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Customized multigene panels in epilepsy: the best things come in small packages

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Abstract

Over the past 10 years, the increasingly important role played by next-generation sequencing panels in the genetic diagnosis of epilepsy has led to a growing list of gene variants and a plethora of new scientific data. To date, however, there is still no consensus on what constitutes the “ideal panel design,” or on the most rational criteria for selecting the best candidates for gene-panel analysis, even though both might optimize the cost-benefit ratio and the diagnostic efficiency of customized gene panels. Even though more and more laboratories are adopting whole-exome sequencing as a first-tier diagnostic approach, interpreting, “in silico,” a set of epilepsy-related genes remains difficult. In the light of these considerations, we performed a systematic review of the targeted gene panels for epilepsy already reported in the available scientific literature, with a view to identifying the best criteria for selecting patients for gene-panel analysis, and the best way to design an “ideal,” gold-standard panel that includes all genes with an established role in epilepsy pathogenesis, as well as those that might help to guide decisions regarding specific medical interventions and treatments. Our analyses suggest that the usefulness and diagnostic power of customized gene panels for epilepsy may be greatest when these panels are confined to rationally selected, relatively small, pools of genes, and applied in more carefully selected epilepsy patients (those with complex forms of epilepsy). A panel containing 64 genes, which includes the 45 genes harboring a significant number of pathogenic variants identified in previous literature, the 32 clinically actionable genes, and the 21 ILAE (International League Against Epilepsy) recommended genes, may represent an “ideal” core set likely able to provide the highest diagnostic efficiency and cost-effectiveness and facilitate gene prioritization when testing patients with whole-exome/whole-genome sequencing.

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References

  1. Forsgren L, Beghi E, Oun A, Sillanpää M (2015) The epidemiology of epilepsy in Europe – a systematic review. Eur J Neurol 12:245–253

    Google Scholar 

  2. Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, Hirsch E, Jain S, Mathern GW, Moshé SL, Nordli DR, Perucca E, Tomson T, Wiebe S, Zhang YH, Zuberi SM (2017) ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 58:512–521

    PubMed  PubMed Central  Google Scholar 

  3. McTague A, Howell KB, Cross JH, Kurian MA, Scheffer IE (2016) The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol 15:304–316

    PubMed  Google Scholar 

  4. Mei D, Parrini E, Marini C, Guerrini R (2017) The impact of next-generation sequencing on the diagnosis and treatment of epilepsy in paediatric patients. Mol Diagn Ther 21:357–373

    CAS  PubMed  Google Scholar 

  5. Jiang T, Shen Y, Chen H, Yuan Z, Mao S, Gao F (2018) Clinical and molecular analysis of epilepsy-related genes in patients with Dravet syndrome. Medicine (Baltimore) 97:e13565

    CAS  Google Scholar 

  6. Harzing AW (2007) Publish or Perish, available from http://www.harzing.com/pop.htm

  7. Lemke JR, Riesch E, Scheurenbrand T, Schubach M, Wilhelm C, Steiner I, Hansen J, Courage C, Gallati S, Bürki S, Strozzi S, Simonetti BG, Grunt S, Steinlin M, Alber M, Wolff M, Klopstock T, Prott EC, Lorenz R, Spaich C, Rona S, Lakshminarasimhan M, Kröll J, Dorn T, Krämer G, Synofzik M, Becker F, Weber YG, Lerche H, Böhm D, Biskup S (2012) Targeted next generation sequencing as a diagnostic tool in epileptic disorders. Epilepsia 53:1387–1398

    CAS  PubMed  Google Scholar 

  8. Carvill GL, Heavin SB, Yendle SC, McMahon J, O’Roak BJ, Cook J, Khan A, Dorschner MO, Weaver M, Calvert S, Malone S, Wallace G, Stanley T, Bye AM, Bleasel A, Howell KB, Kivity S, Mackay MT, Rodriguez-Casero V, Webster R, Korczyn A, Afawi Z, Zelnick N, Lerman-Sagie T, Lev D, Møller RS, Gill D, Andrade DM, Freeman JL, Sadleir LG, Shendure J, Berkovic SF, Scheffer IE, Mefford HC (2013) Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet 45:825–830

