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- Title
Use of a Dynamic Genetic Testing Approach for Childhood-Onset Epilepsy.
- Authors
Balciuniene, Jorune; DeChene, Elizabeth T.; Akgumus, Gozde; Romasko, Edward J.; Cao, Kajia; Dubbs, Holly A.; Mulchandani, Surabhi; Spinner, Nancy B.; Conlin, Laura K.; Marsh, Eric D.; Goldberg, Ethan; Helbig, Ingo; Sarmady, Mahdi; Abou Tayoun, Ahmad
- Abstract
Key Points: Question: What genetic testing approach is most useful in maximizing diagnostic yield for children with idiopathic epilepsy? Findings: In this case series study of 151 patients referred for genetic epilepsy testing from a single academic tertiary hospital, the overall diagnostic yield was 17.9%. An initial exome-based 100-gene panel contributed 10.6%, while parental testing and reflex to exome analysis added 4.7% and 2.7%, respectively, and analysis expansion to 13 recently reported genes uncovered promising findings in 6 patients. Meaning: Exome-based panels may be a useful genetic testing option for children with idiopathic epilepsy, with parental testing being informative in establishing a definitive diagnosis. 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. This case series evaluates an exome-based gene panel approach to maximize diagnostic yield for children with idiopathic epilepsy.
- Subjects
PENNSYLVANIA; CHROMOSOME analysis; DIAGNOSIS of epilepsy; GENETICS of epilepsy; AGE factors in disease; CHI-squared test; COMPARATIVE studies; CONFIDENCE intervals; GENES; GENOMES; KARYOTYPES; LONGITUDINAL method; MAGNETIC resonance imaging; MENTAL illness; GENETIC testing; SAMPLE size (Statistics); STATISTICAL significance; DATA analysis software; DESCRIPTIVE statistics; SEQUENCE analysis
- Publication
JAMA Network Open, 2019, pe192129
- ISSN
2574-3805
- Publication type
Article
- DOI
10.1001/jamanetworkopen.2019.2129