Recurrent pregnancy loss is newly defined as more than two consecutive miscarriages. Recurrent pregnancy loss occurs in <5% of total pregnancies. The cause in approximately 40–60% of recurrent pregnancy loss cases remains elusive and must be determined. We investigated two unrelated Iranian consanguineous families with recurrent pregnancy loss. We performed exome sequencing using DNA from a miscarriage tissue and identified a homozygous NOP14 missense variant (c.[136C>G];[136C>G]) in both families. NOP14 is an evolutionally conserved protein among eukaryotes and is required for 18S rRNA processing and 40S ribosome biogenesis. Interestingly, in zebrafish, homozygous mutation of nop14 (possibly loss of function) resulting from retrovirus-mediated insertional mutagenesis led to embryonic lethality at 5 days after fertilization, mimicking early pregnancy loss in humans. Similarly, it is known that the nop14-null yeast is inviable. These data suggest that the homozygous NOP14 mutation is likely to cause recurrent pregnancy loss. Furthermore, this study shows that exome sequencing is very useful to determine the etiology of unsolved recurrent pregnancy loss.
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We thank all the patients and their families for their participation in this study. We also thank Nobuko Watanabe for her technical assistance. This work was supported by grants from Research on Measures for Intractable Diseases; Comprehensive Research on Disability Health and Welfare, the Strategic Research Program for Brain Science; Initiative on Rare and Undiagnosed Diseases in Pediatrics and Initiative on Rare and Undiagnosed Diseases for Adults from the Japan Agency for Medical Research and Development; Grants-in-Aid for Scientific Research on Innovative Areas (Transcription Cycle) from the Ministry of Education, Science, Sports and Culture of Japan; Grants-in-Aid for Scientific Research (A and B) from the Japan Society for the Promotion of Science; Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems from the Japan Science and Technology Agency; grants from the Ministry of Health, Labor and Welfare; the Takeda Science Foundation; the Yokohama Foundation for Advancement of Medical Science; and the Hayashi Memorial Foundation for Female Natural Scientists.
Conflict of interest
The authors declare that they have no conflict of interest.
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Human Reproduction Update (2019)
Genetic diagnosis in first or second trimester pregnancy loss using exome sequencing: a systematic review of human essential genes
Journal of Assisted Reproduction and Genetics (2019)