Back to Search
Start Over
Next-generation sequencing and comprehensive data reassessment in 263 adult patients with neuromuscular disorders: insights into the gray zone of molecular diagnoses.
- Source :
- Journal of Neurology; Apr2024, Vol. 271 Issue 4, p1937-1946, 10p
- Publication Year :
- 2024
-
Abstract
- 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 03405354
- Volume :
- 271
- Issue :
- 4
- Database :
- Complementary Index
- Journal :
- Journal of Neurology
- Publication Type :
- Academic Journal
- Accession number :
- 176299806
- Full Text :
- https://doi.org/10.1007/s00415-023-12101-6