Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia

三核苷酸重复扩增 优势比 共济失调 医学 全基因组关联研究 遗传学 内科学 基因型 生物 基因 等位基因 单核苷酸多态性 精神科
作者
David Pellerin,Vance Lemmon,Carlo Wilke,Mathilde Renaud,Sarah Fazal,Marie-Josée Dicaire,Carolin K. Scriba,Catherine Ashton,Christopher Yanick,Danique Beijer,Stephan Züchner,Clarissa Rocca,Zane Jaunmuktane,Joshua A. Sonnen,Roxanne Larivière,David Genís,Laura Molina Porcel,Karine Choquet,Rawan Sakalla,Sylvie Provost,Rebecca Robertson,Xavier Allard-Chamard,Martine Tétreault,Sarah J. Reiling,Sara Nagy,Vikas Nishadham,Meera Purushottam,Seena Vengalil,Mainak Bardhan,Atchayaram Nalini,Zhongbo Chen,Jean Mathieu,Rami Massie,Colin H. Chalk,Anne-Louise Lafontaine,François Evoy,Marie-France Rioux,Jiannis Ragoussis,Kym M. Boycott,Marie-Pierre Dubé,Antoine Duquette,Henry Houlden,Gianina Ravenscroft,Nigel G. Laing,Phillipa J. Lamont,Mario A. Saporta,Rebecca Schüle,Ludger Schöls,Roberta La Piana,Matthis Synofzik,Stephan Züchner,Bernard Brais
出处
期刊:The New England Journal of Medicine [Massachusetts Medical Society]
卷期号:388 (2): 128-141 被引量:14
标识
DOI:10.1056/nejmoa2207406
摘要

The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis.We sequenced the genomes of six persons with autosomal dominant LOCA who were members of three French Canadian families and identified a candidate pathogenic repeat expansion. We then tested for association between the repeat expansion and disease in two independent case-control series - one French Canadian (66 patients and 209 controls) and the other German (228 patients and 199 controls). We also genotyped the repeat in 20 Australian and 31 Indian index patients. We assayed gene and protein expression in two postmortem cerebellum specimens and two induced pluripotent stem-cell (iPSC)-derived motor-neuron cell lines.In the six French Canadian patients, we identified a GAA repeat expansion deep in the first intron of FGF14, which encodes fibroblast growth factor 14. Cosegregation of the repeat expansion with disease in the families supported a pathogenic threshold of at least 250 GAA repeats ([GAA]≥250). There was significant association between FGF14 (GAA)≥250 expansions and LOCA in the French Canadian series (odds ratio, 105.60; 95% confidence interval [CI], 31.09 to 334.20; P<0.001) and in the German series (odds ratio, 8.76; 95% CI, 3.45 to 20.84; P<0.001). The repeat expansion was present in 61%, 18%, 15%, and 10% of French Canadian, German, Australian, and Indian index patients, respectively. In total, we identified 128 patients with LOCA who carried an FGF14 (GAA)≥250 expansion. Postmortem cerebellum specimens and iPSC-derived motor neurons from patients showed reduced expression of FGF14 RNA and protein.A dominantly inherited deep intronic GAA repeat expansion in FGF14 was found to be associated with LOCA. (Funded by Fondation Groupe Monaco and others.).
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