epilepsiaEpilepsy and paroxysmal conditionsЭпилепсия и пароксизмальные состояния2077-83332311-4088IRBIS LLC10.17749/2077-8333/epi.par.con.2022.119epilepsia-821Research ArticleORIGINAL ARTICLESОРИГИНАЛЬНЫЕ СТАТЬИWhole-exome sequencing of patients with juvenile myoclonic epilepsyПолноэкзомное секвенирование пациентов с юношеской миоклонической эпилепсиейhttps://orcid.org/0000-0002-4555-7457ТимечкоЕ. Е.TimechkoE. E.

Тимечко Елена Евгеньевна – лаборант лаборатории медицинской генетики центра коллективного пользования «Молекулярные и клеточные технологии»  

WoS ResearcherID: CAF-2677-2022; РИНЦ SPIN-код: 2711-7770

ул. Партизана Железняка, д. 1, Красноярск 660022

Elena E. Timechko – Laboratory Assistant, Laboratory of Medical Genetics, Center of Collective Usage “Molecular and CellularTechnologies”, 

 WoS ResearcherID: CAF-2677-2022; RSCI SPIN-code: 2711-7770

1 Partizan Zheleznyak Str., Krasnoyarsk 660022

https://orcid.org/0000-0003-3149-507XШилкинаО. С.ShilkinaO. S.

Шилкина Ольга Сергеевна – к.м.н., невролог Неврологического центра эпилептологии, нейрогенетики и исследований мозга Университетской клиники 

РИНЦ SPIN-код: 1150-7413

ул. Партизана Железняка, д. 1, Красноярск 660022

Olga S. Shilkina – MD, PhD, Neurologist, Neurological Center of Epileptology, Neurogenetics and Brain Research, University Clinic

RSCI SPIN-code: 1150-7413

1 Partizan Zheleznyak Str., Krasnoyarsk 660022

https://orcid.org/0000-0003-1435-5083ОрешковаН. В.OreshkovaN. V.

Орешкова Наталья Викторовна – к.б.н., заведующая лабораторией геномных исследований и биотехнологии; старший научный сотрудник лаборатории лесной геномики Научно-образовательного центра геномных исследований Института фундаментальной биологии и биотехнологии 

WoS ResearcherID: L-5516-2017; Scopus Author ID: 55793767200; РИНЦ SPIN-код: 4149-9633

ул. Академгородок, д. 50, Красноярск 660036; пр. Свободный, д. 79, Красноярск 660041

Natalya V. Oreshkova – PhD (Biol.), Head of Laboratory of Genomic Research and Biotechnology ; Senior Researcher, Laboratory of Forest Genomics, Scientific and Educational Center for Genomic Research

WoS ResearcherID: L-5516-2017; Scopus Author ID: 55793767200; RSCI SPIN-code: 4149-9633

50 Akademgorodok Str., Krasnoyarsk 660036; 79 Svobodnyy Ave., Krasnoyarsk 660041

https://orcid.org/0000-0003-3889-1956КобаненкоВ. О.KobanenkoV. O.

Кобаненко Владислав Олегович – студент 5-го курса (медицинская кибернетика) 

РИНЦ SPIN-код: 1143-4417

ул. Партизана Железняка, д. 1, Красноярск 660022

Vladislav O. Kobanenko – 5th-Year Student (Medical Cybernetics)

RSCI SPIN-code: 1143-4417

1 Partizan Zheleznyak Str., Krasnoyarsk 660022

https://orcid.org/0000-0002-4795-7550ОсиповаЕ. А.OsipovaE. A.

Осипова Елизавета Алексеевна – студентка 5-го курса (медицинская кибернетика)

 ул. Партизана Железняка, д. 1, Красноярск 660022

Elizaveta A. Osipova – 5th-Year Student (Medical Cybernetics)

1 Partizan Zheleznyak Str., Krasnoyarsk 660022

https://orcid.org/0000-0002-2840-837XШнайдерН. А.ShnayderN. A.

