Analysis of Fibroblast Growth Factor 14 (FGF14) structural variants reveals the genetic basis of the early onset nystagmus locus NYS4 and variable ataxia

<jats:title>Abstract</jats:title><jats:p>Nystagmus (involuntary, rhythmical eye movements) can arise due to sensory eye defects, in association with neurological disorders or as an isolated condition. We identified a family with early onset nystagmus and additional neurological features carrying a partial duplication of <jats:italic>FGF14</jats:italic>, a gene associated with spinocerebellar ataxia type 27 (SCA27) and episodic ataxia. Detailed eye movement analysis revealed oculomotor anomalies strikingly similar to those reported in a previously described four-generation family with early onset nystagmus and linkage to a region on chromosome 13q31.3-q33.1 (NYS4). Since <jats:italic>FGF14</jats:italic> lies within NYS4, we revisited the original pedigree using whole genome sequencing, identifying a 161 kb heterozygous deletion disrupting <jats:italic>FGF14</jats:italic> and <jats:italic>ITGBL1</jats:italic> in the affected individuals, suggesting an <jats:italic>FGF14</jats:italic>-related condition. Therefore, our study reveals the genetic variant underlying NYS4, expands the spectrum of pathogenic <jats:italic>FGF14</jats:italic> variants, and highlights the importance of screening <jats:italic>FGF14</jats:italic> in apparently isolated early onset nystagmus.</jats:p>