Objective: To characterize the preliminary genetic spectrum of the Israeli PD GENEration cohort.

Background: The PD GENEration study (NCT04994015) provides genetic testing and counseling for people with Parkinson’s disease (PD). In 2024, the study expanded to Israel and transitioned from targeted exome sequencing to whole-genome sequencing (WGS), enabling return of results beyond the primary 7-gene PD panel, including secondary PD-related and medically actionable non-PD findings. The Israeli population is particularly informative in this context because of its demographic heterogeneity and the relative enrichment of founder variants in established PD-associated genes, especially LRRK2 and GBA1.

Method: We performed a cross-sectional descriptive analysis of the Israeli PD GENEration cohort who were recruited from three tertiary referral centers. Genetic testing outcomes for the primary 7-gene PD panel were categorized as positive, negative, pending, or withdrawn. Primary PD-associated findings and secondary medically relevant findings identified through WGS were analyzed according to gene and variant.

Results: Between April 2024 and March 2026, 607 participants were recruited. Of these, 119 had a positive PD-associated genetic finding, 450 had negative results, 34 were awaiting results, and 4 had withdrawn from the study, corresponding to an overall positive yield of 19.6% (compared to 12% worldwide). The majority of positive findings involved GBA1 (n=61) and LRRK2 (n=48), followed by PRKN (n=12). No positive variants were identified in PARK7, PINK1, VPS35, or SNCA in this interim analysis. The most commonly identified variants were LRRK2 p.Gly2019Ser (n=42) and GBA1 p.Asn409Ser (n=25), followed by additional GBA1 and LRRK2 (R1441C/H) variants. ATP7B (n=7; founder mutation in Ashkenazi Jews) and POLG (n=4) were the most common positive findings in the secondary PD-related panel. Carriers of BRCA1&2, PMS2, and MSH6 (n=8) were also identified and counseled, highlighting the broader clinical utility of WGS beyond the primary 7-gene panel.

Conclusion: Preliminary findings from the Israeli PD GENEration cohort demonstrate a high prevalence of identifiable PD-associated variants, driven predominantly by GBA1 and LRRK2, but not exclusive to founder mutations in AJ (e.g., LRRK2 R1441C/H). These data underscore the value of systematic multicenter screening in PD in light of forthcoming genetically-targeted precision medicine trials.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/preliminary-genetic-spectrum-of-parkinsons-disease-in-the-israeli-pd-generation-cohort/