Developmental and epileptic encephalopathies after negative or inconclusive genetic testing: what is next?

Abstract

The redefinition of classical electroclinical syndromes and the emergence of neurogenetics has led to a revolution in the field of developmental and epileptic encephalopathies (DEEs). In this context, advances in genetic techniques are leading to the final diagnosis of a large proportion of patients with DEE. However, up to 50% of patients with DEE remain undiagnosed. For patients with uncertain genetic etiology, there is a pressing need for the implementation of new targeted treatments and precision medicine. In some undiagnosed patients, genetic reanalysis with further in-depth or reverse phenotyping are valuable diagnostic tools to clarify new variants of uncertain significance. In other cases, the implementation of new bioinformatic algorithms is required for the update and reassessment of previously generated genetic data. Moreover, many other clinical tools have been developed for the management of patients of DEEs after a negative or inconclusive genetic testing. In this review, we highlight advances and limitations of new diagnostic strategies used in DEE patients without a known genetic etiology. Finally, we provide a wide perspective on aspects that will need further research, especially in non-Mendelian inheritance DEEs, such as those related to somatic mosaicism of the central nervous system or epigenetic and oligogenic mechanisms.

Keywords

Neurodevelopmental disorders / epilepsy / genetic epilepsies / precision medicine / neurogenetics / diagnostic yield

References

[1] EllisCA,BerkovicSF.Epilepsy genetics: clinical impacts and biological insights.Lancet Neurol2020;19:93-100

[2] SymondsJD,StewartK.Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort.Brain2019;142:2303-18 PMCID:PMC6658850

[3] SymondsJD.Epilepsy and developmental disorders: next generation sequencing in the clinic.Eur J Paediatr Neurol2020;24:15-23

[4] HebbarM.Recent advances in epilepsy genomics and genetic testing.F1000Res2020;9:185 PMCID:PMC7076331

[5] KalserJ.The epileptic encephalopathy jungle - from Dr West to the concepts of aetiology-related and developmental encephalopathies.Curr Opin Neurol2018;31:216-22

[6] JohnsonMR.Heredity in epilepsy: neurodevelopment, comorbidity, and the neurological trait.Epilepsy Behav2011;22:421-7

[7] ShankarR,ThomasRH.Epilepsy, an orphan disorder within the neurodevelopmental family.J Neurol Neurosurg Psychiatry2020;91:1245-7

[8] StrianoP.From genetic testing to precision medicine in epilepsy.Neurotherapeutics2020;17:609-15 PMCID:PMC7283411

[9] HeinzenEL.Somatic variants in epilepsy - advancing gene discovery and disease mechanisms.Curr Opin Genet Dev2020;65:1-7 PMCID:PMC7666655

[10] Jesus-RibeiroJ,MeloJD.Genomic and epigenetic advances in focal cortical dysplasia types I and II: a scoping review.Front Neurosci2020;14:580357 PMCID:PMC7862327

[11] BergAT,BrodieMJ.Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009.Epilepsia2010;51:676-85

[12] KorffCM,ZuberiSM.Epileptic activity is a surrogate for an underlying etiology and stopping the activity has a limited impact on developmental outcome.Epilepsia2015;56:1477-81

[13] SpecchioN.Developmental and epileptic encephalopathies: what we do and do not know.Brain2021;144:32-43

[14] SteelD,ZuberiSM.Dravet syndrome and its mimics: beyond SCN1A.Epilepsia2017;58:1807-16

[15] Aledo-SerranoA.[Analysis of the family impact and needs of Dravet's syndrome in Spain].Rev Neurol2020;70:75-83

[16] BrunklausA.Dravet syndrome - from epileptic encephalopathy to channelopathy.Epilepsia2014;55:979-84

[17] RivaA,BalaguraG.Temporal-parietal-occipital epilepsy in GEFS+ associated with SCN1A mutation.Epileptic Disord2021;23:397-401

[18] SchefferIE.SCN1A-related phenotypes: epilepsy and beyond.Epilepsia2019;60 Suppl 3:S17-24

[19] GuerriniR,WirrellEC.Monogenic epilepsies: disease mechanisms, clinical phenotypes, and targeted therapies.Neurology2021;10.1212/WNL.0000000000012744:

[20] ScalaM,SultanT.Homozygous SCN1B variants causing early infantile epileptic encephalopathy 52 affect voltage-gated sodium channel function.Epilepsia2021;62:e82-7

[21] SongM,YangY,LiW.Genome-wide meta-analysis identifies two novel risk loci for epilepsy.Front Neurosci2021;15:722592 PMCID:PMC8397525

[22] SymondsJD.Genetics update: monogenetics, polygene disorders and the quest for modifying genes.Neuropharmacology2018;132:3-19

[23] PeruccaP,BerkovicSF.The genetics of epilepsy.Annu Rev Genomics Hum Genet2020;21:205-30

[24] TakataA,SaitsuH.Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy.Nat Commun2019;10:2506 PMCID:PMC6555845

