Advances in the Molecular Pathophysiology, Genetics, and Treatment of Primary Ovarian Insufficiency

Primary ovarian insufficiency (POI) affects similar to 1% of women before 40 years of age. The recent leap in genetic knowledge obtained by next generation sequencing (NGS) together with animal models has further elucidated its molecular pathogenesis, identifying novel genes/pathways. Mutations of > 60 genes emphasize high genetic heterogeneity. Genome-wide association studies have revealed a shared genetic background between POI and reproductive aging. NGS will provide a genetic diagnosis leading to genetic/therapeutic counseling: first, defects in meiosis or DNA repair genes may predispose to tumors; and second, specific gene defects may predict the risk of rapid loss of a persistent ovarian reserve, an important determinant in fertility preservation. Indeed, a recent innovative treatment of POI by in vitro activation of dormant follicles proved to be successful.Peer reviewe

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

Background 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 Universite? Paris Saclay, Agence Nationale de Biome?decine.Copyright (c) 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)Peer reviewe

Genetic Landscape of Primary Ovarian Insufficiency : New Links to Meiosis/DNA Repair Genes, New Molecular Pathways Identified and Implications for Personalized Medicine

L’insuffisance ovarienne primitive (IOP), problème de santé publique, atteint 1-3,7% des femmes avant 40 ans. Elle est responsable d’infertilité et de diminution de longévité. Nous avons pour la première fois impliqué BRCA2, gène majeur de prédisposition aux cancers du sein et de l’ovaire, dans une IOP isolée confirmant le lien génétique entre infertilité et cancer. Nous avons développé un diagnostic génétique de haute performance dans 29.3% des cas d’une cohorte sans précédent de 375 IOP. Neuf nouveaux gènes sont impliqués dans la réparation d’ADN, ou dans de nouvelles voies : l’inflammation, la transcription/traduction et la mitophagie, et correspondent à de potentielles futures cibles thérapeutiques. La génétique permet une médecine personnalisée pour i) prévenir/guérir les comorbidités pour les gènes de susceptibilité aux tumeurs/cancers, ou pour les IOP syndromiques génétiquement révélés ii) prédire une réserve ovarienne résiduelle et donc un pronostic de fertilité.Primary ovarian insufficiency (POI), a public health problem, affects 1-3.7% of women before the age of 40. It is responsible for infertility and reduced longevity. For the first time, we implicated BRCA2, a major predisposition gene for breast and ovarian cancer, in an isolated POI confirming the genetic link between infertility and cancer. We have developed high-performance genetic diagnosis in 29.3% of cases from an unprecedented cohort of 375 pateints. Nine new genes are involved in DNA repair, or in new pathways: inflammation, transcription/translation and mitophagy, and correspond to potential future therapeutic targets. Genetics enables personalized medicine to i) prevent/cure comorbidities for tumor/cancer susceptibility genes, or for genetically revealed syndromic POI ii) predict residual ovarian reserve and hence fertility prognosis

Architecture génétique de l'insuffisance ovarienne primitive : Nouveaux liens avec les Gènes de Méiose/Réparation de l’ADN, nouvelles voies moléculaires identifiées et implication pour une Médecine Personnalisée

Primary ovarian insufficiency (POI), a public health problem, affects 1-3.7% of women before the age of 40. It is responsible for infertility and reduced longevity. For the first time, we implicated BRCA2, a major predisposition gene for breast and ovarian cancer, in an isolated POI confirming the genetic link between infertility and cancer. We have developed high-performance genetic diagnosis in 29.3% of cases from an unprecedented cohort of 375 pateints. Nine new genes are involved in DNA repair, or in new pathways: inflammation, transcription/translation and mitophagy, and correspond to potential future therapeutic targets. Genetics enables personalized medicine to i) prevent/cure comorbidities for tumor/cancer susceptibility genes, or for genetically revealed syndromic POI ii) predict residual ovarian reserve and hence fertility prognosis.L’insuffisance ovarienne primitive (IOP), problème de santé publique, atteint 1-3,7% des femmes avant 40 ans. Elle est responsable d’infertilité et de diminution de longévité. Nous avons pour la première fois impliqué BRCA2, gène majeur de prédisposition aux cancers du sein et de l’ovaire, dans une IOP isolée confirmant le lien génétique entre infertilité et cancer. Nous avons développé un diagnostic génétique de haute performance dans 29.3% des cas d’une cohorte sans précédent de 375 IOP. Neuf nouveaux gènes sont impliqués dans la réparation d’ADN, ou dans de nouvelles voies : l’inflammation, la transcription/traduction et la mitophagie, et correspondent à de potentielles futures cibles thérapeutiques. La génétique permet une médecine personnalisée pour i) prévenir/guérir les comorbidités pour les gènes de susceptibilité aux tumeurs/cancers, ou pour les IOP syndromiques génétiquement révélés ii) prédire une réserve ovarienne résiduelle et donc un pronostic de fertilité

