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RFC1 repeat expansions: A recurrent cause of sensory and autonomic neuropathy with cough and ataxia

Beijer, Danique; Dohrn, Maike F; De Winter, Jonathan; Fazal, Sarah; Cortese, Andrea; Stojkovic, Tanya; Fernández-Eulate, Gorka; ... Baets, Jonathan; + view all (2022) RFC1 repeat expansions: A recurrent cause of sensory and autonomic neuropathy with cough and ataxia. European Journal of Neurology , 29 (7) pp. 2156-2161. 10.1111/ene.15310. Green open access

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Abstract

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.

Type: Article
Title: RFC1 repeat expansions: A recurrent cause of sensory and autonomic neuropathy with cough and ataxia
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/ene.15310
Publisher version: https://doi.org/10.1111/ene.15310
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: RFC1 repeat-primed PCR, afferent ataxia, autonomic dysfunction, chronic cough, next generation sequencing
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
URI: https://discovery.ucl.ac.uk/id/eprint/10145678
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