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Significance of exome sequencing for diagnosis of epilepsy in children

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Introduction. Epilepsy is a neurological disorder characterized by periodic seizure attacks. Around 70–80% of epilepsy cases have a hereditary component.

Aim: to identify the genetic factors of pharmacoresistant epilepsy in children.

Materials and methods. Fifty two patients with epilepsy and psychomotor / speech retardation were examined. We used the next generation sequencing (NGS) technique, which is the targeted exome sequencing, the “Hereditary epilepsy” panel of genes, and the whole exome sequencing assay.

Results. Mutations were detected in 30 (57.7%) patients, while 22 patients had no mutations. In the latter cases, either epilepsy was of non-hereditary nature or the tested nucleotide sequence was located in the non-coding part of the gene (intron); in addition, a chromosomal rearrangement could be involved.

Conclusion. The obtained data illustrate a diagnostic significance of the whole exome sequencing and encourage the interaction between an epileptologist and a geneticist in the diagnostic procedure. Identification of the genetic base of the disease is of great importance for genetic counseling and for selecting an antiepileptic therapy in this group of patients.

The authors declare about the absence of conflict of interest with respect to this publication. Authors contributed equally to this article.

About the Authors

T. V. Kozhanova
St. Luka’s Clinical Research Center for Children; Pirogov Russian National Research Medical University
Russian Federation

Tatyana V. Kozhanova – MD, PhD, Researcher of the genetic group of the scientific department, laboratory geneticist,

associate professor, department of neurology, neurosurgery and medical genetics, pediatric faculty

S. S. Zhilina
St. Luka’s Clinical Research Center for Children; Pirogov Russian National Research Medical University
Russian Federation

Svetlana S. Zhilina – MD, PhD, Lead researcher of the genetic group of the scientific department, geneticist

associate professor, department of neurology, neurosurgery and medical genetics, pediatric faculty

T. I. Meshheryakova
St. Luka’s Clinical Research Center for Children
Russian Federation
Tatyana I. Meshheryakova – MD, PhD, Lead Researcher-Geneticist, Research Department,

K. V. Osipova
St. Luka’s Clinical Research Center for Children
Russian Federation
Karina V. Osipova – MD, PhD, Head of the Psychoneurology Department

S. O. Ayvazyan
St. Luka’s Clinical Research Center for Children
Russian Federation
Sergey O. Ayvazyan – MD, PhD, Head, Resistant Epilepsy Unit

A. G. Prityko
St. Luka’s Clinical Research Center for Children; Pirogov Russian National Research Medical University
Russian Federation

Andrey G. Prityko – МD., PhD., Professor of Russian Academy of Natural Sciences, Director

Head of the department of maxillofacial surgery and dentistry, Faculty of Pediatrics


1. Fisher R.S., Cross J.H., French J.A., Higurashi N., Hirsch E., Jansen F.E., Lagae L., Moshé S.L., Peltola J., Roulet Perez E., Scheffer I.E., Zuberi S.M. Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017; 58 (4): 522-530.

2. Moller R.S., Dahl H.A., Helbig I. The contribution of next generation sequencing to epilepsy genetics. Expert Rev. Mol. Diagn. 2015; 15: 1531-1538.

3. Annegers J.F., Hauser W.A., Anderson V.E., Kurland, L.T. The risks of seizure disorders among relatives of patients with childhood onset epilepsy. Neurology. 1982; 32: 174-179.

4. Scheffer I.E., Berkovic S.F. Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes. Brain. 1997; 120: 479-490.

5. Jallon P., Loiseau P., Loiseau J.C. on behalf of Groupe. Newly Diagnosed Unprovoked Epileptic Seizures: Presentation at Diagnosis in CAROLE Study. Epilepsia. 2001; 42: 464-475.

6. Myers C. T., Mefford, H. C. Advancing epilepsy genetics in the genomic era. Genome Med. 2015; 7: 91.

7. Poduri A., Lowenstein D. Epilepsy genetics-past, present, and future. Curr. Opin. Genet. Dev. 2011; 21: 325-332.

8. Dunn P., Albury C.L., Maksemous N., Benton M.C., Sutherland H.G., Smith R.A., Haupt L.M., Griffiths L.R. Next Generation Sequencing Methods for Diagnosis of Epilepsy Syndromes. Front Genet. 2018; 9: 20. 2018.

9. Berkovic S.F. Genetics of epilepsy in clinical practice. Epil. Curr. 2015; 15: 192-196.

10. Wang J., Lin Z.J., Liu L., Xu H.Q., Shi Y.W., Yi Y.H., He N., Liao WP. Epilepsy-associated genes. Seizure. 2017; 44: 11-20.

11. Shi Y. W., Yu M. J., Long Y. S., Qin B., He N., Meng H., Liu X.R., Deng W.Y., Gao M.M., Yi Y.H., Li B.M., Liao W.P. Mosaic SCN1A mutations in familial partial epilepsy with antecedent febrile seizures. Genes Brain Behav. 2012; 11: 170-176.

12. Halvorsen M., Petrovski S., Shellhaas R., Tang Y., Crandall L., Goldstein D., Devinsky O. Mosaic mutations in early-onset genetic diseases. Genet. Med. 2016; 18: 746-749.

