Objective: To characterize the genetic architecture of Parkinson’s disease (PD) in an understudied African-Arab cohort by analyzing pathogenic variants in known PD genes across releases (GP2 R9-R11), and identifying novel or rare candidate variants for further investigation.

Background: The genetic basis of PD remains profoundly under-characterized in African and Arab populations. Most genomic studies have focused on European ancestry cohorts, limiting equitable diagnostic and therapeutic advances.

Method: We analyzed exome and genome sequencing data from a large African-Arab PD cohort, including affected individuals and matched controls. Variants in established PD genes were annotated using GP2 releases R9, R10, and R11 to track reclassifications and assess diagnostic yield. Novel and rare variants of interest were identified for functional follow-up.

Results: Pathogenic or likely pathogenic variants in known PD genes were identified in a substantial proportion of cases, with no such findings in controls, confirming high specificity. Findings were dominated by LRRK2, GBA1, and PINK1, accounting for >90% of genetic diagnoses. LRRK2 p.Gly2019Ser was the most prevalent pathogenic allele, representing the majority of findings. GBA1 variants (p.Asn409Ser, p.Asn227Ser, p.Gly241Arg) and PINK1 homozygous p.Gln456Ter were recurrently observed. Var tracking from R9 to R11 revealed key reclassifications: PRKN p.Arg402Cys was downgraded to “Benign,” resolving a prior ambiguous finding, while GBA1 p.Asn409Ser was solidified as a risk factor. Novel candidates included a likely pathogenic DNAJC6 p.Gln1140Ter variant, a rare VPS35 p.Ala737Val allele with very low population frequency, and a VPS13C p.Thr1172Ile variant of uncertain significance.

Conclusion: This large-scale analysis of an AfrAbia PD cohort demonstrates that a significant proportion of cases carry pathogenic variants in known genes, with LRRK2 p.Gly2019Ser as a major contributor. The absence of pathogenic findings in controls reinforces diagnostic specificity. Novel candidates (DNAJC6, VPS35) highlight population-specific genetic contributions requiring functional validation. Dynamic Var reclassifications underscore the need for periodic genomic data reanalysis. These findings advocate for expanded inclusion of underrepresented populations in PD genetics to ensure equitable advances in research and clinical care.

References: NA

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MDS Abstracts - https://www.mdsabstracts.org/abstract/harmonized-analysis-of-parkinsons-disease-associated-variants-in-the-afrabia-pd-genomic-consortium-cohort/