EBioMedicine (Oct 2022)

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

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

Journal volume & issue
Vol. 84
p. 104246

Abstract

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Summary: 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.

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