Epilepsi Genetiği
Özet
Epilepsi, çocukluk yaş grubunda erişkinlere göre daha sık görülen Dünya Sağlık Örgütü verilerine göre 70 milyondan fazla kişiyi etkilediği bilinen oldukça sık görülen bir hastalık grubudur. Epilepsiler güçlü bir genetik yatkınlığa sahiptirler, genetik faktörlerin etiyolojide saptanma oranı her geçen gün artış göstermektedir. Genetik tanı; tanı konulma sürecinin sonlanması, uygun tedavi tercihi, prognoz tayini ve tekrarlama riski hatta bazen hedefe yönelik tedaviye yönlendirme gibi avantajlar sağlar. Genetik testlerin doğru kullanımı ve yorumlanması epilepsi hastalarının yönetiminde hekimler ve hastalar için oldukça önemlidir.
Epilepsy is a very common disease group that is more common in childhood than in adults and is known to affect more than 70 million people, according to World Health Organization data. Epilepsies have a strong genetic predisposition, and the rate of detection of genetic factors in etiology is increasing day by day. Genetic diagnosis; It provides advantages such as ending the diagnosis process, choosing the appropriate treatment, determining prognosis and risk of recurrence, and sometimes even directing to targeted treatment. Correct use and interpretation of genetic tests are very important for physicians and patients in the management of epilepsy patients.
Referanslar
Blazekovic A, Gotovac Jercic K, Meglaj S, et al. Genetics of Pediatric Epilepsy: Next-Generation Sequencing in Clinical Practice. Genes (Basel). 2022;13(8):1466.
Loscher W, Potschka H, Sisodiya SM, et al. Drug resistance in epilepsy: clinical impact, potential mechanisms, and new innovative treatment options. Pharmacol Rev. 2020;72:606–38.
Fiest KM, Sauro KM, Wiebe S, et al. Prevalence and incidence of epilepsy: a systematic review and meta-analysis of international studies. Neurology. 2017;88:296–303.
Thijs RD, Surges R, O’Brien TJ, et al. Epilepsy in adults. Lancet. 2019;393:689–70.
Thomas RH, Berkovic SF. The hidden genetics of epilepsy-a clinically important new paradigm. Nat Rev Neurol. 2014;10:283–92.
Peljto AL, Barker‐Cummings C, Vasoli VM, et al. Familial risk of epilepsy: a population‐based study. Brain 2014;137(Pt 3):795–805.
Han X, Fang F. Research progress on mitochondrial-related epilepsy in children. Chin J Pract Pediatrics. 2020;35:805–11.
Knowles JK, Helbig I, Metcalf CS, et al. Precision medicine for genetic epilepsy on the horizon: recent advances, present challenges, and suggestions for continued progress. Epilepsia. 2022;63:2461–75)
Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):512-521.
Myers KA. Genetic Epilepsy Syndromes. Continuum (Minneap Minn). 2022;28(2):339-362.
Perucca P. Genetics of Focal Epilepsies: What Do We Know and Where Are We Heading?. Epilepsy Curr. 2018;18(6):356-362.
Tinuper P, Bisulli F, Cross JH, et al. Definition and diagnostic criteria of sleep-related hypermotor epilepsy. Neurology. 2016;86(19):1834-1842.
Derry CP, Heron SE, Phillips F, et al. Severe autosomal dominant nocturnal frontal lobe epilepsy associated with psychiatric disorders and intellectual disability. Epilepsia. 2008;49(12):2125-2129.
Ottman R, Risch N, Hauser WA, et al. Localization of a gene for partial epilepsy to chromosome 10q. Nat Genet. 1995;10(1):56-60.
Michelucci R, Poza JJ, Sofia V, et al. Autosomal dominant lateral temporal epilepsy: clinical spectrum, new epitempin mutations, and genetic heterogeneity in seven European families. Epilepsia. 2003;44(10):1289-1297.
Dibbens LM, de Vries B, Donatello S, et al. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet. 2013;45(5):546-551.
Bar-Peled L, Chantranupong L, Cherniack AD, et al. A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science. 2013;340(6136):1100-1106.
Ricos MG, Hodgson BL, Pippucci T, et al. Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Ann Neurol. 2016;79(1):120-131.
