Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort
Authors: Vollstedt Eva‐Juliane , Schaake Susen , Lohmann Katja , Padmanabhan Shalini , Brice Alexis , Lesage Suzanne , Tesson Christelle , Vidailhet Marie , Wurster Isabel , Hentati Faycel , Mirelman Anat , Giladi Nir , Marder Karen , Waters Cheryl , Fahn Stanley , Kasten Meike , Brüggemann Norbert , Borsche Max , Foroud Tatiana , Tolosa Eduardo , Garrido Alicia , Annesi Grazia , Gagliardi Monica , Bozi Maria , Stefanis Leonidas , Ferreira Joaquim J. , Correia Guedes Leonor , Avenali Micol , Petrucci Simona , Clark Lorraine , Fedotova Ekaterina Y. , Abramycheva Natalya Y. , Alvarez Victoria , Menéndez‐González Manuel , Jesús Maestre Silvia , Gómez‐Garre Pilar , Mir Pablo , Belin Andrea Carmine , Ran Caroline , Lin Chin‐Hsien , Kuo Ming‐Che , Crosiers David , Wszolek Zbigniew K. , Ross Owen A. , Jankovic Joseph , Nishioka Kenya , Funayama Manabu , Clarimon Jordi , Williams‐Gray Caroline H. , Camacho Marta , Cornejo‐Olivas Mario , Torres‐Ramirez Luis , Wu Yih‐Ru , Lee‐Chen Guey‐Jen , Morgadinho Ana , Pulkes Teeratorn , Termsarasab Pichet , Berg Daniela , Kuhlenbäumer Gregor , Kühn Andrea A. , Borngräber Friederike , de Michele Giuseppe , De Rosa Anna , Zimprich Alexander , Puschmann Andreas , Mellick George D. , Dorszewska Jolanta , Carr Jonathan , Ferese Rosangela , Gambardella Stefano , Chase Bruce , Markopoulou Katerina , Satake Wataru , Toda Tatsushi , Rossi Malco , Merello Marcelo , Lynch Timothy , Olszewska Diana A. , Lim Shen‐Yang , Ahmad‐Annuar Azlina , Tan Ai Huey , Al‐Mubarak Bashayer , Hanagasi Hasmet , Koziorowski Dariusz , Ertan Sibel , Genç Gençer , de Carvalho Aguiar Patricia , Barkhuizen Melinda , Pimentel Marcia M.G. , Saunders‐Pullman Rachel , van de Warrenburg Bart , Bressman Susan , Toft Mathias , Appel‐Cresswell Silke , Lang Anthony E. , Skorvanek Matej , Boon Agnita J.W. , Krüger Rejko , Sammler Esther M. , Tumas Vitor , Zhang Bao‐rong , Garraux Gaetan , Chung Sun Ju , Kim Yun Joong , Winkelmann Juliane , Sue Carolyn M. , Tan Eng‐King , Damásio Joana , Klivényi Péter , Kostic Vladimir S. , Arkadir David , Martikainen Mika , Borges Vanderci , Hertz Jens Michael , Brighina Laura , Spitz Mariana , Suchowersky Oksana , Riess Olaf , Das Parimal , Mollenhauer Brit , Gatto Emilia M. , Petersen Maria Skaalum , Hattori Nobutaka , Wu Ruey‐Meei , Illarioshkin Sergey N. , Valente Enza Maria , Aasly Jan O. , Aasly Anna , Alcalay Roy N. , Thaler Avner , Farrer Matthew J. , Brockmann Kathrin , Corvol Jean‐Christophe , Klein Christine ,   the MJFF Global Genetic Parkinson's Disease Study Group
Published: January 2023

Background

As gene‐targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial‐ready cohorts is limited.

Objective

The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD‐linked variants; (2) provide harmonized and quality‐controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD.

Methods

We conducted a worldwide, systematic online survey to collect individual‐level data on individuals with PD‐linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ‐1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed.

Results

We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ‐1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published.

Conclusions

Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD‐linked variants; (2) provide harmonized and quality‐controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene‐targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.