Genetic Variants and Disease Mechanisms: Lessons from Monogenic Childhood Epilepsies

Abstract

The elucidation of the molecular basis of monogenic epilepsies is advancing rapidly. For clinicians, knowing not only the affected gene, but also the patient's exact genetic variant and gaining insight into its effect on RNA, protein, cell, and organism level is becoming increasingly important. As different variants in the same gene can lead to opposing functional effects, an understanding of their nature is crucial for informed treatment choices. Correctly counseling patients, parents, and families regarding the patient's prognosis and the risk to other family members of being affected or having an affected child is only possible with detailed knowledge of the genetic and functional alterations underlying the condition. This review aims to provide a comprehensive overview of genetic variants and their effects, following them from the DNA to the organism level. Protein-level outcomes, such as gain- and loss-of-function mechanisms as well as dominant-negative effects, will be illustrated using examples from monogenic epilepsies. Their downstream impact on cellular function and phenotype will be traced to shed light on the mechanisms by which different variants in the same gene can result in diverging clinical presentations. In doing so, we illustrate key genetic concepts relevant to clinical practice to help inform clinical interpretation of genetic variants and facilitate therapeutic decision-making.

Keywords

monogenic epilepsy - genetic variants - variant effects - gain-of-function - dominant-negative - loss-of-function