Crompton DE, Scheffer IE, Taylor I, et al. Familial mesial temporal lobe epilepsy: a benign epilepsy syndrome showing complex inheritance. Brain. 2010;133(11):3221-3231.
Perucca P, Crompton DE, Bellows ST, et al. Familial mesial temporal lobe epilepsy and the borderland of déjà vu. Ann Neurol. 2017;82(2):166-176.
Gooley S, Crompton DE, Berkovic SF. ILAE Genetic Literacy Series: familial focal epilepsy syndromes. Epileptic Disord. 2022;24(2):221-228.
Jallon P, Latour P. Epidemiology of idiopathic generalized epilepsies. Epilepsia. 2005;46 Suppl 9:10-14.
Mullen SA, Berkovic SF; ILAE Genetics Commission. Genetic generalized epilepsies. Epilepsia. 2018;59(6):1148-1153.
Wallace RH, Marini C, Petrou S, et al. Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet. 2001;28(1):49-52.
Cossette P, Liu L, Brisebois K, et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet. 2002;31(2):184-189.
De Vivo DC, Trifiletti RR, Jacobson RI, Ronen GM, Behmand RA, Harik SI. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med. 1991;325(10):703-709.
Suls A, Dedeken P, Goffin K, et al. Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1. Brain. 2008;131(Pt 7):1831-1844.
Arsov T, Mullen SA, Damiano JA, et al. Early onset absence epilepsy: 1 in 10 cases is caused by GLUT1 deficiency. Epilepsia. 2012;53(12):e204-e207.
Perucca P, Perucca E. Identifying mutations in epilepsy genes: Impact on treatment selection. Epilepsy Res. 2019;152:18-30.
Helbig I, Mefford HC, Sharp AJ, et al. 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet. 2009;41(2):160-162.
Howell KB, Eggers S, Dalziel K, et al. A population-based cost-effectiveness study of early genetic testing in severe epilepsies of infancy. Epilepsia. 2018;59(6):1177-1187.
Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010;51(4):676-685.
McTague A, Howell KB, Cross JH, Kurian MA, Scheffer IE. The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol. 2016;15(3):304-316.
Dravet C. The core Dravet syndrome phenotype. Epilepsia. 2011;52 Suppl 2:3-9.
Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet. 2001;68(6):1327-1332.
Marini C, Scheffer IE, Nabbout R, et al. The genetics of Dravet syndrome. Epilepsia. 2011;52 Suppl 2:24-29.
Steel D, Symonds JD, Zuberi SM, Brunklaus A. Dravet syndrome and its mimics: Beyond SCN1A. Epilepsia. 2017;58(11):1807-1816.
Specchio N, Curatolo P. Developmental and epileptic encephalopathies: what we do and do not know. Brain. 2021;144(1):32-43.
Wirrell EC, Laux L, Donner E, et al. Optimizing the Diagnosis and Management of Dravet Syndrome: Recommendations From a North American Consensus Panel. Pediatr Neurol. 2017;68:18-34.e3.
Lindy AS, Stosser MB, Butler E, et al. Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders. Epilepsia. 2018;59(5):1062-1071.
Okuda K, Kobayashi S, Fukaya M, et al. CDKL5 controls postsynaptic localization of GluN2B-containing NMDA receptors in the hippocampus and regulates seizure susceptibility. Neurobiol Dis. 2017;106:158-170.
Ricciardi S, Ungaro F, Hambrock M, et al. CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons. Nat Cell Biol. 2012;14(9):911-923.
Hector RD, Kalscheuer VM, Hennig F, et al. CDKL5 variants: Improving our understanding of a rare neurologic disorder. Neurol Genet. 2017;3(6):e200. Published 2017 Dec 15.
Pisano T, Numis AL, Heavin SB, et al. Early and effective treatment of KCNQ2 encephalopathy. Epilepsia. 2015;56(5):685-691.
Orhan G, Bock M, Schepers D, et al. Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. Ann Neurol. 2014;75(3):382-394.
Devaux J, Abidi A, Roubertie A, et al. A Kv7.2 mutation associated with early onset epileptic encephalopathy with suppression-burst enhances Kv7/M channel activity. Epilepsia. 2016;57(5):e87-e93.
