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