PDF(Pubmed)
Abstract：
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.
摘要：
七个基因的变异（LRRK2，GBA1，PRKN，SNCA,PINK1，PARK7和VPS35）已被正式裁定为帕金森氏病的因果关系；但是，由于很少提供临床检测，患有帕金森病的人通常不知道自己的遗传状况。因此,遗传信息没有纳入临床护理，和变种靶向精准医学试验努力招募帕金森病患者。了解使用已建立的基因小组进行基因检测的产量，地理上不同的北美人口会帮助病人，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接近帕金森病中的重要性。PDGENEration是一个正在进行的多中心，观察性研究（NCT04057794，NCT04994015）为美国（包括波多黎各）的人提供基因检测和结果披露和遗传咨询，加拿大和多米尼加共和国，通过本地临床站点或远程通过自我注册。DNA样本通过下一代测序分析，包括缺失/复制分析（FulgentGenetics），并有针对性地检测7个主要的帕金森病相关基因。被分类为致病性/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的参与者公开。在基线就诊时收集人口统计学和临床特征。在2019年9月至2023年6月之间，该研究招募了超过85个中心的10510名参与者。8301已收到结果。参与者是：59％的男性;86％的白人，2%亚洲人,4%黑人/非洲裔美国人，9％西班牙裔/拉丁美洲人；平均年龄67.4±10.8岁。在13％的参与者中观察到可报告的遗传变异，包括18％的参与者有一个或多个遗传病因的“高风险因素”：早发性（<50岁），高风险祖先（阿什肯纳兹犹太人/巴斯克人/北非柏柏尔人），受影响的一级亲属；以及重要的是,9.1%的人没有这些危险因素。在所有参与者中，有7.7％的人发现了GBA1的可报告变体；在LRRK2中为2.4％；在PRKN中为2.1％；在SNCA中为0.1％；在PINK1，PARK7或VPS35组合中为0.2％。在0.4％的参与者中发现了七个基因中一个以上的变异。大约13%的研究参与者有可报告的遗传变异，没有高风险因素的人的收益率为9%。这支持促进帕金森病基因检测的普及，以及GBA1和LRRK2相关帕金森病的治疗试验。
