Epilepsy; monogenic; Literature review; Genetics; Variant function; Epilepsy genes
Résumé :
[en] Many epilepsy-associated genes have been identified over the last three decades, revealing a remarkable molecular heterogeneity with the shared outcome of recurrent seizures. Information about the genetic landscape of epilepsies is scattered throughout the literature and answering the simple question of how many genes are associated with epilepsy is not straightforward. Here, we present a computationally driven analytical review of epilepsy-associated genes using the complete scientific literature in PubMed. Based on our search criteria, we identified a total of 738 epilepsy-associated genes. We further classified these genes into two Tiers. A broad gene list of 738 epilepsy-associated genes (Tier 2) and a narrow gene list composed of 143 epilepsy-associated genes (Tier 1). Our search criteria do not reflect the degree of association. The average yearly number of identified epilepsy-associated genes between 1992 and 2021 was 4.8. However, most of these genes were only identified in the last decade (2010–2019). Ion channels represent the largest class of epilepsy-associated genes. For many of these, both gain- and loss-of-function effects have been associated with epilepsy in recent years. We identify 28 genes frequently reported with heterogenous variant effects which should be considered for variant interpretation. Overall, our study provides an updated and manually curated list of epilepsy-related genes together with additional annotations and classifications reflecting the current genetic landscape of epilepsy.
Centre de recherche :
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Scheffer, I.E., Berkovic, S., Capovilla, G., et al. ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology. Epilepsia 58:4 (2017), 512–521, 10.1111/epi.13709.
Epi 25 Collaborative. Ultra-rare genetic variation in the epilepsies: a whole-exome sequencing study of 17,606 individuals. Am. J. Hum. Genet. 105:2 (2019), 267–282, 10.1016/j.ajhg.2019.05.020.
Heyne, H.O., Singh, T., Stamberger, H., et al. De novo variants in neurodevelopmental disorders with epilepsy. Nat. Genet. 50:7 (2018), 1048–1053, 10.1038/s41588-018-0143-7.
Epi4K Consortium, Epilepsy Phenome/Genome Project Allen, A.S., et al. De novo mutations in epileptic encephalopathies. Nature 501:7466 (2013), 217–221, 10.1038/nature12439.
Coppola, A., Cellini, E., Stamberger, H., et al. Diagnostic implications of genetic copy number variation in epilepsy plus. Epilepsia 60:4 (2019), 689–706, 10.1111/epi.14683.
Lindy, A.S., Stosser, M.B., Butler, E., et al. Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders. Epilepsia 59:5 (2018), 1062–1071, 10.1111/epi.14074.
Sheidley, B.R., Malinowski, J., Bergner, A.L., et al. Genetic testing for the epilepsies: a systematic review. Epilepsia 63:2 (2022), 375–387, 10.1111/epi.17141.
Ellis, C.A., Petrovski, S., Berkovic, S.F., Epilepsy genetics: clinical impacts and biological insights. Lancet Neurol., 2019, 10.1016/S1474-4422(19)30269-8 Published online September 4.
ILAE. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nat. Commun., 9(1), 2018, 10.1038/s41467-018-07524-z 5269-5269.
Pérez-Palma, E., Helbig, I., Klein, K.M., et al. Heterogeneous contribution of microdeletions in the development of common generalised and focal epilepsies. J. Med. Genet. 54:9 (2017), 598–606, 10.1136/jmedgenet-2016-104495.
Niestroj, L.M., Perez-Palma, E., Howrigan, D.P., et al. Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17 458 subjects. Brain 143:7 (2020), 2106–2118, 10.1093/brain/awaa171.
McRae, J.F., Clayton, S., Fitzgerald, T.W., et al. Prevalence and architecture of de novo mutations in developmental disorders. Nature 542:7642 (2017), 433–438, 10.1038/nature21062.
Heyne, H.O., Artomov, M., Battke, F., et al. Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy. Genet. Med. 21:11 (2019), 2496–2503, 10.1038/s41436-019-0531-0.
Sanders, S.J., Campbell, A.J., Cottrell, J.R., et al. Progress in understanding and treating SCN2A-mediated disorders. Trends Neurosci., 2018, 10.1016/j.tins.2018.03.011 Published online.
Brunklaus, A., Du, J., Steckler, F., et al. Biological concepts in human sodium channel epilepsies and their relevance in clinical practice. Epilepsia 61:3 (2020), 387–399, 10.1111/epi.16438.
