Association of the carriage of BRD2 rs206787 and rs516535 and GJD2 rs3743123 polymorphisms with juvenile myoclonic epilepsy in Caucasian patients of Siberia

In recent years, the genetics of juvenile myoclonic epilepsy (JME) has been actively studied; the association of JME with the carriage of polymorphic allelic variants of the BRD2 (EJM3 locus) and GJD2 (EJM2 locus) genes has been established.
Objective: to establish risk factors for JME in terms of a genetic predisposition; specifically, polymorphic allelic variants rs206787 and rs516535 in the BRD2 gene and rs3743123 in the GJD2 gene.
Patients and methods: Examinations were made in 79 patients with JME and in 150 healthy volunteers, who were Caucasian and resided in the Siberian Federal District (SFD) and underwent determination of the carriage of single nucleotide polymorphisms (SNPs) rs206787 and rs516535 in the BRD2 gene and rs3743123 in the GJD2 gene by real-time polymerase chain reaction.
Results and discussion. In 2003, American scientists from New York showed that the alleles associated with the development of JME with an autosomal recessive inheritance pattern might be located in the BRD2 gene. Patients with JME are assumed to have an autosomal dominant inheritance pattern of mutations in the BRD2 gene. British scientists revealed that different populations were found to have an association of SNP rs3918149 and no relationship of BRD2 rs206787 to the development of JME in Caucasians, as well as ascertained local linkage disequilibrium in the BRD2 gene. Our investigation has established complete linkage disequilibrium between the loci in patients with JME and in healthy individuals and no association of the carriage of SNPs rs206787 and rs516535 in the BRD2 gene with the development of JME in the patients residing in the SFD (p >0.05). German scientists studied the impact of SNP in the BRD2 gene on a predisposition to a photoparoxysmal response in patients with JME/genetic generalized epilepsy. Our investigation has indicated the association of the carriage of TT/TT haplotype for SNP rs206787 and rs516535 in the BRD2 gene with a photoparoxysmal response in patients with JME (odds ratio (OR), 3.6; 95% confidence interval (CI), 1.37–9.48; p=0.02). We have confirmed that in the studied sample, the carriage of the T allele in the GJD2 gene (rs3743123) in the homozygous form is associated with the development of JME in Caucasian patients residing in the SFD and is a risk factor for JME (OR, 2.66; 95% CI, 1.24–5.74; p=0.04). The clinically significant association of this SNP in the GJD2 gene with the development of JME had been also previously demonstrated in two independent studies conducted in the European populations in the UK and Germany. There is a rise in the proportion of homozygotes in JME patients versus the control group, suggesting that the 588T allele under consideration increases the risk for JME in the homozygous state in the autosomal recessive inheritance pattern.
Conclusion. The findings suggest that it is necessary to genotype Caucasian patients with JME, who reside in Siberia, for determination of the carriage of the TT/TT haplotype in terms of the investigated SNPs in the BRD2 gene (EJM 3 locus) and the carriage the T allele (rs3743123) in the GJD2 gene via a personalized approach to predicting the course of JME, as well as for identification of persons at risk for JME in the families having a history of this disease.

1. Karlov VA, Freidkova NV. Juvenile myoclonic epilepsy. In: Karlov VA, editor. Epilepsiya u detei i vzroslykh zhenshchin i muzhchin [Epilepsy in children and adults women and men]. Moscow: Meditsina; 2010. P. 244–8.

2. Petrukhin AS, Kalinina LV, Anpilogova IE. Clinical-epidemiological characteristics of epilepsy in children living in Tulskaya territory. Pediatriya. Zhurnal im. G.N. Speranskogo. 2004; 83(6):101-3. (In Russ.)

3. Mukhin KYu. Juvenile myoclonic epilepsy (Jantz syndrome). In: Mukhin KYu, Petrukhin AS. Idiopaticheskie formy epilepsii: sistematika, diagnostika, terapiya [Idiopathic forms of epilepsy: systematics, diagnosis, therapy]. Moscow: Art-Biznes-Tsentr; 2000. P. 120–35.

4. Martinez-Juarez IE, Alonso ME, Medina MT, et al. Juvenile myoclonic epilepsy subsyndromes: family studies and long-term follow-up. Brain. 2006 May;129(Pt 5):1269-80. Epub 2006 Mar 6.