[25] GreenbergDA.How should we be searching for genes for common epilepsy?.Epilepsia2012;53 Suppl 4:72-80 PMCID:PMC3746521

[26] LeuC,SmithAW.Epi25 ConsortiumPolygenic burden in focal and generalized epilepsies.Brain2019;142:3473-81 PMCID:PMC6821205

[27] LiuX,ZhengG.Gene and phenotype expansion of unexplained early infantile epileptic encephalopathy.Front Neurol2021;12:633637 PMCID:PMC8215605

[28] Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders.Nature2017;542:433-8 PMCID:PMC6016744

[29] AllenAS,CossetteP.Epi4K Consortium, Epilepsy Phenome/Genome ProjectDe novo mutations in epileptic encephalopathies.Nature2013;501:217-21 PMCID:PMC3773011

[30] MilhM,ChouchaneM.Epileptic and nonepileptic features in patients with early onset epileptic encephalopathy and STXBP1 mutations.Epilepsia2011;52:1828-34

[31] WildB.STXBP1-related developmental and epileptic encephalopathy.Pediatr Neurol Briefs2019;33:6 PMCID:PMC6942547

[32] AbramovD,BurréJ.STXBP1 encephalopathies: clinical spectrum, disease mechanisms, and therapeutic strategies.J Neurochem2021;157:165-78 PMCID:PMC7812771

[33] SuriM,LaskowskiRA.DDD StudyProtein structure and phenotypic analysis of pathogenic and population missense variants in STXBP1.Mol Genet Genomic Med2017;5:495-507 PMCID:PMC5606886

[34] LiuX,SunC.Prevalence of epilepsy in autism spectrum disorders: a systematic review and meta-analysis.Autism2021;:13623613211045029

[35] SwietlikEM,MartinJM.'There and back again'-forward genetics and reverse phenotyping in pulmonary arterial hypertension.Genes (Basel)2020;11:1408 PMCID:PMC7760524

[36] SamantaD.PCDH19-related epilepsy syndrome: a comprehensive clinical review.Pediatr Neurol2020;105:3-9

[37] Aledo-SerranoÁ,Gil-NagelA.Antiseizure medication withdrawal in seizure-free patients with PCDH19-related epilepsy: a multinational cohort survey.Seizure2020;80:259-61

[38] SadleirLG,KingC.Levetiracetam efficacy in PCDH19 girls clustering epilepsy.Eur J Paediatr Neurol2020;24:142-7

[39] ChakravortyS.Gene and variant annotation for mendelian disorders in the era of advanced sequencing technologies.Annu Rev Genomics Hum Genet2017;18:229-56

[40] SayersEW,BoltonEE.Database resources of the national center for biotechnology information.Nucleic Acids Res2021;49:D10-7 PMCID:PMC7778943

[41] ByrneS,DelantyN.Precision therapy in the genetic epilepsies of childhood.Dev Med Child Neurol2021;

[42] SobreiraNLM,BuskeOJ.Matchmaker Exchange ConsortiumMatchmaker exchange.Curr Protoc Hum Genet2017;95:9.31.1-9.31.15 PMCID:PMC6016856

[43] WohlerE,GriffithS.PhenoDB, GeneMatcher and VariantMatcher, tools for analysis and sharing of sequence data.Orphanet J Rare Dis2021;16:365 PMCID:PMC8371856

[44] AzzaritiDR.Genomic data sharing for novel mendelian disease gene discovery: the matchmaker exchange.Annu Rev Genomics Hum Genet2020;21:305-26

[45] MøllerRS,RubboliG,JohannesenKM.From next-generation sequencing to targeted treatment of non-acquired epilepsies.Expert Rev Mol Diagn2019;19:217-28

[46] Aledo-SerranoÁ,ToledanoR.Sodium channel blockers for the treatment of epilepsy in CDKL5 deficiency disorder: findings from a multicenter cohort.Epilepsy Behav2021;118:107946

[47] WuAC,LuC.Ending the diagnostic odyssey - is whole-genome sequencing the answer?.JAMA Pediatr2020;174:821-2 PMCID:PMC7928067

[48] Espinosa-JovelC,Aledo-SerranoÁ,Gil-NagelA.Epidemiological profile of epilepsy in low income populations.Seizure2018;56:67-72

[49] RaspaM,TothD.Barriers and facilitators to genetic service delivery models: scoping review.Interact J Med Res2021;10:e23523 PMCID:PMC7952239

[50] Aledo-SerranoA,ToledanoR.Diagnostic gap in genetic epilepsies: a matter of age.Epilepsy Behav2020;111:107266

[51] RichardsS,BaleS.ACMG Laboratory Quality Assurance CommitteeStandards 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 Med2015;17:405-24 PMCID:PMC4544753

[52] FrebourgT.The challenge for the next generation of medical geneticists.Hum Mutat2014;35:909-11