Шнайдер Наталья Алексеевна – д.м.н., профессор, ведущий научный сотрудник центра коллективного пользования «Молекулярные и клеточные технологии» ; ведущий научный сотрудник отделения персонализированной психиатрии и неврологии  

WoS ResearcherID: M-7084-2014; РИНЦ SPIN-код: 1952-3043

 ул. Партизана Железняка, д. 1, Красноярск 660022;  ул. Бехтерева, д. 3, Санкт-Петербург 192019

Natalya A. Shnayder – Dr. Med. Sc., Professor, Leading Researcher, Center of Collective Usage “Molecular and CellularTechnologies” ; Leading Researcher, Department ofPersonalized Psychiatry and Neurology

WoS ResearcherID: M-7084-2014; RSCI SPIN-code: 1952-3043

1 Partizan Zheleznyak Str., Krasnoyarsk 660022; 3 Bekhterev Str., Saint Petersburg 192019

 

https://orcid.org/0000-0003-4639-6365ДмитренкоД. В.DmitrenkoD. V.

Дмитренко Диана Викторовна – д.м.н., заведующая кафедрой медицинской генетики и клинической нейрофизиологииИнститута профессионального образования  

WoS ResearcherID: H-7787-2016; РИНЦ SPIN-код: 9180-6623

ул. Партизана Железняка, д. 1, Красноярск 660022

Diana V. Dmitrenko – Dr. Med. Sc., Chief of Chair of Medical Genetics and Clinical Neurophysiology, Institute of ProfessionalEducation

WoS ResearcherID: H-7787-2016; RSCI SPIN-code: 9180-6623

1 Partizan Zheleznyak Str., Krasnoyarsk 660022

mart2802@yandex.ruФедеральное государственное бюджетное образовательное учреждение высшего образования «Красноярский государственный медицинский университет им. профессора В.Ф. Войно-Ясенецкого» Министерства здравоохранения Российской ФедерацииРоссияVoino-Yasenetsky Krasnoyarsk State Medical UniversityRussian FederationФедеральное государственное бюджетное научное учреждение «Федеральный исследовательский центр «Красноярский научный центр Сибирского отделения Российской академии наук»; Институт фундаментальной биологии и биотехнологии Федерального государственного автономного образовательного учреждения высшего образования «Сибирский федеральный университет»РоссияFederal Research Center “Krasnoyarsk Scientific Center of the Siberian Branch of the Russian Academy of Sciences”; Institute of Fundamental Biology and Biotechnology, Siberian Federal UniversityRussian FederationФедеральное государственное бюджетное образовательное учреждение высшего образования «Красноярский государственный медицинский университет им. профессора В.Ф. Войно-Ясенецкого» Министерства здравоохранения Российской Федерации; Федеральное государственное бюджетное учреждение «Национальный медицинский исследовательский центр психиатрии и неврологии им. В.М. Бехтерева» Министерства здравоохранения Российской ФедерацииРоссияVoino-Yasenetsky Krasnoyarsk State Medical University ; Bekhterev National Medical Research Centre for Psychiatry and NeurologyRussian Federation202215102022143254266Copyright © Timechko E.E., Shilkina O.S., Oreshkova N.V., Kobanenko V.O., Osipova E.A., Shnayder N.A., Dmitrenko D.V., 20222022Тимечко Е.Е., Шилкина О.С., Орешкова Н.В., Кобаненко В.О., Осипова Е.А., Шнайдер Н.А., Дмитренко Д.В.Timechko E.E., Shilkina O.S., Oreshkova N.V., Kobanenko V.O., Osipova E.A., Shnayder N.A., Dmitrenko D.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.epilepsia.su/jour/article/view/821Background

Background. Juvenile myoclonic epilepsy (JME) is the most common type of idiopathic generalized epilepsy with onset in adolescence and adulthood. During medical genetic counseling in probands with JME, aggravated epilepsy-related heredity is often detected. However, specific genetic variants of JME predisposition remain inconclusive. The use of contemporary methods of genetic analysis, particularly whole-exome and whole-genome sequencing, allows to detect, confirm and strengthen an association of any certain pathological phenotype with one or another pathogenic variant in a number of genes.

