Commentary Open Access
Volume 1 | Issue 1 | DOI: https://doi.org/10.33696/genetics.1.005

Commentary on NOBOX Mutations in Premature Ovarian Insufficiency

  • 1Fertility Clinic, Department of Obstetrics and Gynecology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
  • 2Institut de Pathologie et de Génétique (IPG), Gosselies, Belgium
  • 3Centre for Medical Genetics, Reproduction and Genetics and Regenerative Medicine research cluster, Reproduction and Genetics research group, Vrije Universiteit Brussel-UZ Brussel, Brussels, Belgium
  • 4Brussels Interuniversity Genomics High Throughput core (Bright Core), Brussels, Belgium
  • 5Department of Genetics, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
  • 6Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
+ Affiliations - Affiliations

Corresponding Author

Prof. Anne Delbaere, anne.delbaere@erasme.ulb.ac.be

Received Date: February 11, 2022

Accepted Date: February 24, 2022


NOBOX is an ovarian specific transcription factor that plays an important role in follicular growth and survival. Nineteen NOBOX variants have been previously associated with premature ovarian insufficiency (POI). Disease severity in patients with heterozygous and homozygous mutations largely overlap however, hampering genotype-phenotype correlations. We recently reported the first case of biallelic truncating mutations (NM_001080413.3 (NOBOX):c.826C>T, p.(Arg276*) and NM_001080413.3(NOBOX):c.1421del, p.(Gly474Alafs*76)) of NOBOX in two Belgian sisters with POI. Both variants were identified by whole exome sequencing (WES) and classified as pathogenic following ACMG guidelines. Our findings suggest that haploinsufficiency of NOBOX can be well tolerated. Furthermore, compound heterozygosity for the two NOBOX variants was very likely responsible for the severe POI phenotype in the two sisters, who presented with primary amenorrhea (PA), delayed puberty and hypergonadotropic hypogonadism. In addition, we searched for NOBOX variants in a cohort of 151 unrelated POI patients and showed a prevalence of NOBOX mutations of 1.3%, contrasting with previous reports of NOBOX mutation prevalence in POI patients up to 9%. A new NOBOX variant was identified in our cohort (NM_001080413.3 (NOBOX): c.259C>A, p.(Pro87Thr)) and reported for the first time in the present paper.


NOBOX gene, Delayed puberty, Premature ovarian insufficiency, Next generation sequencing, Hypergonadotropic hypogonadism, Amenorrhea

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