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Nanopore long-read sequencing analysis reveals ZIC1 dysregulation caused by a de novo 3q inversion with a breakpoint located 7 kb downstream of ZIC1

Journal of Human Genetics volume 69, pages 47–52 (2024)Cite this article

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Abstract

Zic family member 1 (ZIC1), a gene located on chromosome 3q24, encodes a transcription factor with zinc finger domains that is essential for the normal development of the cerebellum. Heterozygous loss-of-function of ZIC1 causes Dandy-Walker malformation, while heterozygous gain-of-function leads to a multiple congenital anomaly syndrome characterized by craniosynostosis, brain abnormalities, facial features, and learning disability. In this study, we present the results of genetic analysis of a male patient with clinically suspected Gomez-Lopez-Hernandez syndrome. The patient displayed multiple congenital abnormalities, including bicoronal craniosynostosis, characteristic facial features, cerebellar malformation with rhombencephalosynapsis, and temporal alopecia, and a de novo inversion of chromosome 3q. Breakpoint analysis using a Nanopore long-read sequencer revealed a breakpoint in the distal centromere of 3q24 located 7 kb downstream of the 3′ untranslated region of ZIC1. On the basis of the clinical similarities, we concluded that the abnormalities in this patient were caused by the transcriptional dysregulation of ZIC1. We hypothesize the underlying molecular mechanisms of transcriptional dysregulation of ZIC1 such as the abnormalities in topologically associated domains encompassing ZIC1. This study highlights the usefulness of long-read sequencing in the analysis of de novo balanced chromosomal abnormalities.

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Acknowledgements

We thank the patient and his parents for participating in this work. This study was supported by Research on Rare and Intractable Diseases from the Ministry of Health, Labour, and Welfare, Japan, the Initiative on Rare and Undiagnosed Diseases (grant number 18ek0109301), Japan Agency for Medical Research and Development (grant number 18kk0205014), Japan Society for the Promotion of Science KAKENHI (grant numbers JP17K19536 and 20K16945), and Core Research for Evolutional Science and Technology.

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Authors and Affiliations

  1. Division of Medical Genetics, Kanagawa Children’s Medical Center, Yokohama, Japan

    Hiroaki Murakami, Tatsuro Kumaki & Kenji Kurosawa

  2. Department of Pediatric Medical Care, Gifu Prefectural General Medical Center, Gifu, Japan

    Hiroaki Murakami

  3. Clinical Research Institute, Kanagawa Children’s Medical Center, Yokohama, Japan

    Yumi Enomoto & Kenji Kurosawa

  4. Department of Radiology, Kanagawa Children’s Medical Center, Yokohama, Japan

    Noriko Aida

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  1. Hiroaki Murakami
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Correspondence to Hiroaki Murakami or Kenji Kurosawa.

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Murakami, H., Enomoto, Y., Kumaki, T. et al. Nanopore long-read sequencing analysis reveals ZIC1 dysregulation caused by a de novo 3q inversion with a breakpoint located 7 kb downstream of ZIC1. J Hum Genet 69, 47–52 (2024). https://doi.org/10.1038/s10038-023-01205-6

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