CACNA1C gene mutation in Thai young adult with sudden unexplained death
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Published:
Dec 29, 2020
Keywords:
Molecular autopsy Sudden unexplained death syndrome Sudden death Cardiac ion channelopathies
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Abstract
Sudden unexplained death syndrome (SUDS) is an unexpected natural death in young healthy adults, especially Southeastern Asian populations, wherein no severe diseases can be detected to explain death’s cause. Several studies confirmed that SUDS associated with genetically changed cardiac ion channels. However, CACNA1C mutations in SUDS are rarely reported in the Thai population. This study aimed to characterize CACNA1C gene mutation in Thai young adults who died with SUDS. Characteristics data of 32 SUDS cases in the Thai population were collected. Blood samples were collected from 27 males and 5 females of which categorized as an unexplained cause of death in a postmortem examination. Genomic DNA was extracted, amplified, and screened for nine variants mutation of CACNA1C gene, using pyrosequencing assay. Most cases were domiciled in the central region of Thailand. Men aged 19 - 39 years old (mean age 29.44 ± 5.59) is the most common SUDS cases. In a total of 32 cases, we detected 7 cases (21.9 %) with heterozygous A/G, c.720016 G > A within exon 44. The variation was defined as a missense mutation of p. R1880Q at C-terminus of α1C subunit of the L-type cardiac calcium channel. The heterozygous missense mutation of p. R1880Q of CACNA1C gene was identified in Thai SUDS. However, there is no evidence of studies about the effect of function and pathogenicity of CACNA1C-R1880Q. Further study is needed to clarify the role of this variant in the functional effect of pathogenesis in SUDS.
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1.
Thitinilnithi J, Samosornsuk W, Srisuwan S, Waiyawuth W, Samosornsuk S. CACNA1C gene mutation in Thai young adult with sudden unexplained death. Arch AHS [Internet]. 2020 Dec. 29 [cited 2024 Dec. 19];32(3):22-31. Available from: https://he01.tci-thaijo.org/index.php/ams/article/view/240555
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24. Zheng J, Huang E, Tang S, Wu Q, Huang L, Zhang D, et al. A case control study of sudden unexplained nocturnal death syndrome in the southern Chinese Han population. Am J Forensic Med Pathol 2015;36:39–43.
25. Chen Z, Mu J, Chen X. Sudden unexplained nocturnal death syndrome in Central China (Hubei): a 16-year retrospective study of autopsy cases. Medicine 2016;95:e2882.
26. Zheng J, Zheng D, Su T, Cheng J. Sudden unexplained nocturnal death syndrome: the hundred years’ enigma. J Am Heart Assoc 2018;7(5): e007837.
27. Valladares EM, Eljammal SM, Motivala S, Ehlers CL, Irwin MR. Sex differences in cardiac sympathovagal balance and vagal tone during nocturnalsleep. Sleep Med 2008; 9: 310–16.
28. Cheng J, Makielski C J, Yuan P, Shi N, Zhou F, Ye B,, et al. Sudden unexplained nocturnal death syndrome in southern China: epidemiological survey and SCN5A gene screening. Am J Forensic Med Pathol. 2011 Dec;32(4):359-63.
29. Charoenpan P, Muntarbhorn K, Boongird P, Puavilai G, Ratanaprakarn R, Indraprasit S, et al. Nocturnal physiological and 15 biochemicalchanges in sudden unexplained death syndrome: a preliminary report of a case control study.Southeast. Asian J Trop Med Public Health. 1994; 25:335–340.
30. Steinhaus DA, Vittinghoff E, Moffatt E, Hart AP, Ursell P, Tseng ZH. Characteristics of sudden arrhythmic death in a diverse, urban community. Am Heart J. 2012;163:25–31.
31. Sutphin BS, Boczek NJ, Barajas-Martínez H, Hu D, Ye D, Tester DJ, et al. Molecular and Functional Characterization of Rare CACNA1C Variants in Sudden Unexplained Death in the Young. Congenit Heart Dis. 2016;11(6):683-692.
32. Risgaard B, Jabbari R, Refsgaard L, Holst AG, Haunsø S, Sadjadieh A, et al. High prevalence of genetic variants previously associated with Brugada syndrome in new exome data. Clin Genet 2013: 84(5): 489–495.
