Whole-exome sequencing is the molecular-genetic test of the first-line in developmental and epileptic encephalopathies

Introduction. Developmental and epileptic encephalopathy are severe developmental disorders of the nervous system, characterized by recurrent epileptic seizures that begin over the neonatal period or childhood, accompanied by psychomotor retardation and intellectual disability. Massively parallel sequencing is a technology used to determine the complete nucleotide sequence of DNA or RNA. The technology is characterized by the high productivity and speed, marking the beginning of the golden age of genetics, allowing large volumes of DNA to be sequenced quickly and efficiently at lower costs. The aim of this study is to evaluate the effectiveness of whole-exome sequencing as a first-line genetic test in patients with developmental and epileptic encephalopathy and detect the structure of identified variants in the Russian population.

Materials and methods. Patients with drug-resistant seizures, onset in neonatal and early childhood, hospitalized in the Psychoneurological Department during 2017–2023. All patients underwent clinical and genealogical analysis, video-EEG and MRI of the brain, and whole-exome sequencing.

Results. The main result obtained in the study analysis of patients who underwent whole exome sequencing for the period of 2017-2023 was the detection rate of variants in genes associated with developmental and epileptic encephalopathy (21.7%; 71/331). Of these, 35/71 (49.3%) had pathogenic and probably pathogenic variants of the nucleotide sequence. Based on the results of whole exome sequencing patients were selected for the most effective targeted antiepileptic drugs.

Conclusion. The use of whole-exome sequencing as a first-line molecular genetic test in patients with developmental and epileptic encephalopathy has been shown to be highly effective. Making an accurate genetic diagnosis is a fundamental background for precision therapy. Personalized medicine, that is, the attempt to personalize prevention, diagnosis, and treatment as much as possible according to the characteristics and needs of the patient, should be the main goal of clinical research and a new direction of modern medicine.

Compliance with ethical standards. Patient management was carried out according to the principles of the Declaration of Helsinki of the World Medical Association (2013). Informed consent was obtained from the parents of patients to conduct a genetic study (whole exome sequencing).

Contribution:
Kozhanova T.V. — concept, writing text;
Zhilina S.S. — concept, editing;
Meshcheryakova T.I. — editing;
Abramov A.A. — editing;
Ayvasyan S.O. — editing;
Zavadenko N.N. — editing;
All co-authors — are responsible for the integrity of all parts of the manuscript and approval of its final version.

Conflict of interest. The authors declare no conflict of interest.

Acknowledgment. The study had no sponsorship.

Received: April 23, 2024
Accepted: June 14, 2024
Published July 31, 2024

1. Wirrell E., Tinuper P., Perucca E., Moshé S.L. Introduction to the epilepsy syndrome papers. Epilepsia. 2022; 63(6): 1330–2. https://doi.org/10.1111/epi.17262

2. Kalser J., Cross J.H. The epileptic encephalopathy jungle – from Dr. West to the concepts of aetiology-related and developmental encephalopathies. Curr. Opin. Neurol. 2018; 31(2): 216–22. https://doi.org/10.1097/WCO.0000000000000535

3. Guerrini R., Conti V., Mantegazza M., Balestrini S., Galanopoulou A.S., Benfenati F. Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum. Physiol. Rev. 2023; 103(1): 433–513. https://doi.org/10.1152/physrev.00063.2021

4. Siniatchkin M., Capovilla G. Functional neuroimaging in epileptic encephalopathies. Epilepsia. 2013; 54(Suppl. 8): 27–33. https://doi.org/10.1111/epi.12420

5. Raga S., Specchio N., Rheims S., Wilmshurst J.M. Developmental and epileptic encephalopathies: recognition and approaches to care. Epileptic Disord. 2021; 23(1): 40–52. https://doi.org/10.1684/epd.2021.1244

6. Berg A.T., Berkovic S.F., Brodie M.J., Buchhalter J., Cross J.H., van Emde Boas W., et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia. 2010; 51(4): 676–85. https://doi.org/10.1111/j.1528-1167.2010.02522.x

7. Scheffer I.E., Liao J. Deciphering the concepts behind “Epileptic encephalopathy” and “Developmental and epileptic encephalopathy”. Eur. J. Paediatr. Neurol. 2020; 24: 11–4. https://doi.org/10.1016/j.ejpn.2019.12.023

