@article{8bb14e470f224b53947c5790022cea58,
title = "RFC1 repeat expansions: A recurrent cause of sensory and autonomic neuropathy with cough and ataxia",
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 = "afferent ataxia, autonomic dysfunction, chronic cough, next-generation sequencing, RFC1 repeat-primed PCR",
author = "Danique Beijer and Dohrn, {Maike F.} and {De Winter}, Jonathan and Sarah Fazal and Andrea Cortese and Tanya Stojkovic and Gorka Fern{\'a}ndez-Eulate and Gauthier Remiche and Mattia Gentile and {Van Coster}, Rudy and Claudia Dufke and Matthis Synofzik and {De Jonghe}, Peter and Stephan Z{\"u}chner and Jonathan Baets",
note = "Funding Information: DB is supported by a DOCPRO4 Antwerp University Research Fund (BOF) project grant under agreement number DOCPRO2016–33497. This work has been supported by a NINDS grant to S.Z. (5R01NS072248‐10). MD has received funding by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG, DO 2386/1‐1). Her work is being supported by a grant from the Interdisciplinary Centre for Clinical Research within the Faculty of Medicine at the RWTH Aachen University (IZKF TN1‐9/IA 532009). JDW is funded by the Goldwasser‐Emsens fellowship. A.C. thanks the Medical Research Council (MR/T001712/1), the Fondazione CARIPLO (2019‐1836), the Italian Ministry of Health Ricerca Corrente 2018–2019, the Inherited Neuropathy Consortium (INC) and Fondazione Regionale per la Ricerca Biomedica for grant support. This work was supported by the Horizon 2020 research and innovation programme (grant 779257 Solve‐RD to MS and JB) and the European Joint Programme on Rare Diseases (EJP RD) under the EJP RD COFUND‐EJP No. 825575 (PROSPAX consortium, to MS, and SZ as an associated partner, with MS hereby supported by the Deutsche Forschungsgemeinschaft (DFG)). DB received funding from the University of Antwerp under Grant Agreement KP‐BOF‐2021, No. FFB210049 and MFD received financial reimbursement for consulting and advisory board activities and travel support to attend scientific meetings by Akcea Therapeuticals Inc., Alnylam Pharmaceuticals Inc., Amicus Therapeutics, and Pfizer Pharmaceuticals. MFD further received research funding by Pfizer Pharmaceuticals (ASPIRE 2018). MD has received funding by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG, DO 2386/1‐1). Her work is being supported by a grant from the Interdisciplinary Centre for Clinical Research within the Faculty of Medicine at the RWTH Aachen University (IZKF TN1‐9/IA 532009). GR received financial support in order to attend to several scientific meeting between 2008 and 2021 (Genzyme‐Sanofi, CSL Behring, Santhera, Pfizer) and institutional financial compensations for various consulting missions between 2009 and 2021 (Genzyme‐Sanofi, CSL Behring, Alnylam, Alexion and AFMPS). GR was involved as on site/local Principal Investigator (PI) for clinical trial, from 2016 (Genzyme‐Sanofi, Momenta, Alnylam) and a member of the INAMI/RIZIV commission for metabolic diseases (Pompe and Fabry). GR is also a consulting member for the Belgian Society of Medical Oncology (BSMO) concerning neurologic complication of immunotherapies (2018‐2021). MS received consultancy honoraria from Orphazyme Pharmaceuticals, Ionis Pharmaceuticals and Janssen Pharma¬ceuticals, all unrelated to the current project and manuscript. JB is supported by a Senior Clinical Researcher mandate of the Research Fund ‐ Flanders (FWO) under grant agreement number 1805021N. JB has received ad hoc consultancy compensation from Roche, Sanofi and Alnylam and support for congress participation from Sanofi and Biogen Publisher Copyright: {\textcopyright} 2022 European Academy of Neurology",
year = "2022",
doi = "10.1111/ene.15310",
language = "English (US)",
journal = "European Journal of Neurology",
issn = "1351-5101",
publisher = "Wiley-Blackwell",
}