Grâce a l'action de depistage systematique, la prise en charge therapeutique precoce en periode neonatale des enfants avec hypothyroidie congenitale permet un developpement normal (physique et psychomoteur) de ces enfants. Le pronostic a long terme est fonction de la severite de l'hypothyroidie et surtout de la qualite du traitement qui doit faire l'objet d'une surveillance reguliere afin de maintenir les hormones thyroidiennes dans des valeurs normales. L'affection est en relation avec une anomalie de developpement complet (athyreose) ou partiel (ectopie) de la glande thyroide ou a un deficit dans la biosynthese des hormones (Thyrotropin-releasing hormone) ou en TSH (Thyroid-stimulating hormone), isolee ou plus souvent associee a d'autres deficits hypophysaires (insuffisance hypophysaire congenitale) et, plus recemment rapportee, la resistance a la TSH ou au TRH. La resistance peripherique a l'action des hormones thyroidiennes est exceptionnelle. Les progres de la genetique moleculaire ont permis ces dernieres annees la comprehension de certaines de ces formes, dont l'hypothyroidie congenitale.
The use of next-generation sequencing (NGS) has recently enabled the discovery of genetic causes of primary ovarian insufficiency (POI) with high genetic heterogeneity. In contrast, the causes of diminished ovarian reserve (DOR) remain poorly understood. Here, we identified by NGS and whole exome sequencing (WES) the cause of isolated DOR in a 14-year-old patient. Two frameshift mutations in BRCA1 (NM_007294.4) were found: in exon 8 (c.470_471del; p.Ser157Ter) and in exon 11 (c.791_794del, p.Ser264MetfsTer33). Unexpectedly, the patient presented no signs of Fanconi anemia (FA), i.e., no developmental abnormalities or indications of bone marrow failure. However, high chromosomal fragility was found in the patient’s cells, consistent with an FA diagnosis. RT-PCR and Western-blot analysis support the fact that the c. 791_794del BRCA1 allele is transcribed and translated into a shorter protein (del11q), while no expression of the full-length BRCA1 protein was found. DNA damage response (DDR) studies after genotoxic agents demonstrate normal activation of the early stages of the DDR and FANC/BRCA pathway. This is consistent with the maintenance of residual repair activity for the del11q BRCA1 isoform. Our observation is the first implication of bi-allelic BRCA1 mutations in isolated ovarian dysfunction or infertility in humans, without clinical signs of FA, and highlights the importance of BRCA1 in ovarian development and function.
Background: Primary ovarian insufficiency (POI), a public health problem, affects 1-3.7% of women under 40 yielding infertility and decreased longevity. Most causes are unknown. Recently, genetic causes were identified, mostly in single families. We studied an unprecedented cohort of POI to unravel its molecular pathophysiology.Methods: 318 patients with 66 families were studied using targeted (88 genes) or exome sequencing with pathogenic/likely-pathogenic variant selection. Mitomycin-induced chromosome breakages were studied in patients’ lymphocytes.Findings: A high-yield of 36.5 % supports a clinical genetic diagnosis of POI. We found 77 new variants, involved 13 novel genes: AKT1, LAST2, ELAVL2, NLRP11, CENPE, SYCP3, XPNPEP2, SPATA33, CCDC150, CCDC185, including DNA repair genes MCM81P, HELQ, SWI5 yielding high chromosomal fragility, and confirmed the causal role of BNC1, ERCC6, BMPR1A, BMPR1B, BMPR2, CAV1, SPIDR, RCBTB1, ATG7. In 10.4% of cases, POI is the unique phenotype of a multi-organ genetic disease. New pathways were identified: Hippo-AKT, a novel therapeutic target of POI during in vitro follicular activation (IVA), inflammation, post-transcriptional/translational regulations, mitochondrial autophagy providing future therapeutic targets. Three new genes had been involved in 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 leading to personalized medicine to i) prevent/cure comorbidities for tumor/cancer susceptibility genes that could affect longevity, or for genetically-revealed syndromic POI, ii) predict residual ovarian reserve. Genetics could select responder patients to IVA, greatly improving its success in treating infertility.Funding Information: This study was supported by Université Paris Sud-Paris Saclay, Hôpitaux Universitaires Paris Saclay (AH, MM), the Institut National de la Santé et de la Recherche Médicale-INSERM (AH, MM), and by the Agence Nationale de Biomédecine (AH, MM) Declaration of Interests: The authors declare no conflict of interest.Ethics Approval Statement: The study was approved by all the institutions involved and by the Agence de Biomedecine (reference number PFS12-002). Written informed consent was received from participants prior to inclusion in the study.
