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Observational Study
. 2024 Aug 1;147(8):2652-2667.
doi: 10.1093/brain/awae188.

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

Ana Westenberger  1 , Volha Skrahina  2 , Tatiana Usnich  1 , Christian Beetz  2 , Eva-Juliane Vollstedt  1 , Björn-Hergen Laabs  3 , Jefri J Paul  2 , Filipa Curado  2 , Snezana Skobalj  2 , Hanaa Gaber  2   4 , Maria Olmedillas  2 , Xenia Bogdanovic  2 , Najim Ameziane  2 , Nathalie Schell  1 , Jan Olav Aasly  5   6 , Mitra Afshari  7 , Pinky Agarwal  8 , Jason Aldred  9 , Fernando Alonso-Frech  10 , Roderick Anderson  11 , Rui Araújo  12   13 , David Arkadir  14 , Micol Avenali  15   16 , Mehmet Balal  17 , Sandra Benizri  18 , Sagari Bette  19 , Perminder Bhatia  20 , Michael Bonello  21 , Pedro Braga-Neto  22   23 , Sarah Brauneis  9 , Francisco Eduardo Costa Cardoso  24 , Francesco Cavallieri  25 , Joseph Classen  26 , Lisa Cohen  27 , Della Coletta  28 , David Crosiers  29   30 , Paskal Cullufi  31 , Khashayar Dashtipour  32 , Meltem Demirkiran  17 , Patricia de Carvalho Aguiar  33 , Anna De Rosa  34 , Ruth Djaldetti  35   36 , Okan Dogu  37 , Maria Gabriela Dos Santos Ghilardi  38   39 , Carsten Eggers  40   41 , Bulent Elibol  42 , Aaron Ellenbogen  43   44 , Sibel Ertan  45 , Giorgio Fabiani  46 , Björn H Falkenburger  47 , Simon Farrow  48 , Tsviya Fay-Karmon  36   49 , Gerald J Ferencz  50 , Erich Talamoni Fonoff  38   39 , Yara Dadalti Fragoso  51 , Gençer Genç  52 , Arantza Gorospe  53 , Francisco Grandas  54 , Doreen Gruber  55 , Mark Gudesblatt  56 , Tanya Gurevich  57 , Johann Hagenah  58 , Hasmet A Hanagasi  59 , Sharon Hassin-Baer  36   49 , Robert A Hauser  60 , Jorge Hernández-Vara  61 , Birgit Herting  62 , Vanessa K Hinson  63 , Elliot Hogg  64 , Michele T Hu  65 , Eduardo Hummelgen  66 , Kelly Hussey  60 , Jon Infante  67 , Stuart H Isaacson  19 , Serge Jauma  68 , Natalia Koleva-Alazeh  69 , Gregor Kuhlenbäumer  70 , Andrea Kühn  71 , Irene Litvan  72 , Lydia López-Manzanares  73 , McKenzie Luxmore  74 , Sujeena Manandhar  8 , Veronique Marcaud  75 , Katerina Markopoulou  76   77 , Connie Marras  78 , Mark McKenzie  79 , Michele Matarazzo  80 , Marcelo Merello  81 , Brit Mollenhauer  82   83 , John C Morgan  84 , Stephen Mullin  85 , Thomas Musacchio  86 , Bennett Myers  87 , Anna Negrotti  88 , Anette Nieves  89 , Zeev Nitsan  90   91 , Nader Oskooilar  92 , Özgür Öztop-Çakmak  45 , Gian Pal  93 , Nicola Pavese  94 , Antonio Percesepe  95 , Tommaso Piccoli  96 , Carolina Pinto de Souza  97 , Tino Prell  98   99 , Mark Pulera  100 , Jason Raw  101 , Kathrin Reetz  102   103 , Johnathan Reiner  35   36 , David Rosenberg  104 , Marta Ruiz-Lopez  105 , Javier Ruiz Martinez  106 , Esther Sammler  107   108 , Bruno Lopes Santos-Lobato  109 , Rachel Saunders-Pullman  110 , Ilana Schlesinger  111 , Christine M Schofield  112 , Artur F Schumacher-Schuh  113 , Burton Scott  74 , Ángel Sesar  114 , Stuart J Shafer  115 , Ray Sheridan  116 , Monty Silverdale  117 , Rani Sophia  118 , Mariana Spitz  119 , Pantelis Stathis  120 , Fabrizio Stocchi  121 , Michele Tagliati  65 , Yen F Tai  122 , Annelies Terwecoren  123 , Sven Thonke  124 , Lars Tönges  125   126 , Giulia Toschi  25 , Vitor Tumas  127 , Peter Paul Urban  128 , Laura Vacca  121 , Wim Vandenberghe  129   130 , Enza Maria Valente  15   131 , Franco Valzania  25 , Lydia Vela-Desojo  132 , Caroline Weill  15 , David Weise  133   134 , Joanne Wojcieszek  135 , Martin Wolz  136 , Gilad Yahalom  137 , Gul Yalcin-Cakmakli  42 , Simone Zittel  138 , Yair Zlotnik  139 , Krishna K Kandaswamy  2 , Alexander Balck  1   140 , Henrike Hanssen  1   140 , Max Borsche  1   140 , Lara M Lange  1   140 , Ilona Csoti  68 , Katja Lohmann  1 , Meike Kasten  1 , Norbert Brüggemann  1   140 , Arndt Rolfs  2   141 , Christine Klein  1 , Peter Bauer  2   142
Affiliations
Observational Study