[53] Achkar CM, Harrer M, Smith L, et al; GABRB2 Working Group. Characterization of the GABRB2-associated neurodevelopmental disorders.Ann Neurol2021;89:573-86

[54] BamshadMJ,ChongJX.Mendelian gene discovery: fast and furious with no end in sight.Am J Hum Genet2019;105:448-55 PMCID:PMC6731362

[55] StrandeNT,BuchananAH.Evaluating the clinical validity of gene-disease associations: an evidence-based framework developed by the clinical genome resource.Am J Hum Genet2017;100:895-906 PMCID:PMC5473734

[56] CarvillGL,MyersCT.Damaging de novo missense variants in EEF1A2 lead to a developmental and degenerative epileptic-dyskinetic encephalopathy.Hum Mutat2020;41:1263-79 PMCID:PMC7292794

[57] HarrisonSM,RehmHL.Overview of specifications to the ACMG/AMP variant interpretation guidelines.Curr Protoc Hum Genet2019;103:e93 PMCID:PMC6885382

[58] Moyses-OliveiraM,ErdinS.New gene discoveries highlight functional convergence in autism and related neurodevelopmental disorders.Curr Opin Genet Dev2020;65:195-206

[59] Gago-VeigaAB,García-MoralesI,BernarJ.Specificity of electroclinical features in the diagnosis of ring chromosome 20.Epilepsy Behav2018;80:215-20

[60] PeronA,NorthrupH.Genetics, genomics, and genotype-phenotype correlations of TSC: insights for clinical practice.Am J Med Genet C Semin Med Genet2018;178:281-90

[61] ScalaM,BisulliF.Advances in genetic testing and optimization of clinical management in children and adults with epilepsy.Expert Rev Neurother2020;20:251-69

[62] JiangT,JiangL.Application of trio-whole exome sequencing in genetic diagnosis and therapy in chinese children with epilepsy.Front Mol Neurosci2021;14:699574 PMCID:PMC8417468

[63] BayatA,RubboliG.Epilepsy syndromes in the first year of life and usefulness of genetic testing for precision therapy.Genes (Basel)2021;12:1051 PMCID:PMC8307222

[64] AmadoriE,CeredaGS.Targeted re-sequencing for early diagnosis of genetic causes of childhood epilepsy: the Italian experience from the 'beyond epilepsy' project.Ital J Pediatr2020;46:92 PMCID:PMC7339579

[65] LeblondCS,MalesysS.Operative list of genes associated with autism and neurodevelopmental disorders based on database review.Mol Cell Neurosci2021;113:103623

[66] ZacherP,BrandhoffF.The genetic landscape of intellectual disability and epilepsy in adults and the elderly: a systematic genetic work-up of 150 individuals.Genet Med2021;23:1492-7 PMCID:PMC8354852

[67] ZouD,LiaoJ.Genome sequencing of 320 Chinese children with epilepsy: a clinical and molecular study.Brain2021;awab233

[68] MyersKA,DymentDA.Epilepsy genetics: current knowledge, applications, and future directions.Clin Genet2019;95:95-111

[69] EldomeryMK,HarelT.Lessons learned from additional research analyses of unsolved clinical exome cases.Genome Med2017;9:26 PMCID:PMC5361813

[70] GhoshSG,BeetzC.Undiagnosed Diseases NetworkA relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome.Eur J Hum Genet2021;29:271-9 PMCID:PMC7868361

[71] Basel-SalmonL,Markus-BustaniK.Improved diagnostics by exome sequencing following raw data reevaluation by clinical geneticists involved in the medical care of the individuals tested.Genet Med2019;21:1443-51

[72] Zahrani H, Siriwardena K, Young D, Lehman A, Horvath GA, Goez H. Genomics in Cerebral Palsy phenotype across the lifespan: comparison of diagnostic yield between children and adult population.Mol Genet Metab2021:S1096-7192(21)00758

[73] BozkurtT,IsikU.Re-analysis of whole-exome sequencing data reveals a novel splicing variant in the SLC2A1 in a patient with GLUT1 Deficiency Syndrome 1 accompanied by hemangioma: a case report.BMC Med Genomics2021;14:197 PMCID:PMC8325841

[74] DunnP,MaksemousN.Next generation sequencing methods for diagnosis of epilepsy syndromes.Front Genet2018;9:20 PMCID:PMC5808353

[75] WoernerAC,VockleyJ.The use of whole genome and exome sequencing for newborn screening: challenges and opportunities for population health.Front Pediatr2021;9:663752 PMCID:PMC8326411

[76] VamathevanJ.A review of recent advances in translational bioinformatics: bridges from biology to medicine.Yearb Med Inform2017;26:178-87 PMCID:PMC6239226

[77] KobowK,vonDeimling A.Molecular diagnostics in drug-resistant focal epilepsy define new disease entities.Brain Pathol2021;31:e12963 PMCID:PMC8412082

[78] PetrovskiS.Unraveling the genetics of common epilepsies: approaches, platforms, and caveats.Epilepsy Behav2013;26:229-33