Specchio N, Kasteleijn-Nolst Trenité DG, Piccioli M, et al. Diagnosing photosensitive epilepsy: fancy new versus old fashioned techniques in patients with different epileptic syndromes. Brain Dev. 2011;33(4):294-300.
Kolc KL, Sadleir LG, Scheffer IE, et al. A systematic review and meta-analysis of 271 PCDH19-variant individuals identifies psychiatric comorbidities, and association of seizure onset and disease severity. Mol Psychiatry. 2019;24(2):241-251.
Depienne C, Bouteiller D, Keren B, et al. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females [published correction appears in PLoS Genet. 2009 Apr;5(4). doi: 10.1371/annotation/314060d5-06da-46e0-b9e4-57194e8ece3a]. PLoS Genet. 2009;5(2):e1000381.
Sadat R, Emrick L. Genetic Testing and Counseling and Child Neurology. Neurol Clin. 2021;39(3):705-717.
Helbig I, Heinzen EL, Mefford HC; ILAE Genetics Commission. Primer Part 1-The building blocks of epilepsy genetics. Epilepsia. 2016;57(6):861-868.
Nussbaum RL, McInnes RR, Willard HF. Thompson & Thompson genetics in medicine. 8th editionxi. Elsevier; 2016. p. 546.
Richards S, Aziz N, Bale S, et al. Standards 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 Med. 2015;17(5):405-424.
Chen WL, Mefford HC. Diagnostic Considerations in the Epilepsies-Testing Strategies, Test Type Advantages, and Limitations. Neurotherapeutics. 2021;18(3):1468-1477.
Roizen NJ, Patterson D. Down's syndrome. Lancet. 2003;361(9365):1281-1289.
Nishiwaki T, Hirano M, Kumazawa M, Ueno S. Mosaicism and phenotype in ring chromosome 20 syndrome. Acta Neurol Scand. 2005;111(3):205-208.
Daber RD, Conlin LK, Leonard LD, et al. Ring chromosome 20. Eur J Med Genet. 2012;55(5):381-387.
Jähn JA, von Spiczak S, Muhle H, et al. Iterative phenotyping of 15q11.2, 15q13.3 and 16p13.11 microdeletion carriers in pediatric epilepsies. Epilepsy Res. 2014;108(1):109-116.
Shapira SK, McCaskill C, Northrup H, et al. Chromosome 1p36 deletions: the clinical phenotype and molecular characterization of a common newly delineated syndrome. Am J Hum Genet. 1997;61(3):642-650.
Mefford HC, Sharp AJ, Baker C, et al. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med. 2008;359(16):1685-1699.
Bassuk AG, Geraghty E, Wu S, et al. Deletions of 16p11.2 and 19p13.2 in a family with intellectual disability and generalized epilepsy. Am J Med Genet A. 2013;161A(7):1722-1725.
Coppola A, Cellini E, Stamberger H, et al. Diagnostic implications of genetic copy number variation in epilepsy plus. Epilepsia. 2019;60(4):689-706.
Borlot F, Regan BM, Bassett AS, Stavropoulos DJ, Andrade DM. Prevalence of Pathogenic Copy Number Variation in Adults With Pediatric-Onset Epilepsy and Intellectual Disability. JAMA Neurol. 2017;74(11):1301-1311.
Myers CT, Mefford HC. Advancing epilepsy genetics in the genomic era. Genome Med. 2015;7(1):91. Published 2015 Aug 25.
Calhoun JD, Carvill GL. Unravelling the genetic architecture of autosomal recessive epilepsy in the genomic era. J Neurogenet. 2018;32(4):295-312.
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(6):1138-1147.
Liu Y, Schubert J, Sonnenberg L, et al. Neuronal mechanisms of mutations in SCN8A causing epilepsy or intellectual disability. Brain. 2019;142(2):376-390.
Trudeau MM, Dalton JC, Day JW, Ranum LP, Meisler MH. Heterozygosity for a protein truncation mutation of sodium channel SCN8A in a patient with cerebellar atrophy, ataxia, and mental retardation. J Med Genet. 2006;43(6):527-530.
