Title: | Panel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service |
Author(s): | Westra, D. ; Schouten, M.I. ; Stunnenberg, B.C. ; Kusters, B. ; Saris, C.G.J. ; Erasmus, C.E. ; Engelen, B.G.M. van ; Bulk, S.; Verschuuren-Bemelmans, C.C.; Gerkes, E.H.; Geus, C. de; Zwaag, P.A. van der; Chan, S.; Chung, B.; Barge-Schaapveld, D.; Kriek, M.; Sznajer, Y.; Spaendonck-Zwarts, K.Y. van; Kooi, A.J. van der; Krause, A.; Schonewolf-Greulich, B.; Die-Smulders, C.E. de; Sallevelt, S.; Krapels, I.P.C. ; Rasmussen, M.; Maystadt, I.; Kievit, A.J.; Witting, N.; Pennings, M.; Meijer, R; Gillissen, C.; Kamsteeg, E.J. ; Voermans, N.C. |
Publication year: | 2019 |
Source: | Journal of Neuromuscular Diseases, vol. 6, iss. 2, (2019), pp. 241-258 |
ISSN: | 2214-3599 |
DOI: | https://doi.org/10.3233/JND-180376 |
Publication type: | Article / Letter to editor |
Please use this identifier to cite or link to this item : https://hdl.handle.net/2066/204157 ![]() |
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Subject: | Radboudumc 0: Other Research DCMN: Donders Center for Medical Neuroscience Radboudumc 11: Renal disorders RIMLS: Radboud Institute for Molecular Life Sciences Radboudumc 12: Sensory disorders DCMN: Donders Center for Medical Neuroscience Radboudumc 3: Disorders of movement DCMN: Donders Center for Medical Neuroscience Radboudumc 9: Rare cancers RIHS: Radboud Institute for Health Sciences Tijdelijke code tbv inlezen publicaties Radboudumc - Alleen voor gebruik door Radboudumc |
Organization: | Paediatrics Laboratory Medicine Human Genetics Neurology Pathology |
Journal title: |
Journal of Neuromuscular Diseases
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Volume: | vol. 6 |
Issue: | iss. 2 |
Page start: | p. 241 |
Page end: | p. 258 |
Abstract: |
BACKGROUND: 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.
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