Publication History

Received: 07 August 2025

Accepted: 17 October 2025

Accepted Manuscript online:
27 October 2025

Article published online:
06 November 2025

• References

• 1 Helbig I, Heinzen EL, Mefford HC. International League Against Epilepsy Genetics Commission. Genetic literacy series: primer part 2-paradigm shifts in epilepsy genetics. Epilepsia 2018; 59 (06) 1138-1147
• 2 Helbig I, Heinzen EL, Mefford HC. ILAE Genetics Commission. Primer part 1-the building blocks of epilepsy genetics. Epilepsia 2016; 57 (06) 861-868
• 3 Zimmern V, Minassian B, Korff C. A review of targeted therapies for monogenic epilepsy syndromes. Front Neurol 2022; 13: 829116
• 4 Guerrini R, Balestrini S, Wirrell EC, Walker MC. Monogenic epilepsies: disease mechanisms, clinical phenotypes, and targeted therapies. Neurology 2021; 97 (17) 817-831
• 5 Created in BioRender. Oberlack, A. (2025). Accessed October 29, 2025 at: https://BioRender.com/7zcw9ia
• 6 Perucca P, Bahlo M, Berkovic SF. The genetics of epilepsy. Annu Rev Genomics Hum Genet 2020; 21: 205-230
• 7 Guerrini R, Conti V, Mantegazza M, Balestrini S, Galanopoulou AS, Benfenati F. Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum. Physiol Rev 2023; 103 (01) 433-513
• 8 Ng ACH, Chahine M, Scantlebury MH, Appendino JP. Channelopathies in epilepsy: an overview of clinical presentations, pathogenic mechanisms, and therapeutic insights. J Neurol 2024; 271 (06) 3063-3094
• 9 den Dunnen JT, Dalgleish R, Maglott DR. et al. HGVS recommendations for the description of sequence variants: 2016 update. Hum Mutat 2016; 37 (06) 564-569
• 10 Morales J, Pujar S, Loveland JE. et al. A joint NCBI and EMBL-EBI transcript set for clinical genomics and research. Nature 2022; 604 (7905) 310-315
• 11 Tavtigian SV, Greenblatt MS, Lesueur F, Byrnes GB. IARC Unclassified Genetic Variants Working Group. In silico analysis of missense substitutions using sequence-alignment based methods. Hum Mutat 2008; 29 (11) 1327-1336
• 12 Yampolsky LY, Stoltzfus A. The exchangeability of amino acids in proteins. Genetics 2005; 170 (04) 1459-1472
• 13 Pérez-Palma E, May P, Iqbal S. et al. Identification of pathogenic variant enriched regions across genes and gene families. Genome Res 2020; 30 (01) 62-71
• 14 Subramanian S, Kumar S. Evolutionary anatomies of positions and types of disease-associated and neutral amino acid mutations in the human genome. BMC Genomics 2006; 7 (01) 306
• 15 Malhis N, Jones SJM, Gsponer J. Improved measures for evolutionary conservation that exploit taxonomy distances. Nat Commun 2019; 10 (01) 1556
• 16 Capra JA, Singh M. Predicting functionally important residues from sequence conservation. Bioinformatics 2007; 23 (15) 1875-1882
• 17 Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 2014; 46 (03) 310-315
• 18 Ioannidis NM, Rothstein JH, Pejaver V. et al. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet 2016; 99 (04) 877-885
• 19 Cheng J, Novati G, Pan J. et al. Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science 2023; 381 (6664) eadg7492
• 20 Montanucci L, Brünger T, Boßelmann CM. et al. Evaluating novel in silico tools for accurate pathogenicity classification in epilepsy-associated genetic missense variants. Epilepsia 2024; 65 (12) 3655-3663
• 21 Truty R, Ouyang K, Rojahn S. et al. Spectrum of splicing variants in disease genes and the ability of RNA analysis to reduce uncertainty in clinical interpretation. Am J Hum Genet 2021; 108 (04) 696-708
• 22 Wang R, Helbig I, Edmondson AC, Lin L, Xing Y. Splicing defects in rare diseases: transcriptomics and machine learning strategies towards genetic diagnosis. Brief Bioinform 2023; 24 (05) 1-15
• 23 Daguenet E, Dujardin G, Valcárcel J. The pathogenicity of splicing defects: mechanistic insights into pre-mRNA processing inform novel therapeutic approaches. EMBO Rep 2015; 16 (12) 1640-1655
• 24 Lindeboom RGH, Supek F, Lehner B. The rules and impact of nonsense-mediated mRNA decay in human cancers. Nat Genet 2016; 48 (10) 1112-1118
