Defining causal variants in rare epilepsies: an essential team effort between biomedical scientists, geneticists and epileptologists

McTague, A., Brunklaus, A., Barcia, G., Varadkar, S., Zuberi, S. M., Chatron, N., Parrini, E., Mei, D., Nabbout, R. and Lesca, G. (2022) Defining causal variants in rare epilepsies: an essential team effort between biomedical scientists, geneticists and epileptologists. European Journal of Medical Genetics, 65(7), 104531. (doi: 10.1016/j.ejmg.2022.104531) (PMID:35618197)

Abstract

In the last few years, with the advent of next generation sequencing (NGS), our knowledge of genes associated with monogenic epilepsies has significantly improved. NGS is also a powerful diagnostic tool for patients with epilepsy, through gene panels, exomes and genomes. This has improved diagnostic yield, reducing the time between the first seizure and a definitive molecular diagnosis. However, these developments have also increased the complexity of data interpretation, due to the large number of variants identified in a given patient and due to the phenotypic variability associated with many of the epilepsy-related genes. In this paper, we present examples of variant classification in “real life” clinic situations. We emphasize the importance of accurate phenotyping of the epilepsies including recognising variable/milder phenotypes and expansion of previously described phenotypes. There are some important issues specific to rare epilepsies – mosaicism and reduced penetrance - which affect genetic counselling. These challenges may be overcome through multidisciplinary meetings including epileptologists, pediatric neurologists, and clinical and molecular geneticists, in which every specialist learns from the others in a process which leads to for rapid and accurate diagnosis. This is an important milestone to achieve as targeted therapiesbased on the functional effects of pathogenic variants become available.

• Item Type: Articles
• Additional Information: DM is also supported by the Italian Ministry of Health (RF-2019-12370059). AM is supported by grants from the Medical Research Council (MR/T007087/1), the Rosetrees Trust and Great Ormond Street Hospital Children’s Charity (VS0122).
• Keywords: Genotype, Gene, Multidisciplinary meetings, Phenotype, Epilepsy
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Zuberi, Dr Sameer and Brunklaus, Professor Andreas
• Authors: McTague, A., Brunklaus, A., Barcia, G., Varadkar, S., Zuberi, S. M., Chatron, N., Parrini, E., Mei, D., Nabbout, R., and Lesca, G.
• College/School: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: European Journal of Medical Genetics
• Publisher: Elsevier
• ISSN: 1769-7212
• ISSN (Online): 1878-0849
• Published Online: 23 May 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in European Journal of Medical Genetics 65(7): 104531
• Publisher Policy: Reproduced under a Creative Commons licence