| Autor: |
Pellerin, D, Danzi, MC, Wilke, C, Renaud, M, Fazal, S, Dicaire, M, Scriba, CK, Ashton, C, Yanick, C, Beijer, D, Rebelo, A, Rocca, C, Jaunmuktane, Z, Sonnen, JA, Larivière, R, Genis, D, Porcel, L, Choquet, K, Sakalla, R, Provost, S, Tétreault, M, Reiling, SJ, Nagy, S, Nishadham, V, Purushottam, M, Vengalil, S, Bardhan, M, Nalini, A, Chen, Z, Mathieu, J, Massie, R, Chalk, CH, Lafontaine, A, Evoy, F, Rioux, M, Ragoussis, J, Boycott, KM, Dubé, M, Duquette, A, Houlden, H, Ravenscroft, G, Laing, NG, Lamont, P, Saporta, MA, Schüle, R, Schöls, L, La Piana, R, Synofzik, M, Zuchner, S, Brais, B |
| Zdroj: |
The Canadian Journal of Neurological Sciences; June 2023, Vol. 50 Issue: Supplement 2 pS46-S46, 1p |
| Abstrakt: |
Background: The late-onset cerebellar ataxias (LOCAs) have until recently resisted molecular diagnosis. Contributing to this diagnostic gap is that non-coding structural variations, such as repeat expansions, are not fully accessible to standard short-read sequencing analysis. Methods: We combined bioinformatics analysis of whole-genome sequencing and long-read sequencing to search for repeat expansions in patients with LOCA. We enrolled 66 French-Canadian, 228 German, 20 Australian and 31 Indian patients. Pathogenic mechanisms were studied in post-mortem cerebellum and induced pluripotent stem cell (iPSC)-derived motor neurons from 2 patients. Results: We identified 128 patients who carried an autosomal dominant GAA repeat expansion in the first intron of the FGF14gene. The expansion was present in 61%, 18%, 15% and 10% of patients in the French-Canadian, German, Australian and Indian cohorts, respectively. The pathogenic threshold was determined to be (GAA)≥250, although incomplete penetrance was observed in the (GAA)250-300range. Patients developed a slowly progressive cerebellar syndrome at an average age of 59 years. Patient-derived post-mortem cerebellum and induced motor neurons both showed reduction in FGF14RNA and protein expression compared to controls. Conclusions: This intronic, dominantly inherited GAA repeat expansion in FGF14represents one of the most common genetic causes of LOCA uncovered to date. |
| Databáze: |
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