RFC1 repeat expansions

Subtitle:a recurrent cause of sensory and autonomic neuropathy with cough and ataxia

BACKGROUND Ataxia and cough are rare features in hereditary sensory and autonomic neuropathies (HSAN), a group of diseases of mostly unknown genetic cause. Biallelic repeat expansions in RFC1 are associated with cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). METHODS After unremarkable whole-exome sequencing (WES) analysis, we performed a repeat-primed PCR to detect intronic RFC1 expansions in 12 HSAN families, which all presented with chronic cough. RESULTS In these patients, 75% carried biallelic expansions of the pathogenic AAGGG motif. Compared to RFC1-/- cases, RFC1+/+ patients presented more consistently with positive sensory and autonomic symptoms. Afferent ataxia was more severe in the RFC1+/+ cohort and cerebellar ataxia was a common feature (21%). CONCLUSIONS We demonstrate that RFC1 is a frequent cause of (WES-negative) HSAN with chronic cough and ataxia. The diagnostic yield of RFC1 repeat-primed PCR was surprisingly high, given that HSAN is genetically poorly understood. This combination of symptoms HSAN, ataxia, and chronic cough symptoms represents a new nosological entity within the neuropathy-ataxia spectrum.

Publication year:2022

Keywords:A1 Journal article

Accessibility:Open