Genetic diagnoses in epilepsy: The impact of dynamic exome analysis in a pediatric cohort.
Adolescent
Adult
Age of Onset
Brain Diseases
/ etiology
Child
Child, Preschool
Chromosomes, Human
/ genetics
Cohort Studies
Epilepsy
/ complications
Epilepsy, Generalized
/ genetics
Exome
/ genetics
Female
Genetic Testing
Genetic Variation
Humans
Infant
Male
Microarray Analysis
Phenotype
Exome Sequencing
Young Adult
epilepsy
genetics
phenotype
reanalysis
whole exome sequencing
Journal
Epilepsia
ISSN: 1528-1167
Titre abrégé: Epilepsia
Pays: United States
ID NLM: 2983306R
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
03
07
2019
revised:
18
12
2019
accepted:
20
12
2019
pubmed:
21
1
2020
medline:
11
7
2020
entrez:
21
1
2020
Statut:
ppublish
Résumé
We evaluated the yield of systematic analysis and/or reanalysis of whole exome sequencing (WES) data from a cohort of well-phenotyped pediatric patients with epilepsy and suspected but previously undetermined genetic etiology. We identified and phenotyped 125 participants with pediatric epilepsy. Etiology was unexplained at the time of enrollment despite clinical testing, which included chromosomal microarray (57 patients), epilepsy gene panel (n = 48), both (n = 28), or WES (n = 8). Clinical epilepsy diagnoses included developmental and epileptic encephalopathy (DEE), febrile infection-related epilepsy syndrome, Rasmussen encephalitis, and other focal and generalized epilepsies. We analyzed WES data and compared the yield in participants with and without prior clinical genetic testing. Overall, we identified pathogenic or likely pathogenic variants in 40% (50/125) of our study participants. Nine patients with DEE had genetic variants in recently published genes that had not been recognized as epilepsy-related at the time of clinical testing (FGF12, GABBR1, GABBR2, ITPA, KAT6A, PTPN23, RHOBTB2, SATB2), and eight patients had genetic variants in candidate epilepsy genes (CAMTA1, FAT3, GABRA6, HUWE1, PTCHD1). Ninety participants had concomitant or subsequent clinical genetic testing, which was ultimately explanatory for 26% (23/90). Of the 67 participants whose molecular diagnoses were "unsolved" through clinical genetic testing, we identified pathogenic or likely pathogenic variants in 17 (25%). Our data argue for early consideration of WES with iterative reanalysis for patients with epilepsy, particularly those with DEE or epilepsy with intellectual disability. Rigorous analysis of WES data of well-phenotyped patients with epilepsy leads to a broader understanding of gene-specific phenotypic spectra as well as candidate disease gene identification. We illustrate the dynamic nature of genetic diagnosis over time, with analysis and in some cases reanalysis of exome data leading to the identification of disease-associated variants among participants with previously nondiagnostic results from a variety of clinical testing strategies.
Identifiants
pubmed: 31957018
doi: 10.1111/epi.16427
pmc: PMC7404709
mid: NIHMS1065813
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
249-258Subventions
Organisme : NHLBI NIH HHS
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG008895
Pays : United States
Organisme : NHGRI NIH HHS
ID : 5U01HG009088-02
Pays : United States
Organisme : NINDS NIH HHS
ID : K23 NS107646
Pays : United States
Informations de copyright
Wiley Periodicals, Inc. © 2020 International League Against Epilepsy.
Références
Nature. 2012 Nov 1;491(7422):56-65
pubmed: 23128226
Genet Med. 2016 Sep;18(9):898-905
pubmed: 26795593
Nat Rev Neurol. 2014 May;10(5):293-9
pubmed: 24733164
Epilepsia. 2019 Mar;60(3):406-418
pubmed: 30682224
Clin Genet. 2016 Feb;89(2):198-204
pubmed: 26138355
Am J Hum Genet. 2014 Feb 6;94(2):303-9
pubmed: 24462372
Ann Neurol. 2014 Jun;75(6):943-58
pubmed: 24811917
Epilepsia. 2016 Jun;57(6):994-1003
pubmed: 27173016
Hum Mol Genet. 2014 Sep 15;23(18):4846-58
pubmed: 24781210
Lancet Neurol. 2016 Mar;15(3):304-16
pubmed: 26597089
Epilepsy Res. 2018 Jan;139:73-79
pubmed: 29197668
Epilepsia. 2013 Jul;54(7):1270-81
pubmed: 23647072
Neurology. 2018 May 8;90(19):e1692-e1701
pubmed: 29643084
Genome Biol. 2016 Jun 06;17(1):122
pubmed: 27268795
J Med Genet. 2013 May;50(5):271-9
pubmed: 23468209
Nat Genet. 2015 Jan;47(1):73-7
pubmed: 25420144
Neuron. 2012 Apr 12;74(1):41-8
pubmed: 22500628
Am J Hum Genet. 2017 Oct 5;101(4):623-629
pubmed: 28985496
Ann Neurol. 2016 Jan;79(1):132-7
pubmed: 26285051
Genet Med. 2018 Jun;20(6):645-654
pubmed: 29095811
Bioinformatics. 2016 Oct 15;32(20):3081-3088
pubmed: 27339714
Nature. 2016 Aug 17;536(7616):285-91
pubmed: 27535533
JAMA Pediatr. 2017 Sep 1;171(9):863-871
pubmed: 28759667
Ann Neurol. 2017 Mar;81(3):419-429
pubmed: 28133863
Epilepsia. 2019 May;60(5):797-806
pubmed: 30951195
Nucleic Acids Res. 2012 Jul;40(Web Server issue):W452-7
pubmed: 22689647
Ann Neurol. 2015 Oct;78(4):649-58
pubmed: 26224535
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
Neurology. 2017 Aug 29;89(9):893-899
pubmed: 28733343
Am J Hum Genet. 2018 Jan 4;102(1):44-57
pubmed: 29276004
Genet Med. 2016 Nov;18(11):1143-1150
pubmed: 26986877
Clin Genet. 2015 Jul;88(1):34-40
pubmed: 25046240
Expert Rev Mol Diagn. 2015;15(8):1023-32
pubmed: 26088785
J Hum Genet. 2016 May;61(5):381-7
pubmed: 26818738
Cold Spring Harb Mol Case Stud. 2019 Feb 1;5(1):
pubmed: 30709877
Curr Protoc Hum Genet. 2013 Jan;Chapter 7:Unit7.20
pubmed: 23315928
Ann Neurol. 2018 Jun;83(6):1133-1146
pubmed: 29679388
N Engl J Med. 2014 Aug 21;371(8):733-43
pubmed: 25140959
Ann Neurol. 2016 Jan;79(1):120-31
pubmed: 26505888
Genet Med. 2018 Dec;20(12):1564-1574
pubmed: 29595814