8. Scheffer I.E., Berkovic S., Capovilla G., Connolly M.B., French J., Guilhoto L., et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017; 58(4): 512–21. https://doi.org/10.1111/epi.13709

9. McTague A., Howell K.B., Cross J.H., Kurian M.A., Scheffer I.E. The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol. 2016; 15(3): 304–16. https://doi.org/10.1016/S1474-4422(15)00250-1

10. Caliendo M., Lanzara V., Vetri L., Roccella M., Marotta R., Carotenuto M., et al. Emotional-behavioral disorders in healthy siblings of children with neurodevelopmental disorders. Medicina (Kaunas). 2020; 56(10): 491. https://doi.org/10.3390/medicina56100491

11. Vetri L., Messina L.M., Drago F., D’Aiuto F., Vanadia F., Brighina F., et al. Are paediatric headaches in the emergency department increasing? An Italian experience. Funct. Neurol. 2019; 34(3): 188–95.

12. Esposito M., Orsini A., Striano P. Percorso diagnostico nelle epilessie genetiche. Prospett. Pediatr. 2019; 49: 86–94. (in Italian)

13. Slatko B.E., Gardner A.F., Ausubel F.M. Overview of next-generation sequencing technologies. Curr. Protoc. Mol. Biol. 2018; 122(1): e59. https://doi.org/10.1002/cpmb.59

14. Levy S.E., Boone B.E. Next-generation sequencing strategies. Cold Spring Harb. Perspect. Med. 2019; 9(7): a025791. https://doi.org/10.1101/cshperspect.a025791

15. Richards S., Aziz N., Bale S., Bick D., Das S., Gastier-Foster J., et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 2015; 17(5): 405–24. https://doi.org/10.1038/gim.2015.30

16. Ryzhkova O.P., Kardymon O.L., Prohorchuk E.B., Konovalov F.A., Maslennikov A.B., Stepanov V.A., et al. Guidelines for the interpretation of massive parallel sequencing variants. Meditsinskaya genetika. 2017; 16(7): 4–17. https://elibrary.ru/zjtgdr (in Russian)

17. Demikova N.S., Baranova E.E. Indications for Genome-Wide Sequencing in Patients with Suspected Hereditary Rare Diseases: Textbook [Pokazaniya k polnogenomnomu sekvenirovaniyu u bol’nykh s podozreniem na nasledstvennye redkie zabolevaniya: Uchebnoe posobie]. Moscow; 2022. (in Russian)

18. Ostrander B.E.P., Butterfield R.J., Pedersen B.S., Farrell A.J., Layer R.M., Ward A., et al. Whole-genome analysis for effective clinical diagnosis and gene discovery in early infantile epileptic encephalopathy. NPJ Genom. Med. 2018; 3: 22. https://doi.org/10.1038/s41525-018-0061-8

19. Vetri L., Calì F., Saccone S., Vinci M., Chiavetta N.V., Carotenuto M., et al. Whole exome sequencing as a first-line molecular genetic test in developmental and epileptic encephalopathies. Int. J. Mol. Sci. 2024; 25(2): 1146. https://doi.org/10.3390/ijms25021146

20. Boonsimma P., Ittiwut C., Kamolvisit W., Ittiwut R., Chetruengchai W., Phokaew C., et al. Exome sequencing as first-tier genetic testing in infantile-onset pharmacoresistant epilepsy: diagnostic yield and treatment impact. Eur. J. Hum. Genet. 2023; 31(2): 179–87. https://doi.org/10.1038/s41431-022-01202-x

21. Mercimek-Mahmutoglu S., Patel J., Cordeiro D., Hewson S., Callen D., Donner E.J., et al. Diagnostic yield of genetic testing in epileptic encephalopathy in childhood. Epilepsia. 2015; 56(5): 707–16. https://doi.org/10.1111/epi.12954

22. Palmer E.E., Schofield D., Shrestha R., Kandula T., Macintosh R., Lawson J.A., et al. Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: Evidence of clinical utility and cost effectiveness. Mol. Genet. Genomic Med. 2018; 6(2): 186–99. https://doi.org/10.1002/mgg3.355