Genetic Landscape of a Cohort of 120 Patients with Diminished Ovarian Reserve: Correlation with Infertility
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: <i>LMNA</i>, <i>ERCC6</i>, <i>SOX8</i>, <i>POLG</i>, and <i>BMPR1B</i>. Six genes identified in single families with POI were involved in DOR, <i>GNAS</i>, <i>TGFBR3</i>, <i>XPNPEP2</i>, <i>EXO1</i>, <i>BNC1</i>, <i>ATG</i>, 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.
Authors
- Micheline Misrahi (ORCID: https://orcid.org/0000-0002-5379-8859)
- Abdelkader Heddar (ORCID: https://orcid.org/0000-0002-1966-5462)
- Isabelle Cédrin‐Durnerin (ORCID: https://orcid.org/0000-0003-3166-8014)
- Stefan Lebrun
- Antoine Torre (ORCID: https://orcid.org/0000-0001-6515-6928)
- S. Gricourt
- Claire Bénéteau (ORCID: https://orcid.org/0000-0002-1682-523X)
- Dominique Luton (ORCID: https://orcid.org/0000-0001-9873-419X)
- Inès Braham
- Laure Metayer-Amelot
- H. Fernandez (ORCID: https://orcid.org/0000-0002-6463-1018)
- Sophie Catteau-Jonard (ORCID: https://orcid.org/0000-0003-1285-6423)
- Sylvie Epelboin (ORCID: https://orcid.org/0000-0001-7972-1609)
- Nicolas Chevalier (ORCID: https://orcid.org/0000-0001-7160-4301)
- Léonore Zagdoun
- Maëliss Peigné (ORCID: https://orcid.org/0000-0001-9987-0740)
- Adèle Cantalloube
- Inès Abdennebi (ORCID: https://orcid.org/0000-0002-7501-287X)
- Radka Stoeva (ORCID: https://orcid.org/0000-0002-6383-8201)
- Stéphanie Legrand
- Mohamed Khrouf (ORCID: https://orcid.org/0000-0002-8698-0171)
- Nicolas Gruchy
- Khaled Mahmoud
- Imène Lafraoui
- Annina Lobersztajn
- Claire Poirsier
Institutions
- Inserm (FR)
- Université Paris-Saclay (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- Centre Hospitalier Universitaire de Nice (FR)
- Centre Hospitalier Universitaire de Nantes (FR)
- Sorbonne Université (FR)
- Université Sorbonne Paris Nord (FR)
- Centre Hospitalier Universitaire de Tours (FR)
- Hôpital Jeanne de Flandre (FR)
- Centre Hospitalier Universitaire de Reims (FR)
- Centre Hospitalier Sud Francilien (FR)
- Centre Hospitalier Universitaire de Caen Normandie (FR)
- Centre Hospitalier du Mans (FR)
- Centre Hospitalier de La Rochelle (FR)
- Hôpital Jean-Verdier (FR)
- Génétique Médicale & Génomique Fonctionelle (FR)
- Hôpital Intercommunal de Créteil (FR)
- Bicêtre Hospital (FR)
- Hôpital Tenon (FR)
- Biologie, Génétique et Thérapies ostéoArticulaires et Respiratoires
- Laboratoire de Génétique Médicale (FR)
- Université de Reims Champagne-Ardenne (FR)
- Université de Caen Normandie (FR)
Publication Details
- Journal
- International Journal of Molecular Sciences
- Published
- 2024-11-06
- DOI
- https://doi.org/10.3390/ijms252211915
- Citations
- 2
- Primary Topic
- Reproductive Biology and Fertility
- Type
- article
- Field-Weighted Citation Impact
- 1.09
Funders
- Assistance publique-Hôpitaux de Paris