Boerma RS, Braun KP, van den Broek MP, et al. Remarkable Phenytoin Sensitivity in 4 Children with SCN8A-related Epilepsy: A Molecular Neuropharmacological Approach [published correction appears in Neurotherapeutics. 2016 Jan;13(1):238. van de Broek, Maarten P H [Corrected to van den Broek, Marcel P H]]. Neurotherapeutics. 2016;13(1):192-197.
Heinzen EL. Somatic variants in epilepsy - advancing gene discovery and disease mechanisms. Curr Opin Genet Dev. 2020;65:1-7.
Niestroj LM, Perez-Palma E, Howrigan DP, et al. Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17 458 subjects. Brain. 2020;143(7):2106-2118.
Borlot F, Regan BM, Bassett AS, Stavropoulos DJ, Andrade DM. Prevalence of Pathogenic Copy Number Variation in Adults With Pediatric-Onset Epilepsy and Intellectual Disability. JAMA Neurol. 2017;74(11):1301-1311.
Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749-764.
Krey I, Platzer K, Esterhuizen A, et al. Current practice in diagnostic genetic testing of the epilepsies. Current practice in diagnostic genetic testing of the epilepsies. Epileptic Disord. 2022;24(5):765-786.
Møller RS, Larsen LH, Johannesen KM, et al. Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies. Mol Syndromol. 2016;7(4):210-219.
Allen NM, Conroy J, Shahwan A, et al. Unexplained early onset epileptic encephalopathy: Exome screening and phenotype expansion. Epilepsia. 2016;57(1):e12-e17.
Snoeijen-Schouwenaars FM, van Ool JS, Verhoeven JS, et al. Diagnostic exome sequencing in 100 consecutive patients with both epilepsy and intellectual disability. Epilepsia. 2019;60(1):155-164.
Helbig KL, Farwell Hagman KD, Shinde DN, et al. Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet Med. 2016;18(9):898-905.
Palmer EE, Sachdev R, Macintosh R, et al. Diagnostic Yield of Whole Genome Sequencing After Nondiagnostic Exome Sequencing or Gene Panel in Developmental and Epileptic Encephalopathies. Neurology. 2021;96(13):e1770-e1782.
Stödberg T, Tomson T, Barbaro M, et al. Epilepsy syndromes, etiologies, and the use of next-generation sequencing in epilepsy presenting in the first 2 years of life: A population-based study. Epilepsia. 2020;61(11):2486-2499.
Demarest ST, Brooks-Kayal A. From molecules to medicines: the dawn of targeted therapies for genetic epilepsies. Nat Rev Neurol 2018; 14(12): 735–45.
Truty R, Patil N, Sankar R, et al. Possible precision medicine implications from genetic testing using combined detection of sequence and intragenic copy number variants in a large cohort with childhood epilepsy. Epilepsia Open. 2019;4(3):397-408.
Referanslar
Blazekovic A, Gotovac Jercic K, Meglaj S, et al. Genetics of Pediatric Epilepsy: Next-Generation Sequencing in Clinical Practice. Genes (Basel). 2022;13(8):1466.
Loscher W, Potschka H, Sisodiya SM, et al. Drug resistance in epilepsy: clinical impact, potential mechanisms, and new innovative treatment options. Pharmacol Rev. 2020;72:606–38.
Fiest KM, Sauro KM, Wiebe S, et al. Prevalence and incidence of epilepsy: a systematic review and meta-analysis of international studies. Neurology. 2017;88:296–303.
Thijs RD, Surges R, O’Brien TJ, et al. Epilepsy in adults. Lancet. 2019;393:689–70.
Thomas RH, Berkovic SF. The hidden genetics of epilepsy-a clinically important new paradigm. Nat Rev Neurol. 2014;10:283–92.
Peljto AL, Barker‐Cummings C, Vasoli VM, et al. Familial risk of epilepsy: a population‐based study. Brain 2014;137(Pt 3):795–805.
Han X, Fang F. Research progress on mitochondrial-related epilepsy in children. Chin J Pract Pediatrics. 2020;35:805–11.
Knowles JK, Helbig I, Metcalf CS, et al. Precision medicine for genetic epilepsy on the horizon: recent advances, present challenges, and suggestions for continued progress. Epilepsia. 2022;63:2461–75)
Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):512-521.
