Next-generation sequencing and comprehensive data reassessment in 263 adult patients with neuromuscular disorders: insights into the gray zone of molecular diagnoses.
J Neurol
; 271(4): 1937-1946, 2024 Apr.
Article
em En
| MEDLINE
| ID: mdl-38127101
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.Palavras-chave
Texto completo:
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Bases de dados:
MEDLINE
Assunto principal:
Doenças Musculares
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Doenças Neuromusculares
Limite:
Adult
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Humans
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Male
Idioma:
En
Revista:
J Neurol
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Áustria