Dissecting genetics of spectrum of epilepsies with eyelid myoclonia by exome sequencing

Author:

Coppola Antonietta1ORCID,Krithika S.234,Iacomino Michele5,Bobbili Dheeraj6,Balestrini Simona237ORCID,Bagnasco Irene8,Bilo Leonilda1,Buti Daniela9,Casellato Susanna10,Cuccurullo Claudia1ORCID,Ferlazzo Edoardo11,Leu Costin21213,Giordano Lucio14,Gobbi Giuseppe15,Hernandez‐Hernandez Laura23,Lench Nick16,Martins Helena23,Meletti Stefano1718ORCID,Messana Tullio19,Nigro Vincenzo20,Pinelli Michele20ORCID,Pippucci Tommaso21,Bellampalli Ravishankara23,Salis Barbara22,Sofia Vito23,Striano Pasquale2425ORCID,Striano Salvatore1,Tassi Laura26,Vignoli Aglaia27,Vaudano Anna Elisabetta1718ORCID,Viri Maurizio28,Scheffer Ingrid E.293031ORCID,May Patrick6ORCID,Zara Federico525,Sisodiya Sanjay M.23ORCID

Affiliation:

1. Department of Neuroscience, Reproductive and Odontostomatological Sciences Federico II University Naples Italy

2. Department of Clinical and Experimental Epilepsy UCL Queen Square Institute of Neurology London UK

3. Chalfont Centre for Epilepsy Chalfont St Peter UK

4. School of Life Sciences Anglia Ruskin University Cambridge UK

5. Unit of Medical Genetics IRCCS Istituto Giannina Gaslini Genoa Italy

6. Bioinformatics Core Luxembourg Center for Systems Biomedicine Belvaux Luxembourg

7. Neuroscience Department Meyer Children's Hospital–University of Florence Florence Italy

8. Division of Child Neuropsychiatry Martini Hospital Turin Italy

9. Pediatric Neurology Unit and Laboratories Meyer Children's Hospital—University of Florence Florence Italy

10. Unit of Child Neuropsychiatry University Hospital of Sassari Sassari Italy

11. Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Regional Epilepsy Center Great Metropolitan Hospital, Bianchi‐Melacrino Morelli Reggio Calabria Italy

12. Genomic Medicine Institute, Lerner Research Institute Cleveland Clinic Cleveland Ohio USA

13. Stanley Center of Psychiatric Research Broad Institute of Harvard and Massachusetts Institute of Technology Cambridge Massachusetts USA

14. Unit of Child Neurology and Psychiatry ASST Spedali Civili di Brescia Brescia Italy

15. Child Neurology Unit IRCCS Istituto delle Scienze Neurologiche Bologna Italy

16. MRC Nucleic Acid Therapy Accelerator Research Complex at Harwell, Rutherford Appleton Laboratory Harwell UK

17. Department of Biomedical, Metabolic, and Neural Science University of Modena and Reggio Emilia Modena Italy

18. Neurology Unit OCB Hospital, Azienda Ospedaliera Universitaria di Modena Modena Italy

19. IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Neuropsichiatria Infantile Bologna Italy

20. Telethon Institute of Genetics and Medicine Naples Italy

21. Computational Genomics Unit IRCCS Azienda Ospedaliero–Universitaria di Bologna Bologna Italy

22. Unit of Child Neuropsychiatry ASST Fatebenefratelli Sacco Milan Italy

23. Department of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia,” Section of Neurosciences University of Catania Catania Italy

24. Pediatric Neurology and Muscular Diseases Unit IRCCS Istituto Giannina Gaslini Genoa Italy

25. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health University of Genoa Genoa Italy

26. “Claudio Munari” Epilepsy Surgery Center Niguarda Hospital Milan Italy

27. Department of Health Sciences Università degli Studi di Milano Milan Italy

28. Department of Child Neurology and Psychiatry AOU Maggiore della Carità Novara Novara Italy

29. Department of Medicine, Austin Health, Epilepsy Research Center University of Melbourne Heidelberg Victoria Australia

30. Florey Institute of Neuroscience and Mental Health Heidelberg Victoria Australia

31. Murdoch Children's Research Institute and Department of Paediatrics Royal Children's Hospital, University of Melbourne Parkville Victoria Australia

Abstract

AbstractObjectiveEpilepsy with eyelid myoclonia (EEM) spectrum is a generalized form of epilepsy characterized by eyelid myoclonia with or without absences, eye closure‐induced seizures with electroencephalographic paroxysms, and photosensitivity. Based on the specific clinical features, age at onset, and familial occurrence, a genetic cause has been postulated. Pathogenic variants in CHD2, SYNGAP1, NEXMIF, RORB, and GABRA1 have been reported in individuals with photosensitivity and eyelid myoclonia, but whether other genes are also involved, or a single gene is uniquely linked with EEM, or its subtypes, is not yet known. We aimed to dissect the genetic etiology of EEM.MethodsWe studied a cohort of 105 individuals by using whole exome sequencing. Individuals were divided into two groups: EEM− (isolated EEM) and EEM+ (EEM accompanied by intellectual disability [ID] or any other neurodevelopmental/psychiatric disorder).ResultsWe identified nine variants classified as pathogenic/likely pathogenic in the entire cohort (8.57%); among these, eight (five in CHD2, one in NEXMIF, one in SYNGAP1, and one in TRIM8) were found in the EEM+ subcohort (28.57%). Only one variant (IFIH1) was found in the EEM− subcohort (1.29%); however, because the phenotype of the proband did not fit with published data, additional evidence is needed before considering IFIH1 variants and EEM− an established association. Burden analysis did not identify any single burdened gene or gene set.SignificanceOur results suggest that for EEM, as for many other epilepsies, the identification of a genetic cause is more likely with comorbid ID and/or other neurodevelopmental disorders. Pathogenic variants were mostly found in CHD2, and the association of CHD2 with EEM+ can now be considered a reasonable gene–disease association. We provide further evidence to strengthen the association of EEM+ with NEXMIF and SYNGAP1. Possible new associations between EEM+ and TRIM8, and EEM− and IFIH1, are also reported. Although we provide robust evidence for gene variants associated with EEM+, the core genetic etiology of EEM− remains to be elucidated.

Funder

Fonds National de la Recherche Luxembourg

Publisher

Wiley

Subject

Neurology (clinical),Neurology

Cited by 3 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3