Objective: To identify potential novel variants and genes associated with Parkinson’s disease (PD) in multiplex families.

Background: Identifying novel genes associated with PD is critical for improving our understanding of disease mechanisms and advancing diagnosis, risk prediction, and therapeutic strategies. Although several monogenic causes have been established, a substantial proportion of PD heritability remains unexplained. Studying families with multiple affected individuals provides a powerful approach to detect rare, deleterious variants that segregate with disease and may reveal new PD-associated variants and genes.

Method: We analyzed 334 families within the Global Parkinson’s Genetics Program (GP2, http://gp2.org/) comprising at least two affected individuals or trios, for which segregation reports have been created. The segregation reports were merged and filtered for rare missense, stop-gain, and frameshift variants (gnomAD allele frequency<0.0001) predicted to be deleterious (CADD score≥10). Variants segregating in at least three families were prioritized, and candidate genes were subsequently screened for additional variants in other families. For selected candidates, pedigrees of families carrying the variant were reviewed, and gene function, biological pathways, interaction partners, and prior evidence for associations with PD were evaluated.

Results: On average, 21,537 segregating variants per family (min: 474, max: 129,287) were identified across different modes of inheritance. Variants in seven genes met the filtering criteria, i.e., OR4E1, FAM209B, CORO7, SLC4A1AP, LARP1, RAB32, and TLR4. In addition to RAB32, an established PD gene, previous studies have suggested potential links between LARP1 and TLR4 and PD. Overall, nine families carried at least one of six rare deleterious variants in LARP1and TLR4.

Conclusion: Cross-family variant analyses can effectively prioritize candidate PD genes that may be missed in single-family segregation studies. Follow-up investigations, including the recruitment of additional family members and functional characterization, are warranted to clarify the roles of these candidate genes and their potential contributions to PD pathogenesis.

References: This abstract has been previously presented at the GP2 Regional Investigators Meeting on March 9th, 2026.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cross-family-analysis-of-rare-deleterious-variants-segregating-in-families-with-parkinsons-disease/