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Kodera H, Kato M, Nord AS, Walsh T, Lee M, Yamanaka G, Tohyama J, Nakamura K, Nakagawa E, Ikeda T, Ben-Zeev B, Lev D, Lerman-Sagie T, Straussberg R, Tanabe S, Ueda K, Amamoto M, Ohta S, Nonoda Y, Nishiyama K, Tsurusaki Y, Nakashima M, Miyake N, Hayasaka K, King MC, Matsumoto N, Saitsu H (2013) Targeted capture and sequencing for detection of mutations causing early onset epileptic encephalopathy. Epilepsia 54:1262–1269

    PubMed  Google Scholar 

  10. Carvill GL, Weckhuysen S, McMahon JM, Hartmann C, Møller RS, Hjalgrim H, Cook J, Geraghty E, O'Roak BJ, Petrou S, Clarke A, Gill D, Sadleir LG, Muhle H, von Spiczak S, Nikanorova M, Hodgson BL, Gazina EV, Suls A, Shendure J, Dibbens LM, de Jonghe P, Helbig I, Berkovic SF, Scheffer IE, Mefford HC (2014) GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. Neurology 82:1245–1253

    CAS  PubMed  PubMed Central  Google Scholar 

  11. De Filippo MR, Rizzo F, Marchese G et al (2014) Lack of pathogenic ùs in six patients with MMPSI. Epilepsy Res 108:340–344

    PubMed  Google Scholar 

  12. Ream MA, Mikati MA (2014) Clinical utility of genetic testing in pediatric drug-resistant epilepsy: a pilot study. Epilepsy Behav 37:241–248

    PubMed  Google Scholar 

  13. Coll M, Allegue C, Partemi S et al (2016) Genetic investigation of sudden unexpected death in epilepsy cohort by panel target resequencing. Int J Legal Med 130:331–339

    PubMed  Google Scholar 

  14. Della Mina E, Ciccone R, Brustia F, Bayindir B, Limongelli I, Vetro A, Iascone M, Pezzoli L, Bellazzi R, Perotti G, de Giorgis V, Lunghi S, Coppola G, Orcesi S, Merli P, Savasta S, Veggiotti P, Zuffardi O (2015) Improving molecular diagnosis in epilepsy by a dedicated high-throughput sequencing platform. Eur J Hum Genet 23:354–362

    CAS  PubMed  Google Scholar 

  15. Dimassi S, Simonet T, Labalme A, Boutry-Kryza N, Campan-Fournier A, Lamy R, Bardel C, Elsensohn MH, Roucher-Boulez F, Chatron N, Putoux A, de Bellescize J, Ville D, Schaeffer L, Roy P, Mougou-Zerelli S, Saad A, Calender A, Sanlaville D, Lesca G (2015) Comparison of two next-generation sequencing kits for diagnosis of epileptic disorders with a user-friendly tool for displaying gene coverage, DeCovA. Appl Transl Genom 7:19–25

    PubMed  PubMed Central  Google Scholar 

  16. Jansen LA, Mirzaa GM, Ishak GE et al (2015) PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia. Brain 138:1613–1628

    PubMed  PubMed Central  Google Scholar 

  17. Kwong AK, Ho AC, Fung CW, Wong VC (2015) Analysis of mutations in 7 genes associated with neuronal excitability and synaptic transmission in a cohort of children with non-syndromic infantile epileptic encephalopathy. PLoS One 10:e0126446

    PubMed  PubMed Central  Google Scholar 

  18. Mercimek-Mahmutoglu S, Patel J, Cordeiro D, Hewson S, Callen D, Donner EJ, Hahn CD, Kannu P, Kobayashi J, Minassian BA, Moharir M, Siriwardena K, Weiss SK, Weksberg R, Snead OC 3rd (2015) Diagnostic yield of genetic testing in epileptic encephalopathy in childhood. Epilepsia 56:707–716

    CAS  PubMed  Google Scholar 

  19. Ricos MG, Hodgson BL, Pippucci T, Saidin A, Ong YS, Heron SE, Licchetta L, Bisulli F, Bayly MA, Hughes J, Baldassari S, Palombo F, Epilepsy Electroclinical Study Group, Santucci M, Meletti S, Berkovic SF, Rubboli G, Thomas PQ, Scheffer IE, Tinuper P, Geoghegan J, Schreiber AW, Dibbens LM (2016) Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Ann Neurol 79:120–131

