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Krenn, M.* ; Wagner, M. ; Zulehner, G.* ; Weng, R.* ; Jäger, F.* ; Keritam, O.* ; Sener, M.* ; Brücke, C.* ; Milenkovic, I.* ; Langer, A.* ; Buchinger, D.* ; Habersam, R.* ; Mayerhanser, K.* ; Brugger, M.* ; Brunet, T.* ; Jacob, M.* ; Graf, E.* ; Berutti, R. ; Cetin, H.* ; Hoefele, J.* ; Winkelmann, J. ; Zimprich, F.* ; Rath, J.*

Next-generation sequencing and comprehensive data reassessment in 263 adult patients with neuromuscular disorders: Insights into the gray zone of molecular diagnoses.

J. Neurol., DOI: 10.1007/s00415-023-12101-6 (2023)
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BACKGROUND: Neuromuscular disorders (NMDs) are heterogeneous conditions with a considerable fraction attributed to monogenic defects. Despite the advancements in genomic medicine, many patients remain without a diagnosis. Here, we investigate whether a comprehensive reassessment strategy improves the diagnostic outcomes. METHODS: We analyzed 263 patients with NMD phenotypes that underwent diagnostic exome or genome sequencing at our tertiary referral center between 2015 and 2023. We applied a comprehensive reassessment encompassing variant reclassification, re-phenotyping and NGS data reanalysis. Multivariable logistic regression was performed to identify predictive factors associated with a molecular diagnosis. RESULTS: Initially, a molecular diagnosis was identified in 53 cases (20%), while an additional 23 (9%) had findings of uncertain significance. Following comprehensive reassessment, the diagnostic yield increased to 23%, revealing 44 distinct monogenic etiologies. Reasons for newly obtained molecular diagnoses were variant reclassifications in 7 and NGS data reanalysis in 3 cases including one recently described disease-gene association (DNAJB4). Male sex reduced the odds of receiving a molecular diagnosis (OR 0.42; 95%CI 0.21-0.82), while a positive family history (OR 5.46; 95%CI 2.60-11.76) and a myopathy phenotype (OR 2.72; 95%CI 1.11-7.14) increased the likelihood. 7% were resolved through targeted genetic testing or classified as acquired etiologies. CONCLUSION: Our findings reinforce the use of NGS in NMDs of suspected monogenic origin. We show that a comprehensive reassessment enhances diagnostic accuracy. However, one needs to be aware that genetic diagnoses are often made with uncertainty and can even be downgraded based on new evidence.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Neuromuscular Disease ; Next-generation Sequencing ; Reanalysis; Medical Genetics; American-college; Clinical Exome; Reanalysis; Supports; Genomics; Model
Language english
Publication Year 2023
HGF-reported in Year 2023
ISSN (print) / ISBN 0340-5354
e-ISSN 1432-1459
Journal Journal of Neurology
Publisher Springer
Publishing Place Tiergartenstrasse 17, D-69121 Heidelberg, Germany
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
POF-Topic(s) 30205 - Bioengineering and Digital Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-503200-001
G-503292-001
Grants Medical University of Vienna
DOI 10.1007/s00415-023-12101-6
WOS ID 001127360000001
Scopus ID 85180172637
PubMed ID 38127101
Erfassungsdatum 2024-01-09
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