دورية أكاديمية
أعرض في EDS

Use of a Dynamic Genetic Testing Approach for Childhood-Onset Epilepsy.

التفاصيل البيبلوغرافية
العنوان: Use of a Dynamic Genetic Testing Approach for Childhood-Onset Epilepsy.
المؤلفون: Balciuniene J; Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., DeChene ET; Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Akgumus G; Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Romasko EJ; Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Cao K; Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Dubbs HA; Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Mulchandani S; Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Spinner NB; Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.; Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia., Conlin LK; Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia., Marsh ED; Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia., Goldberg E; Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia., Helbig I; Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia., Sarmady M; Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia., Abou Tayoun A; Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.; now with Department of Genomics, Al Jalila Children's Specialty Hospital, Dubai, United Arab Emirates.
المصدر: JAMA network open [JAMA Netw Open] 2019 Apr 05; Vol. 2 (4), pp. e192129. Date of Electronic Publication: 2019 Apr 05.
نوع المنشور: Evaluation Study; Journal Article
اللغة: English
بيانات الدورية: Publisher: American Medical Association Country of Publication: United States NLM ID: 101729235 Publication Model: Electronic Cited Medium: Internet ISSN: 2574-3805 (Electronic) Linking ISSN: 25743805 NLM ISO Abbreviation: JAMA Netw Open Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Chicago, IL : American Medical Association, [2018]-
مواضيع طبية MeSH: Epilepsy/*diagnosis , Epilepsy/*genetics , Genetic Predisposition to Disease/*genetics , Genetic Testing/*methods , Exome Sequencing/*methods, Child ; Child, Preschool ; Female ; Humans ; Infant ; Male ; Tripeptidyl-Peptidase 1
مستخلص: Importance: Although genetic testing is important for bringing precision medicine to children with epilepsy, it is unclear what genetic testing strategy is best in maximizing diagnostic yield.
Objectives: To evaluate the diagnostic yield of an exome-based gene panel for childhood epilepsy and discuss the value of follow-up testing.
Design, Setting, and Participants: A case series study was conducted on data from clinical genetic testing at Children's Hospital of Philadelphia was conducted from September 26, 2016, to January 8, 2018. Initial testing targeted 100 curated epilepsy genes for sequence and copy number analysis in 151 children with idiopathic epilepsy referred consecutively by neurologists. Additional genetic testing options were offered afterward.
Exposures: Clinical genetic testing.
Main Outcomes and Measures: Molecular diagnostic findings.
Results: Of 151 patients (84 boys [55.6%]; median age, 4.2 years [interquartile range, 1.4-8.7 years]), 16 children (10.6%; 95% CI, 6%-16%) received a diagnosis after initial panel analysis. Parental testing for 15 probands with inconclusive results revealed de novo variants in 7 individuals (46.7%), resulting in an overall diagnostic yield of 15.3% (23 of 151; 95% CI, 9%-21%). Twelve probands with nondiagnostic panel findings were reflexed to exome sequencing, and 4 were diagnostic (33.3%; 95% CI, 6%-61%), raising the overall diagnostic yield to 17.9% (27 of 151; 95% CI, 12%-24%). The yield was highest (17 of 44 [38.6%; 95% CI, 24%-53%]) among probands with epilepsy onset in infancy (age, 1-12 months). Panel diagnostic findings involved 16 genes: SCN1A (n = 4), PRRT2 (n = 3), STXBP1 (n = 2), IQSEC2 (n = 2), ATP1A2, ATP1A3, CACNA1A, GABRA1, KCNQ2, KCNT1, SCN2A, SCN8A, DEPDC5, TPP1, PCDH19, and UBE3A (all n = 1). Exome sequencing analysis identified 4 genes: SMC1A, SETBP1, NR2F1, and TRIT1. For the remaining 124 patients, analysis of 13 additional genes implicated in epilepsy since the panel was launched in 2016 revealed promising findings in 6 patients.
Conclusions and Relevance: Exome-based targeted panels appear to enable rapid analysis of a preselected set of genes while retaining flexibility in gene content. Successive genetic workup should include parental testing of select probands with inconclusive results and reflex to whole-exome trio analysis for the remaining nondiagnostic cases. Periodic reanalysis is needed to capture information in newly identified disease genes.
References: Mol Syndromol. 2016 Sep;7(4):172-181. (PMID: 27781027)
Lancet Neurol. 2016 Mar;15(3):304-16. (PMID: 26597089)
Bioinformatics. 2012 Nov 1;28(21):2747-54. (PMID: 22942019)
Front Genet. 2018 Feb 07;9:20. (PMID: 29467791)
Presse Med. 2018 Mar;47(3):218-226. (PMID: 29277263)
JAMA Pediatr. 2017 Sep 1;171(9):863-871. (PMID: 28759667)
Neurology. 2017 Jan 17;88(3):296-303. (PMID: 27986877)
Genet Med. 2015 May;17(5):405-24. (PMID: 25741868)
PLoS One. 2017 Nov 30;12(11):e0188978. (PMID: 29190809)
Am J Hum Genet. 2017 Jun 1;100(6):895-906. (PMID: 28552198)
Orphanet J Rare Dis. 2018 May 2;13(1):71. (PMID: 29720203)
Neurosci Lett. 2018 Feb 22;667:4-9. (PMID: 28499889)
Epilepsia. 2018 May;59(5):1062-1071. (PMID: 29655203)
Genet Med. 2018 Dec;20(12):1600-1608. (PMID: 29595809)
Genome Med. 2015 Aug 25;7:91. (PMID: 26302787)
Pediatr Neurol. 2017 Dec;77:61-66. (PMID: 29056246)
Clin Genet. 2019 Jan;95(1):95-111. (PMID: 29992546)
Nat Rev Neurol. 2014 May;10(5):283-92. (PMID: 24733163)
Epilepsy Res. 2018 Sep;145:89-92. (PMID: 29933145)
Curr Neurol Neurosci Rep. 2017 May;17(5):45. (PMID: 28405954)
Seizure. 2017 Jan;44:11-20. (PMID: 28007376)
J Mol Diagn. 2018 Sep;20(5):643-652. (PMID: 29936260)
Seizure. 2018 Jul;59:132-140. (PMID: 29852413)
Seizure. 2012 Jan;21(1):3-11. (PMID: 21917483)
Hum Mutat. 2018 Nov;39(11):1476-1484. (PMID: 30311377)
معلومات مُعتمدة: K08 NS097633 United States NS NINDS NIH HHS; U54 HD086984 United States HD NICHD NIH HHS
تواريخ الأحداث: Date Created: 20190413 Date Completed: 20200213 Latest Revision: 20221207
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC6481455
DOI: 10.1001/jamanetworkopen.2019.2129
PMID: 30977854
قاعدة البيانات: MEDLINE
الوصف
تدمد:2574-3805
DOI:10.1001/jamanetworkopen.2019.2129