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Novel EXOSC9 variants cause pontocerebellar hypoplasia type 1D with spinal motor neuronopathy and cerebellar atrophy

Journal of Human Genetics volume 66, pages 401–407 (2021)Cite this article

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Abstract

Pontocerebellar hypoplasia (PCH) is currently classified into 13 subgroups and many gene variants associated with PCH have been identified by next generation sequencing. PCH type 1 is a rare heterogeneous neurodegenerative disorder. The clinical presentation includes early-onset severe developmental delay, progressive motor neuronopathy, and cerebellar and pontine atrophy. Recently two variants in the EXOSC9 gene (MIM: 606180), NM_001034194.1: c.41T>C (p.Leu14Pro) and c.481C>T (p.Arg161*) were identified in four unrelated patients with PCH type 1D (PCH1D) (MIM: 618065). EXOSC9 encodes a component of the exosome complex, which is essential for correct processing and degradation of RNA. We report here two PCH1D families with biallelic EXOSC9 variants: c.239T>G (p.Leu80Arg) and c.484dupA (p.Arg162Lysfs*3) in one family and c.151G>C (p.Gly51Arg) in the other family. Although the patients studied here showed similar clinical features as previously described for PCH1D, relatively greater intellectual development (although still highly restricted) and normal pontine structure were recognized. Our findings expand the clinical consequences of biallelic EXOSC9 variants.

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Fig. 1: Brain MRI of patients.
Fig. 2: The EXOSC9 variants found in this study.

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Acknowledgements

We thank the affected individuals and their families for participating in this study. This work was supported by AMED under the grant numbers JP20ek0109280, JP20dm0107090, JP20ek0109301, and JP20ek0109348 (to N. Matsumoto); JSPS KAKENHI under the grant numbers JP17H01539 (to N. Matsumoto) and JP19H03621 (to N. Miyake); intramural grants 30-6 and 30-7 from the Ministry of Health, Labor, and Welfare (to N. Matsumoto); and the Takeda Science Foundation (to N. Matsumoto and N. Miyake). We thank Jeremy Allen, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

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Authors and Affiliations

  1. Department of Human Genetics, Graduate school of medicine, Yokohama City University, Yokohama, Japan

    Masamune Sakamoto, Kazuhiro Iwama, Futoshi Sekiguchi, Eriko Koshimizu, Satoko Miyatake, Satomi Mitsuhashi, Takeshi Mizuguchi, Atsushi Takata, Noriko Miyake & Naomichi Matsumoto

  2. Department of Pediatrics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan

    Masamune Sakamoto & Kazuhiro Iwama

  3. Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan

    Hideaki Mashimo & Satoko Kumada

  4. Department of Pediatrics, Tokyo Women’s Medical University, Tokyo, Japan

    Keiko Ishigaki

  5. Department of Medical Genetics, Osaka Women’s and Children’s Hospital, Osaka, Japan

    Nobuhiko Okamoto

  6. Medical Genetics Research Center of Genome, Isfahan University of Medical Sciences, Isfahan, Iran

    Mahdiyeh Behnam

  7. Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Mohsen Ghadami

  8. Cardiac Primary Research Center, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran

    Mohsen Ghadami

  9. Clinical Genetics Department, Yokohama City University Hospital, Yokohama, Japan

    Satoko Miyatake

  10. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Hirotomo Saitsu

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  1. Masamune Sakamoto
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Correspondence to Noriko Miyake or Naomichi Matsumoto.

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Sakamoto, M., Iwama, K., Sekiguchi, F. et al. Novel EXOSC9 variants cause pontocerebellar hypoplasia type 1D with spinal motor neuronopathy and cerebellar atrophy. J Hum Genet 66, 401–407 (2021). https://doi.org/10.1038/s10038-020-00853-2

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