Dataset Information

An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14.

ABSTRACT: Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified an intronic (GAA) repeat expansion in fibroblast growth factor 14 (FGF14). Genetic analysis of 95 Australian individuals with adult-onset ataxia identified four (4.2%) with (GAA)_>300 and a further nine individuals with (GAA)_>250. PCR and long-read sequence analysis revealed these were pure (GAA) repeats. In comparison, no control subjects had (GAA)_>300 and only 2/311 control individuals (0.6%) had a pure (GAA)_>250. In a German validation cohort, 9/104 (8.7%) of affected individuals had (GAA)_>335 and a further six had (GAA)_>250, whereas 10/190 (5.3%) control subjects had (GAA)_>250 but none were (GAA)_>335. The combined data suggest (GAA)_>335 are disease causing and fully penetrant (p = 6.0 × 10^-8, OR = 72 [95% CI = 4.3-1,227]), while (GAA)_>250 is likely pathogenic with reduced penetrance. Affected individuals had an adult-onset, slowly progressive cerebellar ataxia with variable features including vestibular impairment, hyper-reflexia, and autonomic dysfunction. A negative correlation between age at onset and repeat length was observed (R² = 0.44, p = 0.00045, slope = -0.12) and identification of a shared haplotype in a minority of individuals suggests that the expansion can be inherited or generated de novo during meiotic division. This study demonstrates the power of genome sequencing and advanced bioinformatic tools to identify novel repeat expansions via model-free, genome-wide analysis and identifies SCA50/ATX-FGF14 as a frequent cause of adult-onset ataxia.

SUBMITTER: Rafehi H

PROVIDER: S-EPMC9892775 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14.

Rafehi Haloom H Read Justin J Szmulewicz David J DJ Davies Kayli C KC Snell Penny P Fearnley Liam G LG Scott Liam L Thomsen Mirja M Gillies Greta G Pope Kate K Bennett Mark F MF Munro Jacob E JE Ngo Kathie J KJ Chen Luke L Wallis Mathew J MJ Butler Ernest G EG Kumar Kishore R KR Wu Kathy Hc KH Tomlinson Susan E SE Tisch Stephen S Malhotra Abhishek A Lee-Archer Matthew M Dolzhenko Egor E Eberle Michael A MA Roberts Leslie J LJ Fogel Brent L BL Brüggemann Norbert N Lohmann Katja K Delatycki Martin B MB Bahlo Melanie M Lockhart Paul J PJ

American journal of human genetics 20221208 1

Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified an intronic (GAA) repeat expansion in fibroblast growth factor 14 (FGF14). Genetic analysis of 95 Australian individuals with adult-onset ataxia identified four (4.2%) with (GAA)<sub>>300</sub> and a further nine individuals with (GAA)<sub>>250</sub>. PCR and long-read sequence analysis revealed these were pure (GAA) repeats. In co ...[more]

PMID: 36493768

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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

An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14.

Publications

An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14.

Similar Datasets

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