PT  - JOURNAL ARTICLE
AU  - Quentin Thomas
AU  - Antonio Vitobello
AU  - Frederic Tran Mau-Them
AU  - Yannis Duffourd
AU  - Agnès Fromont
AU  - Maurice Giroud
AU  - Benoit Daubail
AU  - Agnès Jacquin-Piques
AU  - Marie Hervieu-Begue
AU  - Thibault Moreau
AU  - Guy-Victor Osseby
AU  - Philippine Garret
AU  - Sophie Nambot
AU  - Julian Delanne
AU  - Ange-Line Bruel
AU  - Arthur Sorlin
AU  - Patrick Callier
AU  - Anne-Sophie Denomme-Pichon
AU  - Laurence Faivre
AU  - Yannick Béjot
AU  - Christophe Philippe
AU  - Christel Thauvin-Robinet
AU  - Sébastien Moutton
TI  - High efficiency and clinical relevance of exome sequencing in the daily practice of neurogenetics
AID  - 10.1136/jmedgenet-2020-107369
DP  - 2022 May 01
TA  - Journal of Medical Genetics
PG  - 445--452
VI  - 59
IP  - 5
4099  - http://jmg.bmj.com/content/59/5/445.short
4100  - http://jmg.bmj.com/content/59/5/445.full
SO  - J Med Genet2022 May 01; 59
AB  - 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.All data relevant to the study are included in the article or uploaded as online supplemental information.