Résumé
Consortium: Genomics England Research ConsortiumBackground/Objectives: Alpha-tubulin 4A encoding gene (TUBA4A) has been associated with familial amyotrophic lateral sclerosis (fALS) and fronto-temporal dementia (FTD), based on identification of likely pathogenic variants in patients from distinct ALS and FTD cohorts. Very recently, the p.Glu415Lys TUBA4A variant has been identified in a large Italian family with spastic cerebellar ataxia and in an unrelated sporadic patient with de novo occurrence.Methods: We describe 12 patients from 11 unrelated families harbouring ultra-rare missense variants in TUBA4A. We carefully characterized the patients’ phenotype by providing detailed clinical data and imaging, when available. A rare-variant gene-based burden case-control analysis was performed within the rare disease component of the UK 100,000 Genomes Project (100KGP). Functional studies on microtubules properties were performed on cultured fibroblasts from 3 patients.Results: We report 12 patients presenting with spasticity and/or cerebellar ataxia and harboring a predicted pathogenic TUBA4A missense mutation, including 5 confirmed de novo cases and a mutation previously reported in a large family presenting with spastic ataxia. In addition, gene burden analyses in the UK 100K GP showed enrichment of TUBA4A rare variants in the inherited ataxia group compared to controls (OR: 14.3 [5.0 – 41.2]; P < 10-4). Cultured fibroblasts from 3 patients harboring distinct TUBA4A missense mutations showed significant alterations in microtubule organisation and dynamics, providing insights for TUBA4A variants pathogenicity.Conclusion: Our data confirm the identification of a hereditary spastic ataxia disease gene with variable age of onset, expanding the clinical spectrum of TUBA4A associated phenotypes.Conflict of Interest: None declared