Objective: To evaluate rare genetic variants in early-onset movement disorder (MD) cases in relation to neuropathology.

Background: Accurate diagnosis of neurodegenerative MDs is complicated by overlapping clinical phenotypes, often requiring post-mortem neuropathology. Genetic factors are central to pathogenesis, particularly in early-onset disease, and are critical for interpreting mechanistic studies. Despite progress in characterizing early-onset cases, few cohorts integrate genetic and pathological findings.

Method: Clinical, neuropathological, and genetic data were integrated from 192 brain donors with early-onset (≤50 years) MDs from international, multi-ancestry brain banks with available DNA. Cases included clinically diagnosed Parkinson’s disease (PD) /PD dementia/ Dementia with Lewy Bodies (n = 137), Multiple System Atrophy (n = 36), Progressive Supranuclear Palsy (n = 13), and others (n = 6). Controls (n = 453) without neurodegenerative disease recruited to brain banks were included. Genome sequencing and copy number variant analyses were performed. Proportional analyses compared cases and controls for pathogenic variants and variants of uncertain significance (VUS) in genes associated with neurodegenerative MDs. Neuropathological findings were used to support VUS reclassification.

Results: Pathogenic mutations were identified in seven donors (3.7%). Two carried LRRK2 G2019S; one exhibited neocortical Lewy bodies (LBs), the other TDP-proteinopathy without LBs. In PRKN, one donor was homozygous for R275W and four were compound heterozygotes, with 40% of biallelic PRKN cases lacking LBs. PD cases with non-LB pathology (n = 10, 7.3%) were significantly more likely to carry a pathogenic mutation than PD cases with LBs (n = 127, 92.7%; OR 12.59 [CI 1.55 – 92.42], p = 0.009). GBA1 variants were significantly more frequent in cases than controls (OR 3.92 [CI 1.11 – 21.2], p = 0.021). VUS were not significantly enriched in cases.

Conclusion: Most early-onset cases lack an identified genetic cause. Established pathogenic variants show heterogeneous pathology; notably, non-LB PD cases are more likely to carry a pathogenic mutation. This heterogeneity complicates biomarker development and highlights the need for genetic stratification in clinical trials. Integrating clinical, pathological, and genetic data provides a valuable resource to support future functional validation of likely pathogenic rare variants.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-rare-variation-in-early-onset-neurodegenerative-movement-disorders-a-clinicopathologic-study/