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

Ana Westenberger et al. Brain. .

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.

Keywords: GBA1; LRRK2; Parkinson’s disease; genetic factors; genetic testing; next-generation sequencing.

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Conflict of interest statement

V.S., C.B., J.J.P., F.C., S.S, H.G., M.O., X.B., N.A., K.K.K., A.R., P.B., were or still are employees of CENTOGENE GmbH. A.W. provides consultancy services around research projects for CENTOGENE GmbH. C.K. and N.B. are medical advisors to CENTOGENE GmbH. The other authors report no competing interests.

Figures

Figure 1
Figure 1
Workflow for genetic analysis of the ROPAD study participants, indicating the numbers of analysed patients and the most relevant results. Numbers of individuals with variants in: (i) Parkinson’s disease (PD)-related genes (n = 2743); (ii) atypical parkinsonism genes (n = 973); (iii) dystonia–parkinsonism genes (n = 564); (iv) genes related to neurodegenerative disorders with prominent/predominant (atypical) parkinsonism (n = 470); (v) dystonia/dyskinesia-related genes (n = 1505); and (vi) dementia-related genes (n = 695) do not add up to the number of individuals with pathogenic (P)/likely pathogenic (LP)/PD-relevant risk factors (RFs)/variants of uncertain significance (VUS) detected by gene panel sequencing (n = 5361), given that these groups of patients partly overlap (e.g. some of the patients with variants in dystonia/dyskinesia-related genes also harbour variants in PD-related genes, etc.).
Figure 2
Figure 2
Ethnicity predicted based on the available whole genome sequencing data versus self-reported ethnicity from a subgroup of 2587 ROPAD participants.
Figure 3
Figure 3
Comparison of demographic and age-related variables between idiopathic Parkinson’s disease patients and those with a positive Parkinson’s disease-relevant genetic test (PDGT). (A) Sex (top section in blue = male; bottom section in red = female). (B) Fractions of patients with positive family history (bottom section in red = positive family history; top section in blue = negative family history). (C) Age at onset. (D) Age at diagnosis. (E) Age at enrolment. IPD = idiopathic Parkinson’s disease.
Figure 4
Figure 4
Comparison of demographic and age-related variables between idiopathic Parkinson’s disease patients and four different genetic patient subgroups [positive Parkinson’s disease-relevant genetic test (PDGT) based on GBA1, LRRK2, PRKN/PINK1 or SNCA variants]. (A) Sex (top section in blue = male; bottom section red = female). (B) Fractions of patients with positive family history (bottom section in red = positive family history; top section in blue = negative family history). (C) Age at onset. (D) Age at diagnosis. (E) Age at enrolment. IPD = idiopathic Parkinson’s disease.
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References

    1. Lange LM, Gonzalez-Latapi P, Rajalingam R, et al. . Nomenclature of genetic movement disorders: Recommendations of the international Parkinson and movement disorder society task force—An update. Mov Disord. 2022;37:905–935. - PubMed
    1. Vollstedt E-J, Schaake S, Lohmann K, et al. . Embracing monogenic Parkinson’s disease: The MJFF global genetic PD cohort. Mov Disord. 2023;38:286–303. - PubMed
    1. Tan MMX, Malek N, Lawton MA, et al. . Genetic analysis of Mendelian mutations in a large UK population-based Parkinson’s disease study. Brain. 2019;142:2828–2844. - PMC - PubMed
    1. den Heijer JM, Cullen VC, Quadri M, et al. . A large-scale full GBA1 gene screening in Parkinson’s disease in The Netherlands. Mov Disord. 2020;35:1667–1674. - PMC - PubMed
    1. Benitez BA, Davis AA, Jin SC, et al. . Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson’s disease. Mol Neurodegener. 2016;11:29. - PMC - PubMed

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