Myers KA. Genetic Epilepsy Syndromes. Continuum (Minneap Minn). 2022;28(2):339-362.
Perucca P. Genetics of Focal Epilepsies: What Do We Know and Where Are We Heading?. Epilepsy Curr. 2018;18(6):356-362.
Tinuper P, Bisulli F, Cross JH, et al. Definition and diagnostic criteria of sleep-related hypermotor epilepsy. Neurology. 2016;86(19):1834-1842.
Derry CP, Heron SE, Phillips F, et al. Severe autosomal dominant nocturnal frontal lobe epilepsy associated with psychiatric disorders and intellectual disability. Epilepsia. 2008;49(12):2125-2129.
Ottman R, Risch N, Hauser WA, et al. Localization of a gene for partial epilepsy to chromosome 10q. Nat Genet. 1995;10(1):56-60.
Michelucci R, Poza JJ, Sofia V, et al. Autosomal dominant lateral temporal epilepsy: clinical spectrum, new epitempin mutations, and genetic heterogeneity in seven European families. Epilepsia. 2003;44(10):1289-1297.
Dibbens LM, de Vries B, Donatello S, et al. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet. 2013;45(5):546-551.
Bar-Peled L, Chantranupong L, Cherniack AD, et al. A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science. 2013;340(6136):1100-1106.
Ricos MG, Hodgson BL, Pippucci T, et al. Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Ann Neurol. 2016;79(1):120-131.
Crompton DE, Scheffer IE, Taylor I, et al. Familial mesial temporal lobe epilepsy: a benign epilepsy syndrome showing complex inheritance. Brain. 2010;133(11):3221-3231.
Perucca P, Crompton DE, Bellows ST, et al. Familial mesial temporal lobe epilepsy and the borderland of déjà vu. Ann Neurol. 2017;82(2):166-176.
Gooley S, Crompton DE, Berkovic SF. ILAE Genetic Literacy Series: familial focal epilepsy syndromes. Epileptic Disord. 2022;24(2):221-228.
Jallon P, Latour P. Epidemiology of idiopathic generalized epilepsies. Epilepsia. 2005;46 Suppl 9:10-14.
Mullen SA, Berkovic SF; ILAE Genetics Commission. Genetic generalized epilepsies. Epilepsia. 2018;59(6):1148-1153.
Wallace RH, Marini C, Petrou S, et al. Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet. 2001;28(1):49-52.
Cossette P, Liu L, Brisebois K, et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet. 2002;31(2):184-189.
De Vivo DC, Trifiletti RR, Jacobson RI, Ronen GM, Behmand RA, Harik SI. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med. 1991;325(10):703-709.
Suls A, Dedeken P, Goffin K, et al. Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1. Brain. 2008;131(Pt 7):1831-1844.
Arsov T, Mullen SA, Damiano JA, et al. Early onset absence epilepsy: 1 in 10 cases is caused by GLUT1 deficiency. Epilepsia. 2012;53(12):e204-e207.
Perucca P, Perucca E. Identifying mutations in epilepsy genes: Impact on treatment selection. Epilepsy Res. 2019;152:18-30.
Helbig I, Mefford HC, Sharp AJ, et al. 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet. 2009;41(2):160-162.
Howell KB, Eggers S, Dalziel K, et al. A population-based cost-effectiveness study of early genetic testing in severe epilepsies of infancy. Epilepsia. 2018;59(6):1177-1187.
Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010;51(4):676-685.
McTague A, Howell KB, Cross JH, Kurian MA, Scheffer IE. The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol. 2016;15(3):304-316.
Dravet C. The core Dravet syndrome phenotype. Epilepsia. 2011;52 Suppl 2:3-9.
Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet. 2001;68(6):1327-1332.
Marini C, Scheffer IE, Nabbout R, et al. The genetics of Dravet syndrome. Epilepsia. 2011;52 Suppl 2:24-29.
Steel D, Symonds JD, Zuberi SM, Brunklaus A. Dravet syndrome and its mimics: Beyond SCN1A. Epilepsia. 2017;58(11):1807-1816.
Specchio N, Curatolo P. Developmental and epileptic encephalopathies: what we do and do not know. Brain. 2021;144(1):32-43.
