Assessment of a Targeted Gene Panel for Identification of Genes Associated With Movement Disorders

Solveig Montaut (1, 2) , Christine Tranchant (3) , Nathalie Drouot , Gabrielle Rudolf (4, 2) , Claire Guissart (5) , Julien Tarabeux , Tristan Stemmelen , Amandine Velt , Cécile Fourrage (6) , Patrick Nitschké (7, 8, 9, 10) , Bénédicte Gerard , Jean-Louis Mandel (2, 11) , Michel Koenig (5) , Jamel Chelly (2, 12) , Mathieu Anheim , French Parkinson\textquoterights , Movement Disorders Consortium

1 CHU Strasbourg - Centre Hospitalier Universitaire [Strasbourg]
2 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
3 Service de Neurologie [Strasbourg]
4 FMTS - Fédération de Médecine Translationnelle de Strasbourg
5 LGMR - Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques
6 Equipe Inserm U1163 - The Clinical Bioinformatics laboratory
7 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
8 BIP-D - Plateforme Bioinformatique [SFR Necker]
9 UPD5 - Université Paris Descartes - Paris 5
10 USPC - Université Sorbonne Paris Cité
11 CdF (institution) - Collège de France
12 Laboratoire de Diagnostic Génétique [CHU Strasbourg]

Importance: Movement disorders are characterized by a marked genotypic and phenotypic heterogeneity, complicating diagnostic work in clinical practice and molecular diagnosis. Objective: To develop and evaluate a targeted sequencing approach using a customized panel of genes involved in movement disorders. Design, Setting and Participants: We selected 127 genes associated with movement disorders to create a customized enrichment in solution capture array. Targeted high-coverage sequencing was applied to DNA samples taken from 378 eligible patients at 1 Luxembourgian, 1 Algerian, and 25 French tertiary movement disorder centers between September 2014 and July 2016. Patients were suspected of having inherited movement disorders because of early onset, family history, and/or complex phenotypes. They were divided in 5 main movement disorder groups: parkinsonism, dystonia, chorea, paroxysmal movement disorder, and myoclonus. To compare approaches, 23 additional patients suspected of having inherited cerebellar ataxia were included, on whom whole-exome sequencing (WES) was done. Data analysis occurred from November 2015 to October 2016. Main Outcomes and Measures: Percentages of individuals with positive diagnosis, variants of unknown significance, and negative cases; mutational frequencies and clinical phenotyping of genes associated with movement disorders. Results: Of the 378 patients (of whom 208 were male [55.0%]), and with a median (range) age at disease onset of 31 (0-84) years, probable pathogenic variants were identified in 83 cases (22.0%): 46 patients with parkinsonism (55% of 83 patients), 21 patients (25.3%) with dystonia, 7 patients (8.4%) with chorea, 7 patients (8.4%) with paroxysmal movement disorders, and 2 patients (2.4%) with myoclonus as the predominant phenotype. Some genes were mutated in several cases in the cohort. Patients with pathogenic variants were significantly younger (median age, 27 years; interquartile range [IQR], 5-36 years]) than the patients without diagnosis (median age, 35 years; IQR, 15-46 years; P = .04). Diagnostic yield was significantly lower in patients with dystonia (21 of 135; 15.6%; P = .03) than in the overall cohort. Unexpected genotype-phenotype correlations in patients with pathogenic variants deviating from the classic phenotype were highlighted, and 49 novel probable pathogenic variants were identified. The WES analysis of the cohort of 23 patients with cerebellar ataxia led to an overall diagnostic yield of 26%, similar to panel analysis but at a cost 6 to 7 times greater. Conclusions and Relevance: High-coverage sequencing panel for the delineation of genes associated with movement disorders was efficient and provided a cost-effective diagnostic alternative to whole-exome and whole-genome sequencing.

Mots clés: Prospective Studies; Phenotype; Infant; Genotype; Age of Onset; Humans; Female; Male; Adolescent; Child; Adult; Aged; Middle Aged; 80 and over; Young Adult; Cerebellar Ataxia; Preschool; High-Throughput Nucleotide Sequencing; Chorea; Sequence Analysis; DNA; Dystonic Disorders; Movement Disorders; Myoclonus; Parkinsonian Disorders; Whole Exome Sequencing

Domaines: Sciences du Vivant [q-bio]

Solveig Montaut, Christine Tranchant, Nathalie Drouot, Gabrielle Rudolf, Claire Guissart, et al.. Assessment of a Targeted Gene Panel for Identification of Genes Associated With Movement Disorders. JAMA neurology, 2018, 75 (10), pp.1234--1245. ⟨10.1001/jamaneurol.2018.1478⟩. ⟨hal-02320315⟩