O-305 Next-generation sequencing of a cohort of 100 patients with diminished ovarian reserve reveals an etiology in 27% of cases and may predict the fertility prognosis
Authors: Heddar A , Braham I , Cantalloube A , Beneteau C , Gricourt S , Gruchy N , Epelboin S , Fernandez H , Catteau-Jonard S , Misrahi M 
Published: June 2023

Study question

Identify the genetic cause of a cohort of patients with unexplained Diminished ovarian reserve (DOR) by next-generation sequencing and compare with pregnancy outcome.

Summary answer

A high-yield positive genetic diagnosis was obtained: 27% of cases. Defects of genes involved in DNA repair/meiosis appeared to have an unfavorable prognosis.

What is known already

Ten percent of women undergoing Medically Assisted Procreation-MAP have a DOR defined by an AMH level &lt;1.2 and an antral follicle count (AFC) &lt;5. However, most causes of DOR are unknown. There is no known criteria of success in MAP. Primary ovarian insufficiency (POI) corresponds to a complete cessation of ovarian function in 1-4% of women under 40 years. We have very recently shown in a large cohort of POI that a custom-made target next-generation sequencing (NGS) POI panel allowed a genetic diagnosis in 30% of unexplained POI and leads to personalized medicine (Heddar et al., EBioMedicine. 2022 doi: 10.1016/j.ebiom.2022.104246).

Study design, size, duration

Prospective genetic study of a cohort of 100 patients with undergoing MAP using a custom-made NGS-POI panel comprising 88 validated POI-causing genes. These patients were for 77% European, 20% North African and 3% Asian. The classification of the variants detected were based on the American College of Medical Genetic criteria 2015. Only pathogenic and likely pathogenic variants were used for diagnosis. Candidate gene studies were performed in negative patients.

Participants/materials, setting, methods

One hundred patients aged 16-35 with DOR, normal karyotype and FMR1 gene, were studied with the NGS POI panel. The segregation of the variants in the available families was performed by Sanger sequencing. Cytogenetic studies of chromosomal fragility was performed if necessary. The outcome of the pregnancy (spontaneous or induced) was recorded. A correlation between the result of the genetic study and the outcome of the pregnancy has been performed.

Main results and the role of chance

One family included two sisters, one with POI and the other with DOR, highlighting the proximity of the two syndromes. A high positive genetic yield was found: 27% of cases. Genes were involved 1) in follicular growth and gonadal development (SOX8, AR, NOBOX, BMPR1A, BMPR1B, GNAS) (35%) 2) DNA repair (BNC1, ERCC6, BRCA1, ATM) (31%) 3) metabolism and mitochondrial functions (POLG, STAR) (12%), 4) cellular aging (24%), in particular the LMNA gene.

In a patient with isolated DOR, we identified for the first time, bi-allelic truncating variants of BRCA1, a major breast/ovarian cancer susceptibility gene. Cytogenetic studies revealed increased chromosomal breaks with radial figures typical of Fanconi Anemia (FA). However there was no sign of FA or cancer in the patient and family. This observation is reminiscent of the family with isolated POI and biallelic mutations of BRCA2 (Heddar et al, J Med Genet 2021; DOI: 10.1136/jmedgenet-2019-106672).

Among the 27 patients with an established genetic diagnosis, six were able to obtain a pregnancy. However, no pregnancies were achieved in the DNA repair gene suggesting an unfavorable prognosis for this gene family. On the other hand, patients with mutations of other gene families seem to have a better prognosis of fertility.

Limitations, reasons for caution

The size of the cohort should be implemented to confirm these results. The issues of pregnancy are not available for the whole cohort.

Wider implications of the findings

This is the first genetic study of a cohort of DOR and the first implication of BRCA1 in isolated DOR. It shows i) the need for genetic studies of DOR ii) the genetic link between POI and DOR iii) NGS study could give information on the fertility prognosis of DOR.

Trial registration number

not applicable