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Missense variants in homeobox domain of PBX1 cause coracoclavicular ankylosis

European Journal of Human Genetics volume 34, pages 147–151 (2026)Cite this article

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Abstract

There have been several reports on heterozygous loss of function variants in PBX1 associated with congenital anomalies of the kidney and urinary tract (CAKUT). We report three patients harboring de novo heterozygous missense variants in PBX1, who did not have CAKUT, but instead presented with respiratory failure, developmental delay, and, the most important, a unique skeletal phenotype characterized by broad and short clavicles with coracoclavicular ankylosis and broad ischia with premature fusion of the ischiopubic synchondrosis. All the variants are clustered at the last portion of the homeobox domain. This phenotype is consistent with mouse models with functional dysregulation in Pbx1 or its interacting factor, Emx2. This study highlights a previously not reported phenotype affecting the clavicles and ischia due to PBX1 variants and expands the clinical spectrum of PBX1-related disorders.

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Fig. 1: Skeletal survey of the present patients.
Fig. 2: Schematic representation of the PBX1 (UniProt:P40424), its functional domain, and previously reported pathogenic variants.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. The variants identified in this work and their clinical association have been submitted to ClinVar (Submission ID: SUB15443618, SUB15444197).

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Acknowledgements

We thank the patients and their families for participating in this research.

Funding

This work was supported by the Initiative on Rare and Undiagnosed Diseases (IRUD) (20ek0109301) from the Japan Agency for Medical Research and Development (AMED), a Grant-in-Aid for Research on rare and intractable diseases, Health and Labour Science Research Grants from Ministry of Health, Labour and Welfare of Japan, a Grant from National Center for Child Health and Development (2025A-1), and the Japan Society for Promotion of Science, KAKENHI (grant no. 23K07283 to KKu).

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Author notes

  1. These authors contributed equally: Maki Iwai, Kyra E. Stuurman.

Authors and Affiliations

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

    Maki Iwai, Tatsuro Kumaki & Kenji Kurosawa

  2. Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands

    Kyra E. Stuurman

  3. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada

    Kirsten Meagher & Millan S. Patel

  4. Department of Orthopaedic Surgery, British Columbia Children’s Hospital, University of British Columbia, Vancouver, BC, Canada

    Lise A. Leveille

  5. Department of Pediatric Orthopaedics, Chiba Child & Adult Orthopaedic Clinic, Chiba, Japan

    Takashi Saisu

  6. Department of General Medicine, Kanagawa Children’s Medical Center, Yokohama, Japan

    Satomi Mori

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

    Yumi Enomoto

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

    Noriko Aida

  9. Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan

    Hisato Suzuki, Toshiki Takenouchi & Kenjiro Kosaki

  10. Center for Genetic Medicine, National Center for Child Health and Development, Tokyo, Japan

    Kenji Kurosawa

  11. Department of Radiology, Musashino-Yowakai Hospital, Tokyo, Japan

    Gen Nishimura

Authors
  1. Maki Iwai
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Contributions

MI, KES, KM, LAL, TK, YE, HS, TK, K Kosaki, MSP, K Kurosawa, and GN analyzed and interpreted the data; MI, KES, KM, LAL, TS, SM, NA, MSP, and K Kurosawa, and GN interpreted and described clinical findings; MI, KES, KM, LAL, MSP, K Kurosawa, and GN wrote the manuscript; all authors reviewed and discussed the manuscript during preparation and approved the final manuscript.

Corresponding author

Correspondence to Kenji Kurosawa.

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Competing interests

The authors declare no competing interests.

Ethical approval and consent to participate

The procedures employed were reviewed and approved by the central ethics committee at Tohoku University on November 27, 2018 (CEC No. 2018-2-216). Informed consents were provided by the UBC, CCAOC, and KCMC patients to publish this report.

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Iwai, M., Stuurman, K.E., Meagher, K. et al. Missense variants in homeobox domain of PBX1 cause coracoclavicular ankylosis. Eur J Hum Genet 34, 147–151 (2026). https://doi.org/10.1038/s41431-025-01973-z

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