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Long-read sequencing identifies the pathogenic nucleotide repeat expansion in RFC1 in a Japanese case of CANVAS

Journal of Human Genetics volume 65, pages 475–480 (2020)Cite this article

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Abstract

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 123I-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.

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Acknowledgements

We are grateful to Dr. Yasuhiro Isono and Takashi Wada for conducting auditory and vestibular assessments of the patient. We thank Louise Adam, ELS(D), and Tamsin Sheen, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript. This work was supported by Grants-in-Aid for Scientific Research (HD: JP18K07503; SMiy: JP17K10080; NM: JP17H01539) from the Japan Society for the Promotion of Science; Grants-in-Aid for Young Scientists (MK: JP19K17014; SMit: JP19K07977) from the Japan Society for the Promotion of Science; AMED (NM) under grant numbers JP19ek0109280, JP19dm0107090, JP19ek0109301, JP19ek0109348, JP18am0101108, and JP18kk020501; the Takeda Science Foundation (HD and NM); and a Grant for Strategic Research Promotion from Yokohama City University (FT: #SK2804).

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Authors and Affiliations

  1. Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan

    Haruko Nakamura, Hiroshi Doi, Tetsuya Asano, Takuya Ikeda, Shun Kubota, Misako Kunii, Yu Kitazawa, Mikiko Tada, Mitsuo Okamoto, Hideto Joki, Hideyuki Takeuchi & Fumiaki Tanaka

  2. Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan

    Satomi Mitsuhashi, Satoko Miyatake & Naomichi Matsumoto

  3. Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Kazutaka Katoh

  4. Artificial Intelligence Research Center, National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan

    Kazutaka Katoh & Martin C. Frith

  5. Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa-shi, Chiba, 277-8568, Japan

    Martin C. Frith

  6. Computational Bio Big-Data Open Innovation Laboratory, National Institute of Advanced Industrial Science and Technology, 3-4-1 Okubo, Shinjuku-ku, Tokyo, 169-8555, Japan

    Martin C. Frith

  7. Department of Neurology, Yokohama Brain and Spine Center, Yokohama, 235-0012, Japan

    Yosuke Kudo

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  1. Haruko Nakamura
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Correspondence to Hiroshi Doi or Fumiaki Tanaka.

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Nakamura, H., Doi, H., Mitsuhashi, S. et al. Long-read sequencing identifies the pathogenic nucleotide repeat expansion in RFC1 in a Japanese case of CANVAS. J Hum Genet 65, 475–480 (2020). https://doi.org/10.1038/s10038-020-0733-y

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