Frequency of Known Genetic Variants for Parkinson’s Disease in the PD GENEration Study Cohort
James Beck1, Kamalini Ghosh Galvelis2, Martha Nance3, Anna Naito1, Niccolo Mencacci4, Ignacio Mata5, Anne Hall1, Jeanine Schulze6, Rayza Priscila Hodges7, Anne Marie Wills8, Michael Schwarzschild9, Karen Marder10, Tanya Simuni11, Mandy Miller7, Jennifer Verbrugge6, Lola Cook7, Laura Heathers7, Michelle Totten7, Tatiana Foroud6, Roy Alcalay10
1Parkinson's Foundation, 2Clinical Research, Parkinson's Foundation, 3Park Nicollet Clinic, 4Northwestern University, 5Cleveland Clinic Foundation, 6Indiana University School of Medicine, 7Indiana University, 8MGH, 9Massachusetts General Hospital, 10Columbia University, 11Northwestern University Feinberg School of Medicien
Objective:
Assess the prevalence of pathogenic variants among people with Parkinson’s disease (PWP) through the PD GENEration study’s 7-gene genetic testing panel (LRRK2, GBA, SNCA, PRKN, PINK1, PARK7 and VPS35) and determine predictors of pathogenic variants.
Background:
While precision medicine trials for PD have started, widespread access to clinical genetic testing and counseling for a large North American PD cohort has been limited.
Design/Methods:
This multi-center observational study provides genetic counseling and CLIA-certified genetic testing for PWP in the U.S., Canada and the Dominican Republic. DNA samples (buccal swab or blood) undergo next generation sequencing including deletion/duplication analyses. Pathogenic (P), likely pathogenic (LP) and select risk allele (RA) variants based on the American College of Medical Genetics (ACMG) classification criteria are returned to participants.
Results:
Over 5,500 participants have enrolled in the study between September 5, 2019 and October 1, 2022. Of the 4,080 completed tests, 563 individuals (13.8%) carried a reportable variant (P, LP, RA). The distribution of positive cases include: 338 GBA, 106 LRRK2, 94 PRKN, 6 VPS35, 9 SNCA, 5 PINK1, 5 PARK7, including 22 (0.54%) participants carrying variants in more than one gene. 1,860 out of 4,080 participants were viewed as having a higher genetic risk due to ancestry, positive first-degree family history, or age of onset <50; of those, 385, or 20.7%, were found to have a disease-related genetic variant. Of the other 2,220 participants with none of the above risk factors, 178, or 8.0%, had an abnormal genetic result.
Conclusions:
Genetic testing of well-established PD genes in this North American cohort resulted in a genetic diagnostic yield of 13.8%. Although reportable variants were more likely to be found in individuals who had early-onset PD, high-risk ancestry or a positive family history, a yield of approximately 8.0% was observed in those without these features.