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. 2024 Nov 6;25(22):11915.
doi: 10.3390/ijms252211915.

Genetic Landscape of a Cohort of 120 Patients with Diminished Ovarian Reserve: Correlation with Infertility

Imène Lafraoui  1   2 , Abdelkader Heddar  1   2 , Adèle Cantalloube  3 , Inès Braham  4 , Maëliss Peigné  5 , Claire Beneteau  6 , Solenne Gricourt  3 , Claire Poirsier  7 , Stéphanie Legrand  8 , Radka Stoeva  9 , Laure Metayer-Amelot  10 , Annina Lobersztajn  11 , Soizic Lebrun  12 , Nicolas Gruchy  13 , Inès Abdennebi  14 , Isabelle Cedrin-Durnerin  5 , Hervé Fernandez  15 , Dominique Luton  15 , Antoine Torre  16 , Léonore Zagdoun  17 , Nicolas Chevalier  4 , Mohamed Khrouf  18 , Khaled Mahmoud  18 , Sylvie Epelboin  3 , Sophie Catteau-Jonard  19 , Micheline Misrahi  1   2
Affiliations

Genetic Landscape of a Cohort of 120 Patients with Diminished Ovarian Reserve: Correlation with Infertility

Imène Lafraoui et al. Int J Mol Sci. .

Abstract

Diminished ovarian reserve (DOR) and primary ovarian insufficiency (POI) are major causes of female infertility. We recently found a monogenic etiology in 29.3% of POI, leading to personalized medicine. The genetic landscape of DOR is unknown. A prospective study (2018-2023) of an international cohort of 120 patients with unexplained DOR was performed using a large custom targeted next-generation sequencing panel including all known POI-causing genes. The diagnostic yield, based on the American College of Medical Genetics, was 24, 2%. Genes belong to different pathways: metabolism and mitochondria (29.7%), follicular growth (24.3%), DNA repair/meiosis (18.9%), aging (16.2%), ovarian development (8.1%), and autophagy (2.7%). Five genes were recurrently found: LMNA, ERCC6, SOX8, POLG, and BMPR1B. Six genes identified in single families with POI were involved in DOR, GNAS, TGFBR3, XPNPEP2, EXO1, BNC1, ATG, highlighting their role in maintaining ovarian reserve. In our cohort, 26 pregnancies were recorded, but no pregnancy was observed when meiosis/DNA repair genes were involved, suggesting severely impaired oocyte quality. Additional studies should confirm these preliminary results. This study with a large NGS panel defines the genetic landscape of a large cohort of DOR. It supports routine genetic diagnosis. Genetics could be a biomarker predicting infertility and progression to POI.

Keywords: DNA repair; cohort; diminished ovarian reserve; fertility; gene; genetic counseling; next-generation sequencing; pregnancy; primary ovarian insufficiency.

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Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Hormonal assays and antral follicle counts in the cohort of patients with diminished ovarian reserve. Hormonal assays (FSH, LH, Estradiol and AMH) together with the antral follicle count (AFC) in patients. The Y scale unit is variable according to each parameter represented on the X-axis. Normal range: AMH (7–20.7 pmol/L); respectively, ranges for follicular, ovulatory, luteal phases and menopause are the following: FSH (IU/L): (2.9–12), (6.3–24), (1.5–7), (17–95); LH: (IU/L) (1.5–8), (9.6–80), (0.2–6.5), (8–33); Estradiol (ng/L): (19.5–144.2), (63.9–356.7), (55.8–214.2), (≤32.2).
Figure 2
Figure 2
Genetic studies of a cohort of patients with DOR. Patients were studied by a custom-made targeted NGS comprising 88 genes. (A) Diagnostic yield according to ACMG criteria: variants are classified according to the American College of Medical Genetics (ACMG) guidelines. N = 120: the whole cohort comprises 120 patients with DOR. Vus: variant of unknown significance. Carrier: patients harboring a heterozygous pathogenic variant in a known autosomal recessive POI gene. Positive: the diagnostic yield corresponds to patients carrying pathogenic (P) or likely pathogenic (LP) variants and is 24%. (B) Pathways of genes involved in DOR. The different pathways are indicated with different colors. The pie chart represents the proportion of patients with P or LP variants in a specific pathway: Mitochondria and Metabolism (29.7%), Follicular growth (24.3%), DNA repair and meiosis (18.9%), Aging (16.2%), Ovarian development (8.1%), Autophagy (2.7%). The histograms show the number and type of variants detected in each pathway.
Figure 3
Figure 3
Genes recurrently involved in the cohort of DOR. Variants are classified according to ACMG criteria. Only pathogenic (class 5) and likely pathogenic (class 4) variants are considered for genetic diagnosis as recommended by the ACMG. The number of patients carrying a class 5 or class 4 variant of each gene is indicated.
Figure 4
Figure 4
The histograms show the number of pregnancies recorded in patients with alterations in each genetic pathway. Each pathway is represented by a color code. The occurrence of pregnancies is represented in green with the number of pregnancies indicated for each pathway altered. The number of patients without a pregnancy is shown in red for each pathway altered. Thirteen pregnancies were recorded in patients with an established genetic diagnostic with, in almost all cases, one pregnancy per patient except for two patients with an LMNA defect (two pregnancies for two patients) and the patient with a POLG defect (two pregnancies in one patient).
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