Role of the repeat expansion size in predicting age of onset and severity in RFC1 disease. Currò, R., Dominik, N., Facchini, S., Vegezzi, E., Sullivan, R., Galassi Deforie, V., Fernández-Eulate, G., Traschütz, A., Rossi, S., Garibaldi, M., Kwarciany, M., Taroni, F., Brusco, A., Good, J., Cavalcanti, F., Hammans, S., Ravenscroft, G., Roxburgh, R. H., RFC1 repeat expansion study group, Parolin Schnekenberg, R., Rugginini, B., Abati, E., Manini, A., Quartesan, I., Ghia, A., Lòpez de Munaìn, A., Manganelli, F., Kennerson, M., Santorelli, F. M., Infante, J., Marques, W., Jokela, M., Murphy, S. M., Mandich, P., Fabrizi, G. M., Briani, C., Gosal, D., Pareyson, D., Ferrari, A., Prados, F., Yousry, T., Khurana, V., Kuo, S., Miller, J., Troakes, C., Jaunmuktane, Z., Giunti, P., Hartmann, A., Basak, N., Synofzik, M., Stojkovic, T., Hadjivassiliou, M., Reilly, M. M., Houlden, H., & Cortese, A. Brain: A Journal of Neurology, January, 2024.
doi  abstract   bibtex   
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 multi-variate 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 HR = 2.06, p \textless 0.001; larger allele HR = 1.53, p \textless 0.001) and with a higher hazard of developing disabling symptoms, such as dysarthria or dysphagia (smaller allele HR = 3.40, p \textless 0.001; larger allele HR = 1.71, p = 0.002) or loss of independent walking (smaller allele HR = 2.78, p \textless 0.001; larger allele HR = 1.60; p \textless 0.001) earlier in disease course. Patients with more complex phenotypes carried larger expansions (smaller allele: complex neuropathy RR = 1.30, p = 0.003; CANVAS RR = 1.34, p \textless 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 \textless 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.
@article{curro_role_2024,
	title = {Role of the repeat expansion size in predicting age of onset and severity in {RFC1} disease},
	issn = {1460-2156},
	doi = {10.1093/brain/awad436},
	abstract = {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 multi-variate 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 HR = 2.06, p {\textless} 0.001; larger allele HR = 1.53, p {\textless} 0.001) and with a higher hazard of developing disabling symptoms, such as dysarthria or dysphagia (smaller allele HR = 3.40, p {\textless} 0.001; larger allele HR = 1.71, p = 0.002) or loss of independent walking (smaller allele HR = 2.78, p {\textless} 0.001; larger allele HR = 1.60; p {\textless} 0.001) earlier in disease course. Patients with more complex phenotypes carried larger expansions (smaller allele: complex neuropathy RR = 1.30, p = 0.003; CANVAS RR = 1.34, p {\textless} 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 {\textless} 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.},
	language = {eng},
	journal = {Brain: A Journal of Neurology},
	author = {Currò, Riccardo and Dominik, Natalia and Facchini, Stefano and Vegezzi, Elisa and Sullivan, Roisin and Galassi Deforie, Valentina and Fernández-Eulate, Gorka and Traschütz, Andreas and Rossi, Salvatore and Garibaldi, Matteo and Kwarciany, Mariusz and Taroni, Franco and Brusco, Alfredo and Good, Jean-Marc and Cavalcanti, Francesca and Hammans, Simon and Ravenscroft, Gianina and Roxburgh, Richard H. and {RFC1 repeat expansion study group} and Parolin Schnekenberg, Ricardo and Rugginini, Bianca and Abati, Elena and Manini, Arianna and Quartesan, Ilaria and Ghia, Arianna and Lòpez de Munaìn, Adolfo and Manganelli, Fiore and Kennerson, Marina and Santorelli, Filippo Maria and Infante, Jon and Marques, Wilson and Jokela, Manu and Murphy, Sinéad M. and Mandich, Paola and Fabrizi, Gian Maria and Briani, Chiara and Gosal, David and Pareyson, Davide and Ferrari, Alberto and Prados, Ferran and Yousry, Tarek and Khurana, Vikram and Kuo, Sheng-Han and Miller, James and Troakes, Claire and Jaunmuktane, Zane and Giunti, Paola and Hartmann, Annette and Basak, Nazli and Synofzik, Matthis and Stojkovic, Tanya and Hadjivassiliou, Marios and Reilly, Mary M. and Houlden, Henry and Cortese, Andrea},
	month = jan,
	year = {2024},
	pmid = {38193360},
	keywords = {CANVAS, RFC1, Southern blotting, ataxia, neuropathy, repeat expansions},
	pages = {awad436},
}
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