    CAS  PubMed  Google Scholar 

  20. de Kovel CG, Brilstra EH, van Kempen MJ, van't Slot R, Nijman IJ, Afawi Z, de Jonghe P, Djémié T, Guerrini R, Hardies K, Helbig I, Hendrickx R, Kanaan M, Kramer U, Lehesjoki AE, Lemke JR, Marini C, Mei D, Møller RS, Pendziwiat M, Stamberger H, Suls A, Weckhuysen S, EuroEPINOMICS RES Consortium, Koeleman BP (2016) Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients. Mol Genet Genomic Med 4:568–580

    PubMed  PubMed Central  Google Scholar 

  21. Gokben S, Onay H, Yilmaz S et al (2017) Targeted next generation sequencing: the diagnostic value in early-onset epileptic encephalopathy. Acta Neurol Belg 117:131–138

    PubMed  Google Scholar 

  22. Hildebrand MS, Myers CT, Carvill GL, Regan BM, Damiano JA, Mullen SA, Newton MR, Nair U, Gazina EV, Milligan CJ, Reid CA, Petrou S, Scheffer IE, Berkovic SF, Mefford HC (2016) A targeted resequencing gene panel for focal epilepsy. Neurology 86:1605–1612

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Marchese M, Valvo G, Moro F, Sicca F, Santorelli FM (2016) Targeted gene resequencing (Astrochip) to explore the tripartite synapse in autism-epilepsy phenotype with macrocephaly. NeuroMolecular Med 18:69–80

    CAS  PubMed  Google Scholar 

  24. Møller RS, Larsen LH, Johannesen KM, Talvik I, Talvik T, Vaher U, Miranda MJ, Farooq M, Nielsen JE, Svendsen LL, Kjelgaard DB, Linnet KM, Hao Q, Uldall P, Frangu M, Tommerup N, Baig SM, Abdullah U, Born AP, Gellert P, Nikanorova M, Olofsson K, Jepsen B, Marjanovic D, al-Zehhawi LI, Peñalva SJ, Krag-Olsen B, Brusgaard K, Hjalgrim H, Rubboli G, Pal DK, Dahl HA (2016) Gene panel testing in epileptic encephalopathies and familial epilepsies. Mol Syndromol 7:210–219

    PubMed  PubMed Central  Google Scholar 

  25. Parrini E, Marini C, Mei D et al (2017) Diagnostic targeted resequencing in 349 patients with drug-resistant pediatric epilepsies identifies causative mutations in 30 different genes. Hum Mutat 38:216–225

    CAS  PubMed  Google Scholar 

  26. Segal E, Pedro H, Valdez-Gonzalez K, Parisotto S, Gliksman F, Thompson S, Sabri J, Fertig E (2016) Diagnostic yield of epilepsy panels in children with medication-refractory epilepsy. Pediatr Neurol 64:66–71

    PubMed  Google Scholar 

  27. Terracciano A, Trivisano M, Cusmai R, de Palma L, Fusco L, Compagnucci C, Bertini E, Vigevano F, Specchio N (2016) PCDH19-related epilepsy in two mosaic male patients. Epilepsia 57:e51–e55

    CAS  PubMed  Google Scholar 

  28. Trump N, McTague A, Brittain H et al (2016) Improving diagnosis and broadening the phenotypes in early-onset seizure and severe developmental delay disorders through gene panel analysis. J Med Genet 53:310–317

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Weckhuysen S, Marsan E, Lambrecq V, Marchal C, Morin-Brureau M, An-Gourfinkel I, Baulac M, Fohlen M, Kallay Zetchi C, Seeck M, de la Grange P, Dermaut B, Meurs A, Thomas P, Chassoux F, Leguern E, Picard F, Baulac S (2016) Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia. Epilepsia 57:994–1003

    CAS  PubMed  Google Scholar 

  30. Arafat A, Jing P, Ma Y et al (2017) Unexplained early infantile epileptic encephalopathy in Han Chinese children: next-generation sequencing and phenotype enriching. Sci Rep 7:46227

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Butler KM, da Silva C, Alexander JJ, Hegde M, Escayg A (2017) Diagnostic yield from 339 epilepsy patients screened on a clinical gene panel. Pediatr Neurol 77:61–66

    PubMed  PubMed Central  Google Scholar 

  32. Fung CW, Kwong AK, Wong VC (2017) Gene panel analysis for nonsyndromic cryptogenic neonatal/infantile epileptic encephalopathy. Epilepsia Open 2:236–243

