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

Background: AFG3L2 is a mitochondrial metalloprotease and ATPase. Pathogenic missense and loss-of-function (LoF) variants, have been linked to spinocerebellar ataxia type 28 (SCA28-autosomal dominant), spastic ataxia type 5 (SPAX5-autosomal recessive), and optic atrophy type 12 (OPA12-autosomal dominant). Furthermore, several case reports reported other movement disorders, such as parkinsonism.

Method: We analyzed whole-genome sequencing (WGS), and clinical exome sequencing (CES) data from the 11th release of the Global Parkinson’s Genetics Program (GP2), and whole-exome (WES) data from the UKBiobank. The dataset included 21,858 WGS-GP2, 3,322 WES-UKBiobank, 10,648 CES-GP2 PD patients, and 9,172 WGS-GP2 – 101,999 WES-UK Biobank healthy subjects (HS). We prioritized pathogenic or likely pathogenic missense CADD score >20, LoF variants based on the ACMG classification using Franklin with gnomAD allele frequency (AF) < 0.01. Burden analyses were performed in samples of European descent for the different variant categories using the CMC-Wald and SKAT-O test within RVTest, adjusting for age, sex, and the first 10 principal components.

Results: A total of 51 variants met the filtering criteria across all datasets (25 missense CADD score >20 – 26 LoF). Of these, four missense variants were identified in two of the three analyzed cohorts: p.G645S, p.Y616C, p.P514S, and p.A462V. We identified 15 PD carriers in WGS-GP2 (carrier frequency 6.86×10⁻³) ,14 in CES-GP2 (carrier frequency = 9.55 x 10^-4), of whom 10 had early-onset PD and 12 a positive PD family history, 8 in WES-UKBiobank (carrier frequency = 2.4×10⁻³), while 2 variant carriers were observed in GP2-WGS HS (carrier frequency = 2.18×10^-4). The burden analyses showed a significant enrichment of missense + LoF rare variants in PD cases compared to HS in the UKBiobank (CMC-Wald p = 0.007, OR = 2.72, 95% CI: 1.31–5.63; SKAT-O p = 0.004), whereas no significant results were observed in GP2.

Conclusion: Our findings show that pathogenic variants in AFG3L2 may be associated with PD. Comprehensive clinical characterization of variant carriers, familial segregation analyses, burden tests in other independent cohorts, and functional studies are needed to further understand delineate the contribution of AFG3L2 dysfunction to PD pathogenesis.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/assessing-the-role-of-afg3l2-pathogenic-variants-in-parkinsons-disease/