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Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson's disease study

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dc.contributor.author Westenberger, Ana
dc.contributor.author Skrahina, Volha
dc.contributor.author Usnich, Tatiana
dc.contributor.author Beetz, Christian
dc.contributor.author Vollstedt, Eva-Juliane
dc.contributor.author Laab, Björn-Hergen
dc.contributor.author Paul, Jefri J.
dc.contributor.author Curado, Filipa
dc.contributor.author Skobalj, Snezana
dc.contributor.author Gaber, Hanaa
dc.contributor.author Olmedillas, María
dc.contributor.author Bogdanovic, Xenia
dc.contributor.author Ameziane, Najim
dc.contributor.author Schell, Nathalie
dc.contributor.author Aasly, Jan Olav
dc.contributor.author Afshari, Mitra
dc.contributor.author Agarwal, Pinky
dc.contributor.author Aldred, Jason
dc.contributor.author Alonso Frech, Fernando
dc.contributor.author Anderson, Roderick
dc.contributor.author Merello, Marcelo
dc.date.accessioned 2024-10-08T12:02:03Z
dc.date.available 2024-10-08T12:02:03Z
dc.date.issued 2024-08-01
dc.identifier.citation Westenberger A, Skrahina V, Usnich T, Beetz C, Vollstedt EJ, Laabs BH, Paul JJ, Curado F, Skobalj S, Gaber H, Olmedillas M, Bogdanovic X, Ameziane N, Schell N, Aasly JO, 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 FEC, 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 MG, Eggers C, Elibol B, Ellenbogen A, Ertan S, Fabiani G, Falkenburger BH, Farrow S, Fay-Karmon T, Ferencz GJ, Fonoff ET, Fragoso YD, Genç G, Gorospe A, Grandas F, Gruber D, Gudesblatt M, Gurevich T, Hagenah J, Hanagasi HA, Hassin-Baer S, Hauser RA, Hernández-Vara J, Herting B, Hinson VK, Hogg E, Hu MT, Hummelgen E, Hussey K, Infante J, Isaacson SH, 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 JC, 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 BL, Saunders-Pullman R, Schlesinger I, Schofield CM, Schumacher-Schuh AF, Scott B, Sesar Á, Shafer SJ, Sheridan R, Silverdale M, Sophia R, Spitz M, Stathis P, Stocchi F, Tagliati M, Tai YF, Terwecoren A, Thonke S, Tönges L, Toschi G, Tumas V, Urban PP, Vacca L, Vandenberghe W, Valente EM, Valzania F, Vela-Desojo L, Weill C, Weise D, Wojcieszek J, Wolz M, Yahalom G, Yalcin-Cakmakli G, Zittel S, Zlotnik Y, Kandaswamy KK, Balck A, Hanssen H, Borsche M, Lange LM, Csoti I, Lohmann K, Kasten M, Brüggemann N, Rolfs A, Klein C, Bauer P. Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson's disease study. Brain. 2024 Aug 1;147(8):2652-2667. doi: 10.1093/brain/awae188. es_ES
dc.identifier.uri https://doi.org/10.1093/brain/awae188
dc.identifier.uri https://repositorio.fleni.org.ar/xmlui/handle/123456789/1209
dc.description.abstract 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 lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD. es_ES
dc.language.iso eng es_ES
dc.publisher Oxford University Press es_ES
dc.subject Enfermedad de Parkinson es_ES
dc.subject Parkinson Disease es_ES
dc.subject Pruebas Genéticas es_ES
dc.subject Genetic Testing es_ES
dc.title Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson's disease study es_ES
dc.type info:eu-repo/semantics/article es_ES
dc.description.fil Fil: Merello, Marcelo. Fleni. Departamento de Neurología. Servicio de Movimientos Anormales; Argentina.
dc.relation.ispartofVOLUME 147
dc.relation.ispartofNUMBER 8
dc.relation.ispartofPAGINATION 2652-2667.
dc.relation.ispartofCITY Londres
dc.relation.ispartofTITLE Brain : a journal of neurology.
dc.relation.ispartofISSN 1460-2156
dc.relation.ispartofISBN Inglaterra
dc.type.snrd info:ar-repo/semantics/artículo es_ES


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