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Identification of KANSL1 as a novel pathogenic gene for developmental dysplasia of the hip

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Abstract

Developmental dysplasia of the hip (DDH) is a common anomaly leading to adult osteoarthritis. Environmental and genetic factors contribute to DDH, but its exact genetic mechanism is unclear. In this study, we used whole exome sequencing to identify the causative gene of a DDH pedigree. A rare missense variant in KANSL1 (c.C767T; p.S256F) was identified as the pathogenic cause of DDH. Subsequent mutation screening showed another missense variant in 1 of 200 sporadic patients. Kansl1-mutated mice showed reduced chondrocytes in the acetabulum and a decrease in the cartilage matrix, which may be DDH phenotype-related abnormalities. Furthermore, functional studies showed that cell proliferation was delayed and Mmp13 expression was abnormally upregulated in chondrocytes differentiated from Kansl1 mutant mouse embryonic stem cells. In conclusion, our findings suggest that KANSL1 is a novel pathogenic gene for DDH. The identification of KANSL1 variants has great diagnostic value for identifying individuals with DDH.

Key messages

  • Developmental dysplasia of the hip (DDH) is a common anomaly causing adult osteoarthritis. Environmental and genetic factors contribute to DDH, but its exact genetic mechanism is unclear.

  • Using high-throughput whole exome sequencing, we found a novel variant in KANSL1 that was co-inherited by all severely affected individuals diagnosed with DDH from a three-generation family. Further analysis revealed that a Kansl1 variant in mice reduced the number of chondrocytes and decreased cartilage matrix, and mouse embryonic stem differentiation assay showed cartilage defects.

  • These findings indicate a direct association between KANSL1 and hip development, expanding the pathogenic gene spectrum in DDH and providing insight into potential new targets for diagnosing and treating hip dysplasia.

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Data availability

All data used during the study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank the participants and families involved in the study.

Funding

The study was supported by the National Natural Science Foundation of China (grant number: 81772296) and Liaoning Revitalization Talents Program (grant number: XLYC1908008).

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Authors and Affiliations

  1. Department of Pediatric Orthopedics, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China

    Xiaowen Xu, Ronghua Gui & Lianyong Li

  2. Center for Genetics, National Research Institute for Family Planning, Beijing, China

    Xinying Bi, Tengyan Li & Binbin Wang

  3. Department of Medical Genetics, The Capital Medical University, Beijing, China

    Jing Wang

  4. Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

    Xinying Bi & Binbin Wang

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  1. Xiaowen Xu
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  2. Xinying Bi
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Contributions

Study design: WBB, LLY. Study conduct and data analysis: XXW, WJ, BXY, RHG, LTY. Drafting manuscript: BXY, XXW. Revising manuscript: WBB, LLY. Approving final version of manuscript: WBB, LLY, XXW, BXY, WJ, RHG, LTY.

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Correspondence to Lianyong Li or Binbin Wang.

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Written informed consent was obtained from the patients. This research was approved by the ethical committee of Shengjing Hospital of China Medical University (No.2017PS082K).

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The authors declare no competing interests.

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Xiaowen Xu and Xinying Bi contributed equally to this work.

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Xu, X., Bi, X., Wang, J. et al. Identification of KANSL1 as a novel pathogenic gene for developmental dysplasia of the hip. J Mol Med 100, 1159–1168 (2022). https://doi.org/10.1007/s00109-022-02220-4

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