Introduction: While variants in hundreds of genes have been linked to premature ovarian insufficiency (POI), monogenic disorders account for fewer than half of idiopathic POI cases in adolescents with 46,XX karyotype. This highlights the need for the further genetic investigation across diverse populations. Patients and methods: We recruited 63 Russian patients diagnosed with 46,XX POI before age 18. All underwent FMR1 premutation testing and whole-exome sequencing (WES). Copy number variation (CNV) analysis was conducted on WES data. Segregation studies by Sanger sequencing were performed where samples from the patients’ relatives were available. Results: We identified variants in 15 genes in 38% of the cohort, including 13 causative genes ( FMR1 , DCAF17, FOXL2, STAG3, TP63, BNC1, CPEB1, NOBOX, LMNA, FSHR, SPIDR, MCM8, EIF2B2 ) and 2 candidate genes ( MYRF, LATS1 ). 3.2% of patients carried an FMR1 premutation. WES detected causative single nucleotide variants (SNVs) in 15 patients (17.5% of the cohort). CNV analysis increased the diagnostic yield to 20.6%, identifying 15q25.2 microdeletions ( BNC1 , CPEB1 ) in two patients and FSHR exon 2 deletion in one patient with resistant ovary syndrome. Overall, the combination of molecular genetic approaches established a diagnosis of monogenic POI (pathogenic or likely pathogenic variants) in 23.8% of adolescents with normal female karyotype. 5 patients (7.9%) carried variants of unknown significance in FSHR , LMNA , NOBOX , SPIDR, LATS1 genes, warranting further investigation. Discussion: Our findings demonstrate that WES is an effective diagnostic tool for adolescents with POI and should supplement standard karyotyping and FMR1 testing in routine clinical practice. We report several novel variants in POI-associated genes and propose new gene-disease association.

Пилотный региональный проект по селективному экзомному скринингу новорожденных: первые результаты

Background. Congenital malformations of the genital organs exhibit numerous anatomical variants and are characterized by impaired function due to complete or partial obstruction of the organs. Uterine and/or vaginal abnormalities significantly impair reproductive outcomes and are often associated with abnormalities in other organs and systems. To date, the etiology of congenital malformations of the uterus and/or vagina remains controversial; the possible role of genetic predisposition and molecular genetic predictors for these conditions has not been clarified. Aim. To assess the occurrence of various reproductive system malformations among patients admitted at the federal center, to characterize the known genetic causes of congenital malformations of the female genital organs according to the literature, and to propose an algorithm for genetic testing of adolescent girls diagnosed with malformations of the uterus and/or vagina. Materials and methods. Retrospective analysis of data from 2160 medical records and discharge reports of patients with reproductive system malformations, admitted for examination and treatment to the Department of Gynecology of Children and Adolescents of the Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology from 2013 to 2023. During the analysis, special attention was paid to clinical, history, and instrumental data, as well as the results of genetic counseling and molecular genetic testing. Results. An in-depth genetic testing showed that of the 749 examined patients, 516 (68.9%) had uterine and vaginal aplasia, 107 (14.3%) had partial or total vaginal aplasia with a functioning uterus, and 126 (16.8%) had obstruction of one of the hemivaginas with doubling of the uterus. In all cases, the patients' karyotypes were normal female (46,XX). Conclusion. According to the study results, the main groups of anomalies of the internal reproductive organs (aplasia of the uterus and vagina – Mayer–Rokitansky–Küster–Hauser syndrome; vaginal aplasia with a functioning uterus; anomalies of Müllerian duct fusion – uterine doubling and OHVIRA syndrome) were identified, data on the known genetic mechanisms of the development of these malformations were described, the approach for molecular genetic search for genetic etiology in these groups of patients was proposed.