An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA27B/ATX-FGF14

Rafehi, Haloom; Read, Justin; Szmulewicz, David J.; Davies, Kayli C.; Snell, Penny; Fearnley, Liam G.; Scott, Liam; Thomsen, Mirja; Gillies, Greta; Pope, Kate; Bennett, Mark F; Munro, Jacob E.; Ngo, Kathie J.; Chen, Liming; Wallis, Mathew; Butler, Ernest; Kumar, Kishore R.; Wu, Kathy H C; Tomlinson, Susan; Tisch, Stephen; Malhotra, Abhishek; Lee‐Archer, Matthew; Dolzhenko, Egor; Eberle, Michael A.; Roberts, Leslie; Fogel, Brent L.; Brüggemann, Norbert; Lohmann, Katja; Delatycki, Martin B.; Bahlo, Melanie; Lockhart, Paul J.

doi:10.1016/j.ajhg.2022.11.015

Cited by 96 publications

(167 citation statements)

References 57 publications

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“…Applying this strategy to a cohort of 53 French patients with unsolved LOCA, we identified nine patients (17%) who carried at least one (GAA)≥250 expansion as well as two of their affected relatives. The frequency of the FGF14 GAA expansion in our cohort was similar to that of other reported cohorts of European descent 5,6 .…”

Section: Discussionsupporting

confidence: 90%

Optimized testing strategy for the diagnosis of GAA-FGF14ataxia

Bonnet

Pellerin

Roth

et al. 2023

Preprint

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Background Dominantly inherited GAA repeat expansions inFGF14are a common cause of spinocerebellar ataxia (GAA-FGF14ataxia; SCA27B, late-onset). Molecular confirmation ofFGF14GAA repeat expansions has thus far mostly relied on long-read sequencing, a technology that is not yet widely available in clinical laboratories. Methods We developed and validated a strategy to detectFGF14GAA repeat expansions using long-range PCR, bidirectional repeat-primed PCRs, and Sanger sequencing. We compared this strategy to targeted nanopore sequencing in a cohort of 22 French Canadian patients and next validated it in a cohort of 53 French index patients with unsolved ataxia. Results Diagnosis was accurately confirmed for all 22 French Canadian patients using this strategy. Method comparison showed that capillary electrophoresis of long-range PCR products significantly underestimated expansion sizes compared to nanopore sequencing (slope, 0.87 [95% CI, 0.81 to 0.93]; intercept, 14.58 [95% CI, -2.48 to 31.12]) and gel electrophoresis (slope, 0.84 [95% CI, 0.78 to 0.97]; intercept, 21.34 [95% CI, -27.66 to 40.22]). The latter techniques yielded similar size estimates. Following calibration with internal controls, expansion size estimates were similar between capillary electrophoresis and nanopore sequencing (slope: 0.98 [95% CI, 0.92 to 1.04]; intercept: 10.62 [95% CI, -7.49 to 27.71]), and gel electrophoresis (slope: 0.94 [95% CI, 0.88 to 1.09]; intercept: 18.81 [95% CI, -41.93 to 39.15]). We identified 9 French patients (9/53; 17%) and 2 of their relatives who carried anFGF14(GAA)≥250 expansion. Conclusion This novel strategy reliably detected and sizedFGF14GAA expansions. It compared favorably to long-read sequencing and can readily be implemented in clinical laboratories.

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Section: Discussionsupporting

confidence: 90%

Optimized testing strategy for the diagnosis of GAA-FGF14ataxia

Bonnet

Pellerin

Roth

et al. 2023

Preprint

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“…161 Recently, the intronic GAA repeat expansion in FGF14, a different type of mutation, was also identified as the cause of cerebellar ataxia revealed from an Australian cohort, named SCA50. 162 Interestingly, the intronic FGF14 GAA repeat expansion was found in patients who were previously diagnosed with ILOCA, including 61% in French Canadian, 18% in German, 15% in Australian, and 10% in Indian cohorts from a multicentered study. 163 These findings overall highlight that novel genetic mutations can account for a significant portion of sporadic late-onset ataxia cases.…”

Section: Idiopathic Late-onset Cerebellar Ataxiamentioning

confidence: 94%

Ataxias: Hereditary, Acquired, and Reversible Etiologies

Lin

Kuo

2023

Semin Neurol

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A variety of etiologies can cause cerebellar dysfunction, leading to ataxia symptoms. Therefore, the accurate diagnosis of the cause for cerebellar ataxia can be challenging. A step-wise investigation will reveal underlying causes, including nutritional, toxin, immune-mediated, genetic, and degenerative disorders. Recent advances in genetics have identified new genes for both autosomal dominant and autosomal recessive ataxias, and new therapies are on the horizon for targeting specific biological pathways. New diagnostic criteria for degenerative ataxias have been proposed, specifically for multiple system atrophy, which will have a broad impact on the future clinical research in ataxia. In this article, we aim to provide a review focus on symptoms, laboratory testing, neuroimaging, and genetic testing for the diagnosis of cerebellar ataxia causes, with a special emphasis on recent advances. Strategies for the management of cerebellar ataxia is also discussed.

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“…The short tandem repeat (STR) expansions of DNA were discovered to cause hereditary diseases in the early 1990s and are currently known to be linked with more than 50 developmental, neurodegenerative, or neuromuscular diseases [ 1 ], including fragile X syndrome (FXS), several spinocerebellar ataxias (SCAs, including the most recently reported SCA50/ATX-FGF14 [ 2 , 3 ]), Huntington’s disease (HD), myotonic dystrophies types 1 and 2 (DM1 and DM2), and frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). Repeat expansion diseases are caused by unstable expanded tri-, tetra-, penta-, hexa- or dodecanucleotides that can be located in coding or noncoding gene regions, namely 5′-untranslated regions (UTR), 3′-UTR, introns, or promoters ( Figure 1 ) [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

Advances in Nucleotide Repeat Expansion Diseases: Transcription Gets in Phase

Figueiredo

Loureiro

Macedo-Ribeiro

et al. 2023

Cells

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Unstable DNA repeat expansions and insertions have been found to cause more than 50 neurodevelopmental, neurodegenerative, and neuromuscular disorders. One of the main hallmarks of repeat expansion diseases is the formation of abnormal RNA or protein aggregates in the neuronal cells of affected individuals. Recent evidence indicates that alterations of the dynamic or material properties of biomolecular condensates assembled by liquid/liquid phase separation are critical for the formation of these aggregates. This is a thermodynamically-driven and reversible local phenomenon that condenses macromolecules into liquid-like compartments responsible for compartmentalizing molecules required for vital cellular processes. Disease-associated repeat expansions modulate the phase separation properties of RNAs and proteins, interfering with the composition and/or the material properties of biomolecular condensates and resulting in the formation of abnormal aggregates. Since several repeat expansions have arisen in genes encoding crucial players in transcription, this raises the hypothesis that wide gene expression dysregulation is common to multiple repeat expansion diseases. This review will cover the impact of these mutations in the formation of aberrant aggregates and how they modify gene transcription.

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An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA27B/ATX-FGF14

Cited by 96 publications

References 57 publications

Optimized testing strategy for the diagnosis of GAA-FGF14ataxia

Optimized testing strategy for the diagnosis of GAA-FGF14ataxia

Ataxias: Hereditary, Acquired, and Reversible Etiologies

Advances in Nucleotide Repeat Expansion Diseases: Transcription Gets in Phase

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