Background Successful human reproduction requires normal spermatogenesis, oogenesis, fertilisation and early embryonic development, and abnormalities in any of these processes will result in infertility. Early embryonic arrest is commonly observed in infertile patients with recurrent failure of assisted reproductive technology (ART). However, the genetic basis for early embryonic arrest is largely unknown.
Objective We aim to identify genetic causes of infertile patients characterised by early embryonic arrest.
Methods We pursued exome sequencing in a proband with embryonic arrest from the consanguineous family. We further screened candidate genes in a cohort of 496 individuals diagnosed with early embryonic arrest by Sanger sequencing. Effects of mutations were investigated in HeLa cells, oocytes and embryos.
Results We identified five independent individuals carrying biallelic mutations in NLRP2. We also found three individuals from two families carrying biallelic mutations in NLRP5. These mutations in NLRP2 and NLRP5 caused decreased protein expression in vitro and in oocytes and embryos.
Conclusions NLRP2 and NLRP5 are novel mutant genes responsible for human early embryonic arrest. This finding provides additional potential diagnostic markers for patients with recurrent failure of ART and helps us to better understand the genetic basis of female infertility characterised by early embryonic arrest.
- female infertility
- embryonic arrest
- reproductive medicine
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JM and WW contributed equally.
Contributors JM and WW contributed equally to this work. QS and LW are cocorresponding authors. JM, WW, ZZ, QS and LW conceived and designed the study. JM, WW, BC, LW, XM, JF, YK and XS collected the samples. JM, BC, XM and JF organised the medical records. JM, WW, ZZ, BL, JF and QS performed the experiments. JM, WW, BC, QL, LJ, LH, QS and LW analysed the data. JM and LW wrote the manuscript. All authors reviewed and approved the manuscript.
Funding This work was supported by the National Key Research and Development Program of China (2018YFC1003800; 2017YFC1001500; and 2016YFC1000600), the National Basic Research Program of China (2015CB943300), the National Natural Science Foundation of China (81725006, 81822019,81771649, 81771581 and 81571501), the Shanghai Rising Star Program (17QA1400200), the Natural Science Foundation of Shanghai (17ZR1401900) and the Foundation of Shanghai Health and Family Planning Commission (20154Y0162).
Competing interests None declared.
Ethics approval All studies on human subjects were approved by ethnic committee of Shanghai Ninth Hospital, Shanghai Jiao Tong University (No 20161207).
Provenance and peer review Not commissioned; externally peer reviewed.
Patient consent for publication Not required.