jansen JA, Noorman M, Musa H, Stein M, de Jong S, van der Nagel R et al (2012) Reduced heterogeneous expression of Cx43 results in decreased Nav1.5 expression and reduced sodium current that accounts for arrhythmia vulnerability in conditional Cx43 knockout mice. Heart Rhythm 9:600–607
Hertz CL, Christiansen SL, Ferrero-Miliani L, Dahl M, Weeke PE, LuCamp et al (2015) Next-generation sequencing of 100 candidate genes in young victims of suspected sudden cardiac death with structural abnormalities of the heart. Int J Legal Med. doi:10.1007/s00414-015-1261-8
Alcalde M, Campuzano O, Allegue C, Torres M, Arbelo E, Partemi S et al (2015) Sequenom MassARRAY approach in the arrhythmogenic right ventricular cardiomyopathy post-mortem setting: clinical and forensic implications. Int J Legal Med 129:1–10
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The project was approved for human research by the ethics committee of Sun Yat-sen University.
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The authors declare that they have no competing interests.
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This work was supported by the Key Program (81430046), General Program (81172901) from National Natural Science Foundation of China (to JC), and the grants R56 HL71092 & R01 HL128076-01 from National Institutes of Health of United States of America (to JCM).
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Qianhao Zhao, Yili Chen, Longlun Peng, and Rui Gao contributed equally to this work.
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Zhao, Q., Chen, Y., Peng, L. et al. Identification of rare variants of DSP gene in sudden unexplained nocturnal death syndrome in the southern Chinese Han population. Int J Legal Med 130, 317–322 (2016). https://doi.org/10.1007/s00414-015-1275-2
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DOI: https://doi.org/10.1007/s00414-015-1275-2