Wirrell EC, Laux L, Donner E, et al. Optimizing the Diagnosis and Management of Dravet Syndrome: Recommendations From a North American Consensus Panel. Pediatr Neurol. 2017;68:18-34.e3.
Lindy AS, Stosser MB, Butler E, et al. Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders. Epilepsia. 2018;59(5):1062-1071.
Okuda K, Kobayashi S, Fukaya M, et al. CDKL5 controls postsynaptic localization of GluN2B-containing NMDA receptors in the hippocampus and regulates seizure susceptibility. Neurobiol Dis. 2017;106:158-170.
Ricciardi S, Ungaro F, Hambrock M, et al. CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons. Nat Cell Biol. 2012;14(9):911-923.
Hector RD, Kalscheuer VM, Hennig F, et al. CDKL5 variants: Improving our understanding of a rare neurologic disorder. Neurol Genet. 2017;3(6):e200. Published 2017 Dec 15.
Pisano T, Numis AL, Heavin SB, et al. Early and effective treatment of KCNQ2 encephalopathy. Epilepsia. 2015;56(5):685-691.
Orhan G, Bock M, Schepers D, et al. Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. Ann Neurol. 2014;75(3):382-394.
Devaux J, Abidi A, Roubertie A, et al. A Kv7.2 mutation associated with early onset epileptic encephalopathy with suppression-burst enhances Kv7/M channel activity. Epilepsia. 2016;57(5):e87-e93.
Specchio N, Kasteleijn-Nolst Trenité DG, Piccioli M, et al. Diagnosing photosensitive epilepsy: fancy new versus old fashioned techniques in patients with different epileptic syndromes. Brain Dev. 2011;33(4):294-300.
Kolc KL, Sadleir LG, Scheffer IE, et al. A systematic review and meta-analysis of 271 PCDH19-variant individuals identifies psychiatric comorbidities, and association of seizure onset and disease severity. Mol Psychiatry. 2019;24(2):241-251.
Depienne C, Bouteiller D, Keren B, et al. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females [published correction appears in PLoS Genet. 2009 Apr;5(4). doi: 10.1371/annotation/314060d5-06da-46e0-b9e4-57194e8ece3a]. PLoS Genet. 2009;5(2):e1000381.
Sadat R, Emrick L. Genetic Testing and Counseling and Child Neurology. Neurol Clin. 2021;39(3):705-717.
Helbig I, Heinzen EL, Mefford HC; ILAE Genetics Commission. Primer Part 1-The building blocks of epilepsy genetics. Epilepsia. 2016;57(6):861-868.
Nussbaum RL, McInnes RR, Willard HF. Thompson & Thompson genetics in medicine. 8th editionxi. Elsevier; 2016. p. 546.
Richards S, Aziz N, Bale S, et al. Standards 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 Med. 2015;17(5):405-424.
Chen WL, Mefford HC. Diagnostic Considerations in the Epilepsies-Testing Strategies, Test Type Advantages, and Limitations. Neurotherapeutics. 2021;18(3):1468-1477.
Roizen NJ, Patterson D. Down's syndrome. Lancet. 2003;361(9365):1281-1289.
Nishiwaki T, Hirano M, Kumazawa M, Ueno S. Mosaicism and phenotype in ring chromosome 20 syndrome. Acta Neurol Scand. 2005;111(3):205-208.
Daber RD, Conlin LK, Leonard LD, et al. Ring chromosome 20. Eur J Med Genet. 2012;55(5):381-387.
Jähn JA, von Spiczak S, Muhle H, et al. Iterative phenotyping of 15q11.2, 15q13.3 and 16p13.11 microdeletion carriers in pediatric epilepsies. Epilepsy Res. 2014;108(1):109-116.
Shapira SK, McCaskill C, Northrup H, et al. Chromosome 1p36 deletions: the clinical phenotype and molecular characterization of a common newly delineated syndrome. Am J Hum Genet. 1997;61(3):642-650.
Mefford HC, Sharp AJ, Baker C, et al. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med. 2008;359(16):1685-1699.
Bassuk AG, Geraghty E, Wu S, et al. Deletions of 16p11.2 and 19p13.2 in a family with intellectual disability and generalized epilepsy. Am J Med Genet A. 2013;161A(7):1722-1725.
