Customised targeted massively parallel sequencing enables more precise diagnosis of patients with epilepsy.
NGS
epilepsy
molecular genetics
Journal
Internal medicine journal
ISSN: 1445-5994
Titre abrégé: Intern Med J
Pays: Australia
ID NLM: 101092952
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
revised:
18
01
2021
received:
02
11
2020
accepted:
23
01
2021
pubmed:
3
2
2021
medline:
28
7
2022
entrez:
2
2
2021
Statut:
ppublish
Résumé
Advancement in genetic technology has led to the identification of an increasing number of genes in epilepsy. This will provide a lot of information in clinical practice and improve the diagnosis and treatment of epilepsy. To show the importance of genes in the next-generation sequencing (NGS) panel during the evaluation of epilepsy and to emphasise the importance of genetic studies in different populations for the evaluation of genes that cause disease. This was a single-centre retrospective cohort study of 80 patients who underwent NGS testing with a customised epilepsy panel. In a total of 54 (67.5%) out of 80 patients, pathogenic or likely pathogenic variants and variants of uncertain significance (VOUS) were identified according to the American College of Medical Genetics and Genomics criteria. Pathogenic or likely pathogenic variants (n = 35) were identified in 29 (36.25%) out of 80 individuals. VOUS (n = 34) were identified in 28 (35%) out of 80 patients. Pathogenic, likely pathogenic and VOUS were most frequently identified in TSC2 (n = 11), SCN1A (n = 6) and TSC1 (n = 5) genes. Other common genes were KCNQ2 (n = 3), AMT (n = 3), CACNA1H (n = 3), CLCN2 (n = 3), MECP2 (n = 2), ASAH1 (n = 2) and SLC2A1 (n = 2). NGS-based testing panels contribute to the diagnosis of epilepsy and might change the clinical management by preventing unnecessary and potentially harmful diagnostic procedures and management in patients. Thus, our results highlight the benefit of genetic testing in children suffering with epilepsy.
Sections du résumé
BACKGROUND
Advancement in genetic technology has led to the identification of an increasing number of genes in epilepsy. This will provide a lot of information in clinical practice and improve the diagnosis and treatment of epilepsy.
AIM
To show the importance of genes in the next-generation sequencing (NGS) panel during the evaluation of epilepsy and to emphasise the importance of genetic studies in different populations for the evaluation of genes that cause disease.
METHODS
This was a single-centre retrospective cohort study of 80 patients who underwent NGS testing with a customised epilepsy panel.
RESULTS
In a total of 54 (67.5%) out of 80 patients, pathogenic or likely pathogenic variants and variants of uncertain significance (VOUS) were identified according to the American College of Medical Genetics and Genomics criteria. Pathogenic or likely pathogenic variants (n = 35) were identified in 29 (36.25%) out of 80 individuals. VOUS (n = 34) were identified in 28 (35%) out of 80 patients. Pathogenic, likely pathogenic and VOUS were most frequently identified in TSC2 (n = 11), SCN1A (n = 6) and TSC1 (n = 5) genes. Other common genes were KCNQ2 (n = 3), AMT (n = 3), CACNA1H (n = 3), CLCN2 (n = 3), MECP2 (n = 2), ASAH1 (n = 2) and SLC2A1 (n = 2).
CONCLUSIONS
NGS-based testing panels contribute to the diagnosis of epilepsy and might change the clinical management by preventing unnecessary and potentially harmful diagnostic procedures and management in patients. Thus, our results highlight the benefit of genetic testing in children suffering with epilepsy.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1174-1184Informations de copyright
© 2021 Royal Australasian College of Physicians.
Références
Banerjee PN, Filippi D, Allen Hauser W. The descriptive epidemiology of epilepsy-a review. Epilepsy Res 2009; 85: 31-45.
Hesdorffer DC, Logroscino G, Benn EK, Katri N, Cascino G, Hauser WA. Estimating risk for developing epilepsy: a population-based study in Rochester, Minnesota. Neurology 2011; 76: 23-7.
Fiest KM, Sauro KM, Wiebe S, Patten SB, Kwon CS, Dykeman J et al. Prevalence and incidence of epilepsy: a systematic review and meta-analysis of international studies. Neurology 2017; 88: 296-303.
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, Leibson CL, Hauser WA, Buchhalter JR et al. Familial risk of epilepsy: a population-based study. Brain 2014; 137: 795-805.
Speed D, O'Brien TJ, Palotie A, Shkura K, Marson AG, Balding DJ et al. Describing the genetic architecture of epilepsy through heritability analysis. Brain 2014; 137: 2680-2689.b.
Dunn P, Albury CL, Maksemous N, Benton MC, Sutherland HG, Smith RA et al. Next generation sequencing methods for diagnosis of epilepsy syndromes. Front Genet 2018; 9: 20.
Bamshad MJ, Nickerson DA, Chong JX. Mendelian gene discovery: fast and furious with no end in sight. Am J Hum Genet 2019; 105: 448-55.