• 25 Popp MW, Maquat LE. Leveraging rules of nonsense-mediated mRNA decay for genome engineering and personalized medicine. Cell 2016; 165 (06) 1319-1322
• 26 Torene RI, Guillen Sacoto MJ, Millan F. et al. Systematic analysis of variants escaping nonsense-mediated decay uncovers candidate Mendelian diseases. Am J Hum Genet 2024; 111 (01) 70-81
• 27 Lindeboom RGH, Vermeulen M, Lehner B, Supek F. The impact of nonsense-mediated mRNA decay on genetic disease, gene editing and cancer immunotherapy. Nat Genet 2019; 51 (11) 1645-1651
• 28 Khajavi M, Inoue K, Lupski JR. Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease. Eur J Hum Genet 2006; 14 (10) 1074-1081
• 29 Hug N, Longman D, Cáceres JF. Mechanism and regulation of the nonsense-mediated decay pathway. Nucleic Acids Res 2016; 44 (04) 1483-1495
• 30 Carvill GL, Engel KL, Ramamurthy A. et al; EuroEPINOMICS Rare Epilepsy Syndrome, Myoclonic-Astatic Epilepsy, and Dravet Working Group. Aberrant inclusion of a poison exon causes dravet syndrome and related SCN1A-associated genetic epilepsies. Am J Hum Genet 2018; 103 (06) 1022-1029
• 31 Felker SA, Lawlor JMJ, Hiatt SM. et al. Poison exon annotations improve the yield of clinically relevant variants in genomic diagnostic testing. Genet Med 2023; 25 (08) 100884
• 32 Lin M, Whitmire S, Chen J, Farrel A, Shi X, Guo JT. Effects of short indels on protein structure and function in human genomes. Sci Rep 2017; 7 (01) 9313
• 33 Hurles ME, Dermitzakis ET, Tyler-Smith C. The functional impact of structural variation in humans. Trends Genet 2008; 24 (05) 238-245
• 34 Demidov G, Laurie S, Torella A. et al; Solve-RD consortium. Structural variant calling and clinical interpretation in 6224 unsolved rare disease exomes. Eur J Hum Genet 2024; 32 (08) 998-1004
• 35 Sanchis-Juan A, Stephens J, French CE. et al. Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing. Genome Med 2018; 10 (01) 95
• 36 Blake LE, Roux J, Hernando-Herraez I. et al. A comparison of gene expression and DNA methylation patterns across tissues and species. Genome Res 2020; 30 (02) 250-262
• 37 Liu R, Zhao E, Yu H, Yuan C, Abbas MN, Cui H. Methylation across the central dogma in health and diseases: new therapeutic strategies. Signal Transduct Target Ther 2023; 8 (01) 310
• 38 Chen Z, Morris HR, Polke J. et al. Repeat expansion disorders. Pract Neurol 2025; 25 (03) 204-216
• 39 Chen Y, Dawes R, Kim HC. et al. De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome. Nature 2024; 632 (8026) 832-840
• 40 Fuller ZL, Berg JJ, Mostafavi H, Sella G, Przeworski M. Measuring intolerance to mutation in human genetics. Nat Genet 2019; 51 (05) 772-776
• 41 Lek M, Karczewski KJ, Minikel EV. et al; Exome Aggregation Consortium. Analysis of protein-coding genetic variation in 60,706 humans. Nature 2016; 536 (7616) 285-291
• 42 Karczewski KJ, Francioli LC, Tiao G. et al; Genome Aggregation Database Consortium. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 2020; 581 (7809) 434-443
• 43 Leitão E, Schröder C, Parenti I. et al. Systematic analysis and prediction of genes associated with monogenic disorders on human chromosome X. Nat Commun 2022; 13 (01) 6570
• 44 Wong-Kisiel L. Pyridoxine-dependent epilepsy. In: Epilepsy Case Studies: Pearls for Patient Care. Vol 9783319013. University of Washington, Seattle; 2014: 7-11
• 45 Al-Shekaili H, Ciapaite J, van Karnebeek C, Pena I. PLPBP Deficiency. GeneReviews. Published online February 16, 2023. Accessed August 2, 2025 at: https://www.ncbi.nlm.nih.gov/books/NBK589231/
• 46 Plecko B, Mills P. PNPO Deficiency. University of Washington, Seattle; 1993. . Accessed August 2, 2025 at: https://www.ncbi.nlm.nih.gov/books/NBK581452/
• 47 Kim YG, Kang H, Lee B. et al. A spectrum of nonsense-mediated mRNA decay efficiency along the degree of mutational constraint. Commun Biol 2024; 7 (01) 1461
