High efficiency and clinical relevance of exome sequencing in the daily practice of neurogenetics
Quentin Thomas, Antonio Vitobello, Frédéric Tran Mau‐Them, Yannis Duffourd, Agnès Fromont, Maurice Giroud, Benoît Daubail, Agnès Jacquin-Piques, Marie Hervieu‐Bègue, Thibault Moreau, Guy‐Victor Osseby, Philippine Garret, Sophie Nambot, Julian Delanne, Ange‐Line Bruel, Arthur Sorlin, Patrick Callier, Anne‐Sophie Denommé‐Pichon, Laurence Faivre, Yannick Béjot, Christophe Philippe, Christel Thauvin‐Robinet, Sébastien Moutton
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.