Dataset Information

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

ABSTRACT:

Background

The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis.

Methods

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.

Results

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.

Conclusions

A dominantly inherited deep intronic GAA repeat expansion in FGF14 was found to be associated with LOCA. (Funded by Fondation Groupe Monaco and others.).

SUBMITTER: Pellerin D

PROVIDER: S-EPMC10042577 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

Deep Intronic <i>FGF14</i> GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.

Pellerin David D Danzi Matt C MC Wilke Carlo C Renaud Mathilde M Fazal Sarah S Dicaire Marie-Josée MJ Scriba Carolin K CK Ashton Catherine C Yanick Christopher C Beijer Danique D Rebelo Adriana A Rocca Clarissa C Jaunmuktane Zane Z Sonnen Joshua A JA Larivière Roxanne R Genís David D Molina Porcel Laura L Choquet Karine K Sakalla Rawan R Provost Sylvie S Robertson Rebecca R Allard-Chamard Xavier X Tétreault Martine M Reiling Sarah J SJ Nagy Sara S Nishadham Vikas V Purushottam Meera M Vengalil Seena S Bardhan Mainak M Nalini Atchayaram A Chen Zhongbo Z Mathieu Jean J Massie Rami R Chalk Colin H CH Lafontaine Anne-Louise AL Evoy François F Rioux Marie-France MF Ragoussis Jiannis J Boycott Kym M KM Dubé Marie-Pierre MP Duquette Antoine A Houlden Henry H Ravenscroft Gianina G Laing Nigel G NG Lamont Phillipa J PJ Saporta Mario A MA Schüle Rebecca R Schöls Ludger L La Piana Roberta R Synofzik Matthis M Zuchner Stephan S Brais Bernard B

The New England journal of medicine 20221214 2

<h4>Background</h4>The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis.<h4>Methods</h4>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 19 ...[more]

PMID: 36516086

Similar Datasets

Project description:BackgroundSCA27B caused by FGF14 intronic heterozygous GAA expansions with at least 250 repeats accounts for 10-60% of cases with unresolved cerebellar ataxia. We aimed to assess the size and frequency of FGF14 expanded alleles in individuals with cerebellar ataxia as compared with controls and to characterize genetic and clinical variability.MethodsWe sized this repeat in 1876 individuals from France sampled for research purposes in this cross-sectional study: 845 index cases with cerebellar ataxia and 324 affected relatives, 475 controls, as well as 119 cases with spastic paraplegia, and 113 with familial essential tremor.FindingsA higher frequency of expanded allele carriers in index cases with ataxia was significant only above 300 GAA repeats (10.1%, n = 85) compared with controls (1.1%, n = 5) (p < 0.0001) whereas GAA250-299 alleles were detected in 1.7% of both groups. Eight of 14 index cases with GAA250-299 repeats had other causal pathogenic variants (4/14) and/or discordance of co-segregation (5/14), arguing against GAA causality. We compared the clinical signs in 127 GAA≥300 carriers to cases with non-expanded GAA ataxia resulting in defining a key phenotype triad: onset after 45 years, downbeat nystagmus, episodic ataxic features including diplopia; and a frequent absence of dysarthria. All maternally transmitted alleles above 100 GAA were unstable with a median expansion of +18 repeats per generation (r2 = 0.44; p < 0.0001). In comparison, paternally transmitted alleles above 100 GAA mostly decreased in size (-15 GAA (r2 = 0.63; p < 0.0001)), resulting in the transmission bias observed in SCA27B pedigrees.InterpretationSCA27B diagnosis must consider both the phenotype and GAA expansion size. In carriers of GAA250-299 repeats, the absence of documented familial transmission and a presentation deviating from the key SCA27B phenotype, should prompt the search for an alternative cause. Affected fathers have a reduced risk of having affected children, which has potential implications for genetic counseling.FundingThis work was supported by the Fondation pour la Recherche Médicale, grant number 13338 to JLM, the Association Connaître les Syndrome Cérébelleux - France (to GS) and by the European Union's Horizon 2020 research and innovation program under grant agreement No 779257 ("SOLVE-RD" to GS). DP holds a Fellowship award from the Canadian Institutes of Health Research (CIHR). SK received a grant (01GM1905C) from the Federal Ministry of Education and Research, Germany, through the TreatHSP network. This work was supported by the Australian Government National Health and Medical Research Council grants (GNT2001513 and MRFF2007677) to MB and PJL.

Project description:Background and objectivesGAA-FGF14 ataxia (SCA27B) is a recently reported late-onset cerebellar ataxia (LOCA) caused by a GAA repeat expansion in intron 1 of the FGF14 gene. Initial studies reviewing MR images of GAA-FGF14 ataxia patients revealed variable degree of cerebellar atrophy in 74-97% of them. A more detailed brain imaging characterization of GAA-FGF14 ataxia is now needed to provide 1) supportive diagnostic features and earlier disease recognition and 2) further information about the pathophysiology of the disease.MethodsWe reviewed the brain MRIs of 35 patients (median age at MRI 63 years; range 28-88 years; 16 females) from Quebec (n=27), Nancy (n=3), Perth (n=3) and Bengaluru (n=2) including longitudinal studies for 7 subjects. We performed qualitative analyses to assess the presence and degree of atrophy in vermis, cerebellar hemispheres, brainstem, cerebral hemispheres, and corpus callosum, as well as white matter involvement. Following the identification of the superior cerebellar peduncles involvement, we verified its presence in 54 GAA-FGF14 ataxia patients from four independent cohorts (Tübingen n=29; Donostia n=12; Innsbruck n=7; Cantabria n=6). To assess lobular atrophy, we also performed quantitative cerebellar segmentation in 5 subjects and 5 age-matched controls.ResultsCerebellar atrophy of variable degree was documented in 33 subjects (94.3%); limited to the vermis in 11 subjects, extended to the hemispheres in 22. We observed bilateral involvement of the superior cerebellar peduncles (SCPs) in 22 subjects (62.8%). We confirmed this finding in 30/54 (55.6%) GAA-FGF14 positive subjects from the validation cohorts. Additional findings were: cerebral atrophy in 15 subjects (42.9%), ventricular enlargement in 13 (37.1%), corpus callosum thinning in 7 (20%), and brainstem atrophy in 1 (2.8%). Cerebellar segmentation showed reduced volumes of lobules X and IV in affected individuals.DiscussionOur study confirms that cerebellar atrophy is a key feature of GAA-FGF14 ataxia. The frequent SCP involvement observed in different cohorts may be specific to GAA-FGF14 ataxia, and its detection can support and accelerate the diagnosis. The predominant involvement of vestibulocerebellar lobule X correlates with the finding of downbeat nystagmus frequently observed in GAA-FGF14 ataxia patients.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

Deep Intronic <i>FGF14</i> GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

Deep Intronic &lt;i&gt;FGF14&lt;/i&gt; GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Deep Intronic <i>FGF14</i> GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.