• 48 Sato H, Singer RH. Cellular variability of nonsense-mediated mRNA decay. Nat Commun 2021; 12 (01) 7203
• 49 Benkirane M, Marelli C, Guissart C. et al. High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families. Genet Med 2021; 23 (11) 2160-2170
• 50 Thuma TBT, Procopio RA, Jimenez HJ, Gunton KB, Pulido JS. Hypomorphic variants in inherited retinal and ocular diseases: a review of the literature with clinical cases. Surv Ophthalmol 2024; 69 (03) 337-348
• 51 Yang H, Wang D, Engelstad K. et al. Glut1 deficiency syndrome and erythrocyte glucose uptake assay. Ann Neurol 2011; 70 (06) 996-1005
• 52 Rotstein M, Engelstad K, Yang H. et al. Glut1 deficiency: inheritance pattern determined by haploinsufficiency. Ann Neurol 2010; 68 (06) 955-958
• 53 Gallagher D, Pérez-Palma E, Bruenger T. et al. Genotype-phenotype associations in 1018 individuals with SCN1A-related epilepsies. Epilepsia 2024; 65 (04) 1046-1059
• 54 Voskobiynyk Y, Battu G, Felker SA. et al. Aberrant regulation of a poison exon caused by a non-coding variant in a mouse model of Scn1a-associated epileptic encephalopathy. PLoS Genet 2021; 17 (01) e1009195
• 55 Carvill GL, Matheny T, Hesselberth J, Demarest S. Haploinsufficiency, dominant negative, and gain-of-function mechanisms in epilepsy: matching therapeutic approach to the pathophysiology. Neurotherapeutics 2021; 18 (03) 1500-1514
• 56 Happ HC, Schneider PN, Hong JH. et al. Long-read sequencing and profiling of RNA-binding proteins reveals the pathogenic mechanism of aberrant splicing of an SCN1A poison exon in epilepsy.
• 57 Monk D, Mackay DJG, Eggermann T, Maher ER, Riccio A. Genomic imprinting disorders: lessons on how genome, epigenome and environment interact. Nat Rev Genet 2019; 20 (04) 235-248
• 58 Eggermann T, Monk D, de Nanclares GP. et al. Imprinting disorders. Nat Rev Dis Primers 2023; 9 (01) 33
• 59 Judson MCC, Wallace MLL, Sidorov MSS. et al. GABAergic neuron-specific loss of Ube3a causes Angelman syndrome-like EEG abnormalities and enhances seizure susceptibility. Neuron 2016; 90 (01) 56-69
• 60 Roden WH, Peugh LD, Jansen LA. Altered GABA(A) receptor subunit expression and pharmacology in human Angelman syndrome cortex. Neurosci Lett 2010; 483 (03) 167-172
• 61 Joensuu T, Lehesjoki AE, Kopra O. Molecular background of EPM1-Unverricht-Lundborg disease. Epilepsia 2008; 49 (04) 557-563
• 62 Singh S, Hämäläinen RH. The roles of cystatin B in the brain and pathophysiological mechanisms of progressive myoclonic epilepsy type 1. Cells 2024; 13 (02) 170
• 63 Zschocke J, Byers PH, Wilkie AOM. Mendelian inheritance revisited: dominance and recessiveness in medical genetics. Nat Rev Genet 2023; 24 (07) 442-463
• 64 Weckhuysen S, George AL. KCNQ2- and KCNQ3-Associated Epilepsy. Cambridge University Press; 2022.
• 65 Millevert C, Weckhuysen S. ILAE Genetics Commission. ILAE Genetic Literacy Series: Self-limited familial epilepsy syndromes with onset in neonatal age and infancy. Epileptic Disord 2023; 25 (04) 445-453
• 66 Adam MP, Feldman J, Mirzaa GM. KCNQ3-Related Disorders. Published online 2014:1993–2024
• 67 Miceli F, Soldovieri MV, Joshi N, Weckhuysen S, Cooper E, Taglialatela M. KCNQ2-Related Disorders. University of Washington, Seattle; 1993. . Accessed October 31, 2024 at: https://www.ncbi.nlm.nih.gov/books/NBK32534/
• 68 Miceli F, Striano P, Soldovieri MV. et al. A novel KCNQ3 mutation in familial epilepsy with focal seizures and intellectual disability. Epilepsia 2015; 56 (02) e15-e20
• 69 Sands TT, Balestri M, Bellini G. et al. Rapid and safe response to low-dose carbamazepine in neonatal epilepsy. Epilepsia 2016; 57 (12) 2019-2030
• 70 Soldovieri MV, Boutry-Kryza N, Milh M. et al. Novel KCNQ2 and KCNQ3 mutations in a large cohort of families with benign neonatal epilepsy: first evidence for an altered channel regulation by syntaxin-1A. Hum Mutat 2014; 35 (03) 356-367
• 71 Orhan G, Bock M, Schepers D. et al. Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. Ann Neurol 2014; 75 (03) 382-394
