RT期刊文章SR电子T1截断变体RFC1小脑共济失调、神经病变和前庭反射综合征的研究进展[j]; [j]; [j]半岛投注体育官网签证官100 5 A1 Riccardo Ronco A1塞西莉亚Perini A1 Riccardo Curro A1纳塔莉亚杜米尼克A1斯特凡诺Facchini A1爱丽丝Gennari A1斯图尔特罗伯特·西蒙A1斯凯A1萨拉伊A1 Elisa Vegezzi A1的Ilaria Quartesan A1 Amar El-Saddig A1盖拉文A1阿里安娜Tucci A1阿格涅斯卡Szymura A1路易斯爱德华多·诺维德·法瑞斯A1亚历山大·加里A1梅根Delfeld A1 Priscilla Kandikatla A1 Nifang妞妞A1 Sanjukta Tawde A1约瑟夫·肖A1詹姆斯赶在A1玛丽·m·赖利A1尼克·w·伍德A1名叫Emmanuele Crespan A1克里斯托弗Gomez A1 Jin Yun Helen Chen A1 Jeremy Dan Schmahmann A1 David Gosal A1 Henry Houlden A1 Soma Das A1 Andrea Cortese YR 2023 UL //www.ebmtp.com/content/100/5/e543.abstract AB Background and Objective Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive neurodegenerative disease characterized by adult-onset and slowly progressive sensory neuropathy, cerebellar dysfunction, and vestibular impairment. In most cases, the disease is caused by biallelic (AAGGG)n repeat expansions in the second intron of the replication factor complex subunit 1 (RFC1). However, a small number of cases with typical CANVAS do not carry the common biallelic repeat expansion. The objective of this study was to expand the genotypic spectrum of CANVAS by identifying sequence variants in RFC1-coding region associated with this condition.Methods Fifteen individuals diagnosed with CANVAS and carrying only 1 heterozygous (AAGGG)n expansion in RFC1 underwent whole-genome sequencing or whole-exome sequencing to test for the presence of a second variant in RFC1 or other unrelated gene. To assess the effect of truncating variants on RFC1 expression, we tested the level of RFC1 transcript and protein on patients' derived cell lines.Results We identified 7 patients from 5 unrelated families with clinically defined CANVAS carrying a heterozygous (AAGGG)n expansion together with a second truncating variant in trans in RFC1, which included the following: c.1267C>T (p.Arg423Ter), c.1739_1740del (p.Lys580SerfsTer9), c.2191del (p.Gly731GlufsTer6), and c.2876del (p.Pro959GlnfsTer24). Patient fibroblasts containing the c.1267C>T (p.Arg423Ter) or c.2876del (p.Pro959GlnfsTer24) variants demonstrated nonsense-mediated mRNA decay and reduced RFC1 transcript and protein.Discussion Our report expands the genotype spectrum of RFC1 disease. Full RFC1 sequencing is recommended in cases affected by typical CANVAS and carrying monoallelic (AAGGG)n expansions. In addition, it sheds further light on the pathogenesis of RFC1 CANVAS because it supports the existence of a loss-of-function mechanism underlying this complex neurodegenerative condition.CANVAS=cerebellar ataxia, neuropathy, and vestibular areflexia syndrome; ESP=Exome Sequencing Project; NHLBI=National Heart, Lung, and Blood Institute; RFC1=replication factor complex subunit 1; VVOR=visually enhanced vestibulo-ocular reflex; WES=whole-exome sequencing; WGS=whole-genome sequencing

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