GAA ‐ FGF14 Expansions and CACNA1A Variants: Phenotypic Overlap and Diagnostic Implications

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Abstract
Background: An intronic (GAA)•(TTC) repeat expansion in FGF14 was recently identified as the cause of spinocerebellar ataxia 27B (SCA27B), a disorder presenting with both chronic cerebellar ataxia and episodic symptoms. The phenotype of SCA27B overlaps with that of CACNA1A spectrum disorders. Objective: The objective of this work was to investigate the prevalence of GAA‐ FGF14 repeat expansions in patients with ataxia so far considered to be related to underlying CACNA1A variants. Methods: This is a cross‐sectional multicenter study. Results: GAA‐ FGF14 testing showed pathogenic expansions (≥250 repeats) in 6/67 (9%) patients carrying CACNA1A variants. All patients with a pathogenic GAA‐ FGF14 expansion had a disease onset >40 years and carried variants of uncertain significance (VUSs) in CACNA1A . Genetic reevaluation led to the reclassification of CACNA1A VUSs as likely benign in four of six patients, who were ultimately diagnosed with SCA27B. Conclusions: Late‐onset ataxia cases previously considered as CACNA1A ‐related disorder should be reevaluated and tested for SCA27B, particularly if related to a VUS in CACNA1A . © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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