| Title: |
Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson's disease study |
| Authors: |
Westenberger, A.; Skrahina, V.; Usnich, T.; Beetz, C.; Vollstedt, E. J.; Laabs, B. H.; Paul, J. J.; Curado, F.; Skobalj, S.; Gaber, H.; Olmedillas, M.; Bogdanovic, X.; Ameziane, N.; Schell, N.; Aasly, J. O.; Afshari, M.; Agarwal, P.; Aldred, J.; Alonso-Frech, F.; Anderson, R.; Araújo, R.; Arkadir, D.; Avenali, M.; Balal, M.; Benizri, S.; Bette, S.; Bhatia, P.; Bonello, M.; Braga-Neto, P.; Brauneis, S.; Cardoso, F. E. C.; Cavallieri, F.; Classen, J.; Cohen, L.; Coletta, D.; Crosiers, D.; Cullufi, P.; Dashtipour, K.; Demirkiran, M.; de Carvalho Aguiar, P.; De Rosa, A.; Djaldetti, R.; Dogu, O.; Dos Santos Ghilardi, M. G.; Eggers, C.; Elibol, B.; Ellenbogen, A.; Ertan, S.; Fabiani, G.; Falkenburger, B. H.; Farrow, S.; Fay-Karmon, T.; Ferencz, G. J.; Fonoff, E. T.; Fragoso, Y. D.; Genç, G.; Gorospe, A.; Grandas, F.; Gruber, D.; Gudesblatt, M.; Gurevich, T.; Hagenah, J.; Hanagasi, H. A.; Hassin-Baer, S.; Hauser, R. A.; Hernández-Vara, J.; Herting, B.; Hinson, V. K.; Hogg, E.; Hu, M. T.; Hummelgen, E.; Hussey, K.; Infante, J.; Isaacson, S. H.; Jauma, S.; Koleva-Alazeh, N.; Kuhlenbäumer, G.; Kühn, A.; Litvan, I.; López-Manzanares, L.; Luxmore, M.; Manandhar, S.; Marcaud, V.; Markopoulou, K.; Marras, C.; McKenzie, M.; Matarazzo, M.; Merello, M.; Mollenhauer, B.; Morgan, J. C.; Mullin, S.; Musacchio, T.; Myers, B.; Negrotti, A.; Nieves, A.; Nitsan, Z.; Oskooilar, N.; Öztop-Çakmak, Ö; Pal, G.; Pavese, N.; Percesepe, A.; Piccoli, T.; Pinto de Souza, C.; Prell, T.; Pulera, M.; Raw, J.; Reetz, K.; Reiner, J.; Rosenberg, D.; Ruiz-Lopez, M.; Ruiz Martinez, J.; Sammler, E.; Santos-Lobato, B. L.; Saunders-Pullman, R.; Schlesinger, I.; Schofield, C. M.; Schumacher-Schuh, A. F.; Scott, B.; Sesar, Á; Shafer, S. J.; Sheridan, R.; Silverdale, M.; Sophia, R.; Spitz, M.; Stathis, P.; Stocchi, F.; Tagliati, M.; Tai, Y. F.; Terwecoren, A.; Thonke, S.; Tönges, L.; Toschi, G.; Tumas, V.; Urban, P. P.; Vacca, L.; Vandenberghe, W.; Valente, E. M.; Valzania, F.; Vela-Desojo, L.; Weill, C.; Weise, D.; Wojcieszek, J.; Wolz, M.; Yahalom, G.; Yalcin-Cakmakli, G.; Zittel, S.; Zlotnik, Y.; Kandaswamy, K. K.; Balck, A.; Hanssen, H.; Borsche, M.; Lange, L. M.; Csoti, I.; Lohmann, K.; Kasten, M.; Brüggemann, N.; Rolfs, A.; Klein, C.; Bauer, P. |
| Contributors: |
Geriatric Medicine; Sheridan, Ray |
| Publisher Information: |
Oxford University Press |
| Publication Year: |
2024 |
| Collection: |
RD&E Research Repository (Royal Devon and Exeter NHS Foundation Trust) |
| Subject Terms: |
Humans; Parkinson Disease/genetics; Male; Female; Middle Aged; Aged; Genetic Testing/methods; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics; Glucosylceramidase/genetics; alpha-Synuclein/genetics; Genetic Predisposition to Disease; Ubiquitin-Protein Ligases/genetics; Cohort Studies; Protein Kinases/genetics; Mutation; Adult; Gba1; Lrrk2; Parkinson’s disease; genetic factors; genetic testing; next-generation sequencing; or still are employees of CENTOGENE GmbH. A.W. provides consultancy services; around research projects for CENTOGENE GmbH. C.K. and N.B. are medical advisors; to CENTOGENE GmbH. The other authors report no competing interests |
| Description: |
Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/39087914/; Brain : a journal of neurology; PMC11292909; https://hdl.handle.net/11287/623382 |
| DOI: |
10.1093/brain/awae188 |
| Availability: |
https://hdl.handle.net/11287/623382; https://doi.org/10.1093/brain/awae188 |
| Rights: |
© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. |
| Accession Number: |
edsbas.E7751771 |
| Database: |
BASE |