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A 3000-year-old founder variant in the DRC1 gene causes primary ciliary dyskinesia in Japan and Korea

Journal of Human Genetics (2024)Cite this article

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Abstract

Primary ciliary dyskinesia (PCD) is a genetic disorder characterized by ciliary structural abnormalities and dysfunction, leading to chronic rhinosinusitis, otitis media with effusion, bronchiectasis, and infertility. Approximately half of Japanese PCD cases are attributed to variants in the dynein regulatory complex subunit 1 (DRC1) gene, predominantly featuring homogeneous deletions of exons 1–4 spanning 27,748 base pairs on chromosome 2. Here, we report 10 new PCD cases (9 families) in addition to 29 previously reported cases (24 families) caused by DRC1 variants. Among these 39 cases, biallelic DRC1 exon 1–4 deletions were detected in 38 (97.4%). These DRC1 deletions exhibited an identical breakpoint in all PCD cases in the Japanese and Korean populations, strongly suggesting a founder effect. In this study, we performed haplotype analysis, using a whole-exome sequencing dataset of 18 Japanese PCD patients harboring large biallelic DRC1 deletions. We estimated that the founder allele likely emerged 115.1 generations ago (95% confidence interval: 33.7–205.1), suggesting an origin of approximately 3050 years ago, coinciding with the transition from the Jomon period to the early Yayoi period in Japan. Considering the formation of the modern Japanese population, the founder with the DRC1 exon 1–4 deletion likely lived on the Korean peninsula, with the allele later transmitted to Japan through migration. This study provides insights into the origin of the DRC1 copy number variant, the most frequent PCD variant in the Japanese and Korean populations, highlighting the importance of understanding population-specific genetic variations in the context of human migration and disease prevalence.

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Data availability

Data generated in the course of this study have not been made publicly available in order to safeguard patient privacy and confidentiality. Investigators interested in accessing the data are encouraged to contact the corresponding author directly. Upon request, only anonymized data will be provided, contingent upon the approval of the study investigators and in compliance with all applicable privacy regulations and ethical guidelines.

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Acknowledgements

We are grateful to the patient with PCD and their family members, who made this research possible. We thank the Center for Molecular Biology and Genetics at Mie University for performing the whole-exome sequencing.

Funding

This research was funded by JSPS Grants-in-Aid for Scientific Research (Grant Numbers 16K11210, 19K09886, 22K09665, and 22H03077) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Takeda Science Foundation, and the Japan Agency for Medical Research and Development (AMED, Grant Number JP19ek0109410).

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Authors and Affiliations

  1. Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan

    Ryotaro Hashizume

  2. Department of Genomic Medicine, Mie University Hospital, Tsu, Japan

    Ryotaro Hashizume & Kazuhiko Takeuchi

  3. Department of Otorhinolaryngology, Head & Neck Surgery, Mie University Graduate School of Medicine, Tsu, Japan

    Yifei Xu & Kazuhiko Takeuchi

  4. Department of Clinical Laboratory, Mie University Hospital, Tsu, Japan

    Makoto Ikejiri

  5. Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

    Shimpei Gotoh

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  1. Ryotaro Hashizume
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Correspondence to Kazuhiko Takeuchi.

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Hashizume, R., Xu, Y., Ikejiri, M. et al. A 3000-year-old founder variant in the DRC1 gene causes primary ciliary dyskinesia in Japan and Korea. J Hum Genet (2024). https://doi.org/10.1038/s10038-024-01289-8

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