The aim of this study is to investigate the potential link between AFG3L2 rare pathogenic/likely pathogenic variants with Parkinson’s disease (PD).

AFG3L2 is a mitochondrial metalloprotease and ATPase. Pathogenic variants have been linked to spinocerebellar ataxia type 28 (SCA28), spastic ataxia type 5 (SPAX5), and optic atrophy type 12 (OPA12). Furthermore, several case reports reported movement disorders, including parkinsonism.

We analyzed whole-genome sequencing (WGS) data from the 10th release of the Global Parkinson’s Genetics Program (GP2), clinical exome sequencing (CES) from the 8th GP2 release, and whole-exome (WES) data from the UKBiobank. The dataset included 12,375 WGS-GP2, 3,322 WES-UKBiobank, 10,454 CES-GP2 PD patients and 3,531 WGS-GP2; 101,999 WES-UKBiobank healthy subjects (HS). We prioritized pathogenic or likely pathogenic missense variants based on the ACMG using Franklin and LoF variants with gnomAD minor allele frequency (MAF) <1×10?². Burden analyses were performed with UKBiobank adjusting for age, sex, and the first 10 principal components.

A total of 46 variants met the filtering criteria across all datasets. Three recurrent variants (p.G645S, p.P514S, p.A462V) were identified in a total of 8 PD patients. We identified 11 variant PD carriers in WGS-GP2 (frequency 8 × 10?4), 12 in CES-GP2 (freq 1.1 × 10?³), 8 in WES-UKBiobank (freq 2.4 × 10⁻³), while no variant carriers were observed in GP2-WGS HS. The burden analyses showed a significant enrichment of missense + LoF rare variants in PD cases compared to HS (Fisher’s exact test, p = 0.014; Wald test, p = 0.007, OR = 2.72, 95% CI: 1.31–5.63; SKAT-O, p < 0.004).

Our findings suggest that pathogenic variants in AFG3L2 may be associated with PD. Comprehensive clinical characterization of variant carriers, detailed familial segregation analyses, burden tests in other curated cohorts, and functional studies are currently underway to conclusively delineate the contribution of AFG3L2 dysfunction to PD pathogenesis.