• 72 Weckhuysen S, Mandelstam S, Suls A. et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol 2012; 71 (01) 15-25
• 73 Miceli F, Soldovieri MV, Ambrosino P. et al. Genotype-phenotype correlations in neonatal epilepsies caused by mutations in the voltage sensor of K(v)7.2 potassium channel subunits. Proc Natl Acad Sci U S A 2013; 110 (11) 4386-4391
• 74 Rusina E, Simonti M, Duprat F, Cestèle S, Mantegazza M. Voltage-gated sodium channels in genetic epilepsy: up and down of excitability. J Neurochem 2024; 168 (12) 3872-3890
• 75 Mantegazza M, Broccoli V. SCN1A/Na_V 1.1 channelopathies: mechanisms in expression systems, animal models, and human iPSC models. Epilepsia 2019; 60 (Suppl. 03) S25-S38
• 76 Scheffer IE, Zuberi S, Mefford HC, Guerrini R, McTague A. Developmental and epileptic encephalopathies. Nat Rev Dis Primers 2024; 10 (01) 1-19
• 77 Hedrich UBS, Lauxmann S, Lerche H. SCN2A channelopathies: mechanisms and models. Epilepsia 2019; 60 (Suppl. 03) S68-S76
• 78 Bryson A, Reid C, Petrou S. Fundamental neurochemistry review: GABA_A receptor neurotransmission and epilepsy: Principles, disease mechanisms and pharmacotherapy. J Neurochem 2023; 165 (01) 6-28
• 79 Bonardi CM, Heyne HO, Fiannacca M. et al. KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum. Brain 2021; 144 (12) 3635-3650
• 80 Hinckley CA, Zhu Z, Chu JH. et al. Functional evaluation of epilepsy-associated KCNT1 variants in multiple cellular systems reveals a predominant gain of function impact on channel properties. Epilepsia 2023; 64 (08) 2126-2136
• 81 Barcia G, Fleming MR, Deligniere A. et al. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat Genet 2012; 44 (11) 1255-1259
• 82 McTague A, Nair U, Malhotra S. et al. Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy. Neurology 2018; 90 (01) e55-e66
• 83 Tang QY, Zhang FF, Xu J. et al. Epilepsy-related slack channel mutants lead to channel over-activity by two different mechanisms. Cell Rep 2016; 14 (01) 129-139
• 84 Kim GE, Kronengold J, Barcia G. et al. Human slack potassium channel mutations increase positive cooperativity between individual channels. Cell Rep 2014; 9 (05) 1661-1672
• 85 Absalom NL, Liao VWY, Johannesen KMH. et al. Gain-of-function and loss-of-function GABRB3 variants lead to distinct clinical phenotypes in patients with developmental and epileptic encephalopathies. Nat Commun 2022; 13 (01) 1822
• 86 Mohammadi NA, Ahring PK, Yu Liao VW. et al. Distinct neurodevelopmental and epileptic phenotypes associated with gain- and loss-of-function GABRB2 variants. EBioMedicine 2024; 106: 105236
• 87 Lin SXN, Ahring PK, Keramidas A. et al. Correlations of receptor desensitization of gain-of-function GABRB3 variants with clinical severity. Brain 2024; 147 (01) 224-239
• 88 Thompson CH, Potet F, Abramova TV. et al. Epilepsy-associated SCN2A (NaV1.2) variants exhibit diverse and complex functional properties. J Gen Physiol 2023; 155 (10) e202313375
• 89 Kobayashi Takahashi Y, Tabata K, Baba S. et al. SCN1A gain of function effects in Dravet syndrome: Insights into clinical phenotypes and therapeutic implications. Epilepsia Open 2025; 10 (04) 1236-1243
• 90 Berg AT, Thompson CH, Myers LS. et al. Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders. Brain 2024; 147 (08) 2761-2774
• 91 Kan ASH, Kusay AS, Mohammadi NA. et al. Understanding paralogous epilepsy-associated GABA_A receptor variants: Clinical implications, mechanisms, and potential pitfalls. Proc Natl Acad Sci U S A 2024; 121 (50) e2413011121
• 92 Koch NA, Sonnenberg L, Hedrich UBS, Lauxmann S, Benda J. Loss or gain of function? Effects of ion channel mutations on neuronal firing depend on the neuron type. Front Neurol 2023; 14: 1194811
• 93 Meisler MH, Hill SF, Yu W. Sodium channelopathies in neurodevelopmental disorders. Nat Rev Neurosci 2021; 22 (03) 152-166
• 94 Bryson A, Petrou S. SCN1A channelopathies: Navigating from genotype to neural circuit dysfunction. Front Neurol 2023; 14: 1173460
