Abstract：
Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is an inherited late-onset neurological disease caused by bi-allelic AAGGG pentanucleotide expansions within intron 2 of RFC1. Despite extensive studies, the pathophysiological mechanism of these intronic expansions remains elusive. We screened by clinical exome sequencing two unrelated patients presenting with late-onset ataxia. A repeat-primer polymerase chain reaction was used for RFC1 AAGGG intronic expansion identification. RFC1 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction. We identified the first two CANVAS affected patients who are compound heterozygous for RFC1 truncating variants (p.Arg388* and c.575delA, respectively) and a pathological AAGGG expansion. RFC1 expression studies in whole blood showed a significant reduction of RFC1 mRNA for both patients compared to three patients with bi-allelic RFC1 expansions. In conclusion, this observation provides clues that suggest bi-allelic RFC1 conditional loss-of-function as the cause of the disease.
摘要：
小脑共济失调,神经病和前庭反射综合征(CANVAS)是一种遗传性迟发性神经系统疾病,由RFC1内含子2内的双等位基因AAGGG五核苷酸扩增引起.尽管进行了广泛的研究,这些内含子扩张的病理生理机制仍然难以捉摸。我们通过临床外显子组测序筛选了两名表现为迟发性共济失调的无关患者。重复引物聚合酶链反应用于RFC1AAGGG内含子扩增鉴定。通过定量逆转录-聚合酶链反应评估RFC1mRNA表达。我们确定了前两名受CANVAS影响的患者，他们是RFC1截断变体的复合杂合（p。Arg388*和c.575delA，分别）和病理性AAGGG扩增。全血中的RFC1表达研究显示，与三名具有双等位基因RFC1扩增的患者相比，两名患者的RFC1mRNA均显着降低。总之,这一观察结果提供了提示双等位基因RFC1条件性功能丧失是该疾病的原因的线索.
