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

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Harvard

Westra, D, Schouten, MI, Stunnenberg, BC, Kusters, B, Saris, CGJ, Erasmus, CE, van Engelen, BG, Bulk, S, Verschuuren-Bemelmans, CC, Gerkes, EH, de Geus, C, van der Zwaag, PA, Chan, S, Chung, B, Barge-Schaapveld, DQCM, Kriek, M, Sznajer, Y, van Spaendonck-Zwarts, K, van der Kooi, AJ, Krause, A, Schönewolf-Greulich, B, de Die-Smulders, C, Sallevelt, SCEH, Krapels, IPC, Rasmussen, M, Maystadt, I, Kievit, AJA, Witting, N, Pennings, M, Meijer, R, Gillissen, C, Kamsteeg, E-J & Voermans, NC 2019, 'Panel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service' Journal of Neuromuscular Diseases, vol. 6, no. 2, pp. 241-258. https://doi.org/10.3233/JND-180376

APA

Westra, D., Schouten, M. I., Stunnenberg, B. C., Kusters, B., Saris, C. G. J., Erasmus, C. E., ... Voermans, N. C. (2019). Panel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service. Journal of Neuromuscular Diseases, 6(2), 241-258. https://doi.org/10.3233/JND-180376

CBE

Westra D, Schouten MI, Stunnenberg BC, Kusters B, Saris CGJ, Erasmus CE, van Engelen BG, Bulk S, Verschuuren-Bemelmans CC, Gerkes EH, de Geus C, van der Zwaag PA, Chan S, Chung B, Barge-Schaapveld DQCM, Kriek M, Sznajer Y, van Spaendonck-Zwarts K, van der Kooi AJ, Krause A, Schönewolf-Greulich B, de Die-Smulders C, Sallevelt SCEH, Krapels IPC, Rasmussen M, Maystadt I, Kievit AJA, Witting N, Pennings M, Meijer R, Gillissen C, Kamsteeg E-J, Voermans NC. 2019. Panel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service. Journal of Neuromuscular Diseases. 6(2):241-258. https://doi.org/10.3233/JND-180376

MLA

Vancouver

Westra D, Schouten MI, Stunnenberg BC, Kusters B, Saris CGJ, Erasmus CE et al. Panel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service. Journal of Neuromuscular Diseases. 2019;6(2):241-258. https://doi.org/10.3233/JND-180376

Author

Westra, Dineke ; Schouten, Meyke I ; Stunnenberg, Bas C ; Kusters, Benno ; Saris, Christiaan G J ; Erasmus, Corrie E ; van Engelen, Baziel G ; Bulk, Saskia ; Verschuuren-Bemelmans, Corien C ; Gerkes, E H ; de Geus, Christa ; van der Zwaag, P A ; Chan, Sophelia ; Chung, Brian ; Barge-Schaapveld, Daniela Q C M ; Kriek, Marjolein ; Sznajer, Yves ; van Spaendonck-Zwarts, Karin ; van der Kooi, Anneke J ; Krause, Amanda ; Schönewolf-Greulich, Bitten ; de Die-Smulders, Christine ; Sallevelt, Suzanne C E H ; Krapels, Ingrid P C ; Rasmussen, Magnhild ; Maystadt, Isabelle ; Kievit, Anneke J A ; Witting, Nanna ; Pennings, Maartje ; Meijer, Rowdy ; Gillissen, Christian ; Kamsteeg, Erik-Jan ; Voermans, Nicol C. / Panel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service. In: Journal of Neuromuscular Diseases. 2019 ; Vol. 6, No. 2. pp. 241-258.

Bibtex

@article{1eafee9eebeb4af7a7bcdb7ef6b9a497,
title = "Panel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service",
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.",
author = "Dineke Westra and Schouten, {Meyke I} and Stunnenberg, {Bas C} and Benno Kusters and Saris, {Christiaan G J} and Erasmus, {Corrie E} and {van Engelen}, {Baziel G} and Saskia Bulk and Verschuuren-Bemelmans, {Corien C} and Gerkes, {E H} and {de Geus}, Christa and {van der Zwaag}, {P A} and Sophelia Chan and Brian Chung and Barge-Schaapveld, {Daniela Q C M} and Marjolein Kriek and Yves Sznajer and {van Spaendonck-Zwarts}, Karin and {van der Kooi}, {Anneke J} and Amanda Krause and Bitten Sch{\"o}newolf-Greulich and {de Die-Smulders}, Christine and Sallevelt, {Suzanne C E H} and Krapels, {Ingrid P C} and Magnhild Rasmussen and Isabelle Maystadt and Kievit, {Anneke J A} and Nanna Witting and Maartje Pennings and Rowdy Meijer and Christian Gillissen and Erik-Jan Kamsteeg and Voermans, {Nicol C}",
year = "2019",
doi = "10.3233/JND-180376",
language = "English",
volume = "6",
pages = "241--258",
journal = "Journal of Neuromuscular Diseases",
issn = "2214-3599",
publisher = "I O S Press",
number = "2",

}

RIS

TY - JOUR

T1 - Panel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service

AU - Westra, Dineke

AU - Schouten, Meyke I

AU - Stunnenberg, Bas C

AU - Kusters, Benno

AU - Saris, Christiaan G J

AU - Erasmus, Corrie E

AU - van Engelen, Baziel G

AU - Bulk, Saskia

AU - Verschuuren-Bemelmans, Corien C

AU - Gerkes, E H

AU - de Geus, Christa

AU - van der Zwaag, P A

AU - Chan, Sophelia

AU - Chung, Brian

AU - Barge-Schaapveld, Daniela Q C M

AU - Kriek, Marjolein

AU - Sznajer, Yves

AU - van Spaendonck-Zwarts, Karin

AU - van der Kooi, Anneke J

AU - Krause, Amanda

AU - Schönewolf-Greulich, Bitten

AU - de Die-Smulders, Christine

AU - Sallevelt, Suzanne C E H

AU - Krapels, Ingrid P C

AU - Rasmussen, Magnhild

AU - Maystadt, Isabelle

AU - Kievit, Anneke J A

AU - Witting, Nanna

AU - Pennings, Maartje

AU - Meijer, Rowdy

AU - Gillissen, Christian

AU - Kamsteeg, Erik-Jan

AU - Voermans, Nicol C

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

U2 - 10.3233/JND-180376

DO - 10.3233/JND-180376

M3 - Journal article

VL - 6

SP - 241

EP - 258

JO - Journal of Neuromuscular Diseases

JF - Journal of Neuromuscular Diseases

SN - 2214-3599

IS - 2

ER -

ID: 58279602