TY - JOUR T1 - RFC1在小脑性共济失调、神经病变和前庭反射综合征中的变异体JF - Neurology JO - Neurology SP - e543 LP - e554 DO - 10.1212/WNL.0000半岛投注体育官网000000201486六世- 100 - 5盟Riccardo Ronco AU -塞西莉亚Perini盟Riccardo Curro盟盟纳塔莉亚多米尼克-斯特凡诺Facchini盟爱丽丝Gennari AU -罗伯特·西蒙盟-斯图尔特斯凯盟-萨拉伊AU - Elisa Vegezzi盟Ilaria Quartesan AU - Amar El-Saddig盟盖拉文非盟-阿里安娜Tucci AU -阿格涅斯卡Szymura AU -路易斯爱德华多·法瑞斯诺维德盟-亚历山大·加里盟梅根Delfeld AU -普里西拉Kandikatla AU - Nifang妞妞盟Sanjukta Tawde AU -约瑟夫·肖AU -詹姆斯赶在非盟-玛丽·m·赖利AU - Nick W. Wood AU - Emmanuele Crespan AU - Christopher Gomez AU - Jin Yun Helen Chen AU - Jeremy Dan Schmahmann AU - David Gosal AU - Henry Houlden AU - Soma Das AU - Andrea Cortese Y1 - 2023/01/31 UR - //www.ebmtp.com/content/100/5/e543.abstract N2 - 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 ER -