Neurology. Genetics · 2025
High Prevalence of the Intronic GAA-FGF14 Repeat Expansion in Dutch Patients With Late-Onset Ataxia.
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Ignjatijevic Ana, Boorsma Femke, Wierenga Elles, Vansenne Fleur, Verschuuren-Bemelmans Corien C, de Vries Jeroen, Verbeek Dineke S, Westers Helga, van Diemen Cleo C
Аннотация
BACKGROUND AND OBJECTIVES: A pathogenic GAA repeat expansion in the first intron of the fibroblast growth factor 14 (FGF14) gene was recently identified as a common cause of late-onset spinocerebellar ataxia in various populations. In our hospital, approximately 85% of adult-onset ataxia cases remain genetically unsolved and the prevalence of the GAA-FGF14 repeat expansion is unknown. We, therefore, screened 248 Dutch individuals with adult-onset spinocerebellar ataxia for GAA-FGF14 repeat expansions using a combination of long-range PCR (LR-PCR) and repeat-primed PCR (RP-PCR) and assessed their clinical presentation.
METHODS: Genomic DNA samples from 248 genetically unsolved patients with adult-onset ataxia were first tested by LR-PCR spanning the intronic FGF14 repeat locus to detect expanded alleles. The correct repeat motif was verified by RP-PCR of the GAA and another prevalent repeat, GAAGGA. GAA-positive repeats were accurately sized with fluorescent LR-PCR and fragment length analysis. Three samples were validated using Oxford Nanopore Technologies long-read sequencing. Clinical data of the patients with GAA≥250-FGF14 were collected retrospectively.
RESULTS: The (likely) pathogenic GAA≥250-FGF14 repeat expansion was identified in 28 patients, resulting in a total diagnostic yield of 11%. These patients commonly presented with late-onset gait ataxia, vertigo, and nystagmus. Nine individuals had a GAAGGA expansion that is considered nonpathogenic.
DISCUSSION: We conclude that GAA-FGF14 repeat expansions are one of the most common known genetic causes of late-onset spinocerebellar ataxia in patients referred to our hospital, which is comparable with studies in other populations. The inclusion of GAA-FGF14 genetic testing will significantly improve the diagnostic yield.
METHODS: Genomic DNA samples from 248 genetically unsolved patients with adult-onset ataxia were first tested by LR-PCR spanning the intronic FGF14 repeat locus to detect expanded alleles. The correct repeat motif was verified by RP-PCR of the GAA and another prevalent repeat, GAAGGA. GAA-positive repeats were accurately sized with fluorescent LR-PCR and fragment length analysis. Three samples were validated using Oxford Nanopore Technologies long-read sequencing. Clinical data of the patients with GAA≥250-FGF14 were collected retrospectively.
RESULTS: The (likely) pathogenic GAA≥250-FGF14 repeat expansion was identified in 28 patients, resulting in a total diagnostic yield of 11%. These patients commonly presented with late-onset gait ataxia, vertigo, and nystagmus. Nine individuals had a GAAGGA expansion that is considered nonpathogenic.
DISCUSSION: We conclude that GAA-FGF14 repeat expansions are one of the most common known genetic causes of late-onset spinocerebellar ataxia in patients referred to our hospital, which is comparable with studies in other populations. The inclusion of GAA-FGF14 genetic testing will significantly improve the diagnostic yield.