A comparison of genomic diagnostics in adults and children with epilepsy and comorbid intellectual disability.
Journal
European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
06
08
2019
accepted:
25
02
2020
revised:
13
02
2020
pubmed:
3
4
2020
medline:
2
6
2021
entrez:
3
4
2020
Statut:
ppublish
Résumé
Next generation sequencing provides an important opportunity for improved diagnosis in epilepsy. To date, the majority of diagnostic genetic testing is conducted in the paediatric arena, while the utility of such testing is less well understood in adults with epilepsy. We conducted whole exome sequencing (WES) and copy number variant analyses in an Irish cohort of 101 people with epilepsy and co-morbid intellectual disability to compare the diagnostic yield of genomic testing between adult and paediatric patients. Variant interpretation followed American College of Medical Genetics and Genomics (ACMG) guidelines. We demonstrate that WES, in combination with array-comparative genomic hybridisation, provides a diagnostic rate of 27% in unrelated adult epilepsy patients and 42% in unrelated paediatric patients. We observe a 2.7% rate of ACMG-defined incidental findings. Our findings indicate that WES has similar utility in both adult and paediatric cohorts and is appropriate for diagnostic testing in both epilepsy patient groups.
Identifiants
pubmed: 32238909
doi: 10.1038/s41431-020-0610-3
pii: 10.1038/s41431-020-0610-3
pmc: PMC7381648
doi:
Types de publication
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1066-1077Références
Covanis A, Guekht A, Li S, Secco M, Shakir R, Perucca E. From global campaign to global commitment: The World Health Assembly’s Resolution on epilepsy. Epilepsia. 2015;56:1651–7.
pubmed: 26391429
Myers CT, Mefford HC. Advancing epilepsy genetics in the genomic era. Genome Med BioMed Cent. 2015;7:91.
Allen AS, Berkovic SF, Cossette P, Delanty N, Dlugos D, Eichler EE, et al. De novo mutations in epileptic encephalopathies. Nature. 2013;501:217–21.
pubmed: 23934111
Pagnamenta AT, Murakami Y, Taylor JM, Anzilotti C, Howard MF, Miller V, et al. Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders. Eur J Hum Genet. 2017;25:669–79.
pubmed: 28327575
pmcid: 5477361
Wright CF, Fitzgerald TW, Jones WD, Clayton S, McRae JF, Van Kogelenberg M, et al. Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data. Lancet. 2015;385:1305–14.
pubmed: 25529582
pmcid: 4392068
Hamdan FF, Myers CT, Cossette P, Lemay P, Spiegelman D, Laporte AD, et al. High rate of recurrent de novo mutations in developmental and epileptic encephalopathies. Am J Hum Genet. 2017;101:664–85.
pubmed: 29100083
pmcid: 5673604
Ortega-Moreno L, Giráldez BG, Soto-Insuga V, Pozo RL Del, Rodrigo-Moreno M, Alarcón-Morcillo C. et al. Molecular diagnosis of patients with epilepsy and developmental delay using a customized panel of epilepsy genes. PLoS ONE. 2017;12:e0188978.
pubmed: 29190809
pmcid: 5708701
Allen NM, Conroy J, Shahwan A, Lynch B, Correa RG, Pena SDJ, et al. Unexplained early onset epileptic encephalopathy: exome screening and phenotype expansion. Epilepsia. 2016;57:e12–7.
pubmed: 26648591
Snoeijen-Schouwenaars FM, van Ool JS, Verhoeven JS, van Mierlo P, Braakman HMH, Smeets EE, et al. Diagnostic exome sequencing in 100 consecutive patients with both epilepsy and intellectual disability. Epilepsia. 2019;60:155–64.
pubmed: 30525188
Thevenon J, Duffourd Y, Masurel-Paulet A, Lefebvre M, Feillet F, El Chehadeh-Djebbar S, et al. Diagnostic odyssey in severe neurodevelopmental disorders: toward clinical whole-exome sequencing as a first-line diagnostic test. Clin Genet. 2016;89:700–7.
pubmed: 26757139
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.
pubmed: 26795593
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.
pubmed: 25741868
pmcid: 4544753
Olson H, Shen Y, Avallone J, Sheidley BR, Pinsky R, Bergin AM, et al. Copy number variation plays an important role in clinical epilepsy. Ann Neurol. 2014;75:943–58.
pubmed: 24811917
pmcid: 4487364
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;74:1301–11.
pubmed: 28846756
pmcid: 5710585
Mefford HC. Copy number matters in epilepsy. Epilepsy Curr. 2015;15:180–2.
pubmed: 26316861
pmcid: 4532226
Galizia EC, Srikantha M, Palmer R, Waters JJ, Lench N, Ogilvie CM, et al. Array comparative genomic hybridization: results from an adult population with drug-resistant epilepsy and co-morbidities. Eur J Med Genet. 2012;55:342–8.
pubmed: 22342432
pmcid: 3526772
Coppola A, Cellini E, Stamberger H, Saarentaus E, Cetica V, Lal D, et al. Diagnostic implications of genetic copy number variation in epilepsy plus. Epilepsia. 2019;60:689–706.
pubmed: 30866059
pmcid: 6488157
Kearney HM, Thorland EC, Brown KK, Quintero-Rivera F, South ST. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med. 2011;13:680–5.
