Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
J Hum Genet. 2020 May;65(5):475-480. doi: 10.1038/s10038-020-0733-y. Epub 2020 Feb 18.
Recently, a recessively inherited intronic repeat expansion in replication factor C1 (RFC1) was identified in cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Here, we describe a Japanese case of genetically confirmed CANVAS with autonomic failure and auditory hallucination. The case showed impaired uptake of iodine-123-metaiodobenzylguanidine and I-ioflupane in the cardiac sympathetic nerve and dopaminergic neurons, respectively, by single-photon emission computed tomography. Long-read sequencing identified biallelic pathogenic (AAGGG)n nucleotide repeat expansion in RFC1 and heterozygous benign (TAAAA)n and (TAGAA)n expansions in brain expressed, associated with NEDD4 (BEAN1). Enrichment of the repeat regions in RFC1 and BEAN1 using a Cas9-mediated system clearly distinguished between pathogenic and benign repeat expansions. The haplotype around RFC1 indicated that the (AAGGG)n expansion in our case was on the same ancestral allele as that of European cases. Thus, long-read sequencing facilitates precise genetic diagnosis of diseases with complex repeat structures and various expansions.
最近，在小脑共济失调伴多发性神经病和双侧前庭反射消失综合征（CANVAS）中发现了复制因子 C1（RFC1）的隐性遗传内含子重复扩展。在这里，我们描述了一例具有自主神经功能衰竭和幻听的日本基因确诊 CANVAS 病例。该病例的单光子发射计算机断层扫描显示心脏交感神经和多巴胺能神经元分别摄取碘-123-间碘苄胍和碘-103 碘代高苯丙氨酸受损。长读测序在 RFC1 中发现了双等位基因致病性（AAGGG）n 核苷酸重复扩展，在脑表达的与 NEDD4（BEAN1）相关的杂合良性（TAAAA）n 和（TAGAA）n 扩展。使用 Cas9 介导的系统对 RFC1 和 BEAN1 中的重复区域进行富集，可清楚地区分致病性和良性重复扩展。RFC1 周围的单倍型表明，我们病例中的（AAGGG）n 扩展与欧洲病例的相同祖先等位基因相同。因此，长读测序有助于对具有复杂重复结构和各种扩展的疾病进行精确的遗传诊断。
