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

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  • Dineke Westra
  • Meyke I Schouten
  • Bas C Stunnenberg
  • Benno Kusters
  • Christiaan G J Saris
  • Corrie E Erasmus
  • Baziel G van Engelen
  • Saskia Bulk
  • Corien C Verschuuren-Bemelmans
  • E H Gerkes
  • Christa de Geus
  • P A van der Zwaag
  • Sophelia Chan
  • Brian Chung
  • Daniela Q C M Barge-Schaapveld
  • Marjolein Kriek
  • Yves Sznajer
  • Karin van Spaendonck-Zwarts
  • Anneke J van der Kooi
  • Amanda Krause
  • Bitten Schönewolf-Greulich
  • Christine de Die-Smulders
  • Suzanne C E H Sallevelt
  • Ingrid P C Krapels
  • Magnhild Rasmussen
  • Isabelle Maystadt
  • Anneke J A Kievit
  • Nanna Witting
  • Maartje Pennings
  • Rowdy Meijer
  • Christian Gillissen
  • Erik-Jan Kamsteeg
  • Nicol C Voermans
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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.

Original languageEnglish
JournalJournal of Neuromuscular Diseases
Issue number2
Pages (from-to)241-258
Number of pages18
Publication statusPublished - 2019

ID: 58279602