5. Shilkina OS, Petrov KV, Diuzhakova AV, et al. Frequency of juvenile myoclonic epilepsy phenotypes in Siberia. World J Neurosci. 2016; (6):32-6. doi:10.4236/wjns.2016.61004.

6. Shnaider NA, Shilkina OS, Petrov KV, et al. Clinical-genetics heterogeneity of juvenile myoclonic epilepsy. Epilepsiya i paroksizmal'nye sostoyaniya. 2016;(2):20-36. (In Russ.) doi:10.17749/2077-8333.2016.8.2.020-036.

7. Belousova ED. Genetics of epilepsy: What for and how to examine children with epilepsy. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2014;6(1S):4-8. (In Russ.) doi:10.14412/2074-2711-2014-1S-4-8.

8. Greenberg DA, Stewart WC. How should we be searching for genes for common epilepsy? A critique and a prescription. Epilepsia. 2012 Sep;53 Suppl 4:72-80. doi: 10.1111/j.1528-1167.2012.03616.x.

9. Delgado-Escueta AV, Koeleman BP, Bailey JN, et al. The quest for juvenile myoclonic epilepsy genes. Epilepsy Behav. 2013 Jul;28 Suppl 1:S52-7. doi: 10.1016/j.yebeh.2012.06.033.

10. Online Mendelian Inheritance in Man. http://www.omim.org/

11. Delgado-Escueta AV. Advances in genetics of juvenile myoclonic epilepsies. Epilepsy Curr. 2007 May-Jun;7(3):61-7. doi: 10.1111/j.1535-7511.2007.00171.x.

12. Bosco D, Haefliger JA, Meda P. Connexins: key mediators of endocrine function. Physiol Rev. 2011 Oct;91(4):1393-445. doi: 10.1152/physrev.00027.2010.

13. Pal DK, Durner M, Klotz I, et al. Complex inheritance and parent-of-origin effect in juvenile myoclonic epilepsy. Brain Dev. 2006 Mar; 28(2):92-8. Epub 2006 Jan 18.

14. Shang E, Wang X, Wen D, et al. Double bromodomain-containing gene Brd2 is essential for embryonic development in mouse. Dev Dyn. 2009 Apr;238(4):908-17. doi: 10.1002/dvdy.21911.

15. Pal DK, Greenberg DA. Major susceptibility genes for common idiopathic epilepsies: ELP4 in Rolandic epilepsy and BRD2 in juvenile myoclonic epilepsy. In: Noebels JL, Avoli M, Rogawski MA, et al, editors. Source. Jasper's Basic Mechanisms of the Epilepsies. 4th edition. Bethesda: National Center for Biotechnology Information; 2012.

16. Pal DK, Evgrafov OV, Tabares P, et al. BRD2 (RING3) is a probable major susceptibility gene for common juvenile myoclonic epilepsy. Am J Hum Genet. 2003 Aug;73(2): 261-70. Epub 2003 Jun 25. doi: 10.1086/377006

17. De Kovel CG, Pinto D, de Haan GJ, et al. Association analysis of BRD2 (RING3) and epilepsy in a Dutch population. Epilepsia. 2007 Nov;48(11):2191-2. doi: 10.1111/j.1528-1167.2007.01306.x

18. Lorenz S, Taylor KP, Gehrmann A, et al. Association of BRD2 polymorphisms with photoparoxysmal response. Neurosci Lett. 2006 May 29;400(1-2):135-9. Epub 2006 Mar 3.

19. Cavalleri G. Haplotype mapping in epilepsy genetics and pharmacogenetics. University College London; 2013. http://discovery.ucl.ac.uk/id/eprint/1445351

20. Mas C, Taske N, Deutsch S, et al. Association of theconnexin 36 gene with juvenile myoclonic epilepsy. J Med Genet. 2004 Jul; 41(7):e93.

21. Hempelmann A, Heils A, Sander T. Confirmatory evidence for an association of the connexin-36 gene with juvenile myoclonic epilepsy. Epilepsy Res. 2006 Oct;71(2-3):223-8. Epub 2006 Jul 28.