    PubMed  PubMed Central  Google Scholar 

  33. Ortega-Moreno L, Giráldez BG, Soto-Insuga V et al (2017) Molecular diagnosis of patients with epilepsy and developmental delay using a customized panel of epilepsy genes. PLoS One 12:e0188978

    PubMed  PubMed Central  Google Scholar 

  34. Perucca P, Scheffer IE, Harvey AS, James PA, Lunke S, Thorne N, Gaff C, Regan BM, Damiano JA, Hildebrand MS, Berkovic SF, O’Brien TJ, Kwan P (2017) Real-world utility of whole exome sequencing with targeted gene analysis for focal epilepsy. Epilepsy Res 131:1–8

    CAS  PubMed  Google Scholar 

  35. Wang Y, Du X, Bin R et al (2017) Genetic variants identified from epilepsy of unknown etiology in Chinese children by targeted exome sequencing. Sci Rep 7:40319

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhang Q, Li J, Zhao Y, Bao X, Wei L, Wang J (2017) Gene mutation analysis of 175 Chinese patients with early-onset epileptic encephalopathy. Clin Genet 91:717–724

    CAS  PubMed  Google Scholar 

  37. Esterhuizen AI, Mefford HC, Ramesar RS, Wang S, Carvill GL, Wilmshurst JM (2018) Dravet syndrome in South African infants: tools for an early diagnosis. Seizure 62:99–105

    PubMed  PubMed Central  Google Scholar 

  38. Hesse AN, Bevilacqua J, Shankar K, Reddi HV (2018) Retrospective genotype-phenotype analysis in a 305 patient cohort referred for testing of a targeted epilepsy panel. Epilepsy Res 144:53–61

    PubMed  Google Scholar 

  39. Ko A, Youn SE, Kim SH, Lee JS, Kim S, Choi JR, Kim HD, Lee ST, Kang HC (2018) Targeted gene panel and genotype-phenotype correlation in children with developmental and epileptic encephalopathy. Epilepsy Res 141:48–55

    CAS  PubMed  Google Scholar 

  40. Kothur K, Holman K, Farnsworth E, Ho G, Lorentzos M, Troedson C, Gupta S, Webster R, Procopis PG, Menezes MP, Antony J, Ardern-Holmes S, Dale RC, Christodoulou J, Gill D, Bennetts B (2018) Diagnostic yield of targeted massively parallel sequencing in children with epileptic encephalopathy. Seizure 59:132–140

    PubMed  Google Scholar 

  41. Lee CG, Lee J, Lee M (2018) Multi-gene panel testing in Korean patients with common genetic generalized epilepsy syndromes. PLoS One 13:e0199321

    PubMed  PubMed Central  Google Scholar 

  42. Liu J, Tong L, Song S, et al (2018) Novel and de novo mutations in pediatric refractory epilepsy. Mol Brain 11:48. Erratum in: Mol Brain 2018;11:59

  43. Miao P, Feng J, Guo Y, Wang J, Xu X, Wang Y, Li Y, Gao L, Zheng C, Cheng H (2018) Genotype and phenotype analysis using an epilepsy-associated gene panel in Chinese pediatric epilepsy patients. Clin Genet 94:512–520

    CAS  PubMed  Google Scholar 

  44. Rim JH, Kim SH, Hwang IS et al (2018) Efficient strategy for the molecular diagnosis of intractable early-onset epilepsy using targeted gene sequencing. BMC Med Genet 11:6

    Google Scholar 

  45. Staněk D, Laššuthová P, Štěrbová K et al (2018) Detection rate of causal variants in severe childhood epilepsy is highest in patients with seizure onset within the first four weeks of life. Orphanet J Rare Dis 13:71

    PubMed  PubMed Central  Google Scholar 

  46. Tsai MH, Chan CK, Chang YC et al (2018) Molecular genetic characterization of patients with focal epilepsy using a customized targeted resequencing gene panel. Front Neurol 9:515

    PubMed  PubMed Central  Google Scholar 

  47. Tumienė B, Maver A, Writzl K, Hodžić A, Čuturilo G, Kuzmanić-Šamija R, Čulić V, Peterlin B (2018) Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice. Clin Genet 93:1057–1062

