Parkinson’s disease variant detection and disclosure: PD GENEration, a North American study
Authors: Cook Lola , Verbrugge Jennifer , Schwantes-An Tae-Hwi , Schulze Jeanine , Foroud Tatiana , Hall Anne , Marder Karen S , Mata Ignacio F , Mencacci Niccolò E , Nance Martha A , Schwarzschild Michael A , Simuni Tanya , Bressman Susan , Wills Anne-Marie , Fernandez Hubert H , Litvan Irene , Lyons Kelly E , Shill Holly A , Singer Carlos , Tropea Thomas F , Vanegas Arroyave Nora , Carbonell Janfreisy , Cruz Vicioso Rossy , Katus Linn , Quinn Joseph F , Hodges Priscila D , Meng Yan , Strom Samuel P , Blauwendraat Cornelis , Lohmann Katja , Casaceli Cynthia , Rao Shilpa C , Ghosh Galvelis Kamalini , Naito Anna , Beck James C , Alcalay Roy N 
Published: July 2024

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 &gt;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 (&lt;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.