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. 2019;6(2):241-258.
doi: 10.3233/JND-180376.

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

Dineke Westra  1 , Meyke I Schouten  1 , Bas C Stunnenberg  2 , Benno Kusters  3 , Christiaan G J Saris  2 , Corrie E Erasmus  4 , Baziel G van Engelen  2 , Saskia Bulk  5 , Corien C Verschuuren-Bemelmans  6 , E H Gerkes  6 , Christa de Geus  6 , P A van der Zwaag  6 , Sophelia Chan  7 , Brian Chung  7 , Daniela Q C M Barge-Schaapveld  8 , Marjolein Kriek  8 , Yves Sznajer  9 , Karin van Spaendonck-Zwarts  10 , Anneke J van der Kooi  11 , Amanda Krause  12 , Bitten Schönewolf-Greulich  13 , Christine de Die-Smulders  14 , Suzanne C E H Sallevelt  14 , Ingrid P C Krapels  14 , Magnhild Rasmussen  15 , Isabelle Maystadt  16 , Anneke J A Kievit  17 , Nanna Witting  18 , Maartje Pennings  1 , Rowdy Meijer  1 , Christian Gillissen  1 , Erik-Jan Kamsteeg  1 , Nicol C Voermans  2
Affiliations
Free article

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

Dineke Westra et al. J Neuromuscul Dis. 2019.
Free article

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.

Keywords: Neuromuscular diseases; exome sequencing; genetics; myopathies; neurology.

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