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.
KW - exome sequencing
KW - genetics
KW - myopathies
KW - neurology
KW - Neuromuscular diseases
UR - http://www.scopus.com/inward/record.url?scp=85066892378&partnerID=8YFLogxK
U2 - 10.3233/JND-180376
DO - 10.3233/JND-180376
M3 - Journal article
C2 - 31127727
SN - 2214-3599
VL - 6
SP - 241
EP - 258
JO - Journal of Neuromuscular Diseases
JF - Journal of Neuromuscular Diseases
IS - 2
ER -