Klepper, J., Diefenbach, S., Kohlschütter, A., Voit, T., Effects of the ketogenic diet in the glucose transporter 1 deficiency syndrome. Prostaglandins Leukot. Essent. Fatty Acids 70:3 (2004), 321–327, 10.1016/j.plefa.2003.07.004.
Wei, C.H., Allot, A., Leaman, R., Lu, Z., PubTator central: automated concept annotation for biomedical full text articles. Nucleic Acids Res. 47:W1 (2019), W587–W593, 10.1093/nar/gkz389.
Rehm HL, Berg JS, Brooks LD, et al. ClinGen — The Clinical Genome Resource. https://doi.org/10.1056/NEJMsr1406261. doi:10.1056/NEJMsr1406261.
Stenson, P.D., Ball, E.V., Mort, M., et al. Human gene mutation Database (HGMD): 2003 update. Hum. Mutat. 21:6 (2003), 577–581, 10.1002/humu.10212.
Quinlan, A.R., Hall, I.M., BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26:6 (2010), 841–842, 10.1093/bioinformatics/btq033.
Raudvere, U., Kolberg, L., Kuzmin, I., et al. Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 47:W1 (2019), W191–W198, 10.1093/nar/gkz369.
Safran, M., Rosen, N., Twik, M., et al. The GeneCards suite. Abugessaisa, I., Kasukawa, T., (eds.) Practical Guide to Life Science Databases, 2021, Springer, 27–56, 10.1007/978-981-16-5812-9_2.
Slegers, R.J., Blumcke, I., Low-grade developmental and epilepsy associated brain tumors: a critical update 2020. Acta Neuropathol. Commun., 8(1), 2020, 27, 10.1186/s40478-020-00904-x.
Schneider, A.L., Myers, C.T., Muir, A.M., et al. FBXO28 causes developmental and epileptic encephalopathy with profound intellectual disability. Epilepsia 62:1 (2021), e13–e21, 10.1111/epi.16784.
Schwarz N, Seiffert S, Pendziwiat M, et al. Spectrum of phenotypic, genetic, and functional characteristics in epilepsy patients with KCNC2 pathogenic variants. Neurology. Published online March 21, 2022:10.1212/WNL.0000000000200660. doi:10.1212/WNL.0000000000200660.
DiStefano, M.T., Goehringer, S., Babb, L., et al. The Gene Curation Coalition: a global effort to harmonize gene-disease evidence resources. Genet. Med. 24:8 (2022), 1732–1742, 10.1016/j.gim.2022.04.017.
Frazer, J., Notin, P., Dias, M., et al. Disease variant prediction with deep generative models of evolutionary data. Nature 599:7883 (2021), 91–95, 10.1038/s41586-021-04043-8.
Kircher, M., Witten, D.M., Jain, P., O'Roak, B.J., Cooper, G.M., Shendure, J., A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 46:3 (2014), 310–315, 10.1038/ng.2892.
Lal, D., May, P., Perez-Palma, E., et al. Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders. Genome Med., 12(1), 2020, 28, 10.1186/s13073-020-00725-6.
Brünger, T., Pérez-Palma, E., Montanucci, L., et al. Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes. Brain, 2022, awac305, 10.1093/brain/awac305 Published online August 29.
Pérez-Palma, E., May, P., Iqbal, S., et al. Identification of pathogenic variant enriched regions across genes and gene families. Genome Res. 30:1 (2020), 62–71, 10.1101/gr.252601.119.
Heyne, H.O., Baez-Nieto, D., Iqbal, S., et al. Predicting functional effects of missense variants in voltage-gated sodium and calcium channels. Sci. Transl. Med., 12(556), 2020, eaay6848, 10.1126/scitranslmed.aay6848.
Brunklaus, A., Pérez-Palma, E., Ghanty, I., et al. Development and validation of a prediction model for early diagnosis of SCN1A-related epilepsies. Neurology 98:11 (2022), e1163–e1174, 10.1212/WNL.0000000000200028.
López-Rivera JA, Pérez-Palma E, Symonds J, et al. A catalogue of new incidence estimates of monogenic neurodevelopmental disorders caused by de novo variants. Brain. Published online May 2020. doi:10.1093/brain/awaa051.
Symonds, J.D., Elliott, K.S., Shetty, J., et al. Early childhood epilepsies: epidemiology, classification, aetiology, and socio-economic determinants. Brain 144:9 (2021), 2879–2891, 10.1093/brain/awab162.
