Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson’s disease study
Authors: Westenberger Ana , Skrahina Volha , Usnich Tatiana , Beetz Christian , Vollstedt Eva-Juliane , Laabs Björn-Hergen , Paul Jefri J , Curado Filipa , Skobalj Snezana , Gaber Hanaa , Olmedillas Maria , Bogdanovic Xenia , Ameziane Najim , Schell Nathalie , Aasly Jan Olav , Afshari Mitra , Agarwal Pinky , Aldred Jason , Alonso-Frech Fernando , Anderson Roderick , Araújo Rui , Arkadir David , Avenali Micol , Balal Mehmet , Benizri Sandra , Bette Sagari , Bhatia Perminder , Bonello Michael , Braga-Neto Pedro , Brauneis Sarah , Cardoso Francisco Eduardo Costa , Cavallieri Francesco , Classen Joseph , Cohen Lisa , Coletta Della , Crosiers David , Cullufi Paskal , Dashtipour Khashayar , Demirkiran Meltem , de Carvalho Aguiar Patricia , De Rosa Anna , Djaldetti Ruth , Dogu Okan , dos Santos Ghilardi Maria Gabriela , Eggers Carsten , Elibol Bulent , Ellenbogen Aaron , Ertan Sibel , Fabiani Giorgio , Falkenburger Björn H , Farrow Simon , Fay-Karmon Tsviya , Ferencz Gerald J , Fonoff Erich Talamoni , Fragoso Yara Dadalti , Genç Gençer , Gorospe Arantza , Grandas Francisco , Gruber Doreen , Gudesblatt Mark , Gurevich Tanya , Hagenah Johann , Hanagasi Hasmet A , Hassin-Baer Sharon , Hauser Robert A , Hernández-Vara Jorge , Herting Birgit , Hinson Vanessa K , Hogg Elliot , Hu Michele T , Hummelgen Eduardo , Hussey Kelly , Infante Jon , Isaacson Stuart H , Jauma Serge , Koleva-Alazeh Natalia , Kuhlenbäumer Gregor , Kühn Andrea , Litvan Irene , López-Manzanares Lydia , Luxmore McKenzie , Manandhar Sujeena , Marcaud Veronique , Markopoulou Katerina , Marras Connie , McKenzie Mark , Matarazzo Michele , Merello Marcelo , Mollenhauer Brit , Morgan John C , Mullin Stephen , Musacchio Thomas , Myers Bennett , Negrotti Anna , Nieves Anette , Nitsan Zeev , Oskooilar Nader , Öztop-Çakmak Özgür , Pal Gian , Pavese Nicola , Percesepe Antonio , Piccoli Tommaso , Pinto de Souza Carolina , Prell Tino , Pulera Mark , Raw Jason , Reetz Kathrin , Reiner Johnathan , Rosenberg David , Ruiz-Lopez Marta , Ruiz Martinez Javier , Sammler Esther , Santos-Lobato Bruno Lopes , Saunders-Pullman Rachel , Schlesinger Ilana , Schofield Christine M , Schumacher-Schuh Artur F , Scott Burton , Sesar Ángel , Shafer Stuart J , Sheridan Ray , Silverdale Monty , Sophia Rani , Spitz Mariana , Stathis Pantelis , Stocchi Fabrizio , Tagliati Michele , Tai Yen F , Terwecoren Annelies , Thonke Sven , Tönges Lars , Toschi Giulia , Tumas Vitor , Urban Peter Paul , Vacca Laura , Vandenberghe Wim , Valente Enza Maria , Valzania Franco , Vela-Desojo Lydia , Weill Caroline , Weise David , Wojcieszek Joanne , Wolz Martin , Yahalom Gilad , Yalcin-Cakmakli Gul , Zittel Simone , Zlotnik Yair , Kandaswamy Krishna K , Balck Alexander , Hanssen Henrike , Borsche Max , Lange Lara M , Csoti Ilona , Lohmann Katja , Kasten Meike , Brüggemann Norbert , Rolfs Arndt , Klein Christine , Bauer Peter 
Published: August 2024

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.