33. Dorschner MO, Amendola LM, Turner EH, Robertson PD., Shirts BH. , Gallego CJ, et al. Actionable, pathogenic incidental findings in 1,000 participants' exomes. Am J Hum Genet. 2013;93(4):631–640.
34. Amendola LM, Dorschner MO, Robertson PD, Salama JS, Hart R, Shirts BH, et al. Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Genome Res. 2015;25(3):305–315.
35. Campuzano O, Brugada G-S, Fernandez-Falgueras A., Cesar S, Coll M, Mates J, et al. Genetic interpretation and clinical translation of minor genes related to Brugada syndrome. Human Mutation. 2019;40:749–764.
2. Gervacio-Domingo G, Punzalan FE, Amarillo ML, Dans A. Sudden unexplained death during sleep occurred commonly in the general population in the Philippines: A sub study of the national nutrition and health survey. J Clin Epidemiol. 2007; 60: 567–571.
3. Tungsanga K, Sriboonlue P. Sudden unexplained death syndrome in north-east Thailand. Int J Epidemiol.1993; 22:81-87.
4. Priori SG, Aliot E, Blomstrom-Lundqvist C, Bossaert L, L. Bossaert, G. Breithardt, P. Brugada, et al. Task Force on Sudden Cardiac Death, European Society of Cardiology. Summary of recommendations. Ital. Heart J. Suppl. 2002; 3: 1051-1065.
5. Campuzano O., Beltran-Alvares P., Iglesias A., Scornik F, Perez G, Brugada R. Genetics and cardiac channelopathies. Genet Med. 2010; 12: 260-267.
6. Nademanee K, Veerakul G, Nimmannit S, Chaowakul V, Bhuripanyo K, Likittanasombat K, et al. Arrhythmogenic marker for the sudden unexplained death syndrome in Thai men, Circulation. 1996; 96: 2595–2600.
7. Vatta M, Dumaine R, Varghese G, Richard, Wataru S, Naohiko Ai, et al. Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome. Hum Mol Genet 2002;11:337-45.
8. Sangwatanaroj S, Yanatasneejit P, Sunsaneewitayakul B, Sitthisook S. Linkage analyses and SCN5A mutations screening in five sudden unexplained death syndrome (Lai-tai) families. J Med Assoc Thail 2002; 85: S54–S61.
9. Makarawate P, Chaosuwannakit N , Vannaprasaht S, Sahasthas D, Koo SH, Lee EJD, et al. SCN5A Genetic Polymorphisms Associated With Increased Defibrillator Shocks in Brugada Syndrome. J Am Heart Assoc. 2017; 6(6). pii: e005009
10. Pitiwararom R, Vongpaisarnsin K, Hoonwijit U. SCN5A gene exome sequencing profile in sudden unexplained nocturnal death syndrome in Thai population. Chula Med J. 2019; 63: 111 – 118.
11. Yanatatsaneejit P. Detection of SCN5Agene mutation and linkage analysis study in SCN5A, KCND2 and KCND3 gene in sudden unexplained death syndrome families. Bangkok: Chulalongkorn University; 2001.
https://cuir.car.chula.ac.th/handle/123456789/9396
12. Chen Q, Kirsch GE, Zhang D, Genetic basis and molecular mechanism for idiopatic ventricular fibrillation. Nature. 1998;392:293-296.
13. Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, et al. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm 2010;7:33-46.
14. Antzelevitch C, Pollevick GD, Coideiro JM, Casis O, Sanguinetti M.C, Aizawa Y., et al. Loss of function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST segment elevation, short QT intervals, and sudden cardiac death. Circulation. 2007;115: :442-9.
15. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, et al. Cav1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell. 2004;119:19–31.
16. Barrett CF, Tsien RW. The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of CaV1.2 L-type calcium channels. Proc Natl Acad Sci U S A. 2008;105(6):2157–2162.
17. Fukuyama M, Wang Q, Kato K, Ohno S, Ding WG, Toyoda F, et al. Long QT syndrome type 8: novel CACNA1C mutations causing QT prolongation and variant phenotypes. Europace. 2014;16:1828–1837.
18. Burashnikov E, Pfeiffer R, Barajas-Martinez H, Delpón E, Hu D, Desai M, et al. Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death. Heart Rhythm. 2010;7(12):1872–82.
