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Genotype-phenotype correlations
Original research
Biallelic variants in ZFP36L2 cause female infertility characterised by recurrent preimplantation embryo arrest
  1. Wei Zheng1,2,
  2. Qian-Qian Sha3,
  3. Huiling Hu2,
  4. Fei Meng1,
  5. Qinwei Zhou1,
  6. Xueqin Chen2,
  7. Shuoping Zhang1,
  8. Yifan Gu1,2,
  9. Xian Yan1,
  10. Lei Zhao1,
  11. Yurong Zong1,
  12. Liang Hu1,2,
  13. Fei Gong1,2,
  14. Guangxiu Lu1,2,
  15. Heng-Yu Fan4,
  16. Ge Lin1,2
  1. 1 Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-XIANGYA, Changsha, Hunan, China
  2. 2 Labortatory of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem and Reproductive Engineering, Central South University, Changsha, Hunan, China
  3. 3 Fertility Preservation Laboratory, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China
  4. 4 Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
  1. Correspondence to Dr Ge Lin; linggf{at}hotmail.com; Heng-Yu Fan; hyfan{at}zju.edu.cn

Abstract

Background Recurrent preimplantation embryo developmental arrest (RPEA) is the most common cause of assisted reproductive technology treatment failure associated with identified genetic abnormalities. Variants in known maternal genes can only account for 20%–30% of these cases. The underlying genetic causes for the other affected individuals remain unknown.

Methods Whole exome sequencing was performed for 100 independent infertile females that experienced RPEA. Functional characterisations of the identified candidate disease-causative variants were validated by Sanger sequencing, bioinformatics and in vitro functional analyses, and single-cell RNA sequencing of zygotes.

Results Biallelic variants in ZFP36L2 were associated with RPEA and the recurrent variant (p.Ser308_Ser310del) prevented maternal mRNA decay in zygotes and HeLa cells.

Conclusion These findings emphasise the relevance of the relationship between maternal mRNA decay and human preimplantation embryo development and highlight a novel gene potentially responsible for RPEA, which may facilitate genetic diagnoses.

  • reproductive medicine
  • human genetics

Data availability statement

Data are available upon reasonable request. The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

https://doi.org/10.1136/jmedgenet-2021-107933

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    Data availability statement

    Data are available upon reasonable request. The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

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    Footnotes

    • WZ and Q-QS contributed equally.

    • H-YF and GL contributed equally.

    • Contributors WZ and GL designed the study; WZ analysed the data and wrote the draft of this manuscript; WZ, QS, HH, FM, XC and QZ performed the research; SZ, YG, XY, LZ, YZ, LH and FG performed the clinical work; GL and H-YF helped in editing and improving the manuscript.

    • Funding This work was supported by the National Key Research and Development Program of China (grant numbers 2018YFC1003100 and 2020YFF0426502), the National Natural Science Foundation of China (grant numbers 82001633, 31930031 and 91949108), China Postdoctoral Science Foundation (grant numbers 2020M682575 and 2021T140198), the Changsha Municipal Natural Science Foundation (grant number kq2007022), Hunan Provincial Grant for Innovative Province Construction (grant number 2019SK4012) and the Scientific Research Foundation of Reproductive and Genetic Hospital of CITIC XIANGYA (grant number YNXM-201913).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.