拥抱单基因帕金森病：迈克尔·J·福克斯基金会全球遗传性帕金森病队列研究

Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort.

作者信息

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

机构信息

Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.

Research Programs, The Michael J. Fox Foundation for Parkinson's Research, New York, New York, USA.

出版信息

Mov Disord. 2023 Feb;38(2):286-303. doi: 10.1002/mds.29288. Epub 2023 Jan 24.

DOI:10.1002/mds.29288

PMID:36692014

Abstract

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.

摘要

背景

随着针对帕金森病（PD）的基因靶向治疗越来越多地被开发出来，识别和表征特定基因致病变异的携带者势在必行。目前，全球估计患有单基因PD的受试者中，只有一小部分在文献中有记载，临床数据和适合临床试验的队列的可用性也很有限。

目的

目标是（1）建立一个由患有和未患有PD相关变异的个体组成的国际队列；（2）为每个纳入的个体提供统一且质量可控的临床特征数据；（3）进一步促进单基因PD领域研究人员的合作。

方法

我们在全球范围内进行了一项系统的在线调查，以收集关于携带SNCA、LRRK2、VPS35、PRKN、PINK1、DJ-1中PD相关变异的个体以及GBA中选定的致病和风险变异的个体层面数据，以及相应的人口统计学、临床和基因数据。所有登记的病例都经过了全面的质量检查，并对变异的致病性评分和基因型-表型关系进行了分析。

结果

我们收集了3888名变异携带者的数据用于分析，这些数据由全球92个中心（42个国家）报告。在纳入的个体中，3185人被诊断为PD（即1306例LRRK2、115例SNCA、23例VPS35、429例PRKN、75例PINK1、13例DJ-1和1224例GBA），703人未患病（即328例LRRK2、32例SNCA、3例VPS35、1例PRKN、1例PINK1和338例GBA）。我们总共识别出269种不同的致病变异；我们队列中的1322名个体（34%）被表明此前未被发表过。