19. Liu X, Shen Y, Xie J, Bao H, Cao Q, Wan R, et al. A mutation in the CACNA1C gene leads to early repolarization syndrome with incomplete penetrance: A Chinese family study. PLoS ONE. 2017;12(5):1-18.
20. Tatsanavivat P, Chiravatkul A, Klungboonkrong, Chaisiri S, Jarerntanyaruk L, Munger RG, et al. Sudden and unexplained deaths in sleep (Lai tai) of young men in rural northeastern Thailand. Int J Epidemiol 1992;21:904–10.
21. Srettabunjong S, Sudden Unexplained Nocturnal Death Syndrome: Epidemiological and Morphological Characteristics in Thai Autopsy Cases. J Forensic Sci : 64(3):773-777.
22. Suktitipat B, Sathirareuangchai S, Roothumnong E, Thongnoppakhun W, Wangkiratikant P, Vorasan N et al. Molecular investigation by whole exome sequencing revealed a high proportion of pathogenic variants among Thai victims of sudden unexpected death syndrome. PLoS One. 2017;12(7):e0180056. doi: 10.1371
23. Zhang L, Tester DJ, Lang D, Chen Y, Zheng J, Gao R, et al. Does sudden unexplained nocturnal death syndrome remain the autopsy-negative disorder: a gross, microscopic, and molecular autopsy investigation in Southern China. Mayo Clin Proc 2016;91:1503–14.
24. Zheng J, Huang E, Tang S, Wu Q, Huang L, Zhang D, et al. A case control study of sudden unexplained nocturnal death syndrome in the southern Chinese Han population. Am J Forensic Med Pathol 2015;36:39–43.
25. Chen Z, Mu J, Chen X. Sudden unexplained nocturnal death syndrome in Central China (Hubei): a 16-year retrospective study of autopsy cases. Medicine 2016;95:e2882.
26. Zheng J, Zheng D, Su T, Cheng J. Sudden unexplained nocturnal death syndrome: the hundred years’ enigma. J Am Heart Assoc 2018;7(5): e007837.
27. Valladares EM, Eljammal SM, Motivala S, Ehlers CL, Irwin MR. Sex differences in cardiac sympathovagal balance and vagal tone during nocturnalsleep. Sleep Med 2008; 9: 310–16.
28. Cheng J, Makielski C J, Yuan P, Shi N, Zhou F, Ye B,, et al. Sudden unexplained nocturnal death syndrome in southern China: epidemiological survey and SCN5A gene screening. Am J Forensic Med Pathol. 2011 Dec;32(4):359-63.
29. Charoenpan P, Muntarbhorn K, Boongird P, Puavilai G, Ratanaprakarn R, Indraprasit S, et al. Nocturnal physiological and 15 biochemicalchanges in sudden unexplained death syndrome: a preliminary report of a case control study.Southeast. Asian J Trop Med Public Health. 1994; 25:335–340.
30. Steinhaus DA, Vittinghoff E, Moffatt E, Hart AP, Ursell P, Tseng ZH. Characteristics of sudden arrhythmic death in a diverse, urban community. Am Heart J. 2012;163:25–31.
31. Sutphin BS, Boczek NJ, Barajas-Martínez H, Hu D, Ye D, Tester DJ, et al. Molecular and Functional Characterization of Rare CACNA1C Variants in Sudden Unexplained Death in the Young. Congenit Heart Dis. 2016;11(6):683-692.
32. Risgaard B, Jabbari R, Refsgaard L, Holst AG, Haunsø S, Sadjadieh A, et al. High prevalence of genetic variants previously associated with Brugada syndrome in new exome data. Clin Genet 2013: 84(5): 489–495.
33. Dorschner MO, Amendola LM, Turner EH, Robertson PD., Shirts BH. , Gallego CJ, et al. Actionable, pathogenic incidental findings in 1,000 participants' exomes. Am J Hum Genet. 2013;93(4):631–640.
34. Amendola LM, Dorschner MO, Robertson PD, Salama JS, Hart R, Shirts BH, et al. Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Genome Res. 2015;25(3):305–315.
35. Campuzano O, Brugada G-S, Fernandez-Falgueras A., Cesar S, Coll M, Mates J, et al. Genetic interpretation and clinical translation of minor genes related to Brugada syndrome. Human Mutation. 2019;40:749–764.