Objective To assess the efficiency and relevance of clinical exome sequencing (cES) as a first-tier or second-tier test for the diagnosis of progressive neurological disorders in the daily practice of Neurology and Genetic Departments.
Methods Sixty-seven probands with various progressive neurological disorders (cerebellar ataxias, neuromuscular disorders, spastic paraplegias, movement disorders and individuals with complex phenotypes labelled ‘other’) were recruited over a 4-year period regardless of their age, gender, familial history and clinical framework. Individuals could have had prior genetic tests as long as it was not cES. cES was performed in a proband-only (60/67) or trio (7/67) strategy depending on available samples and was analysed with an in-house pipeline including software for CNV and mitochondrial-DNA variant detection.
Results In 29/67 individuals, cES identified clearly pathogenic variants leading to a 43% positive yield. When performed as a first-tier test, cES identified pathogenic variants for 53% of individuals (10/19). Difficult cases were solved including double diagnoses within a kindred or identification of a neurodegeneration with brain iron accumulation in a patient with encephalopathy of suspected mitochondrial origin.
Conclusion This study shows that cES is a powerful tool for the daily practice of neurogenetics offering an efficient (43%) and appropriate approach for clinically and genetically complex and heterogeneous disorders.
- neurodegenerative diseases
- molecular diagnostic techniques
- clinical laboratory techniques
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Contributors QT collected and analysed data and wrote the manuscript. AV collected and analysed the data. FTM-T collected and analysed the data. AF collected and analysed the data. MG collected and analysed the data. BD collected and analysed the data. AJ-P collected and analysed the data. MH-B collected and analysed the data. TM collected and analysed the data. G-VO collected and analysed the data. SN collected and analysed the data. A-LB collected and analysed the data. AS collected and analysed the data. PC collected and analysed the data. A-SD-P collected and analysed the data. LF collected and analysed the data. YB collected and analysed the data. CP collected and analysed the data. CT-R designed the study, collected and analysed the data, and wrote the manuscript. SM collected and analysed the data and wrote the manuscript. The last two authors co-directed the works (CT-R, SM).
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Disclaimer The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as online supplemental information.
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