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Background: The intricate molecular pathways and genetic factors that underlie the pathophysiology of cervical insufficiency (CI) remain largely unknown and understudied. Methods: We sequenced exomes from 114 patients in Latvia and Lithuania, diagnosed with a short cervix, CI, or a history of CI in previous pregnancies. To probe the well-known link between CI and connective tissue dysfunction, we introduced a connective tissue dysfunction assessment questionnaire, incorporating Beighton and Brighton scores. The phenotypic data obtained from the questionnaire was correlated with the number of rare damaging variants identified in genes associated with connective tissue disorders (in silico NGS panel). SKAT, SKAT-O, and burden tests were performed to identify genes associated with CI without a priori hypotheses. Pathway enrichment analysis was conducted using both targeted and genome-wide approaches. Results: No patient could be assigned monogenic connective tissue disorder neither genetically, neither clinically upon clinical geneticist evaluation. Expanding our exploration to a genome-wide perspective, pathway enrichment analysis replicated the significance of extracellular matrix-related pathways as important contributors to CI's development. A genome-wide burden analysis unveiled a statistically significant prevalence of rare damaging variants in genes and pathways associated with steroids (p-adj = 5.37E-06). Rare damaging variants, absent in controls (internal database, n = 588), in the progesterone receptor (PGR) (six patients) and glucocorticoid receptor (NR3C1) (two patients) genes were identified within key functional domains, potentially disrupting the receptors' affinity for DNA or ligands. Conclusion: Cervical insufficiency in non-syndromic patients is not attributed to a single connective tissue gene variant in a Mendelian fashion but rather to the cumulative effect of multiple inherited gene variants highlighting the significance of the connective tissue pathway in the multifactorial nature of CI. PGR or NR3C1 variants may contribute to the pathophysiology of CI and/or preterm birth through the impaired progesterone action pathways, opening new perspectives for targeted interventions and enhanced clinical management strategies of this condition. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women, affecting up to 16.6% of reproductive-age women. PCOS symptoms in adolescents comprise oligomenorrhoea/amenorrhoea and biochemical and/or clinical hyperandrogenism. Long-term health risks of PCOS patients include infertility, metabolic syndrome, type 2 diabetes and cardiovascular disease. Genetic factors have been proven to play a role in development of the syndrome and its symptoms. Objective: To investigate single nucleotide variants (SNVs) in the GNRHR, ESR2, LHCGR and FSHR genes in adolescent patients with PCOS and their association with PCOS symptoms. Methods: We conducted a cross-sectional study comprising of 152 adolescents: 63 patients with PCOS, 22 patients at risk of developing PCOS and 67 healthy controls. Participants were recruited from out-patients attending a gynaecologist at the Children's Clinical University Hospital, Riga, Latvia, between January 2017 and December 2020. Genomic DNA was extracted from whole blood, and SNVs in the GNRHR, ESR2, LHCGR and FSHR genes were genotyped. The distributions of SNV genotypes were compared among the three groups and genotype-phenotype associations within the PCOS group were evaluated. Results: No statistically significant differences were found in the distributions of genotypes for GNRHR (rs104893837), ESR2 (rs4986938), LHCGR (rs2293275) and FSHR (rs6166, rs6165, rs2349415) among PCOS patients, risk patients and healthy controls. Within the PCOS group, ESR2 rs4986938 minor allele homozygous patients had a significantly higher level of total testosterone than major allele homozygous patients and heterozygous patients. A significantly higher total testosterone level was also observed in PCOS patients carrying the LHCGR rs2293275 minor allele compared with major allele homozygous patients. Conclusions: The SNVs ESR2 rs4986938 and LHCGR rs2293275 play a role in the phenotypic characteristics of PCOS. To fully uncover their influence on the development of PCOS and its symptoms, further studies of larger cohorts and a follow up of this study sample through to adulthood are required. Furthermore, studies of adolescent PCOS patients conducted prior to the latest European Society of Human Reproduction and Embryology (ESHRE) criteria (2018) should be re-evaluated as the study groups might include risk patients according to these updated criteria, thereby potentially significantly impacting the published results. [ABSTRACT FROM AUTHOR]