New insights into the genetic basis of premature ovarian insufficiency: Novel causative variants and candidate genes revealed by genomic sequencing

Jaillard, S., Bell, K., Akloul, L., Walton, K., McElreavy, K., Stocker, W.A., Beaumont, M., Harrisson, C., Jääskeläinen, T., Palvimo, J.J., Robevska, G., Launay, E., Satié, A.P., Listyasari, N., Bendavid, C., Sreenivasan, R., Duros, S., van den Bergen, J., Henry, C., Domin-Bernhard, M., Cornevin, L., Dejucq-Rainsford, N., Belaud-Rotureau, M.A., Odent, S., Ayers, K.L., Ravel, C., Tucker, E.J., Sinclair, A.H.
Maturitas   141: 9-19 (Journal)
Registered Authors
Ayers, Katie Louise, Sreenivasan, Rajini
Female infertility, Genomics, Premature ovarian insufficiency
MeSH Terms
  • Adolescent
  • Cell Cycle Proteins/genetics
  • DNA Helicases/genetics
  • Female
  • Genomics
  • Growth Differentiation Factor 9/genetics
  • Humans
  • Infertility, Female
  • Karyopherins/genetics*
  • Menopause, Premature/genetics
  • Microfilament Proteins/genetics*
  • Nuclear Receptor Interacting Protein 1/genetics*
  • Ovarian Diseases
  • Ovarian Reserve/genetics*
  • Primary Ovarian Insufficiency/genetics*
  • Receptors, Cytoplasmic and Nuclear/genetics*
  • Whole Exome Sequencing
  • Young Adult
33036707 Full text @ Maturitas
Ovarian deficiency, including premature ovarian insufficiency (POI) and diminished ovarian reserve (DOR), represents one of the main causes of female infertility. POI is a genetically heterogeneous condition but current understanding of its genetic basis is far from complete, with the cause remaining unknown in the majority of patients. The genes that regulate DOR have been reported but the genetic basis of DOR has not been explored in depth. Both conditions are likely to lie along a continuum of degrees of decrease in ovarian reserve. We performed genomic analysis via whole exome sequencing (WES) followed by in silico analyses and functional experiments to investigate the genetic cause of ovarian deficiency in ten affected women. We achieved diagnoses for three of them, including the identification of novel variants in STAG3, GDF9, and FANCM. We identified potentially causative FSHR variants in another patient. This is the second report of biallelic GDF9 and FANCM variants, and, combined with functional support, validates these genes as bone fide autosomal recessive "POI genes". We also identified new candidate genes, NRIP1, XPO1, and MACF1. These genes have been linked to ovarian function in mouse, pig, and zebrafish respectively, but never in humans. In the case of NRIP1, we provide functional support for the deleterious nature of the variant via SUMOylation and luciferase/β-galactosidase reporter assays. Our study provides multiple insights into the genetic basis of POI/DOR. We have further elucidated the involvement of GDF9, FANCM, STAG3 and FSHR in POI pathogenesis, and propose new candidate genes, NRIP1, XPO1, and MACF1, which should be the focus of future studies.
Genes / Markers
Show all Figures
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes