Objective: To assess the frequency of reportable variants in major genes associated with Parkinson’s disease (PD) and identify clinical predictors of positive genetic test results.

Background: Seven genes (SNCA, LRRK2, GBA, VPS35, PRKN, PINK1, PARK7) are established in the literature as associated with PD. The genetic diagnostic yield and predictive clinical features in a large North American cohort are unknown.

Method: PD GENEration is a multi-center, observational study, offering genetic testing to individuals with PD in North America. DNA samples are analyzed by next-generation sequencing and deletion/duplication analysis (CLIA-certified; Fulgent Genetics). Variants classified as pathogenic or likely pathogenic, including those considered actionable, are disclosed. During the clinical phase of the study, demographics, medical and family histories, as well as data from neurological assessments were collected.

Results: From September 2019 to November 2021, the study enrolled 1,982 participants across 12 sites. General cohort characteristics were: 43% female; 94% White, 2% Asian, 1% Black, 5% Hispanic/Latino; and a mean age of 65 years (S.D. 10). There were 18% of participants with early-onset PD (age < 50 years), 18% of high-risk ancestry, and 26% with a positive family history of PD. Of 1,959 individuals tested, 290 participants (14.8%) had a reportable variant including 181 with variants in GBA (9.2%); 56 in LRRK2 (2.9%); 51 in PRKN (2.6%) (14 biallelic); 8 in SNCA (0.41%), and 6 in the remaining three genes. Eleven (0.56%) participants had variants in more than one gene. Variants were more frequently identified among those from higher risk groups (early age of onset, high-risk ancestry, and a positive family history) (19.8% vs. 10.1%) (P < 0.001).

Conclusion: Genetic testing of well-established PD genes in this North American cohort resulted in a genetic diagnostic yield of 14.8%. 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 10.0% was observed in those without these features. We propose that widespread genetic testing in North America will help identify previously unsuspected individuals with major PD gene variants, and, ultimately, qualify more people for enrollment in precision medicine clinical trials for PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pd-generation-clinical-phase-genetic-diagnostic-yield-and-clinical-characteristics/