Dataset Information

A Wide Spectrum of Genetic Disorders Causing Severe Childhood Epilepsy in Taiwan: A Case Series of Ultrarare Genetic Cause and Novel Mutation Analysis in a Pilot Study.

ABSTRACT:

Background

Pediatric epileptic encephalopathy and severe neurological disorders comprise a group of heterogenous diseases. We used whole-exome sequencing (WES) to identify genetic defects in pediatric patients.

Methods

Patients with refractory seizures using ?2 antiepileptic drugs (AEDs) receiving one AED and having neurodevelopmental regression or having severe neurological or neuromuscular disorders with unidentified causes were enrolled, of which 54 patients fulfilled the inclusion criteria, were enrolled, and underwent WES.

Results

Genetic diagnoses were confirmed in 24 patients. In the seizure group, KCNQ2, SCN1A, TBCID 24, GRIN1, IRF2BPL, MECP2, OSGEP, PACS1, PIGA, PPP1CB, SMARCA4, SUOX, SZT2, UBE3A, 16p13.11 microdeletion, [4p16.3p16.1(68,345-7,739,782)X1, 17q25.1q25.3(73,608,322-81,041,938)X3], and LAMA2 were identified. In the nonseizure group, SCN2A, SPTBN2, DMD, and FBN1 were identified. Ten novel mutations were identified. The recurrent genes included SCN1A, KCNQ2, and TBCID24. Male pediatric patients had a significantly higher (57% vs. 29%; p < 0.05, odds ratio = 3.18) yield than their female counterparts. Seventeen genes were identified from the seizure groups, of which 82% were rare genetic etiologies for childhood seizure and did not appear recurrently in the case series.

Conclusions

Wide genetic variation was identified for severe childhood seizures by WES. WES had a high yield, particularly in male infantile patients.

SUBMITTER: Hong SY

PROVIDER: S-EPMC7765181 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

A Wide Spectrum of Genetic Disorders Causing Severe Childhood Epilepsy in Taiwan: A Case Series of Ultrarare Genetic Cause and Novel Mutation Analysis in a Pilot Study.

Hong Syuan-Yu SY Yang Jiann-Jou JJ Li Shuan-Yow SY Lee Inn-Chi IC

Journal of personalized medicine 20201215 4

<h4>Background</h4>Pediatric epileptic encephalopathy and severe neurological disorders comprise a group of heterogenous diseases. We used whole-exome sequencing (WES) to identify genetic defects in pediatric patients.<h4>Methods</h4>Patients with refractory seizures using ≥2 antiepileptic drugs (AEDs) receiving one AED and having neurodevelopmental regression or having severe neurological or neuromuscular disorders with unidentified causes were enrolled, of which 54 patients fulfilled the inclu ...[more]

PMID: 33333793

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Project description:ImportanceAlthough 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.ObjectivesTo evaluate the diagnostic yield of an exome-based gene panel for childhood epilepsy and discuss the value of follow-up testing.Design, setting, and participantsA 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.ExposuresClinical genetic testing.Main outcomes and measuresMolecular diagnostic findings.ResultsOf 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 relevanceExome-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.

Dataset Information

A Wide Spectrum of Genetic Disorders Causing Severe Childhood Epilepsy in Taiwan: A Case Series of Ultrarare Genetic Cause and Novel Mutation Analysis in a Pilot Study.

Background

Methods

Results

Conclusions

Publications

A Wide Spectrum of Genetic Disorders Causing Severe Childhood Epilepsy in Taiwan: A Case Series of Ultrarare Genetic Cause and Novel Mutation Analysis in a Pilot Study.

Similar Datasets

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