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1000
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Abstract/Summary
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<jats:title>Abstract</jats:title><jats:sec>
<jats:title>Background</jats:title>
<jats:p>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.</jats:p>
</jats:sec><jats:sec>
<jats:title>Methods</jats:title>
<jats:p>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.</jats:p>
</jats:sec><jats:sec>
<jats:title>Results</jats:title>
<jats:p>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 (<jats:italic>DNAJB4</jats:italic>). 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.</jats:p>
</jats:sec><jats:sec>
<jats:title>Conclusion</jats:title>
<jats:p>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.</jats:p>
</jats:sec>
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1000
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Hinweis
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DeepGreen-ID: 2547f1d690e94df1954aeb6c9480926d ; metadata provieded by: DeepGreen (https://www.oa-deepgreen.de/api/v1/), LIVIVO search scope life sciences (http://z3950.zbmed.de:6210/livivo), Crossref Unified Resource API (https://api.crossref.org/swagger-ui/index.html), to.science.api (https://frl.publisso.de/), ZDB JSON-API (beta) (https://zeitschriftendatenbank.de/api/), lobid - Dateninfrastruktur für Bibliotheken (https://lobid.org/resources/search)
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