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

J Assist Reprod Genet. 2020 Oct;37(10):2487-2502. doi: 10.1007/s10815-020-01919-y. Epub 2020 Aug 13.


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.

Keywords: Diminished ovarian reserve; Enrichment analysis; Premature ovarian insufficiency; Whole-exome sequencing.

MeSH terms

  • Adult
  • Computational Biology
  • Exome Sequencing
  • Female
  • Genetic Variation / genetics*
  • Genomics*
  • Humans
  • Mutation / genetics
  • Ovarian Diseases / genetics*
  • Ovarian Diseases / pathology
  • Ovarian Reserve / physiology
  • Ovary / growth & development
  • Ovary / metabolism
  • Primary Ovarian Insufficiency / genetics*
  • Primary Ovarian Insufficiency / pathology
  • Transforming Growth Factor beta / genetics


  • Transforming Growth Factor beta