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

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 KrauseBitten 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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

14 Citations (Web of Science)


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
Pages (from-to)241-258
Number of pages18
JournalJournal of neuromuscular diseases
Issue number2
Publication statusPublished - 2019


  • Adolescent
  • Adult
  • Aged
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Middle Aged
  • Neuromuscular Diseases/diagnosis
  • Whole Exome Sequencing/methods
  • Young Adult
  • Neuromuscular diseases
  • exome sequencing
  • genetics
  • myopathies
  • neurology

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