Helbig KL, Farwell Hagman KD, Shinde DN, Mroske C, Powis Z, Li S et al. Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet Med 2016; 18: 898-905.
Retterer K, Juusola J, Cho MT, Vitazka P, Millan F, Gibellini F et al. Clinical application of whole-exome sequencing across clinical indications. Genet Med 2016; 18: 696-704.
Hebbar M, Mefford HC. Recent advances in epilepsy genomics and genetic testing (version 1; peer review: 2 approved). F1000Research 2020; 9: 185.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J 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: 405-24.
Ng PC, Henikoff SSIFT. Predicting amino acid changes that affect protein function. Nucleic Acids Res 2003; 31: 3812-4.
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P et al. A method and server for predicting damaging missense mutations. Nat Methods 2010; 7: 248-9.
Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 2014; 11: 361-2.
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: 310-5.
Niida Y, Stemmer-Rachamimov AO, Logrip M, Tapon D, Perez R, Kwiatkowski DJ et al. Survey of somatic mutations in tuberous sclerosis complex (TSC) hamartomas suggests different genetic mechanisms for pathogenesis of TSC lesions. Am J Hum Genet 2001; 69: 493-503.
Metzker ML. Sequencing technologies - the next generation. Nat Rev Genet 2010; 11: 31-46.
Rim JH, Kim SH, Hwang IS, Kwon SS, Kim J, Kim HW et al. Efficient strategy for the molecular diagnosis of intractable early-onset epilepsy using targeted gene sequencing. BMC Med Genomics 2018; 11: 6.
Møller RS, Larsen LH, Johannesen KM, Talvik I, Talvik T, Vaher U et al. Gene panel testing in epileptic encephalopathies and familial epilepsies. Mol Syndromol 2016; 7: 210-19.
Butler KM, da Silva C, Alexander JJ, Hegde M, Escayg A. Diagnostic yield from 339 epilepsy patients screened on a clinical gene panel. Pediatr Neurol 2017; 77: 61-6.
Ream MA, Mikati MA. Clinical utility of genetic testing in pediatric drugresistant epilepsy: a pilot study. Epilepsy Behav 2014; 37: 241-8.
Lee J, Lee C, Ki CS, Lee J. Determining the best candidates for next generation sequencing-based gene panel for evaluation of early-onset epilepsy. Mol Genet Genomic Med 2020; 8: e1376.
Johannesen KM, Nikanorova N, Marjanovic D, Pavbro A, Larsen L, Rubboli G et al. Utility of genetic testing for therapeutic decision-making in adults with epilepsy. Epilepsia 2020; 61: 1234-9.
Hoelz H, Herdl C, Gerstl L, Tacke M, Vill K, von Stuelpnagel C et al. Impact on clinical decision making of next-generation sequencing in pediatric epilepsy in a tertiary epilepsy referral center. Clin EEG Neurosci 2020; 51: 61-9.
Alsubaie L, Aloraini T, Amoudi M, Swaid A, Eyiad W, Al Mutairi F et al. Genomic testing and counseling: the contribution of next-generation sequencing to epilepsy genetics. Ann Hum Genet 2020; 84: 431-6.
Nolan D, Carlson M. Whole exome sequencing in pediatric neurology patients: clinical implications and estimated cost analysis. J Child Neurol 2016; 31: 887-94.
Fung CW, Kwong AK, Wong VC. Gene panel analysis for nonsyndromic cryptogenic neonatal/infantile epileptic encephalopathy. Epilepsia Open 2017; 2: 236-43.
Lotte J, Haberlandt E, Neubauer B, Staudt M, Kluger GJ. Bromide in patients with SCN1A-mutations manifesting as Dravet syndrome. Neuropediatrics 2012; 43: 17-21.
Shi XY, Tomonoh Y, Wang WZ, Ishii A, Higurashi N, Kurahashi H et al. Efficacy of antiepileptic drugs for the treatment of Dravet syndrome with different genotypes. Brain Dev 2016; 38: 40-6.
Curatolo P, Nabbout R, Lagae L, Aronica E, Ferreira JC, Feucht M et al. Management of epilepsy associated with tuberous sclerosis complex: updated clinical recommendations. Eur J Paediatr Neurol 2018; 22: 738-48.
Pisano T, Numis AL, Heavin SB, Weckhuysen S, Angriman M, Suls A et al. Early and effective treatment of KCNQ2 encephalopathy. Epilepsia 2015; 56: 685-91.
Sands TT, Balestri M, Bellini G, Mulkey SB, Danhaive O, Bakken EH et al. Rapid and safe response to low-dose carbamazepine in neonatal epilepsy. Epilepsia 2016; 57: 2019-30.
Mikati MA, Jiang YH, Carboni M, Shashi V, Petrovski S, Spillmann R et al. Quinidine in the treatment of KCNT1-positive epilepsies. Ann Neurol 2015; 78: 995-9.