• 95 Ogiwara I, Miyamoto H, Morita N. et al. Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. J Neurosci 2007; 27 (22) 5903-5914
• 96 Brunklaus A, Du J, Steckler F. et al. Biological concepts in human sodium channel epilepsies and their relevance in clinical practice. Epilepsia 2020; 61 (03) 387-399
• 97 Cheah CS, Westenbroek RE, Roden WH. et al. Correlations in timing of sodium channel expression, epilepsy, and sudden death in Dravet syndrome. Channels (Austin) 2013; 7 (06) 468-472
• 98 Berecki G, Howell KB, Heighway J. et al. Functional correlates of clinical phenotype and severity in recurrent SCN2A variants. Commun Biol 2022; 5 (01) 515
• 99 Liang L, Fazel Darbandi S, Pochareddy S. et al. Developmental dynamics of voltage-gated sodium channel isoform expression in the human and mouse brain. Genome Med 2021; 13 (01) 135
• 100 Gazina EV, Leaw BTW, Richards KL. et al. 'Neonatal' Nav1.2 reduces neuronal excitability and affects seizure susceptibility and behaviour. Hum Mol Genet 2015; 24 (05) 1457-1468
• 101 Thompson CH, Ben-Shalom R, Bender KJ, George AL. Alternative splicing potentiates dysfunction of early-onset epileptic encephalopathy SCN2A variants. J Gen Physiol 2020; 152 (03) e201912442
• 102 Liao Y, Deprez L, Maljevic S. et al. Molecular correlates of age-dependent seizures in an inherited neonatal-infantile epilepsy. Brain 2010; 133 (Pt 5): 1403-1414
• 103 Brunklaus A, Feng T, Brünger T. et al. Gene variant effects across sodium channelopathies predict function and guide precision therapy. Brain 2022; 145 (12) 4275-4286
• 104 Berecki G, Bryson A, Polster T, Petrou S. Biophysical characterization and modelling of SCN1A gain-of-function predicts interneuron hyperexcitability and a predisposition to network instability through homeostatic plasticity. Neurobiol Dis 2023; 179: 106059
• 105 Johannesen KM, Liu Y, Koko M. et al. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications. Brain 2022; 145 (09) 2991-3009
• 106 Brunklaus A, Brünger T, Feng T. et al. The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications. Brain 2022; 145 (11) 3816-3831
• 107 Volkers L, Kahlig KM, Das JHG. et al. Febrile temperatures unmask biophysical defects in Nav1.1 epilepsy mutations supportive of seizure initiation. J Gen Physiol 2013; 142 (06) 641-653
• 108 Parthasarathy S, Cohen SR, Fitch E. et al. Optimizing clinical interpretability of functional evidence in epilepsy-related ion channel variants.
• 109 Chen S, Francioli LC, Goodrich JK. et al; Genome Aggregation Database Consortium. A genomic mutational constraint map using variation in 76,156 human genomes. Nature 2024; 625 (7993) 92-100
• 110 Perez G, Barber GP, Benet-Pages A. et al. The UCSC Genome Browser database: 2025 update. Nucleic Acids Res 2025; 53 (D1): D1243-D1249
• 111 Hamosh A, Scott AF, Amberger JS, Bocchini CA, McKusick VA. Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Res 2005; 33 (Database issue): D514-D517
• 112 Rehm HL, Berg JS, Brooks LD. et al; ClinGen. ClinGen–the clinical genome resource. N Engl J Med 2015; 372 (23) 2235-2242
• 113 Landrum MJ, Lee JM, Benson M. et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res 2016; 44 (D1): D862-D868
• 114 Martin AR, Williams E, Foulger RE. et al. PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels. Nat Genet 2019; 51 (11) 1560-1565
• 115 Brunklaus A, Pérez-Palma E, Ghanty I. et al. Development and validation of a prediction model for early diagnosis of SCN1A-related epilepsies. Neurology 2022; 98 (11) e1163-e1174
• 116 Boßelmann CM, Hedrich UBS, Lerche H, Pfeifer N. Predicting functional effects of ion channel variants using new phenotypic machine learning methods. PLOS Comput Biol 2023; 19 (03) e1010959
• 117 Boßelmann CM, Hedrich UBS, Müller P. et al. Predicting the functional effects of voltage-gated potassium channel missense variants with multi-task learning. EBioMedicine 2022; 81: 104115