pubmed: 21681106
Striano P, Coppola A, Paravidino R, Malacarne M, Gimelli S, Robbiano A, et al. Clinical significance of rare copy number variations in epilepsy: a case-control survey using microarray-based comparative genomic hybridization. Arch Neurol. 2012;69:322–30.
pubmed: 22083797
Church DM, Schneider VA, Graves T, Auger K, Cunningham F, Bouk N, et al. Modernizing reference genome assemblies. PLoS Biol. 2011;9:e1001091.
pubmed: 21750661
pmcid: 3130012
Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25(Jul):1754–60.
pubmed: 19451168
pmcid: 2705234
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75.
pubmed: 17701901
pmcid: 1950838
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.
pubmed: 27535533
pmcid: 5018207
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.
pubmed: 20354512
pmcid: 2855889
Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4:1073–81.
pubmed: 19561590
Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014;11:361–2.
pubmed: 24681721
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore M. Online Mendelian Inheritance in Man, OMIM
Kalia SS, Adelman K, Bale SJ, Chung WK, Eng C, Evans JP, et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med. 2017;19:249–55.
pubmed: 27854360
MacDonald JR, Ziman R, Yuen RKC, Feuk L, Scherer SW. The database of genomic variants: a curated collection of structural variation in the human genome. Nucleic Acids Res. 2014;42:D986–92.
pubmed: 24174537
Delanty N, White M, Benson K, McCormack M, Heavin S, Comerford E, et al. Development of a genomics module within an epilepsy-specific electronic health record: toward genomic medicine in epilepsy care. Epilepsia. 2019;epi.16278.
Palmer EE, Schofield D, Shrestha R, Kandula T, Macintosh R, Lawson JA, et al. Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: evidence of clinical utility and cost effectiveness. Mol Genet Genomic Med. 2018;6:186–99.
pubmed: 29314763
pmcid: 5902395
Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013;15:565–74.
pubmed: 23788249
pmcid: 3727274
Saha S, Barnett AG, Foldi C, Burne TH, Eyles DW, Buka SL. et al. Advanced paternal age is associated with impaired neurocognitive outcomes during infancy and childhood. PLoS Med. 2009;6:e1000040.
pmcid: 2653549
Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012;485:237–41.
pubmed: 22495306
pmcid: 3667984
Carvill GL, Heavin SB, Yendle SC, McMahon JM, O’Roak BJ, Cook J, et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet. 2013;45:825–30.
pubmed: 23708187
pmcid: 3704157
Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, et al. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014;42:D980–5.
pubmed: 24234437
Samueli S, Abraham K, Dressler A, Gröppel G, Mühlebner-Fahrngruber A, Scholl T, et al. Efficacy and safety of Everolimus in children with TSC—associated epilepsy—Pilot data from an open single-center prospective study. Orphanet J Rare Dis. 2016;11:145.
pubmed: 27809914
pmcid: 5094073
French JA, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016;388:2153–63.
pubmed: 27613521
EpiPM Consortium. A roadmap for precision medicine in the epilepsies. Lancet Neurol. 2015;14:1219–28.
pmcid: 4663979
Nabbout R, Chemaly N, Chipaux M, Barcia G, Bouis C, Dubouch C, et al. Encephalopathy in children with Dravet syndrome is not a pure consequence of epilepsy. Orphanet J Rare Dis. 2013;8:176.
pubmed: 24225340
pmcid: 4225757
Heyne HO, Singh T, Stamberger H, Abou Jamra R, Caglayan H, Craiu D, et al. De novo variants in neurodevelopmental disorders with epilepsy. Nat Genet. 2018;50:1048–53.
pubmed: 29942082
EuroEPINOMICS-RES Consortium, Epilepsy Phenome/Genome Project and EC, Balling R, Barisic N, Baulac S, Caglayan H, Craiu D, et al. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet. 2014;95:360–70.
Smith LA, Douglas J, Braxton AA, Kramer K. Reporting incidental findings in clinical whole exome sequencing: incorporation of the 2013 ACMG recommendations into current practices of genetic counseling. J Genet Couns. 2015;24:654–62.
pubmed: 25403901
Berkovic SF. Genetics of epilepsy in clinical practice. Epilepsy Curr. 2015;15:192–6.
pubmed: 26316866
pmcid: 4532231
Mefford HC. Clinical genetic testing in epilepsy. Epilepsy Curr. 2015;15:197–201.
pubmed: 26316867
pmcid: 4532232
Forman EB, Gorman KM, Conroy J, Arthur N, Grant C, Ennis S, et al. Cost of exome sequencing in epileptic encephalopathy: is it “worth it”? Arch Dis Child. 2018;103:304.
pubmed: 28939639
Brunklaus A, Ellis R, Reavey E, Forbes GH, Zuberi SM. Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome. Brain. 2012;135:2329–36.
pubmed: 22719002
Poduri A. When should genetic testing be performed in epilepsy patients? Epilepsy Curr. 2017;17:16–22.
pubmed: 28331464
pmcid: 5340549
Poduri A, Sheidley BR, Shostak S, Ottman R. Genetic testing in the epilepsies-developments and dilemmas. Nat Rev Neurol. 2014;10:293–9.
pubmed: 24733164
pmcid: 4090104
Ding L-E, Burnett L, Chesher D. The impact of reporting incidental findings from exome and whole-genome sequencing: predicted frequencies based on modeling. Genet Med. 2015;17:197–204.
pubmed: 25077650
Delanty N, Goldstein DB. Neuron NeuroView diagnostic exome sequencing: a new paradigm in neurology. 2013;80:841–3.