Primary Ovarian Insufficiency (POI) affects ~1% of women under forty leading most often to definitive infertility. About 25% of cases seem to be of genetic origin. The recent leap due to whole exome sequencing has led to the identification of new genes involved. Up to now more than sixty genes have been implicated in POI. Diminished Ovarian Reserve (DOR) also leads to female infertility. DOR is defined by a decreased quantity or quality of follicles based on antral follicle count (AFC < 5) and anti-müllerian hormone plasma levels (AMH<0.51ng/mL). However the etiologies involved remain largely unknown. Here, we studied 66 Caucasian patients with DOR or POI using targeted next generation sequencing comprising 60 genes involved in POI. We identified 3 novel heterozygous missense mutations in CSB-PGBD3. The first mutation, located in exon 5 (c.1339C>T; p.(Arg447Trp)) was identified in a 16 years old patient with DOR (FSH =8.5UI/L, E2=37pg/mL, AFC=6 and AMH=0.6 ng/ml) and irregular menses. Her dizygotic twin sister has regular menses and normal hormonal blood assays up to now (18 years old). Two other novel mutations in CSB-PGDB3 were found in two patients with POI and secondary amenorrhea (17 and 30 years) (2/65=3%). The mutations are located in exons 2 of CSB-PGDB3 c.364C>T; p.(Arg122Cys) and exon 5: c.1389G>t; p.(Gln463His). All three mutations are predicted to be pathogenic by in silico predictive softwares. They involve residues highly conserved during the evolution. CSB-PGBD3, also named ERCC6, encodes a DNA-binding protein involved in repairing DNA damage. Biallelic Mutations of this gene are associated with Cockayne syndrome type B and cerebro-oculo-facio-skeletal syndrome. Heterozygous mutations with a dominant negative effect were found in a single report with a very low incidence (0.7%) in Chinese patients with POI. Our work shows for the first time the implication of a DNA repair gene defect in DOR and reveals that mutations of CSB-PGBD3 have a high prevalence in POI in Europe (3%). It supports the study of CSB-PGBD3 in unexplained DOR and isolated POI. An appropriate genetic counseling and management should be performed in the siblings. Fertility preservation should be performed in heterozygous carriers of mutations, since accumulation of oocyte damage will lead to complete loss of the ovarian reserve in the future. We are presently screening a large cohort of DOR to evaluate the frequency of CSB-PGBD3 mutations.
18 - 21 May 2019
European Society of Endocrinology