Unveiling pathogenic and non-pathogenic FGF14 repeat expansions: identification, sequence, and secondary structure
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Repeat expansions in FGF14 cause autosomal dominant late-onset cerebellar ataxia (SCA27B), with pathogenic thresholds estimated between 250 and 300 AAG repeats. However, the complete sequences of pathogenic and non-pathogenic alleles remain largely unknown. Here, we identify FGF14 repeat expansions as the most commonly missed cause of cerebellar ataxia using a combination of short-read genome sequencing, long-range PCR and nanopore sequencing. We compare FGF14 alleles in 154 patients with ataxia and 802 controls and report an enrichment of pure FGF14 expansions above 180-220 repeats in patients. Conversely, AAGGAG and interrupted alleles are more frequent in controls. Distinct 5'-flanking regions correlate with repeat stability. SCA27B patients have a characteristic phenotype, including frequent episodic ataxia and downbeat nystagmus, similar to those with a novel nonsense variant (SCA27A). Interestingly, pathogenic and non-pathogenic repeats form different secondary structures. Our results emphasize the importance of sequencing both the repeat expansion and its flanking region for accurate clinical interpretation.