    PubMed  Google Scholar 

  48. Zeng Q, Yang X, Zhang J, Liu A, Yang Z, Liu X, Wu Y, Wu X, Wei L, Zhang Y (2018) Genetic analysis of benign familial epilepsies in the first year of life in a Chinese cohort. J Hum Genet 63:9–18

    CAS  PubMed  Google Scholar 

  49. Zhou P, He N, Zhang JW et al (2018) Novel mutations and phenotypes of epilepsy-associated genes in epileptic encephalopathies. Genes Brain Behav 17:e12456

    CAS  PubMed  Google Scholar 

  50. Bevilacqua J, Hesse A, Cormier B, Davey J, Patel D, Shankar K, Reddi HV (2017) Clinical utility of a 377 gene custom next-generation sequencing epilepsy panel. J Genet 96:681–685

    CAS  PubMed  Google Scholar 

  51. Wang J, Gao H, Bao X et al (2017) SCN8A mutations in Chinese patients with early onset epileptic encephalopathy and benign infantile seizures. BMC Med Genet 18:104

    PubMed  PubMed Central  Google Scholar 

  52. Lemke JR, Hendrickx R, Geider K, Laube B, Schwake M, Harvey RJ, James VM, Pepler A, Steiner I, Hörtnagel K, Neidhardt J, Ruf S, Wolff M, Bartholdi D, Caraballo R, Platzer K, Suls A, de Jonghe P, Biskup S, Weckhuysen S (2014) GRIN2B mutations in west syndrome and intellectual disability with focal epilepsy. Ann Neurol 75:147–154

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Chambers C, Jansen LA, Dhamija R (2016) Review of commercially available epilepsy genetic panels. J Genet Couns 25:213–217

    PubMed  Google Scholar 

  54. Gerald B, Ramsey K, Belnap N, Szelinger S, Siniard AL, Balak C, Russell M, Richholt R, de Both M, Claasen AM, Schrauwen I, Huentelman MJ, Craig DW, Rangasamy S, Narayanan V (2018) Neonatal epileptic encephalopathy caused by de novo GNAO1 mutation misdiagnosed as atypical Rett syndrome: cautions in interpretation of genomic test results. Semin Pediatr Neurol 26:28–32

    PubMed  Google Scholar 

  55. Helbig KL, Lauerer RJ, Bahr JC, Souza IA, Myers CT, Uysal B, Schwarz N, Gandini MA, Huang S, Keren B, Mignot C, Afenjar A, Billette de Villemeur T, Héron D, Nava C, Valence S, Buratti J, Fagerberg CR, Soerensen KP, Kibaek M, Kamsteeg EJ, Koolen DA, Gunning B, Schelhaas HJ, Kruer MC, Fox J, Bakhtiari S, Jarrar R, Padilla-Lopez S, Lindstrom K, Jin SC, Zeng X, Bilguvar K, Papavasileiou A, Xing Q, Zhu C, Boysen K, Vairo F, Lanpher BC, Klee EW, Tillema JM, Payne ET, Cousin MA, Kruisselbrink TM, Wick MJ, Baker J, Haan E, Smith N, Sadeghpour A, Davis EE, Katsanis N, Task Force for Neonatal Genomics, Corbett MA, MacLennan A, Gecz J, Biskup S, Goldmann E, Rodan LH, Kichula E, Segal E, Jackson KE, Asamoah A, Dimmock D, McCarrier J, Botto LD, Filloux F, Tvrdik T, Cascino GD, Klingerman S, Neumann C, Wang R, Jacobsen JC, Nolan MA, Snell RG, Lehnert K, Sadleir LG, Anderlid BM, Kvarnung M, Guerrini R, Friez MJ, Lyons MJ, Leonhard J, Kringlen G, Casas K, el Achkar CM, Smith LA, Rotenberg A, Poduri A, Sanchis-Juan A, Carss KJ, Rankin J, Zeman A, Raymond FL, Blyth M, Kerr B, Ruiz K, Urquhart J, Hughes I, Banka S, Deciphering Developmental Disorders Study, Hedrich UBS, Scheffer IE, Helbig I, Zamponi GW, Lerche H, Mefford HC (2018) De novo pathogenic variants in CACNA1E cause developmental and epileptic encephalopathy with contractures, macrocephaly, and dyskinesias. Am J Hum Genet 103:666–678

