Titel: Gene burden analysis identifies UCHL1 as a novel cause of autosomal dominant neurodegeneration with spasticity, ataxia, neuropathy, and optic atrophy
ID: W2-004
Art: Invited talk
Redezeit: 15 min
Session: Workshop 2
Neurodevelopmental Disorders

Referent: Joohyun Park (Tübingen/DE)

Abstract - Text


Objective: The increasing availability of rare disease patients" exome and genome datasets within national and international networks substantially contributes to the success of cohort-based gene burden analyses. Our objective was to apply gene burden approaches for the identification of genetic diagnoses and candidate variants/genes in a large group of patients with spastic paraplegia and ataxia within a routine diagnostic context.

Methods: A case-control  gene burden analysis was conducted on 1,547 selected cases with either spastic paraplegia, ataxia, or spastic ataxia and 3,624 matched controls. Candidate rare variant enrichment was further evaluated using an in-house database of 14,303 exomes and genomes. Individuals with loss-of-function variants (LoFs) in UCHL1 (Ubiquitin C-terminal hydrolase L1) were clinically re-examined and additional UCHL1 families were ascertained through national and international collaborations. Using patients" fibroblasts, we conducted transcriptomics and mass-spectrometry-based proteomics.

Results: Gene burden analysis prioritized UCHL1 as a candidate gene for an autosomal dominant disorder in four unrelated families. Additional individuals harboring 8 heterozygous LoFs (in 10 families) and a highly predicted pathogenic in-frame duplication (in 3 families) in UCHL1, for a total of 33 cases from 17 families, were identified within European networks and the 100,000 Genomes Project in the UK. Affected individuals (mean disease onset 49 years) presented with spasticity (23/30), ataxia (27/30), neuropathy (11/20), optic atrophy (10/17), and intellectual disability in one case, similar to the previously reported recessive families with spastic paraplegia type 79, but overall milder. A combined analysis of untargeted transcriptome and proteome datasets from patient-derived fibroblasts confirmed haploinsufficiency as the likely pathomechanism and showed comparable dysregulation of MME (membrane metallo-endopeptidase or neprilysin) also suggesting a link to amyloid-ß degradation pathways.

Conclusion: Our statistical analysis, in-depth clinical work-up and functional studies establish haploinsufficiency of UCHL1 as a novel disease mechanism for a neurodegenerative disorder.