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oai:recercat.cat:11351/120132025-10-24T10:43:29Zcom_2072_378070com_2072_378040col_2072_378092

00925njm 22002777a 4500 dc Westenberger, Ana author Skrahina, Volha author Usnich, Tatiana author Beetz, Christian author Vollstedt, Eva-Juliane author Laabs, Björn-Hergen author HERNANDEZ-VARA, JORGE author 2024-10-04T09:32:47Z 2024-10-04T09:32:47Z 2024-08-01 Parkinson’s disease; Genetic testing; Next-generation sequencing Enfermedad de Parkinson; Pruebas genéticas; Secuenciación de nueva generación Malaltia de Parkinson; Proves genètiques; Seqüenciació de nova generació 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. Denali Therapeutics Inc. (South San Francisco, CA) partially funded laboratory testing services to CENTOGENE GmbH. http://hdl.handle.net/11351/12013 Anomalies cromosòmiques Parkinson, Malaltia de - Aspectes genètics Cromosomes humans - Anomalies - Diagnòstic ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Genetic Testing DISEASES::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Basal Ganglia Diseases::Parkinsonian Disorders::Parkinson Disease Other subheadings::Other subheadings::Other subheadings::/genetics PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation::Mutation TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::diagnóstico::técnicas y procedimientos diagnósticos::técnicas de laboratorio clínico::pruebas genéticas ENFERMEDADES::enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::enfermedades de los ganglios basales::trastornos parkinsonianos::enfermedad de Parkinson Otros calificadores::Otros calificadores::Otros calificadores::/genética FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética::mutación Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson’s disease study