Session Information
Date: Monday, September 23, 2019
Session Title: Genetics
Session Time: 1:45pm-3:15pm
Location: Les Muses Terrace, Level 3
Objective: Our study aimed at developing a targeted sequencing approach using a customized panel of genes involved in movement disorders (MDs).
Background: MDs are characterized by a marked genotypic and phenotypic heterogeneity, complicating diagnostic work in clinical practice and molecular diagnosis.
Method: 127 MDs-associated genes were selected to design a customized enrichment in solution capture array. Targeted high-coverage sequencing was applied to DNA samples from 378 eligible patients suspected with inherited MDs due to early-onset and/or family history and/or complex phenotype from 25 French, 1 Luxembourg and 1 Algerian tertiary MDs centers, included between September 2014 and July 2016.
Results: Out of the 378 patients, probable pathogenic variants were identified in 83 cases (22%): 46 patients with parkinsonism (ATP13A2, DJ-1, DNAJC13, EIF4G1, GBA, HTRA2, LRRK2, PARKIN, PINK1, PLA2G6, SNCA, VPS35, WDR45), 21 patients with dystonia (ADCY5, ATP13A2, GCH1, GNAL, MECP2, NKX2-1, PARKIN, PRKCG, PRKRA, SLC2A1, SPG11, SUOX, TIMM8A, TOR1A, TUBB4A), 7 patients with chorea (ADCY5, ALDH5A1, VPS13A, XK), 7 patients with paroxysmal MDs (AP4B1, GLRA1, PRRT2) and 2 patients with myoclonus as predominant phenotype (ATP1A3, ATP13A2). Some genes were mutated in several cases in our cohort (PARKIN, GBA, LRRK2, PLA2G6, VPS13A, ATP13A2, DNAJC13, GCH1, ADCY5, AP4B1, DJ-1, GLRA1, VPS35, WDR45). Patients with pathogenic variants were significantly younger (median age of 27 years, 95% CI -Inf to -0.16, P=.04) than the patients without diagnosis. The diagnostic yield was significantly lower in patients with dystonia (15.6%, 95% CI 0.29% to 0.95%; P=.03). Unexpected genotype-phenotype correlations in patients with pathogenic variants deviating from the classic phenotype (PRKRA, PARKIN, PRRT2) were highlighted and 49 novel probable pathogenic variants were identified. Our findings also bring additional supportive (DNAJC13, HTRA2) or unsupportive (GIGYF2) evidences for the implication of candidate genes.
Conclusion: High-coverage sequencing panel for the delineation of genetic causes of MDs was found to be efficient and provided a cost-effective diagnostic alternative to whole-exome and whole-genome sequencing.
To cite this abstract in AMA style:
S. Montaut, C. Tranchant, N. Drouot, G. Rudolf, C. Guissart, J. Tarabeux, T. Stemmelen, A. Velt, C. Fourrage, P. Nitschke, B. Gerard, JL. Mandel, M. Koenig, J. Chelly, M. Anheim. Gene panel testing in movement disorders: an efficient approach highlighting overlaps and heterogeneity [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/gene-panel-testing-in-movement-disorders-an-efficient-approach-highlighting-overlaps-and-heterogeneity/. Accessed May 13, 2025.« Back to 2019 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/gene-panel-testing-in-movement-disorders-an-efficient-approach-highlighting-overlaps-and-heterogeneity/