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Article Dans Une Revue EBioMedicine Année : 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 [AP-HP, Le Kremlin-Bicêtre]
3 Hôpital Paul Brousse
4 YTU - Yildiz Technical University
5 Hôpital 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 CPSR - Clinique de Promotion des Sciences de la Reproduction [Tunis]
20 Service d'endocrinologie [CHU Nice]
21 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
22 IGDR - Institut de Génétique et Développement de Rennes
23 CHU de Saint-Brieuc
24 Centre Hospitalier Antibes - Juan-les-Pins
25 CHU Rouen
26 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
27 Centre Hospitalier de Mulhouse, site du Hasenrain (Mulhouse)
28 CHU ST-E - Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne]
29 IGR - Institut Gustave Roussy
30 CHU Montpellier
31 DEFE - Développement Embryonnaire, Fertilité et Environnement
32 Hôpital Arnaud de Villeneuve [CHRU Montpellier]
33 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
34 UFC - Université de Franche-Comté
35 Laboratoire de génétique clinique [Service de génétique, CHU Poitiers]
36 UP - Université de Poitiers = University of Poitiers
37 Service de Génétique Clinique [CHRU Nancy]
38 BIOTARGEN - Biologie, génétique et thérapies ostéoarticulaires et respiratoires
39 CHU Caen
40 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
41 Centre de génétique humaine [CHRU Besançon]
42 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
43 UM - Université de Montpellier
44 Hôpital Louis Pradel [CHU - HCL]
45 CESP - Centre de recherche en épidémiologie et santé des populations
46 Hôpital Foch [Suresnes]
47 Polyclinique de Navarre
48 MUB - Medical University of Białystok
49 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
50 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
51 Université de Lille
Necati Findikli
Khaled Mahmoud
  • Fonction : Auteur
Stéphanie Legrand
  • Fonction : Auteur
Michel Polak
Genevieve Plu-Bureau

Résumé

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.

Domaines

Génétique
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Dates et versions

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

Licence

Paternité - Pas d'utilisation commerciale - Pas de modification

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Citer

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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