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Papandreou A, McTague A, Trump N, Ambegaonkar G, Ngoh A, Meyer E, Scott RH, Kurian MA (2016) GABRB3 mutations: a new and emerging cause of early infantile epileptic encephalopathy. Dev Med Child Neurol 58:416–420

    PubMed  Google Scholar 

  57. Stražišar BG, Neubauer D, Paro Panjan D, Writzl K (2015) Early-onset epileptic encephalopathy with hearing loss in two siblings with TBC1D24 recessive mutations. Eur J Paediatr Neurol 19:251–256

    PubMed  Google Scholar 

  58. Weber YG, Biskup S, Helbig KL, Von Spiczak S, Lerche H (2017) The role of genetic testing in epilepsy diagnosis and management. Expert Rev Mol Diagn 17:739–750

    CAS  PubMed  Google Scholar 

  59. Orsini A, Zara F, Striano P (2018) Recent advances in epilepsy genetics. Neurosci Lett 667:4–9

    CAS  PubMed  Google Scholar 

  60. EpiPM Consortium (2015) A roadmap for precision medicine in the epilepsies. Lancet Neurol 14:1219–1228

    PubMed Central  Google Scholar 

  61. Dibbens LM, de Vries B, Donatello S, Heron SE, Hodgson BL, Chintawar S, Crompton DE, Hughes JN, Bellows ST, Klein KM, Callenbach PM, Corbett MA, Gardner AE, Kivity S, Iona X, Regan BM, Weller CM, Crimmins D, O'Brien TJ, Guerrero-López R, Mulley JC, Dubeau F, Licchetta L, Bisulli F, Cossette P, Thomas PQ, Gecz J, Serratosa J, Brouwer OF, Andermann F, Andermann E, van den Maagdenberg A, Pandolfo M, Berkovic SF, Scheffer IE (2013) Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet 45(5):546–551

    CAS  PubMed  Google Scholar 

  62. Peng J, Pang N, Wang Y, Wang XL, Chen J, Xiong J, Peng P, Zhu CH, Kessi MB, He F, Yin F (2019) Next-generation sequencing improves treatment efficacy and reduces hospitalization in children with drug-resistant epilepsy. CNS Neurosci Ther 25:14–20

    CAS  PubMed  Google Scholar 

  63. Shen D, Hernandez CC, Shen W, Hu N, Poduri A, Shiedley B, Rotenberg A, Datta AN, Leiz S, Patzer S, Boor R, Ramsey K, Goldberg E, Helbig I, Ortiz-Gonzalez XR, Lemke JR, Marsh ED, Macdonald RL (2017) De novo GABRG2 mutations associated with epileptic encephalopathies. Brain 140:49–67

    PubMed  Google Scholar 

  64. Maljevic S, Reid CA, Petrou S (2017) Models for discovery of targeted therapy in genetic epileptic encephalopathies. J Neurochem 143:30–48

    CAS  PubMed  Google Scholar 

  65. Marini C, Porro A, Rastetter A, Dalle C, Rivolta I, Bauer D, Oegema R, Nava C, Parrini E, Mei D, Mercer C, Dhamija R, Chambers C, Coubes C, Thévenon J, Kuentz P, Julia S, Pasquier L, Dubourg C, Carré W, Rosati A, Melani F, Pisano T, Giardino M, Innes AM, Alembik Y, Scheidecker S, Santos M, Figueiroa S, Garrido C, Fusco C, Frattini D, Spagnoli C, Binda A, Granata T, Ragona F, Freri E, Franceschetti S, Canafoglia L, Castellotti B, Gellera C, Milanesi R, Mancardi MM, Clark DR, Kok F, Helbig KL, Ichikawa S, Sadler L, Neupauerová J, Laššuthova P, Šterbová K, Laridon A, Brilstra E, Koeleman B, Lemke JR, Zara F, Striano P, Soblet J, Smits G, Deconinck N, Barbuti A, DiFrancesco D, LeGuern E, Guerrini R, Santoro B, Hamacher K, Thiel G, Moroni A, DiFrancesco J, Depienne C (2018) HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond. Brain. 141:3160–3178

    PubMed  Google Scholar 

  66. Li X, Poschmann S, Chen Q, Fazeli W, Oundjian NJ, Snoeijen-Schouwenaars FM, Fricke O, Kamsteeg EJ, Willemsen M, Wang QK (2018) De novo BK channel variant causes epilepsy by affecting voltage gating but not Ca(2+) sensitivity. Eur J Hum Genet 26:220–229

