Long-read sequencing identifies the pathogenic nucleotide repeat expansion in RFC1 in a Japanese case of CANVAS
Long-read sequencing identifies the pathogenic nucleotide repeat expansion in RFC1 in a Japanese case of CANVAS
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DOI：
10.1038/s10038-020-0733-y
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发表时间：
2020-02-18
影响因子：
3.5
通讯作者：
Tanaka, Fumiaki
中科院分区：
文献类型：
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作者：
Nakamura, Haruko;Doi, Hiroshi;Tanaka, Fumiaki
最近，在小脑性共济失调伴神经病变和双侧前庭反射消失综合征（CANVAS）中发现了一种重复遗传性复制因子C1（RFC 1）内含子重复序列扩增。在这里，我们描述了一个日本的情况下，基因证实CANVAS与自主神经功能衰竭和幻听。通过单光子发射计算机断层扫描，该病例显示心脏交感神经和多巴胺能神经元分别对碘-123-间碘苄胍和碘-123-碘氟烷的摄取受损。长读段测序鉴定了RFC 1中的双等位基因致病性（AAGGG）n核苷酸重复扩增和脑中表达的杂合良性（TAAAA）n和（TAGAA）n扩增，与NEDD 4（BEAN 1）相关。使用Cas9介导的系统富集RFC 1和BEAN 1中的重复区域清楚地区分了致病性和良性重复扩增。RFC 1周围的单倍型表明，（AAGGG）n扩增在我们的情况下是在相同的祖先等位基因的欧洲情况。因此，长读段测序有助于对具有复杂重复结构和各种扩增的疾病进行精确的遗传诊断。
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-123-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.