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Article: Panel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service

TitlePanel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service
Authors
KeywordsNeuromuscular diseases
exome sequencing
genetics
neurology
myopathies
Issue Date2019
PublisherIOS Press. The Journal's web site is located at https://www.iospress.nl/journal/journal-of-neuromuscular-diseases/
Citation
Journal of Neuromuscular Diseases, 2019, v. 6 n. 2, p. 241-258 How to Cite?
AbstractBackground:Neuromuscular disorders (NMDs) are clinically and genetically heterogeneous. Accurate molecular genetic diagnosis can improve clinical management, provides appropriate genetic counseling and testing of relatives, and allows potential therapeutic trials. Objective:To establish the clinical utility of panel-based whole exome sequencing (WES) in NMDs in a population with children and adults with various neuromuscular symptoms. Methods:Clinical exome sequencing, followed by diagnostic interpretation of variants in genes associated with NMDs, was performed in a cohort of 396 patients suspected of having a genetic cause with a variable age of onset, neuromuscular phenotype, and inheritance pattern. Many had previously undergone targeted gene testing without results. Results:Disease-causing variants were identified in 75/396 patients (19%), with variants in the three COL6-genes (COL6A1, COL6A2 and COL6A3) as the most common cause of the identified muscle disorder, followed by variants in the RYR1 gene. Together, these four genes account for almost 25% of cases in whom a definite genetic cause was identified. Furthermore, likely pathogenic variants and/or variants of uncertain significance were identified in 95 of the patients (24%), in whom functional and/or segregation analysis should be used to confirm or reject the pathogenicity. In 18% of the cases with a disease-causing variant of which we received additional clinical information, we identified a genetic cause in genes of which the associated phenotypes did not match that of the patients. Hence, the advantage of panel-based WES is its unbiased approach. Conclusion:Whole exome sequencing, followed by filtering for NMD genes, offers an unbiased approach for the genetic diagnostics of NMD patients. This approach could be used as a first-tier test in neuromuscular disorders with a high suspicion of a genetic cause. With uncertain results, functional testing and segregation analysis are needed to complete the evidence.
Persistent Identifierhttp://hdl.handle.net/10722/272291
ISSN

 

DC FieldValueLanguage
dc.contributor.authorWestra, D-
dc.contributor.authorSchouten, MI-
dc.contributor.authorStunnenberg, BC-
dc.contributor.authorKusters, B-
dc.contributor.authorSaris, CGJ-
dc.contributor.authorErasmus, CE-
dc.contributor.authorvan Engelen, BG-
dc.contributor.authorBulk, S-
dc.contributor.authorVerschuuren-Bemelmans, CC-
dc.contributor.authorGerkes, EH-
dc.contributor.authorde Geus, C-
dc.contributor.authorvan der Zwaag, PA-
dc.contributor.authorChan, S-
dc.contributor.authorChung, B-
dc.contributor.authorBarge-Schaapveld, DQCM-
dc.contributor.authorKriek, M-
dc.contributor.authorSznajer, Y-
dc.contributor.authorvan Spaendonck-Zwarts, K-
dc.contributor.authorvan der Kooi, AJ-
dc.contributor.authorKrause, A-
dc.contributor.authorSchonewolf-Greulich, B-
dc.contributor.authorde Die-Smu8lders, C-
dc.contributor.authorSallevelt, SCEH-
dc.contributor.authorKrapels, IPC-
dc.contributor.authorRasmussen, M-
dc.contributor.authorMaystadt, I-
dc.contributor.authorKievit, AJA-
dc.contributor.authorWitting, N-
dc.contributor.authorPennings, M-
dc.contributor.authorMeijer, R-
dc.contributor.authorGillissen, C-
dc.contributor.authorKamsteeg, EJ-
dc.contributor.authorVoermans, NC-
dc.date.accessioned2019-07-20T10:39:24Z-
dc.date.available2019-07-20T10:39:24Z-
dc.date.issued2019-
dc.identifier.citationJournal of Neuromuscular Diseases, 2019, v. 6 n. 2, p. 241-258-
dc.identifier.issn2214-3599-
dc.identifier.urihttp://hdl.handle.net/10722/272291-
dc.description.abstractBackground:Neuromuscular disorders (NMDs) are clinically and genetically heterogeneous. Accurate molecular genetic diagnosis can improve clinical management, provides appropriate genetic counseling and testing of relatives, and allows potential therapeutic trials. Objective:To establish the clinical utility of panel-based whole exome sequencing (WES) in NMDs in a population with children and adults with various neuromuscular symptoms. Methods:Clinical exome sequencing, followed by diagnostic interpretation of variants in genes associated with NMDs, was performed in a cohort of 396 patients suspected of having a genetic cause with a variable age of onset, neuromuscular phenotype, and inheritance pattern. Many had previously undergone targeted gene testing without results. Results:Disease-causing variants were identified in 75/396 patients (19%), with variants in the three COL6-genes (COL6A1, COL6A2 and COL6A3) as the most common cause of the identified muscle disorder, followed by variants in the RYR1 gene. Together, these four genes account for almost 25% of cases in whom a definite genetic cause was identified. Furthermore, likely pathogenic variants and/or variants of uncertain significance were identified in 95 of the patients (24%), in whom functional and/or segregation analysis should be used to confirm or reject the pathogenicity. In 18% of the cases with a disease-causing variant of which we received additional clinical information, we identified a genetic cause in genes of which the associated phenotypes did not match that of the patients. Hence, the advantage of panel-based WES is its unbiased approach. Conclusion:Whole exome sequencing, followed by filtering for NMD genes, offers an unbiased approach for the genetic diagnostics of NMD patients. This approach could be used as a first-tier test in neuromuscular disorders with a high suspicion of a genetic cause. With uncertain results, functional testing and segregation analysis are needed to complete the evidence.-
dc.languageeng-
dc.publisherIOS Press. The Journal's web site is located at https://www.iospress.nl/journal/journal-of-neuromuscular-diseases/-
dc.relation.ispartofJournal of Neuromuscular Diseases-
dc.subjectNeuromuscular diseases-
dc.subjectexome sequencing-
dc.subjectgenetics-
dc.subjectneurology-
dc.subjectmyopathies-
dc.titlePanel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service-
dc.typeArticle-
dc.identifier.emailChan, S: sophehs@hku.hk-
dc.identifier.emailChung, B: bhychung@hku.hk-
dc.identifier.authorityChan, S=rp02210-
dc.identifier.authorityChung, B=rp00473-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.3233/JND-180376-
dc.identifier.pmid31127727-
dc.identifier.scopuseid_2-s2.0-85066892378-
dc.identifier.hkuros298765-
dc.identifier.volume6-
dc.identifier.issue2-
dc.identifier.spage241-
dc.identifier.epage258-
dc.publisher.placeNetherlands-

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