FGF14 – Spinocerebellar Ataxia Type 27

Fibroblast growth factor 14 (FGF14; HGNC:3671) encodes an intracellular modulator of voltage-gated sodium channels in cerebellar neurons. Heterozygous variants in FGF14 cause autosomal dominant spinocerebellar ataxia type 27 (SCA27; MONDO:0012247), characterized by adult-onset tremor, gait ataxia, dysarthria, nystagmus and episodic worsening often triggered by fever.

Case series and family studies describe over 32 unrelated probands with FGF14 variants presenting with early tremor (mean age 12 years) and progressive gait ataxia (mean age 24 years) [PMID:29416937]. Segregation of heterozygous deletions and truncating variants in three multi-generation families demonstrates autosomal dominant inheritance: a 202 kb deletion segregating in three generations with fever-sensitive episodic ataxia [PMID:24252256], a novel nonsense variant c.529A>T (p.Lys177Ter) in a father–son pair [PMID:30017992], and a frameshift c.211dup (p.Ile71AsnfsTer27) in an episodic ataxia pedigree [PMID:25566820].

The variant spectrum includes large gene deletions, nonsense and frameshift mutations (e.g., c.529A>T (p.Lys177Ter)) and in-frame deletions, all absent from population databases and healthy controls [PMID:30017992]. A recent report of biallelic truncating c.75del (p.Ala26ProfsTer51) expands the inheritance spectrum but reinforces loss-of-function as the underlying mechanism [PMID:39704271].

Functional studies reveal that FGF14 binds Nav channel α-subunits at the axonal initial segment to regulate current density and gating. Fgf14–/– mice and a knock-in F145S model exhibit cerebellar ataxia with impaired repetitive firing and presynaptic dysfunction at parallel fiber–Purkinje neuron synapses, consistent with haploinsufficiency [PMID:16166153, PMID:26089778, PMID:39484407].

Despite a single recessive case, all primary SCA27 patients carry heterozygous variants with dominant segregation and concordant electrophysiological phenotypes. No studies have refuted this association, and clinical variability—episodic features, psychiatric symptoms—has been well documented.

Collectively, genetic and experimental data fulfill ClinGen Definitive criteria for FGF14–SCA27 association, guiding diagnostic testing. Key Take-home: FGF14 haploinsufficiency underlies autosomal dominant SCA27, warranting targeted genetic analysis in ataxia syndromes with tremor and episodic worsening.

References

• European Journal of Paediatric Neurology • 2014 • A new variable phenotype in spinocerebellar ataxia 27 (SCA 27) caused by a deletion in the FGF14 gene. PMID:24252256
• Tremor and Other Hyperkinetic Movements • 2018 • Spinocerebellar Ataxia 27: A Review and Characterization of an Evolving Phenotype. PMID:29416937
• European Journal of Medical Genetics • 2019 • Spinocerebellar ataxia 27 with a novel nonsense variant (Lys177X) in FGF14. PMID:30017992
• Neurogenetics • 2015 • A novel frameshift mutation in FGF14 causes an autosomal dominant episodic ataxia. PMID:25566820
• Frontiers in Cellular Neuroscience • 2015 • Parallel fiber to Purkinje cell synaptic impairment in a mouse model of spinocerebellar ataxia type 27. PMID:26089778
• The Journal of Physiology • 2005 • Fibroblast growth factor 14 is an intracellular modulator of voltage-gated sodium channels. PMID:16166153
• bioRxiv • 2024 • In Vivo Expression of an SCA27A-linked FGF14 Mutation Results in Haploinsufficiency and Impaired Firing of Cerebellar Purkinje Neurons. PMID:39484407
• Movement Disorders • 2025 • The First Case of Autosomal Recessive Cerebellar Ataxia with Prominent Paroxysmal Non-kinesigenic Dyskinesia Caused by a Truncating FGF14 Variant in a Turkish Patient. PMID:39704271

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