A1 Refereed original research article in a scientific journal
Role of the repeat expansion size in predicting age of onset and severity in RFC1 disease
Authors: Currò Riccardo, Dominik Natalia, Facchini Stefano, Vegezzi Elisa, Sullivan Roisin, Galassi Deforie Valentina, Fernández-Eulate Gorka, Traschütz Andreas, Rossi Salvatore, Garibaldi Matteo, Kwarciany Mariusz, Taroni Franco, Brusco Alfredo, Good Jean-Marc, Cavalcanti Francesca, Hammans Simon, Ravenscroft Gianina, Roxburgh Richard H; RFC1 repeat expansion study group, Parolin Schnekenberg Ricardo, Rugginini Bianca, Abati Elena, Manini Arianna, Quartesan Ilaria, Ghia Arianna, Lòpez de Munaìn Adolfo, Manganelli Fiore, Kennerson Marina, Santorelli Filippo Maria, Infante Jon, Marques Wilson, Jokela Manu, Murphy Sinéad M, Mandich Paola, Fabrizi Gian Maria, Briani Chiara, Gosal David, Pareyson Davide, Ferrari Alberto, Prados Ferran, Yousry Tarek, Khurana Vikram, Kuo Sheng-Han, Miller James, Troakes Claire, Jaunmuktane Zane, Giunti Paola, Hartmann Annette, Basak Nazli, Synofzik Matthis, Stojkovic Tanya, Hadjivassiliou Marios, Reilly Mary M, Houlden Henry, Cortese Andrea
Publisher: Oxford University Press
Publication year: 2024
Journal: Brain
Journal name in source: Brain : a journal of neurology
Journal acronym: Brain
Volume: 147
Issue: 5
First page : 1887
Last page: 1898
ISSN: 0006-8950
eISSN: 1460-2156
DOI: https://doi.org/10.1093/brain/awad436
Web address : https://academic.oup.com/brain/article/147/5/1887/7513227
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/393444555
RFC1 disease, caused by biallelic repeat expansion in RFC1, is clinically heterogeneous in terms of age of onset, disease progression and phenotype. We investigated the role of the repeat size in influencing clinical variables in RFC1 disease. We also assessed the presence and role of meiotic and somatic instability of the repeat. In this study, we identified 553 patients carrying biallelic RFC1 expansions and measured the repeat expansion size in 392 cases. Pearson's coefficient was calculated to assess the correlation between the repeat size and age at disease onset. A Cox model with robust cluster standard errors was adopted to describe the effect of repeat size on age at disease onset, on age at onset of each individual symptoms, and on disease progression. A quasi-Poisson regression model was used to analyse the relationship between phenotype and repeat size. We performed multivariate linear regression to assess the association of the repeat size with the degree of cerebellar atrophy. Meiotic stability was assessed by Southern blotting on first-degree relatives of 27 probands. Finally, somatic instability was investigated by optical genome mapping on cerebellar and frontal cortex and unaffected peripheral tissue from four post-mortem cases. A larger repeat size of both smaller and larger allele was associated with an earlier age at neurological onset [smaller allele hazard ratio (HR) = 2.06, P < 0.001; larger allele HR = 1.53, P < 0.001] and with a higher hazard of developing disabling symptoms, such as dysarthria or dysphagia (smaller allele HR = 3.40, P < 0.001; larger allele HR = 1.71, P = 0.002) or loss of independent walking (smaller allele HR = 2.78, P < 0.001; larger allele HR = 1.60; P < 0.001) earlier in disease course. Patients with more complex phenotypes carried larger expansions [smaller allele: complex neuropathy rate ratio (RR) = 1.30, P = 0.003; cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) RR = 1.34, P < 0.001; larger allele: complex neuropathy RR = 1.33, P = 0.008; CANVAS RR = 1.31, P = 0.009]. Furthermore, larger repeat expansions in the smaller allele were associated with more pronounced cerebellar vermis atrophy (lobules I-V β = -1.06, P < 0.001; lobules VI-VII β = -0.34, P = 0.005). The repeat did not show significant instability during vertical transmission and across different tissues and brain regions. RFC1 repeat size, particularly of the smaller allele, is one of the determinants of variability in RFC1 disease and represents a key prognostic factor to predict disease onset, phenotype and severity. Assessing the repeat size is warranted as part of the diagnostic test for RFC1 expansion.
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Funding information in the publication:
This work was supported by Medical Research Council (MR/T001712/1), Fondazione Cariplo (grant n. 2019-1836), the Inherited Neuropathy Consortium, and Fondazione Regionale per la Ricerca Biomedica (Regione Lombardia, project ID 1751723), PRIN (F53D23002330006 - 20229MMHXP) and National Ataxia Foundation to A.C. R.C. was supported by the European Academy of Neurology (EAN) Research Fellowship 2021. H.H. and M.M.R. thank the MRC, the Wellcome Trust, the MDA, MD UK, Ataxia UK, The MSA Trust, the Rosetrees Trust and the NIHR UCLH BRC for grant support. F.T. thanks the Fondazione Regionale per la Ricerca Biomedica (CP 20/2018 (Care4NeuroRare) and the Italian Ministry of Health (RC) for grant support. D.P. thanks the Italian Ministry of Health (RRC) for grant support. F.M.S. thanks Ricerca Corrente 2022 Ministero della Salute 5X1000 for grant support. M.S. thanks the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) and the European Joint Programme on Rare Diseases for grant support. P.F.C. thanks the Medical Research Council Mitochondrial Biology Unit, the Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease, the Leverhulme Trust (RPG-2018-408), the Medical Research Council, the Alzheimer's Society Project, and the NIHR Cambridge Biomedical Research for grant support. V.K. thanks the Silva Family Ataxia Foundation and the National Ataxia Foundation.
