| Neurogenetics | Rare Neurological Diseases  

Advancements in solving the hereditability of rare neurological disorders: deep intronic expansions in FGF14-ataxia

Deep intronic GAA-expansions in the FGF14 gene have been recently identified as a common cause of late onset cerebellar ataxia, a disease entity that has long resisted a molecular diagnosis. This discovery highlights the need to tackle the unsolved hereditability of rare neurological diseases in our non-coding genome.

In the past two decades, next generation sequencing (NGS) techniques exponentially increased the number of genes associated to inherited ataxias. Due to intrinsic properties of NGS, gene discoveries concerned single nucleotide polymorphisms within exons and adjacent non-coding regions. Overall, positivity rate of NGS remains limited and particularly poor for instance in late onset ataxia cases. To this concern, a first milestone has been set with the discovery of biallelic intronic expansions of a pentanucleotide in RFC1 as a cause of Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) in 2019 (Cortese et al 2019).
An additional milestone has been now achieved with the description of deep intronic GAA expansions in the FGF14 gene as a common cause of late onset cerebellar ataxia (Pellerin et al 2023). As for CANVAS, FGF14 expansion were first detected in ataxia families and thereafter in a relevant proportion of unsolved sporadic cases. Familial and sporadic FGF14 cases share a common phenotype, with recurrence of episodic symptoms at onset and later development of chronic ataxia with down-beat nystagmus. Interestingly, FGF14 encodes fibroblast growth factor 14, a protein involved in the scaffolding and regulation of axonal sodium channels and canonical variants in the FGF14 coding sequence have already been implied in rare cases of episodic ataxia.
Both in the discovery of RFC1 and FGF14 expansions, new computational tools have been applied to individuate nucleotide repeat expansions from short read sequencing data (Dolzhenko et al 2020). The discovery of FGF14 expansions highlight the need to tackle the unsolved hereditability of rare neurological disorder in our non-coding genome.

Key Points:

  • Deep intronic GAA-expansions in the FGF14  gene have been recently identified as a common cause of late onset cerebellar ataxia.
  • FGF14  positive   cases   often   present   with   episodic   phenotype   at   onset   and   later develop chronic ataxia with down-beat nystagmus.
  • FGF14 -ataxia reinforces the paradigm shift which predicts a large hereditability being hidden in repeat expansions in the non-coding genome.


  1. Cortese, A., Simone, R., Sullivan, R. et al. Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nat Genet 51, 649–658 (2019).
  2. Pellerin, D, Danzi, M.C., Wilke, C., et al. Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia. N Engl J Med. 2023 Jan 12;388(2):128-141.
  3. Dolzhenko, E., Bennett, M.F., Richmond, P.A., et al. ExpansionHunter Denovo: a computational method for locating known and novel repeat expansions in short-read sequencing data. Genome Biol 2020;21:102-102.

Author: Elisabetta Indelicato, Center for Rare Movement Disorders Innsbruck

Publish on behalf of the Scientific Panel on Neurogenetics