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Pisano T, Numis AL, Heavin SB, Weckhuysen S, Angriman M, Suls A, Podesta B, Thibert RL, Shapiro KA, Guerrini R, Scheffer IE, Marini C, Cilio MR (2015) Early and effective treatment of KCNQ2 encephalopathy. Epilepsia 56(5):685–691

    CAS  PubMed  Google Scholar 

  68. Heron SE, Smith KR, Bahlo M, Nobili L, Kahana E, Licchetta L, Oliver KL, Mazarib A, Afawi Z, Korczyn A, Plazzi G, Petrou S, Berkovic SF, Scheffer IE, Dibbens LM (2012) Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 44:1188–1190

    CAS  PubMed  Google Scholar 

  69. Wolff M, Johannesen KM, Hedrich UBS et al (2017) Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain 140(5):1316–1336

    PubMed  Google Scholar 

  70. Boerma RS, Braun KP, van den Broek MP, van Berkestijn F, Swinkels ME, Hagebeuk EO, Lindhout D, van Kempen M, Boon M, Nicolai J, de Kovel CG, Brilstra EH, Koeleman BP (2016) Remarkable phenytoin sensitivity in 4 children with SCN8A-related epilepsy: a molecular neuropharmacological approach. Neurotherapeutics 13(1):192–197

    CAS  PubMed  Google Scholar 

  71. Lim JS, Gopalappa R, Kim SH et al (2017) Somatic mutations in TSC1 and TSC2 cause focal cortical dysplasia. Am J Hum Genet 100(3):454–472

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Dunn P, Albury CL, Maksemous N et al (2018) Next generation sequencing methods for diagnosis of epilepsy syndromes. Front Genet 9:20

    PubMed  PubMed Central  Google Scholar 

  73. Lindy AS, Stosser MB, Butler E, Downtain-Pickersgill C, Shanmugham A, Retterer K, Brandt T, Richard G, McKnight D (2018) Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders. Epilepsia 59:1062–1071

    CAS  PubMed  Google Scholar 

  74. Balciuniene J, DeChene ET, Akgumus G, et al. (2019). Use of a dynamic genetic testing approach for childhood-onset epilepsy. JAMA Netw Open 5;2:e192129

    PubMed  PubMed Central  Google Scholar 

  75. Ottman R, Hirose S, Jain S, Lerche H, Lopes-Cendes I, Noebels JL, Serratosa J, Zara F, Scheffer IE (2010) Genetic testing in the epilepsies--report of the ILAE genetics commission. Epilepsia 51:655–670

    PubMed  PubMed Central  Google Scholar 

  76. Jain P, Andrade D, Donner E, Dyment D, Prasad AN, Goobie S, Boycott K, Lines M, Snead OC (2019) Development of criteria for epilepsy genetic testing in Ontario, Canada. Can J Neurol Sci 46:7–13

    PubMed  Google Scholar 

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Acknowledgments

We are indebted to Dr. Catherine J. Wrenn for expert editing of the manuscript and critical advice.

Funding

This study was partially supported by the Italian Ministry of Health-Ricerca Corrente and 5X1000 (to FS) and Epi-IDEA Network project (Italian Ministry of Health) (to FMS).

Author information

Authors and Affiliations

  1. Clinical Neurophysiology, IRCCS Stella Maris Foundation, Pisa, Italy

    Simona Pellacani, Claudia Dosi, Giulia Valvo & Federico Sicca

  2. Molecular Medicine and Neurogenetics, Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Via dei Giacinti 2, 56028, Pisa, Italy

    Francesca Moro, Serena Mero, Federico Sicca & Filippo Maria Santorelli

Authors
  1. Simona Pellacani
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  2. Claudia Dosi
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  3. Giulia Valvo
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  4. Francesca Moro
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  5. Serena Mero
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  6. Federico Sicca
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  7. Filippo Maria Santorelli
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Corresponding authors

Correspondence to Federico Sicca or Filippo Maria Santorelli.

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Pellacani, S., Dosi, C., Valvo, G. et al. Customized multigene panels in epilepsy: the best things come in small packages. Neurogenetics 21, 1–18 (2020). https://doi.org/10.1007/s10048-019-00598-x

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