Coppola A, Cellini E, Stamberger H, et al. Diagnostic implications of genetic copy number variation in epilepsy plus. Epilepsia. 2019;60(4):689-706.
Borlot F, Regan BM, Bassett AS, Stavropoulos DJ, Andrade DM. Prevalence of Pathogenic Copy Number Variation in Adults With Pediatric-Onset Epilepsy and Intellectual Disability. JAMA Neurol. 2017;74(11):1301-1311.
Myers CT, Mefford HC. Advancing epilepsy genetics in the genomic era. Genome Med. 2015;7(1):91. Published 2015 Aug 25.
Calhoun JD, Carvill GL. Unravelling the genetic architecture of autosomal recessive epilepsy in the genomic era. J Neurogenet. 2018;32(4):295-312.
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(6):1138-1147.
Liu Y, Schubert J, Sonnenberg L, et al. Neuronal mechanisms of mutations in SCN8A causing epilepsy or intellectual disability. Brain. 2019;142(2):376-390.
Trudeau MM, Dalton JC, Day JW, Ranum LP, Meisler MH. Heterozygosity for a protein truncation mutation of sodium channel SCN8A in a patient with cerebellar atrophy, ataxia, and mental retardation. J Med Genet. 2006;43(6):527-530.
Boerma RS, Braun KP, van den Broek MP, et al. Remarkable Phenytoin Sensitivity in 4 Children with SCN8A-related Epilepsy: A Molecular Neuropharmacological Approach [published correction appears in Neurotherapeutics. 2016 Jan;13(1):238. van de Broek, Maarten P H [Corrected to van den Broek, Marcel P H]]. Neurotherapeutics. 2016;13(1):192-197.
Heinzen EL. Somatic variants in epilepsy - advancing gene discovery and disease mechanisms. Curr Opin Genet Dev. 2020;65:1-7.
Niestroj LM, Perez-Palma E, Howrigan DP, et al. Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17 458 subjects. Brain. 2020;143(7):2106-2118.
Borlot F, Regan BM, Bassett AS, Stavropoulos DJ, Andrade DM. Prevalence of Pathogenic Copy Number Variation in Adults With Pediatric-Onset Epilepsy and Intellectual Disability. JAMA Neurol. 2017;74(11):1301-1311.
Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749-764.
Krey I, Platzer K, Esterhuizen A, et al. Current practice in diagnostic genetic testing of the epilepsies. Current practice in diagnostic genetic testing of the epilepsies. Epileptic Disord. 2022;24(5):765-786.
Møller RS, Larsen LH, Johannesen KM, et al. Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies. Mol Syndromol. 2016;7(4):210-219.
Allen NM, Conroy J, Shahwan A, et al. Unexplained early onset epileptic encephalopathy: Exome screening and phenotype expansion. Epilepsia. 2016;57(1):e12-e17.
Snoeijen-Schouwenaars FM, van Ool JS, Verhoeven JS, et al. Diagnostic exome sequencing in 100 consecutive patients with both epilepsy and intellectual disability. Epilepsia. 2019;60(1):155-164.
Helbig KL, Farwell Hagman KD, Shinde DN, et al. Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet Med. 2016;18(9):898-905.
Palmer EE, Sachdev R, Macintosh R, et al. Diagnostic Yield of Whole Genome Sequencing After Nondiagnostic Exome Sequencing or Gene Panel in Developmental and Epileptic Encephalopathies. Neurology. 2021;96(13):e1770-e1782.
Stödberg T, Tomson T, Barbaro M, et al. Epilepsy syndromes, etiologies, and the use of next-generation sequencing in epilepsy presenting in the first 2 years of life: A population-based study. Epilepsia. 2020;61(11):2486-2499.
Demarest ST, Brooks-Kayal A. From molecules to medicines: the dawn of targeted therapies for genetic epilepsies. Nat Rev Neurol 2018; 14(12): 735–45.
Truty R, Patil N, Sankar R, et al. Possible precision medicine implications from genetic testing using combined detection of sequence and intragenic copy number variants in a large cohort with childhood epilepsy. Epilepsia Open. 2019;4(3):397-408.
