Genetic Landscape of a Large Cohort of Primary Ovarian Insufficiency: New Genes and Pathways and Implications for Personalized Medicine

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dc.authorid282485en_US
dc.contributor.authorFındıklı, Necati
dc.contributor.authorvd.
dc.date.accessioned2023-03-10T05:48:19Z
dc.date.available2023-03-10T05:48:19Z
dc.date.issued2022
dc.departmentİstanbul Beykent Üniversitesien_US
dc.description.abstractBackground Primary Ovarian Insufficiency (POI), a public health problem, affects 1-3.7% of women under 40 yield ing 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 chromo somal 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 pathogene sis 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 Universit e Paris Saclay, Agence Nationale de Biom edecine.en_US
dc.identifier.doi10.1016/j.ebiom.2022.104246
dc.identifier.issn2255-2863
dc.identifier.pmid36099812en_US
dc.identifier.scopus2-s2.0-85137619153en_US
dc.identifier.scopusqualityN/Aen_US
dc.identifier.urihttps://doi.org/10.1016/j.ebiom.2022.104246
dc.identifier.wosWOS:000877614200002en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherELSEVIERen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.subjectPrimary ovarian insufficiencyen_US
dc.subjectPersonalized medicineen_US
dc.subjectNF-KBen_US
dc.subjectPost - translational regulationen_US
dc.subjectMeiosis/ DNA repair genesen_US
dc.subjectMitophagyen_US
dc.titleGenetic Landscape of a Large Cohort of Primary Ovarian Insufficiency: New Genes and Pathways and Implications for Personalized Medicineen_US
dc.typeArticleen_US

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