Variants in seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7 and VPS35) have been formally adjudicated as causal contributors to Parkinson’s disease; however, individuals with Parkinson’s disease are often unaware of their genetic status since clinical testing is infrequently offered. As a result, genetic information is not incorporated into clinical care, and variant-targeted precision medicine trials struggle to enrol people with Parkinson’s disease. Understanding the yield of genetic testing using an established gene panel in a large, geographically diverse North American population would help patients, clinicians, clinical researchers, laboratories and insurers better understand the importance of genetics in approaching Parkinson’s disease. PD GENEration is an ongoing multi-centre, observational study (NCT04057794, NCT04994015) offering genetic testing with results disclosure and genetic counselling to those in the US (including Puerto Rico), Canada and the Dominican Republic, through local clinical sites or remotely through self-enrolment. DNA samples are analysed by next-generation sequencing including deletion/duplication analysis (Fulgent Genetics) with targeted testing of seven major Parkinson’s disease-related genes. Variants classified as pathogenic/likely pathogenic/risk variants are disclosed to all tested participants by either neurologists or genetic counsellors. Demographic and clinical features are collected at baseline visits. Between September 2019 and June 2023, the study enrolled 10 510 participants across >85 centres, with 8301 having received results. Participants were: 59% male; 86% White, 2% Asian, 4% Black/African American, 9% Hispanic/Latino; mean age 67.4 ± 10.8 years. Reportable genetic variants were observed in 13% of all participants, including 18% of participants with one or more ‘high risk factors’ for a genetic aetiology: early onset (<50 years), high-risk ancestry (Ashkenazi Jewish/Basque/North African Berber), an affected first-degree relative; and, importantly, in 9.1% of people with none of these risk factors. Reportable variants in GBA1 were identified in 7.7% of all participants; 2.4% in LRRK2; 2.1% in PRKN; 0.1% in SNCA; and 0.2% in PINK1, PARK7 or VPS35 combined. Variants in more than one of the seven genes were identified in 0.4% of participants. Approximately 13% of study participants had a reportable genetic variant, with a 9% yield in people with no high-risk factors. This supports the promotion of universal access to genetic testing for Parkinson’s disease, as well as therapeutic trials for GBA1 and LRRK2-related Parkinson’s disease.

中文翻译：

---

帕金森病变异检测和披露：PD GENEration，一项北美研究


七个基因 （LRRK2、GBA1、PRKN、SNCA、PINK1、PARK7 和 VPS35） 的变异已被正式判定为帕金森病的致病因素;然而，帕金森病患者通常不知道他们的遗传状况，因为很少提供临床检测。因此，遗传信息没有被纳入临床护理，变异靶向精准医学试验难以招募帕金森病患者。在大量、地理上多样化的北美人群中使用已建立的基因面板了解基因检测的产量，将有助于患者、临床医生、临床研究人员、实验室和保险公司更好地了解遗传学在治疗帕金森病中的重要性。PD GENEration 是一项正在进行的多中心观察性研究 （NCT04057794， NCT04994015），通过当地临床站点或通过远程注册为美国（包括波多黎各）、加拿大和多米尼加共和国的人们提供基因检测、结果披露和遗传咨询。DNA 样本通过下一代测序进行分析，包括缺失/重复分析 （Fulgent Genetics），并对 7 个主要的帕金森病相关基因进行靶向检测。归类为致病性/可能致病性/风险变异的变异由神经学家或遗传咨询师向所有测试参与者披露。在基线访视时收集人口统计学和临床特征。在 2019 年 9 月至 2023 年 6 月期间，该研究在 >85 中心招募了 10 510 名参与者，其中 8301 名已收到结果。参与者是：59% 为男性;86% 白人，2% 亚裔，4% 黑人/非裔美国人，9% 西班牙裔/拉丁裔;平均年龄 67.4 ± 10.8 岁。 在所有参与者中观察到可报告的遗传变异，包括 18% 的参与者具有一个或多个遗传病因的“高风险因素”：早发性（<50 岁）、高危血统（德系犹太人/巴斯克/北非柏柏尔人）、受影响的一级亲属;而且，重要的是，在没有这些风险因素的人群中，有 9.1% 的人。在所有参与者中发现了 GBA1 中的可报告变异 7.7%;LRRK2 中为 2.4%;PRKN 为 2.1%;SNCA 为 0.1%;PINK1、PARK7 或 VPS35 合计为 0.2%。在 0.4% 的参与者中发现了 7 个基因中不止一个的变异。大约 13% 的研究参与者具有可报告的遗传变异，在没有高风险因素的人群中，产量为 9%。这支持促进帕金森病基因检测的普遍普及，以及 GBA1 和 LRRK2 相关帕金森病的治疗试验。