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Journal Articles EBioMedicine Year : 2022

Genetic landscape of a large cohort of Primary Ovarian Insufficiency: New genes and pathways and implications for personalized medicine

1 Physiopathologie et traitement des maladies du foie
2 Hôpital Bicêtre
3 Hôpital Paul Brousse
4 YTU - Yildiz Technical University
5 CHU Necker - Enfants Malades [AP-HP]
6 CHU Nice - Centre Hospitalier Universitaire de Nice
7 Hôpital Cochin [AP-HP]
8 CHU Nantes - Centre hospitalier universitaire de Nantes
9 TIMONE - Hôpital de la Timone [CHU - APHM]
10 AMU - Aix Marseille Université
11 Hôpital Jean Verdier [AP-HP]
12 CHU Tenon [AP-HP]
13 SU - Sorbonne Université
14 Service d’endocrinologie et nutrition [AP-HP Ambroise-Paré]
15 Unité de Gynécologie Médicale, AP-HP, Hôpital Port-Royal, Université de Paris
16 Service de médecine interne [Mondor]
17 Üsküdar university
18 CHAL - Centre Hospitalier Alpes Léman
19 Service d'endocrinologie [CHU Nice]
20 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital
21 IGDR - Institut de Génétique et Développement de Rennes
22 CHU de Saint-Brieuc
23 Centre Hospitalier Antibes - Juan-les-Pins
24 CHU Rouen
25 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
26 Centre Hospitalier de Mulhouse, site du Hasenrain (Mulhouse)
27 CHU ST-E - Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne]
28 IGR - Institut Gustave Roussy
29 CHU Montpellier
30 DEFE - Développement Embryonnaire, Fertilité et Environnement
31 Hôpital Arnaud de Villeneuve [CHRU Montpellier]
32 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
33 UFC - Université de Franche-Comté
34 Service de génétique clinique [Poitiers]
35 Université de Poitiers
36 Service de Génétique Clinique [CHRU Nancy]
37 BIOTARGEN - Biologie, génétique et thérapies ostéoarticulaires et respiratoires
38 CHU Caen
39 CHU Poitiers - Centre hospitalier universitaire de Poitiers
40 Centre de génétique humaine [CHRU Besançon]
41 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
42 UM - Université de Montpellier
43 Hôpital Louis Pradel [CHU - HCL]
44 CESP - Centre de recherche en épidémiologie et santé des populations
45 Hôpital Foch [Suresnes]
46 Polyclinique de Navarre
47 MUB - Medical University of Białystok
48 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
49 CHU Lille
50 Université de Lille
Necati Findikli
Khaled Mahmoud
  • Function : Author
Stéphanie Legrand
  • Function : Author
Hanen Elloumi
  • Function : Author
Mohamed Khrouf
  • Function : Author
Michel Polak


Background Primary Ovarian Insufficiency (POI), a public health problem, affects 1-3.7% of women under 40 yielding infertility and a shorter lifespan. Most causes are unknown. Recently, genetic causes were identified, mostly in single families. We studied an unprecedented large cohort of POI to unravel its molecular pathophysiology. Methods 375 patients with 70 families were studied using targeted (88 genes) or whole exome sequencing with pathogenic/likely-pathogenic variant selection. Mitomycin-induced chromosome breakages were studied in patients’ lymphocytes if necessary. Findings A high-yield of 29.3% supports a clinical genetic diagnosis of POI. In addition, we found strong evidence of pathogenicity for nine genes not previously related to a Mendelian phenotype or POI: ELAVL2, NLRP11, CENPE, SPATA33, CCDC150, CCDC185, including DNA repair genes: C17orf53(HROB), HELQ, SWI5 yielding high chromosomal fragility. We confirmed the causal role of BRCA2, FANCM, BNC1, ERCC6, MSH4, BMPR1A, BMPR1B, BMPR2, ESR2, CAV1, SPIDR, RCBTB1 and ATG7 previously reported in isolated patients/families. In 8.5% of cases, POI is the only symptom of a multi-organ genetic disease. New pathways were identified: NF-kB, post-translational regulation, and mitophagy (mitochondrial autophagy), providing future therapeutic targets. Three new genes have been shown to affect the age of natural menopause supporting a genetic link. Interpretation We have developed high-performance genetic diagnostic of POI, dissecting the molecular pathogenesis of POI and enabling personalized medicine to i) prevent/cure comorbidities for tumour/cancer susceptibility genes that could affect life-expectancy (37.4% of cases), or for genetically-revealed syndromic POI (8.5% of cases), ii) predict residual ovarian reserve (60.5% of cases). Genetic diagnosis could help to identify patients who may benefit from the promising in vitro activation-IVA technique in the near future, greatly improving its success in treating infertility.


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Dates and versions

hal-03790543 , version 1 (23-11-2022)


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Abdelkader Heddar, Cagri Ogur, Sabrina da Costa, Inès Braham, Line Billaud-Rist, et al.. Genetic landscape of a large cohort of Primary Ovarian Insufficiency: New genes and pathways and implications for personalized medicine. EBioMedicine, 2022, 84, pp.104246. ⟨10.1016/j.ebiom.2022.104246⟩. ⟨hal-03790543⟩
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