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Article: Exome sequencing identifies molecular diagnosis in children with drug-resistant epilepsy

TitleExome sequencing identifies molecular diagnosis in children with drug-resistant epilepsy
Authors
KeywordsChromosomal microarray
Pediatric‐onset drug‐resistant epilepsy
Whole exome sequencing
Issue Date2019
PublisherWiley-Blackwell Publishing, Inc. The Journal's web site is located at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2470-9239
Citation
Epilepsia Open, 2019, v. 4 n. 1, p. 63-72 How to Cite?
AbstractObjective: Early onset drug‐resistant epilepsy is a neurologic disorder in which 2 antiepileptic drugs fail to maintain the seizure‐free status of the patient. Heterogeneous clinical presentations make the diagnosis challenging. We aim to identify the underlying genetic causes of a pediatric cohort with drug‐resistant epilepsy and evaluate whether the findings can provide information on patient management. Methods: We include patients with drug‐resistant epilepsy onset before 18 years of age. Singleton clinical chromosomal microarray (CMA) followed by whole exome sequencing (WES) was performed using genomic DNA. In the first‐tier analysis of the exome data, we aimed to identify disease‐causing mutations in 546 genes known to cause, or to be associated with, epilepsy. For negative cases, we proceeded to exome‐wide analysis. Rare coding variants were interrogated for pathogenicity based on the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: We recruited 50 patients. We identified 6 pathogenic or likely pathogenic mutations, giving a diagnostic yield of 12%. Mutations were found in 6 different genes: SCN8A, SCN1A, MECP2, CDKL5, DEPDC5, and CHD2. The CDKL5 variant was found to be mosaic. One variant of unknown significance (VUS) in KCNT1 was found in a patient with compatible clinical features. Of note, a reported pathogenic SCN5A mutation known to contribute to Brugada syndrome, was also found in the patient with an SCN1A mutation. Significance: Our study suggests that singleton WES is an effective diagnostic tool for drug‐resistant epilepsy. Genetic diagnosis can help to consolidate the clinical diagnosis, to facilitate phenotypic expansion, and to influence treatment and management options for seizure control in our patients. In our study, a significant portion of the genetic findings are known to be associated with an increased risk of sudden unexpected death in epilepsy (SUDEP). These findings could assist with more appropriate management in patients with epilepsy.
Persistent Identifierhttp://hdl.handle.net/10722/266024
ISSN

 

DC FieldValueLanguage
dc.contributor.authorTsang, HY-
dc.contributor.authorLeung, KC-
dc.contributor.authorHo, CCA-
dc.contributor.authorYeung, KS-
dc.contributor.authorMak, CCY-
dc.contributor.authorPei, LCS-
dc.contributor.authorYu, HC-
dc.contributor.authorKan, SYA-
dc.contributor.authorChan, YK-
dc.contributor.authorKwong, KL-
dc.contributor.authorLee, SL-
dc.contributor.authorYung, AWY-
dc.contributor.authorFung, CW-
dc.contributor.authorChung, BHY-
dc.date.accessioned2018-12-17T02:16:34Z-
dc.date.available2018-12-17T02:16:34Z-
dc.date.issued2019-
dc.identifier.citationEpilepsia Open, 2019, v. 4 n. 1, p. 63-72-
dc.identifier.issn2470-9239-
dc.identifier.urihttp://hdl.handle.net/10722/266024-
dc.description.abstractObjective: Early onset drug‐resistant epilepsy is a neurologic disorder in which 2 antiepileptic drugs fail to maintain the seizure‐free status of the patient. Heterogeneous clinical presentations make the diagnosis challenging. We aim to identify the underlying genetic causes of a pediatric cohort with drug‐resistant epilepsy and evaluate whether the findings can provide information on patient management. Methods: We include patients with drug‐resistant epilepsy onset before 18 years of age. Singleton clinical chromosomal microarray (CMA) followed by whole exome sequencing (WES) was performed using genomic DNA. In the first‐tier analysis of the exome data, we aimed to identify disease‐causing mutations in 546 genes known to cause, or to be associated with, epilepsy. For negative cases, we proceeded to exome‐wide analysis. Rare coding variants were interrogated for pathogenicity based on the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: We recruited 50 patients. We identified 6 pathogenic or likely pathogenic mutations, giving a diagnostic yield of 12%. Mutations were found in 6 different genes: SCN8A, SCN1A, MECP2, CDKL5, DEPDC5, and CHD2. The CDKL5 variant was found to be mosaic. One variant of unknown significance (VUS) in KCNT1 was found in a patient with compatible clinical features. Of note, a reported pathogenic SCN5A mutation known to contribute to Brugada syndrome, was also found in the patient with an SCN1A mutation. Significance: Our study suggests that singleton WES is an effective diagnostic tool for drug‐resistant epilepsy. Genetic diagnosis can help to consolidate the clinical diagnosis, to facilitate phenotypic expansion, and to influence treatment and management options for seizure control in our patients. In our study, a significant portion of the genetic findings are known to be associated with an increased risk of sudden unexpected death in epilepsy (SUDEP). These findings could assist with more appropriate management in patients with epilepsy.-
dc.languageeng-
dc.publisherWiley-Blackwell Publishing, Inc. The Journal's web site is located at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2470-9239-
dc.relation.ispartofEpilepsia Open-
dc.rightsThis is the peer reviewed version of the following article: [Epilepsia Open, 2019, v. 4 n. 1, p. 63-72], which has been published in final form at [http://dx.doi.org/10.1002/epi4.12282]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectChromosomal microarray-
dc.subjectPediatric‐onset drug‐resistant epilepsy-
dc.subjectWhole exome sequencing-
dc.titleExome sequencing identifies molecular diagnosis in children with drug-resistant epilepsy-
dc.typeArticle-
dc.identifier.emailLeung, KC: gleungkc@hku.hk-
dc.identifier.emailHo, CCA: accho@hku.hk-
dc.identifier.emailYeung, KS: ksyyeung@hku.hk-
dc.identifier.emailPei, LCS: slcpei@hku.hk-
dc.identifier.emailKan, SYA: kansya@hkucc.hku.hk-
dc.identifier.emailChan, YK: ykchanc@hku.hk-
dc.identifier.emailLee, SL: slleem@hku.hk-
dc.identifier.emailYung, AWY: ayung@hkucc.hku.hk-
dc.identifier.emailFung, CW: fcw1209m@hkucc.hku.hk-
dc.identifier.emailChung, BHY: bhychung@hku.hk-
dc.identifier.authorityChan, YK=rp00453-
dc.identifier.authorityChung, BHY=rp00473-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1002/epi4.12282-
dc.identifier.hkuros296420-
dc.identifier.volume4-
dc.identifier.issue1-
dc.identifier.spage63-
dc.identifier.epage72-
dc.publisher.placeUnited States-

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