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Role of the repeat expansion size in predicting age of onset and severity in RFC1 disease

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?

 Fuente: Brain, 2024, awad436

 Editorial: Oxford University Press

 Fecha de publicación: 09/01/2024

 Nº de páginas: 31

 Tipo de publicación: Artículo de Revista

 DOI: 10.1093/brain/awad436

 ISSN: 0006-8950,1460-2156

 Url de la publicación: https://doi.org/10.1093/brain/awad436

Autoría

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

MANNANS, SIMON

RAVENSCROFT, GIANINA

ROXBURGH, RICHARD H.