13. Stosser M.B., Lindy A.S., Butler E., Retterer K., Piccirillo-Stosser C.M., Richard G., McKnight D.A. High frequency of mosaic pathogenic variants in genes causing epilepsy-related neurodevelopmental disorders. Genet. Med. 2017; 20 (4): 403-410.

14. Gajecka M. Unrevealed mosaicism in the next-generation sequencing era. Mol. Genet. Genomics. 2016; 291: 513-530.

15. Poduri A., Sheidley B. R., Shostak S., Ottman R. Genetic testing in the epilepsies-developments and dilemmas. Nat. Rev. Neurol. 2014; 10: 293-299.

16. Choi M., Scholl U.I., Ji W., Liu T., Tikhonova I.R., Zumbo P. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 19096-19101.

17. Stavropoulos D.J., Merico D., Jobling R., Bowdin S., Monfared N., Thiruvahindrapuram B., et al. Whole-genome sequencing expands diagnostic utility and improves clinical management in paediatric medicine. Npj Genomic Med. 2016; 1: 15012.

18. Chrystoja C.C., Diamandis, E.P. Whole genome sequencing as a diagnostic test: challenges and opportunities. Clin. Chem. 2014; 60: 724-733.

19. Lohmann K., Klein C. Next generation sequencing and the future of genetic diagnosis. Neurotherapeutics. 2014; 11: 699-707.

20. Delahaye-Duriez A., Srivastava P., Shkura K., Langley S.R., Laaniste L., Moreno-Moral A., Danis B., Mazzuferi M., Foerch P., Gazina EV., Richards K., Petrou S., Kaminski RM., Petretto E., Johnson MR. Rare and common epilepsies converge on a shared gene regulatory network providing opportunities for novel antiepileptic drug discovery. Genome Biology. 2016; 17: 245.

21. Hunt A.D. Jr., Stokes J. Jr., Mc C.W., Stroud H.H. Pyridoxine dependency: report of a case of intractable convulsions in an infant controlled by pyridoxine. Pediatrics. 1954; 13: 140-145.

22. Mills P. B., Struys E., Jakobs C., Plecko B., Baxter P., Baumgartner M., Willemsen M.A., Omran H., Tacke U., Uhlenberg B., Weschke B., Clayton P.T. Mutations in antiquitin in individuals with pyridoxinedependent seizures. Nat. Med. 2006; 12: 307-309.

23. Yang Y., Muzny D.M., Reid J.G., Bainbridge M.N., Willis A., Ward P.A. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N. Engl. J. Med. 2013; 369: 1502-1511.

24. Yang Y., Muzny D.M., Xia F., Niu Z., Person R., Ding Y. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. 2014; 312: 1870-1879.

25. Jiang Y.H., Yuen R.K., Jin X., Wang M., Chen N., Wu X., Ju J, Mei J, Shi Y, He M, Wang G, Liang J, Wang Z, Cao D, Carter MT, Chrysler C, Drmic IE, Howe JL, Lau L, Marshall CR, Merico D, Nalpathamkalam T, Thiruvahindrapuram B, Thompson A, Uddin M, Walker S, Luo J, Anagnostou E, Zwaigenbaum L, Ring RH, Wang J, Lajonchere C, Wang J, Shih A, Szatmari P, Yang H, Dawson G, Li Y, Scherer SW. Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. Am. J. Hum. Genet. 2013; 93: 249-263.

26. Gilissen C., Hehir-Kwa J.Y., Thung D. T., M., van de Vorst van Bon B. W., Willemsen M.H., Kwint M., Janssen I.M., Hoischen A., Schenck A., Leach R., Klein R., Tearle R., Bo T., Pfundt R., Yntema H.G., de Vries B.B., Kleefstra T., Brunner H.G., Vissers L.E., Veltman J.A. Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014; 511: 344-347.

27. Robertson J., Hatton C., Emerson E., Baines S. Prevalence of epilepsy among people with intellectual disabilities: a systematic review. Seizure. 2015; 29: 46-62.

28. Leonard H., Wen X. The epidemiology of mental retardation: challenges and opportunities in the new millennium. Ment Retard Dev Disabil Res Rev. 2002; 8: 117-34.

29. Ropers H.H. Genetics of early onset cognitive impairment. Annu Rev Genomics Hum Genet. 2010; 11: 161-87.

30. Topper S., Ober C., Das S. Exome sequencing and the genetics of intellectual disability. Clin Genet. 2011; 80: 117-26. https://doi. org/10.1111/j.1399-0004.2011.01720.x.

31. Orsini A., Zara F., Striano P. Recent advances in epilepsy genetics. Neurosci Lett. 2018; 667: 4-9.

32. Myers K.A., Johnstone D.L., Dyment D.A. Epilepsy genetics: Current knowledge, applications, and future directions. Clin Genet. 2019; 95 (1): 95-111.


For citations:

Kozhanova T.V., Zhilina S.S., Meshheryakova T.I., Osipova K.V., Ayvazyan S.O., Prityko A.G. Significance of exome sequencing for diagnosis of epilepsy in children. Epilepsy and paroxysmal conditions. 2019;11(4):379-387. (In Russ.)

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