Genetic landscape of a large cohort of Primary Ovarian Insufficiency: New genes and pathways and implications for personalized medicine.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Heddar Abdelkader, Ogur Cagri, Da Costa Sabrina, Braham Inès, Billaud-Rist Line, Findikli Necati, Beneteau Claire, Reynaud Rachel, Mahmoud Khaled, Legrand Stéphanie, Marchand Maud, Cedrin-Durnerin Isabelle, Cantalloube Adèle, Peigne Maeliss, Bretault Marion, Dagher-Hayeck Benedicte, Perol Sandrine, Droumaguet Celine, Cavkaytar Sabri, Nicolas-Bonne Carole, Elloumi Hanen, Khrouf Mohamed, Rougier-LeMasle Charlotte, Fradin Melanie, Le Boette Elsa, Luigi Perrine, Guerrot Anne-Marie, Ginglinger Emmanuelle, Zampa Amandine, Fauconnier Anais, Auger Nathalie, Paris Françoise, Brischoux-Boucher Elise, Cabrol Christelle, Brun Aurore, Guyon Laura, Berard Melanie, Riviere Axelle, Gruchy Nicolas, Odent Sylvie, Gilbert-Dussardier Brigitte, Isidor Bertrand, Piard Juliette, Lambert Laetitia, Hamamah Samir, Guedj Anne Marie, Brac de la Perriere Aude, Fernandez Hervé, Raffin-Sanson Marie-Laure, Polak Michel, Letur Hélène, Epelboin Sylvie, Plu-Bureau Genevieve, Wołczyński Sławomir, Hieronimus Sylvie, Aittomaki Kristiina, Catteau-Jonard Sophie, Misrahi Micheline
Аннотация
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.