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Identification of novel biallelic LRRC6 variants in male Chinese patients with primary ciliary dyskinesia and infertility

  • Genetics
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Abstract

Purpose

The aim of this study is to identify the genetic cause of primary ciliary dyskinesia (PCD) and male infertility in two unrelated Han Chinese families.

Methods

We performed whole-exome sequencing in two unrelated male Han Chinese patients suffering from infertility and PCD to identify the pathogenic variants. Ultrastructural and immunostaining analyses of patient’s spermatozoa were performed to characterize the effect of the variants. The pathogenicity of the variants was validated using patient’s spermatozoa by western blotting and immunostaining analysis. Intracytoplasmic sperm injection (ICSI) was conducted in the affected families.

Results

Three variants in leucine-rich repeat containing 6 (LRRC6) [patient 1(compound heterozygote): NM_012472: c.538C > T, (p.R180*) and c.64dupT, (p.S22Ffs*19); patient 2 (homozygote): c.863C > A, (p.P288H)] were identified in two unrelated patients with PCD and male infertility. These variants were predicated deleterious and were absent or rare in human population genome data. LRRC6-mutant spermatozoa showed a highly aberrant morphology and ultrastructure with lacked inner and outer dynein arms. The LRRC6 protein was present along the normal sperm flagella, and was significantly decreased in the mutated spermatozoa. Interestingly, both patients were able to conceive through ICSI and birthed a healthy baby.

Conclusion

Our results extend the LRRC6 variant spectrum and provide reproductive guidance to families suffering from PCD-linked infertility caused by LRRC6 variants.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank all the affected individuals and their families for participating in and supporting this study. This work was supported by the National Natural Science Foundation of China (81971447 and 82171608 to Y-Q.T, 82101961 to C.T), a key grant from the Prevention and Treatment of Birth Defects from Hunan Province (2019SK1012 to Y-Q.T), Postgraduate Scientific Research Innovation Project of Hunan Province(CX20220519 to YR.W), and research grants from CITIC-Xiangya (YNXM-202004 and YNXM-202006).

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Author notes

  1. Yunhao Li and Yong Li contributed equally to this work.

Authors and Affiliations

  1. Hunan Guangxiu Hospital, Hunan Normal University, Changsha, 410081, China

    Yunhao Li & Yue-Qiu Tan

  2. Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, 410008, China

    Yong Li, Ying Wang, Lanlan Meng, Chen Tan, Juan Du, Yue-Qiu Tan, Hongchuan Nie, Qianjun Zhang, Ge Lin, Huan Zhang & Chaofeng Tu

  3. Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, 410008, China

    Lanlan Meng, Juan Du, Yue-Qiu Tan, Hongchuan Nie, Qianjun Zhang, Guangxiu Lu, Ge Lin, Huanzhu Li, Huan Zhang & Chaofeng Tu

  4. College of Life Sciences, Hunan Normal University, Changsha, China

    Huanzhu Li

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  1. Yunhao Li
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Contributions

Chaofeng Tu, Huan Zhang, and Huanzhu Li designed the study. Ying Wang, Lanlan Meng, and Chen Tan performed the variant analysis. Yunhao Li, Yong Li, Juan Du, Yue-Qiu Tan, and Hongchuan Nie carried out the evaluation of the pathogenicity of variations and spermatozoa functional analyses. Qianjun Zhang, Guangxiu Lu, and Ge Lin worked on the clinical study. Yunhao Li, Yong Li, Chaofeng Tu, Huan Zhang, and Huanzhu Li wrote the paper. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Huanzhu Li, Huan Zhang or Chaofeng Tu.

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10815_2022_2681_MOESM1_ESM.pptx

Figure S1. Computed tomography of the patient’s lungs revealing diffuse bronchiectasis but not situs inversus. (PPTX 244 KB)

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Li, Y., Li, Y., Wang, Y. et al. Identification of novel biallelic LRRC6 variants in male Chinese patients with primary ciliary dyskinesia and infertility. J Assist Reprod Genet 40, 41–51 (2023). https://doi.org/10.1007/s10815-022-02681-z

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