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Novel variants in women with premature ovarian function decline identified via whole-exome sequencing

  • Genetics
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

To investigate the potential etiologies of premature ovarian insufficiency (POI) and diminished ovarian reserve (DOR).

Methods

Fourteen women with sporadic POI and 6 women with DOR were enrolled. We used whole-exome sequencing (WES) and bioinformatics analysis to identify variants in a subset of 599 selected POI candidate genes. The identified genes were subjected to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and protein-protein interaction (PPI) network analyses to uncover key genes and pathways.

Results

Among the 20 patients, 79 heterozygous variants were detected in 49 genes, which were classified as “likely pathogenic” or “variants of uncertain significance” according to the guidelines of the American College of Medical Genetics and Genomics. Most patients (17/20) carried two or more variants. Monoacylglycerol O-acyltransferase 1 mutations were found in six patients, and cytochrome P450 family 26 subfamily B member 1 and Bardet-Biedl syndrome 9 mutations were each found in four patients. Some variants were shared between DOR and POI. Enrichment analyses showed that the identified genes participate in key ovarian processes, such as follicular development, gonadal development, meiosis, Fanconi anemia, homologous recombination, and transforming growth factor β signaling. A PPI network revealed interactions between these proteins.

Conclusion

Premature ovarian function decline may be polygenic, and overlap exists between the genetic backgrounds of DOR and POI. WES and in silico analyses may be a useful clinical tool for etiological diagnosis and risk prediction for high-risk women in the future.

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Acknowledgments

The authors are deeply grateful to all participants involved in this study and all the doctors and researchers who participated in the study.

Funding

This study was supported by the National Key Research and Development Program [grant number 2018YFC1002105]; CAMS Innovation Fund for Medical Sciences (CIFMS) [grant number 2017-I2M-1-002].

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  1. Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, 100730, People’s Republic of China

    Ruiyi Tang & Qi Yu

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All authors contributed to the study conception and design, material preparation, data collection, and analysis. The first draft of the manuscript was written by R. T, and Q. Y revised it. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Qi Yu.

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Tang, R., Yu, Q. Novel variants in women with premature ovarian function decline identified via whole-exome sequencing. J Assist Reprod Genet 37, 2487–2502 (2020). https://doi.org/10.1007/s10815-020-01919-y

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