THE NEW MOLECULAR GENETIC MARKERS OF THE SUDDEN CARDIAC DEATH IDENTIFIED BY NEXT-GENERATION SEQUENCING

DOI: https://doi.org/10.29296/24999490-2018-05-05

А.А. Ivanova(1), V.N. Maksimov(1, 2), S.K. Malutina(1, 2), K.N. Kolesnik(1), A.V. Aleshkina(1), S.V. Savchenko(2, 3), V.P. Novoselov(2, 3), М.I. Voevoda(1) 1-Research Institutе of Internal and Preventive Medicine, Branch of the Federal Research Center Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, B. Bogatkova str., 175/1, Novosibirsk, 630089, Russian Federation; 2-Novosibirsk State Medical University, Krasny Prospekt, 52, Novosibirsk, 630091, Russian Federation; 3-Novosibirsk Regional Office of Forensic Medical Examination, Nemirovicha-Danchenko, 134, Novosibirsk, 630087, Russian Federation Е-mail: [email protected]

The aim of the study is an investigation of the association between mutations A1744S of MYH7, 9928_9929insE of TTN, T171M of CACNA1C, A189T of JPH2, S434Y of VCL, H4552R of RYR2, Y1495X of SCN5A and the sudden cardiac death (SCD). Investigating mutations were identified as mutations associated with SCD in foreign next-generation sequencing studies. Materials and methods. The SCD group was formed using WHO criteria and criteria of European Society of Cardiology for SCD (n=391 cases, aged 53,2±8,7 years, among them men amounted to 72,7%, women – 27,3%), the control group was selected according to the gender and age from the DNA bank of HAPIEE, MONICA (n=400, aged 53,1±8,3 years, men amounted to 68,3%, women – 31,7%). In cases from the SCD group DNA was isolated by phenol-chloroform extraction of the myocardial tissue, and in cases from the control group, venous blood was taken. Genotyping was done by polymerase chain reaction-restriction fragment length polymorphism. Confirming sequencing was done using the method of capillary electrophoresis with the Hitachi 3500 Genetic Analyzer (Applied Biosystems, USA). Results. No carriers of rare alleles of mutations A1744S of MYH7, 9928_9929insE of TTN, T171M of CACNA1C, A189T of JPH2, S434Y of VCL, H4552R of RYR2, Y1495X of SCN5A were found in SCD neither in control groups. Carriers of heterozygous genotype were found in the SCD (4,1%) and control (3,8%) groups. No statistical significance was found in allele and genotype frequencies between groups, even in separating by the gender and age.
Keywords: 
Conclusions. The mutations A1744S of MYH7, 9928_9929insE of TTN, T171M of CACNA1C, A189T of JPH2, S434Y of VCL
Список литературы: 
  1. Shlyahto E.V., Arutyunov G.P., Belenkov Yu.N., Ardashev A.V. Nacional`nye Rekomendacii po opredeleniyu riska i profilaktike vnezapnoy serdechnoy smerti. Arhiv`` vnutrenney mediciny. 2013; 4: 5–15. [Shljahto E.V., Arutjunov G.P., Belenkov Ju.N., Ardashev A.V. Recommendations for risk assessment and prevention of sudden cardiac death Archive of internal medicine. 2013; 4: 5–15 (in Russian)]
  2. Priori S.G., Blomström-Lundqvist C., Mazzanti A., Blom N., Borggrefe M., Camm J., Elliott P.M., Fitzsimons D., Hatala R., Hindricks G., Kirchhof P., Kjeldsen K., Kuck K.H., Hernandez-Madrid A., Nikolaou N., Norekvål T.M., Spaulding C., Van Veldhuisen D.J. The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). G Ital Cardiol. 2016; 17 (2): 108–70.
  3. Narula N., Tester D.J., Paulmichl A., Maleszewski J.J., Ackerman M.J. Post-mortem Whole exome sequencing with gene-specific analysis for autopsy-negative sudden unexplained death in the young: a case series. Pediatr Cardiol. 2015; 36 (4): 768–78.
