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

Danique Beijer; Maike F Dohrn; Jonathan De Winter; Sarah Fazal; Andrea Cortese; Tanya Stojkovic; Gorka Fernández-Eulate; Gauthier Remiche; Mattia Gentile; Rudy Van Coster; Claudia Dufke; Matthis Synofzik; Peter De Jonghe; Stephan Züchner; Jonathan Baets

doi:10.1111/ene.15310

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

Eur J Neurol. 2022 Jul;29(7):2156-2161. doi: 10.1111/ene.15310. Epub 2022 Mar 23.

Authors

Danique Beijer^{1

2

3}, Maike F Dohrn^{3

4}, Jonathan De Winter^{1

2

5}, Sarah Fazal³, Andrea Cortese^{6

7}, Tanya Stojkovic⁸, Gorka Fernández-Eulate^{8

9}, Gauthier Remiche¹⁰, Mattia Gentile¹¹, Rudy Van Coster¹², Claudia Dufke^{13

14}, Matthis Synofzik^{15

16}, Peter De Jonghe⁵, Stephan Züchner³, Jonathan Baets^{1

2

5}

Affiliations

¹ Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
² Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
³ Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA.
⁴ Department of Neurology, Medical Faculty RWTH Aachen University, Aachen, Germany.
⁵ Neuromuscular Reference Center, Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.
⁶ Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UK.
⁷ Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
⁸ Reference Center for Neuromuscular Diseases, Neuro-myology Department, Pitié-Salpêtrière University Hospital, APHP, Paris, France.
⁹ Neuro-Metabolism Unit, Reference Center for Lysosomal Diseases, Neurology Department, Pitié-Salpêtrière University Hospital, APHP, Paris, France.
¹⁰ Centre de Référence Neuromusculaire, Department of Neurology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
¹¹ Medical Genetic Unit, Department of Reproductive Pregnancy Risk, ASL BARI, Bari, Italy.
¹² Division of Pediatric Neurology and Metabolism, Department of Pediatrics, University Hospital Ghent, Ghent, Belgium.
¹³ Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
¹⁴ Center for Rare Diseases, University of Tuebingen, Tuebingen, Germany.
¹⁵ Division Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany.
¹⁶ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.

PMID: 35253317
DOI: 10.1111/ene.15310

Abstract

Background and purpose: 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, and vestibular areflexia syndrome (CANVAS). This study aimed to investigate the prevalence of RFC1 repeat expansions in a cohort of HSAN patients.

Methods: After unremarkable whole-exome sequencing (WES) analysis, we performed repeat-primed PCR to detect intronic RFC1 expansions in 12 HSAN families, who all presented with chronic cough.

Results: In these patients, 75% carried biallelic expansions of the pathogenic AAGGG motif. Compared with RFC1-/- cases, RFC1+/+ cases 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 HSAN, ataxia, and chronic cough symptoms represents a new nosological entity within the neuropathy-ataxia spectrum.

Keywords: RFC1 repeat-primed PCR; afferent ataxia; autonomic dysfunction; chronic cough; next-generation sequencing.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Ataxia
Bilateral Vestibulopathy*
Cerebellar Ataxia* / diagnosis
Cerebellar Ataxia* / genetics
Cough / genetics
Hereditary Sensory and Autonomic Neuropathies* / genetics
Humans
Peripheral Nervous System Diseases* / complications
Vestibular Diseases*

Abstract

Publication types

MeSH terms

Grants and funding