Objective

Objective: to analyze the results of whole exome sequencing in patients with JME and seek for JME associations.

Material and methods

Material and methods. The study included 7 patients with established JME diagnosis and 1 proband child without clinical signs of epilepsy. Whole exome sequencing was carried out by using MiSeq (Illumina, USA), bioinformatics analysis was performed on the Genomenal platform (Novel Software Systems, Russia).

Results

Results. Heterozygous carriage of pathogenic variants in the genes of recessive diseases was revealed: SACS, AHI1, CEP164, ANO10, RMND1, POMGNT1, FLG, ACTB. The analysis of the identified genetic variants in the patients examined showed no association with the clinical picture of the disease. Heterozygous missense mutations in CLCN2, EFHC1, JRK, ME2 genes and frameshift mutation in the CACNB4 gene were detected.

 Conclusion

 Conclusion. In recent years, significant efforts were made to identify genes which predispose to JME. During our study, monogenic and/or polygenic pathogenic variants in patients with JME and a child of proband with JME were not identified. The high genetic heterogeneity of JME can explain numerous unsuccessful attempts to find genes predisposing to JME. Further research is necessary to confirm variants associated with potential JME. Advances in genomic technology can expand our understanding of the genetics of this pathology.

Актуальность

Актуальность. Ювенильная миоклоническая эпилепсия (ЮМЭ) является наиболее распространенным типом идиопатической генерализованной эпилепсии с дебютом в подростковом и взрослом возрасте. При медико-генетическом консультировании у пробандов с ЮМЭ нередко выявляется отягощенная наследственность по эпилепсии. Однако конкретные генетические варианты предрасположенности к ЮМЭ остаются неубедительными. Использование современных методов генетического анализа, в частности проведение полноэкзомного и полногеномного секвенирования, позволяет обнаружить, подтвердить и упрочнить ассоциативную связь определенного патологического фенотипа с наличием того или иного патогенного варианта в ряде генов.

Цель

Цель: анализ результатов полноэкзомного секвенирования у пациентов с ЮМЭ и поиск ассоциативных связей с заболеванием.

Материал и методы

Материал и методы. В исследование включены 7 пациентов с установленным диагнозом ЮМЭ и 1 ребенок пробанда без клинических признаков эпилепсии. Полноэкзомное секвенирование проведено с использованием аппарата MiSeq (Illumina, США), биоинформатический анализ осуществлен на платформе Genomenal (Novel Software Systems, Россия).

Результаты

Результаты. Выявлено гетерозиготное носительство патогенных вариантов в генах рецессивных заболеваний: SACS, AHI1, CEP164, ANO10, RMND1, POMGNT1, FLG, ACTB. При анализе обнаруженных генетических вариантов у обследованных пациентов ассоциаций с клинической картиной заболевания не установлено. Отмечены гетерозиготные миссенсмутации в генах CLCN2, EFHC1, JRK, ME2 и frameshift-мутация в гене CACNB4.

Заключение

Заключение. В последние годы значительные усилия направлены на идентификацию генов предрасположенности к ЮМЭ. В проведенном нами исследовании моногенных и/или полигенных патогенных вариантов у пациентов с ЮМЭ и ребенка пробанда с ЮМЭ не выявлено. Высокая генетическая гетерогенность заболевания может объяснить многочисленные безуспешные попытки найти гены предрасположенности к ЮМЭ. Необходимы дальнейшие исследования для подтверждения вариантов, ассоциированных с развитием ЮМЭ. Достижения в области геномных технологий могут расширить наше понимание генетики данной патологии.

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The authors declare that there are no conflicts of interest present.