Titre :

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

Auteur(s) :

Heddar, Abdelkader [Auteur]
Ogur, Cagri [Auteur]
Da Costa, Sabrina [Auteur]
Braham, Inès [Auteur]
Billaud-Rist, Line [Auteur]
Findlinki, Necati [Auteur]
Beneteau, Claire [Auteur]
Reynaud, Rachel [Auteur]
Mahmoud, Khaled [Auteur]
Legrand, Stéphanie [Auteur]
Marchand, Maud [Auteur]
Cedrin-Durnerin, Isabelle [Auteur]
Cantalloube, Adèle [Auteur]
Peigne, Maeliss [Auteur]
Hôpital Jean Verdier [AP-HP]
Bretault, Marion [Auteur]
Dagher-Hayeck, Benedicte [Auteur]
Perol, Sandrine [Auteur]
Droumaguet, Celine [Auteur]
Cavkaytar, Sabri [Auteur]
Nicolas-Bonne, Carole [Auteur]
Elloumi, Hanen [Auteur]
Khrouf, Mohamed [Auteur]
Rougier-Lemasle, Charlotte [Auteur]
Fradin, Melanie [Auteur]
Le Boette, Elsa [Auteur]
Luigi, Perrine [Auteur]
Guerrot, Anne-Marie [Auteur]
Ginglinger, Emmanuelle [Auteur]
Zampa, Amandine [Auteur]
Fauconnier, Anais [Auteur]
Auger, Nathalie [Auteur]
Paris, Françoise [Auteur]
Brischoux-Boucher, Elise [Auteur]
Cabrol, Christelle [Auteur]
Brun, Aurore [Auteur]
Guyon, Laura [Auteur]
Berard, Melanie [Auteur]
Riviere, Axelle [Auteur]
Gruchy, Nicolas [Auteur]
Odent, Sylvie [Auteur]
Gilbert-Dussardier, Brigitte [Auteur]
Isidor, Bertrand [Auteur]
Piard, Juliette [Auteur]
Lambert, Laetitia [Auteur]
Hamamah, Samir [Auteur]
Guedj, Anne Marie [Auteur]
Brac De La Perriere, Aude [Auteur]
Fernandez, Hervé [Auteur]
Raffin-Sanson, Marie-Laure [Auteur]
Polak, Michel [Auteur]
Letur, Hélène [Auteur]
Epelboin, Sylvie [Auteur]
Plu-Bureau, Genevieve [Auteur]
Wołczyński, Sławomir [Auteur]
Hieronimus, Sylvie [Auteur]
Aittomaki, Kristiina [Auteur]
Jonard-Catteau, Sophie [Auteur]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Misrahi, Micheline [Auteur]

Titre de la revue :

EBioMedicine

Numéro :

84

Pagination :

104246

Éditeur :

Elsevier

Date de publication :

2022-10

ISSN :

2352-3964

Mot(s)-clé(s) en anglais :

Primary ovarian insufficiency
Personalized medicine
NF-KB
Post-translational regulation
Meiosis
DNA repair genes
Mitophagy

Discipline(s) HAL :

Sciences du Vivant [q-bio]
Sciences du Vivant [q-bio]/Génétique

Résumé en anglais : [en]

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, ...
Lire la suite >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. Funding Université Paris Saclay, Agence Nationale de Biomédecine.Lire moins >

Langue :

Anglais

Comité de lecture :

Oui

Audience :

Internationale

Vulgarisation :

Non

Autre(s) projet(s) ou source(s) de financement :

Université Paris Sud-Paris Saclay
Hôpitaux Universitaires Paris Saclay
Agence Nationale de Biomédecine
Institut National de la Santé et de la Recherche Médicale-INSERM

Établissement(s) :

Université de Lille
Inserm
CHU Lille

Collections :

• Autres travaux scientifiques

Date de dépôt :

2024-01-16T00:42:41Z
2025-02-19T14:54:08Z