A novel phenotype combining primary ovarian insufficiency growth retardation and pilomatricomas with MCM8 mutation.

CONTEXT: Primary Ovarian insufficiency (POI) affects 1% of women aged <40 years and leads most often to definitive infertility with adverse health outcomes. Very recently, genes involved in deoxyribonucleic acid (DNA) repair have been shown to cause POI. OBJECTIVE: To identify the cause of a familial POI in a consanguineous Turkish family. DESIGN: Exome sequencing was performed in the proposita and her mother. Chromosomal breaks were studied in lymphoblastoid cell lines treated with mitomycin (MMC). SETTING AND PATIENTS: The proposita presented intrauterine and postnatal growth retardation, multiple pilomatricomas in childhood, and primary amenorrhea. She was treated with growth hormone (GH) from age 14 to 18 years. RESULTS: We identified a novel nonsense variant in exon 9 of the minichromosome maintenance complex component 8 gene (MCM8) NM_001281522.1: c0.925C > T/p.R309* yielding either a truncated protein or nonsense-mediated messenger ribonucleic acid decay.The variant was homozygous in the daughter and heterozygous in the mother. MMC induced DNA breaks and aberrant metaphases in the patient's lymphoblastoid cells. The mother's cells had intermediate but significantly higher chromosomal breaks compared with a control. CONCLUSION: We describe a novel phenotype of syndromic POI related to a novel truncating MCM8 variant. We show for the first time that spontaneous tumors (pilomatricomas) are associated with an MCM8 genetic defect, making the screening of this gene necessary before starting GH therapy in patients with POI with short stature, especially in a familial or consanguineous context. Appropriate familial monitoring in the long term is necessary, and fertility preservation should be considered in heterozygous siblings to avoid rapid follicular atresia

1p36 deletion syndrome: Review and mapping with further characterization of the phenotype, a new cohort of 86 patients

International audienceChromosome 1p36 deletion syndrome (1p36DS) is one of the most common terminaldeletion syndromes (incidence between 1/5000 and 1/10,000 live births in theAmerican population), due to a heterozygous deletion of part of the short arm ofchromosome 1. The 1p36DS is characterized by typical craniofacial features, develop-mental delay/intellectual disability, hypotonia, epilepsy, cardiomyopathy/congenitalheart defect, brain abnormalities, hearing loss, eyes/vision problem, and short stature.The aim of our study was to (1) evaluate the incidence of the 1p36DS in the Frenchpopulation compared to 22q11.2 deletion syndrome and trisomy 21; (2) review thepostnatal phenotype related to microarray data, compared to previously publish pre-natal data. Thanks to a collaboration with the ACLF (Association des Cytogénéticiensde Langue Française), we have collected data of 86 patients constituting, to the bestof our knowledge, the second-largest cohort of 1p36DS patients in the literature. Weestimated an average of at least 10 cases per year in France. 1p36DS seems to bemuch less frequent than 22q11.2 deletion syndrome and trisomy 21. Patients pre-sented mainly dysmorphism, microcephaly, developmental delay/intellectual disabil-ity, hypotonia, epilepsy, brain malformations, behavioral disorders, cardiomyopathy,or cardiovascular malformations and, pre and/or postnatal growth retardation. Car-diac abnormalities, brain malformations, and epilepsy were more frequent in distaldeletions, whereas microcephaly was more common in proximal deletions. Mappingand genotype–phenotype correlation allowed us to identify four critical regionsresponsible for intellectual disability. This study highlights some phenotypic variabil-ity, according to the deletion position, and helps to refine the phenotype of 1p36DS,allowing improved management and follow-up of patient