  4. Tan Z.P., Xie L., Deng Y., Chen J.L., Zhang W.Z., Wang J., Yang J.F., Yang Y.F. Whole-exome sequencing identifies Y1495X of SCN5A to be associated with familial conduction disease and sudden death. Sci Rep. 2014; 4: 5616.
  5. Sambrook J., Russell D.W. Purification of nucleic acids by extraction with phenol:chloroform. CSH Protoc. 2006; 1.
  6. TTN titin [Homo sapiens (human)]. Database Gene. https://www.ncbi.nlm.nih.gov/gene/7273.
  7. Hinson J.T., Chopra A., Nafissi N. et al. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy. Science. 2015; 349 (6251): 982–6.
  8. Pernigo S., Fukuzawa A., Pandini A., Holt M., Kleinjung J., Gautel M., Steiner R.A. The crystal structure of the human titin:obscurin complex reveals a conserved yet specific muscle M-band zipper module. J. Mol. Biol. 2015; 427 (4): 718–36.
  9. Carmignac V., Salih M.A., Quijano-Roy S., Marchand S., Rayess M.M., Mukhtar M.M., Urtizberea J.A., Labeit S., Guicheney P., Leturcq F., Gautel M., Fardeau M., Campbell K.P., Richard I., Estournet B., Ferreiro A. C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy. Ann. Neurol. 2007; 61 (4): 340–51.
  10. Baydar Ç.L., Özen M. A hypertrophic and dilated cardiomyopathic sudden cardiac death case; de novo mutations in TTN and SGCD genes. Anatol J. Cardiol. 2016; 16 (11): 887–8.
  11. rs368327166. Database dbSNP. https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=368327166.
  12. Larsen M.K., Nissen P.H., Berge K.E., Leren T.P., Kristensen I.B., Jensen H.K., Banner J. Molecular autopsy in young sudden cardiac death victims with suspected cardiomyopathy. Forensic Sci Int. 2012; 219 (1–3): 33–8.
  13. Cann F., Corbett M., O’Sullivan D., Tennant S., Hailey H., Grieve J.H., Broadhurst P., Rankin R., Dean J.C. Phenotype-driven molecular autopsy for sudden cardiac death. Clin. Genet. 2017; 91 (1): 22–9.
  14. CACNA1C calcium voltage-gated channel subunit alpha1 C [Homo sapiens (human)] Database Gene. https://www.ncbi.nlm.nih.gov/gene/775.
  15. Beavers D.L., Wang W., Ather S., Voigt N., Garbino A., Dixit S.S., Landstrom A.P., Li N., Wang Q., Olivotto I., Dobrev D., Ackerman M.J., Wehrens X.H. Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RYR2 stabilization. J. Am. Coll. Cardiol. 2013; 62 (21): 2010–9.
  16. rs730880254. Database dbSNP. https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=730880254.
  17. rs757541730. Database dbSNP. https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=757541730.
  18. Cheng J., Kyle J.W., Wiedmeyer B., Lang D., Vaidyanathan R., Makielski J.C. Vinculin variant M94I identified in sudden unexplained nocturnal death syndrome decreases cardiac sodium current. Sci Rep. 2017; 7: 42953.
  19. rs768299786. Database dbSNP. https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=768299786.
  20. Hertz C.L., Christiansen S.L., Ferrero-Miliani L., Fordyce S.L., Dahl M., Holst A.G., Ottesen G.L., Frank-Hansen R., Bundgaard H., Morling N. Next-generation sequencing of 34 genes in sudden unexplained death victims in forensics and in patients with channelopathic cardiac diseases. Int J. Legal Med. 2015; 129 (4): 793–800.
  21. Magnani J.W., Brody J.A., Prins B.P., Arking D.E., Lin H., Yin X., Liu C.T., Morrison A.C., Zhang F., Spector T.D., Alonso A., Bis J.C., Heckbert S.R., Lumley T., Sitlani C.M., Cupples L.A., Lubitz S.A., Soliman E.Z., Pulit S.L., Newton-Cheh C., O’Donnell C.J., Ellinor P.T., Benjamin E.J., Muzny D.M., Gibbs R.A., Santibanez J., Taylor H.A., Rotter J.I., Lange L.A., Psaty B.M., Jackson R.Z, Rich S.S., Boerwinkle E., Jamshidi Y., Sotoodehnia N. Sequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Circ Cardiovasc Genet. 2014; 7 (3): 365–73.