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High efficiency and clinical relevance of exome sequencing in the daily practice of neurogenetics

Abstract : 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.
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Submitted on : Monday, June 21, 2021 - 3:47:30 PM
Last modification on : Wednesday, June 23, 2021 - 11:10:43 AM




Quentin Thomas, Antonio Vitobello, Frederic Tran Mau-Them, Yannis Duffourd, Agnès Fromont, et al.. High efficiency and clinical relevance of exome sequencing in the daily practice of neurogenetics. Journal of Medical Genetics, BMJ Publishing Group, In press, pp.jmedgenet-2020-107369. ⟨10.1136/jmedgenet-2020-107369⟩. ⟨hal-03266264⟩



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