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

Article type: Research Article

Authors: Westra, Dineke^a | Schouten, Meyke I.^a | Stunnenberg, Bas C.^b | Kusters, Benno^c | Saris, Christiaan G.J.^b | Erasmus, Corrie E.^d | van Engelen, Baziel G.^b | Bulk, Saskia^e | Verschuuren-Bemelmans, Corien C.^f | Gerkes, E.H.^f | de Geus, Christa^f | van der Zwaag, P.A.^f | Chan, Sophelia^g | Chung, Brian^g | Barge-Schaapveld, Daniela Q.C.M.^h | Kriek, Marjolein^h | Sznajer, Yvesⁱ | van Spaendonck-Zwarts, Karin^j | van der Kooi, Anneke J.^k | Krause, Amanda^l | Schönewolf-Greulich, Bitten^m | de Die-Smulders, Christineⁿ | Sallevelt, Suzanne C.E.H.ⁿ | Krapels, Ingrid P.C.ⁿ | Rasmussen, Magnhild^o | Maystadt, Isabelle^p | Kievit, Anneke J.A.^q | Witting, Nanna^r | Pennings, Maartje^a | Meijer, Rowdy^a | Gillissen, Christian^a | Kamsteeg, Erik-Jan^{a; 1} | Voermans, Nicol C.^{b; 1; *}

Affiliations: [a] Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands | [b] Department of Neurology, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands | [c] Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands | [d] Department of Pediatric Neurology, Radboud University Medical Center, Nijmegen, The Netherlands | [e] Service de Génétique Humaine, CHU de Liège, Liège, Belgium | [f] Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands | [g] Department of Pediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong | [h] Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands | [i] Center de Génétique Humaine, Clinique Universitaires Saint Luc, Bruxelles, Belgium | [j] Department of Clinical Genetics, Amsterdam University Medical Centre, Amsterdam, The Netherlands | [k] Department of Neurology, Amsterdam Medical Center, Amsterdam UMC, University of Amsterdam, Neuroscience institute, Amsterdam, The Netherlands | [l] Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, The University of the Witwatersrand, Johannesburg, South Africa | [m] Department of Clinical Genetics, Rigshospitalet Copenhagen, Denmark | [n] Department of Clinical Genetics, Maastricht University Medical Center+, Maastricht, The Netherlands | [o] Department of Child Neurology and Unit for Congenital and Inherited Neuromuscular Disorders, Oslo University Hospital, Oslo, Norway | [p] Center de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium | [q] Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands | [r] Department of Neurology, Rigshospitalet, Copenhagen, Denmark

Correspondence: [*] Correspondence to: Nicol Voermans Neurology, 935 Radboud University Medical Center P.O. Box 9101 6500 HB Nijmegen The Netherlands. Tel.: +31 24 3616600; E-mail: Nicol.Voermans@radboudumc.nl.

Note: [1] Contributed equally.

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, neurology, myopathies

DOI: 10.3233/JND-180376

Journal: Journal of Neuromuscular Diseases, vol. 6, no. 2, pp. 241-258, 2019