Biallelic IntronicAAGGGExpansion of RFC1 is Related to Multiple System Atrophy
Biallelic IntronicAAGGGExpansion of RFC1 is Related to Multiple System Atrophy
复制标题
RFC1的双等位内含子AAGGG扩展与多系统萎缩有关
DOI：
10.1002/ana.25902
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发表时间：
2020-10-03
影响因子：
11.2
通讯作者：
Jiang, Hong
中科院分区：
文献类型：
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作者：
Wan, Linlin;Chen, Zhao;Jiang, Hong
目的：RFC 1基因的隐性双等位基因重复扩增（AAGGG）（exp）是晚发性共济失调的常见病因。对于小脑共济失调、神经病和前庭反射消失综合征（CANVAS），隐性双等位基因（AAGGG）（exp）基因型存在于92%的病例中。本研究旨在探讨是否五核苷酸重复（PNR）与多系统萎缩（MSA），共享一个频谱的症状CANVAS.Methods：在这项研究中，我们筛选了致病（AAGGG）（exp）重复和其他5个PNR在104例中国散发性成人发病共济失调病因不明（SAOA）患者，282 MSA患者，和203名未受影响的个人。采用多种分子遗传学检测，包括长距离聚合酶链反应（PCR）、重复引物PCR（RP-PCR）、桑格测序和Southern印迹。结果：在1例SAOA和3例MSA患者中发现了双等位基因（AAGGG）（exp）。另外，1例MSA患者具有致病性不确定的（AAGGG）（exp）/（AAAGG）（exp）基因型。我们还描述了我们的队列中不同PNR的载波频率。此外，我们总结了受影响患者的不同表型，表明RFC 1中的双等位基因（AAGGG）（exp）可能与MSA相关，应在MSA诊断工作流程中进行常规筛查。我们的研究结果扩大了RFC 1相关疾病的临床表型谱，并提出了MSA可能与CANVAS具有相同遗传背景的可能性，这对于重新评估当前CANVAS和MSA诊断标准至关重要。
Objective: A recessive biallelic repeat expansion, (AAGGG)(exp), in theRFC1gene has been reported to be a frequent cause of late-onset ataxia. For cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), the recessive biallelic (AAGGG)(exp) genotype was present in similar to 92% of cases. This study aimed to examine whether the pentanucleotide repeat (PNR) was related to multiple system atrophy (MSA), which shares a spectrum of symptoms with CANVAS.Methods: In this study, we screened the pathogenic (AAGGG)(exp) repeat and 5 other PNRs in 104 Chinese sporadic adult-onset ataxia of unknown aetiology (SAOA) patients, 282 MSA patients, and 203 unaffected individuals. Multiple molecular genetic tests were used, including long-range polymerase chain reaction (PCR), repeat-primed PCR (RP-PCR), Sanger sequencing, and Southern blot. Comprehensive clinical assessments were conducted, including neurological examination, neuroimaging, nerve electrophysiology, and examination of vestibular function.Results: We identified biallelic (AAGGG)(exp) in 1 SAOA patient and 3 MSA patients. Additionally, 1 MSA patient had the (AAGGG)(exp)/(AAAGG)(exp) genotype with uncertain pathogenicity. We also described the carrier frequency for different PNRs in our cohorts. Furthermore, we summarized the distinct phenotypes of affected patients, suggesting that biallelic (AAGGG)(exp) inRFC1could be associated with MSA and should be screened routinely in the MSA diagnostic workflow.Interpretation: Our results expanded the clinical phenotypic spectrum ofRFC1-related disorders and raised the possibility that MSA might share the same genetic background as CANVAS, which is crucial for re-evaluating the current CANVAS and MSA diagnostic criteria.