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

作者：Ana Westenberger, Volha Skrahina, Tatiana Usnich, Christian Beetz, Eva-Juliane Vollstedt, Björn‐Hergen Laabs, Jefri J Paul, Filipa Curado, Snezana Skobalj, Hanaa Gaber, Maria Olmedillas, Xenia Bogdanović, Najim Ameziane, Nathalie Schell, Jan Aasly, Mitra Afshari, Pinky Agarwal, Jason Aldred, Fernando Alonso‐Frech, Roderick Anderson, Rui Araújo, David Arkadir, Micol Avenali, Mehmet Balal, Sandra Benizri, Sagari Betté, Perminder Bhatia, Michael Bonello, Pedro Braga‐Neto, Sarah Brauneis, Francisco Cardoso, Francesco Cavallieri, Joseph Claßen, Lisa J. Cohen, Della Coletta, David Crosiers, Paskal Cullufi, Khashayar Dashtipour, Meltem Demirkıran, Patrícia de Carvalho Aguiar, Anna De Rosa, Ruth Djaldetti, Okan Doğu, Maria Gabriela dos Santos Ghilardi, Carsten Eggers, Bülent Elibol, Aaron Ellenbogen, Sibel Ertan, G Fabiani, Björn Falkenburger, S. Farrow, Tsviya Fay-Karmon, Gerald J Ferencz, Erich Talamoni Fonoff, Yára Dadalti Fragoso, Gençer Genç, A Gorospe, Francisco Grandas, Doreen Gruber, Mark Gudesblatt, Tanya Gurevich, Johann Hagenah, Haşmet Hanağası, Sharon Hassin-Baer, Robert A. Hauser, Jorge Hernández‐Vara, Birgit Herting, Vanessa K. Hinson, Elliot Hogg, Michele T Hu, Eduardo Hummelgen, Kelly Hussey, Jon Infante, Stuart Isaacson, Serge Jaumà, Natalia Koleva‐Alazeh, Gregor Kuhlenbäumer, Andrea A. Kühn, Irene Litvan, Lydia López Manzanares, McKenzie Luxmore, Sujeena Manandhar, V. Marcaud, Katerina Markopoulou, Connie Marras, Mark McKenzie, Michele Matarazzo, Marcelo Merello, Brit Mollenhauer, John C. Morgan, Stephen Mullin, Thomas Musacchio, Bennett Myers, Anna Negrotti, Anette Nieves, Zeev Nitsan, Nader Oskooilar, Özgür Öztop Çakmak, Gian Pal, Nicola Pavese, Antonio Percesepe, Tommaso Piccoli, Carolina Pinto Souza, Tino Prell, Mark Pulera, Jason Raw, Kathrin Reetz, Johnathan Reiner, David Rosenberg, Marta Ruíz-López, Javier Ruiz-Martı́nez, Esther Sammler, Bruno Lopes Santos‐Lobato, Rachel Saunders‐Pullman, Ilana Schlesinger, Christine Schofield, Artur Francisco Schumacher Schuh, B.L. Scott, Ángel Sesar, S. James Shafer, Ray Sheridan, Monty Silverdale, Rani Sophia, Mariana Spitz, Pantelis Stathis, Fabrizio Stocchi, Michele Tagliati, Yen Tai, Annelies Terwecoren, Sven Thonke, Lars Tönges, Giulia Toschi, Vítor Tumas, Péter Urbán, Laura Vacca, Wim Vandenberghe, Enza Maria Valente, Franco Valzania, Lydia Vela, Caroline Weill, David Weise, Joanne Wojcieszek, Martin Wolz, Gilad Yahalom, Gül Yalçın Çakmaklı, Simone Zittel, Yair Zlotnik, Krishna Kumar Kandaswamy, Alexander Balck, Henrike Hanßen, Max Borsche, Lara M. Lange, Ilona Csóti, Katja Lohmann, Meike Kasten, Norbert Brüggemann, Arndt Rolfs, Christine Klein, Peter Bauer · 发表于：Brain · 年份：2024 · DOI：10.1093/brain/awae188 · 被引用次数：102 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Autism Spectrum Disorder Research、CRISPR and Genetic Engineering

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%), SN...