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Article: Diagnostic value of whole‐exome sequencing in Chinese pediatric‐onset neuromuscular patients

TitleDiagnostic value of whole‐exome sequencing in Chinese pediatric‐onset neuromuscular patients
Authors
Keywordsintegrated approach
neuromuscular disorders
pediatric‐onset
whole‐exome sequencing
Issue Date2020
PublisherWiley Open Access. The Journal's web site is located at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2324-9269
Citation
Molecular Genetics & Genomic Medicine, 2020, Epub How to Cite?
AbstractBACKGROUND: Neuromuscular disorders (NMDs) comprise a group of heterogeneous genetic diseases with a broad spectrum of overlapping the clinical presentations that makes diagnosis challenging. Notably, the recent introduction of whole-exome sequencing (WES) is introducing rapid changes on the genetic diagnosis of NMDs. We aimed to investigate the diagnostic value of WES for pediatric-onset NMDs. METHODS: We applied integrated diagnostic approach and performed WES in 50 Chinese subjects (30 males, 20 females) with undiagnosed pediatric-onset NMDs despite previous specific tests. The patients were categorized in four subgroups according to phenotyping and investigation findings. Variants on NMDs gene list and open exome analysis for those with initial negative findings were identified. RESULTS: WES identified causative variants in ACTA1 (n = 2), POMT1, COL6A1 (n = 2), MTMR2, LMNA, SELENON, DNM2, TGFB1, MPZ, IGHMBP2, and LAMA2 in 13 patients. Two subjects have variants of uncertain significance (VUSs) in TTN and SCN11A, unlikely to be pathogenic due to incompatible phenotypes. The mean interval time from symptom onset to genetic diagnosis was 10.4 years (range from 1 month to 33 years). The overall diagnostic yield of WES in our cohort was 26%. Open exome analysis was necessary to identify the pathogenic variant in TGFB1 that caused skeletal dysplasia with neuromuscular presentation. CONCLUSION: Our study shows a clear role of WES in the pathway of integrated diagnostic approach to shorten the diagnostic odyssey in patients with rare NMDs.
Persistent Identifierhttp://hdl.handle.net/10722/281894
ISSN
2019 Impact Factor: 1.995

 

DC FieldValueLanguage
dc.contributor.authorTSANG, HY-
dc.contributor.authorChiu, ATG-
dc.contributor.authorKwong, BMH-
dc.contributor.authorLIANG, R-
dc.contributor.authorYu, MHC-
dc.contributor.authorYEUNG, K-S-
dc.contributor.authorHo, WHL-
dc.contributor.authorMAK, CCY-
dc.contributor.authorLEUNG, GKC-
dc.contributor.authorPEI, SLC-
dc.contributor.authorFung, JLF-
dc.contributor.authorWong, VCN-
dc.contributor.authorFrancesco, M-
dc.contributor.authorChung, BHY-
dc.contributor.authorChan, SHS-
dc.date.accessioned2020-04-03T07:23:17Z-
dc.date.available2020-04-03T07:23:17Z-
dc.date.issued2020-
dc.identifier.citationMolecular Genetics & Genomic Medicine, 2020, Epub-
dc.identifier.issn2324-9269-
dc.identifier.urihttp://hdl.handle.net/10722/281894-
dc.description.abstractBACKGROUND: Neuromuscular disorders (NMDs) comprise a group of heterogeneous genetic diseases with a broad spectrum of overlapping the clinical presentations that makes diagnosis challenging. Notably, the recent introduction of whole-exome sequencing (WES) is introducing rapid changes on the genetic diagnosis of NMDs. We aimed to investigate the diagnostic value of WES for pediatric-onset NMDs. METHODS: We applied integrated diagnostic approach and performed WES in 50 Chinese subjects (30 males, 20 females) with undiagnosed pediatric-onset NMDs despite previous specific tests. The patients were categorized in four subgroups according to phenotyping and investigation findings. Variants on NMDs gene list and open exome analysis for those with initial negative findings were identified. RESULTS: WES identified causative variants in ACTA1 (n = 2), POMT1, COL6A1 (n = 2), MTMR2, LMNA, SELENON, DNM2, TGFB1, MPZ, IGHMBP2, and LAMA2 in 13 patients. Two subjects have variants of uncertain significance (VUSs) in TTN and SCN11A, unlikely to be pathogenic due to incompatible phenotypes. The mean interval time from symptom onset to genetic diagnosis was 10.4 years (range from 1 month to 33 years). The overall diagnostic yield of WES in our cohort was 26%. Open exome analysis was necessary to identify the pathogenic variant in TGFB1 that caused skeletal dysplasia with neuromuscular presentation. CONCLUSION: Our study shows a clear role of WES in the pathway of integrated diagnostic approach to shorten the diagnostic odyssey in patients with rare NMDs.-
dc.languageeng-
dc.publisherWiley Open Access. The Journal's web site is located at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2324-9269-
dc.relation.ispartofMolecular Genetics & Genomic Medicine-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectintegrated approach-
dc.subjectneuromuscular disorders-
dc.subjectpediatric‐onset-
dc.subjectwhole‐exome sequencing-
dc.titleDiagnostic value of whole‐exome sequencing in Chinese pediatric‐onset neuromuscular patients-
dc.typeArticle-
dc.identifier.emailHo, WHL: hohoklai@hku.hk-
dc.identifier.emailFung, JLF: jasflf@connect.hku.hk-
dc.identifier.emailWong, VCN: vcnwong@hku.hk-
dc.identifier.emailChung, BHY: bhychung@hku.hk-
dc.identifier.emailChan, SHS: sophehs@hku.hk-
dc.identifier.authorityWong, VCN=rp00334-
dc.identifier.authorityChung, BHY=rp00473-
dc.identifier.authorityChan, SHS=rp02210-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1002/mgg3.1205-
dc.identifier.pmid32154989-
dc.identifier.scopuseid_2-s2.0-85081262114-
dc.identifier.scopuseid_2-s2.0-85081262114-
dc.identifier.hkuros309630-
dc.identifier.volumeEpub-
dc.publisher.placeUnited Kingdom-

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