Objective: To identify rare genetic variants contributing to Parkinson’s disease (PD) using analysis of multiplex families and large-scale genomic datasets.

Background: Rare variants identified through family-based sequencing remain a powerful strategy for gene discovery in PD. SLC25A12 encodes the mitochondrial aspartate-glutamate carrier AGC1, a key regulator of neuronal energy metabolism and N-acetylaspartate synthesis. Biallelic loss-of-function variants cause a severe early-onset encephalopathy with hypomyelination. The contribution of heterozygous SLC25A12 variants to PD has not been systematically evaluated.

Method: Whole-genome sequencing (WGS) was performed in a multiplex European PD family with three affected relatives (one sibling and two cousins). Shared variants among affected individuals were identified and filtered for rarity (MAF <0.001) with CADD score >20. Co-segregating variants were evaluated based on predicted functional impact, population frequency, and biological plausibility. Candidate variants were subsequently screened in GP2 release 11 datasets across all ancestries and specifically European ancestry (46,515 PD cases and 16,576 controls) and replicated in the ROPAD cohort to identify carriers and assess enrichment. Gene-level rare-variant burden testing for candidates was performed using SKAT-O restricted to rare coding variants and stratified by ancestry.

Results: In the multiplex family, SLC25A12 p.Arg32Cys was present in all three affected individuals. Across GP2 datasets, nine additional unrelated PD cases carrying the same variant (eight European ancestry and one Middle Eastern ancestry) and two European ancestry controls were identified. In GP2 Europeans, carrier frequency was higher in cases (MAF = 9.67 × 10⁻⁵) than in controls (6.0 × 10⁻⁵). Affected individuals had a mean AAO of 50.8 years. Independently, variant frequency in ROPAD (3.2 × 10⁻⁴) exceeded that in gnomAD (4.0 × 10⁻⁵). Meta-analysis across the two cohorts yielded an OR of 4.11 (95% CI 1.36–12.44), p = 0.012. Rare-variant burden analysis in GP2 demonstrated an association between rare nonsynonymous SLC25A12 variants and PD in individuals of European ancestry (p = 0.006).

Conclusion: These data suggest that rare heterozygous SLC25A12 variants may increase susceptibility to PD in European ancestry populations. Functional studies are ongoing to clarify the role of mitochondrial aspartate-glutamate transport in PD pathogenesis.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/rare-heterozygous-slc25a12-variants-are-associated-with-parkinsons-disease/