Background Central precocious puberty (CPP) results from premature activation of the hypothalamic–pituitary–gonadal (HPG) axis. While hormonal mechanisms underlying pubertal initiation are well established, the molecular regulatory processes accompanying altered pubertal timing remain incompletely understood. Circulating microRNAs (miRNAs), detectable either freely or within extracellular vesicles (EVs), represent a molecular layer of post-transcriptional regulation associated with pubertal development. Methods Serum samples from female patients diagnosed with CPP and age-matched healthy female controls were analyzed by small RNA sequencing to identify differentially expressed miRNAs. Selected miRNAs were validated by quantitative real-time PCR (RT–qPCR) in an expanded cohort using serum RNA and RNA isolated from serum-derived EVs. Functional enrichment analysis was conducted using experimentally validated miRNA target genes. Results Small RNA sequencing identified ten miRNAs with significantly altered expression levels in CPP (adjusted p-value < 0.05, |log2FC| > 0.5). Pathway enrichment analysis highlighted biological processes related to neurodevelopment, growth regulation and cellular maturation. RT–qPCR validation confirmed reduced serum expression of miR-125a-5p, miR-125b-5p and miR-99b-5p in CPP patients. All selected miRNAs were detectable in serum-derived EVs. Notably, miR-148a-3p exhibited a statistically significant increase specifically within the EV-associated fraction of CPP samples. Conclusions This study provides a comprehensive analysis of the circulating miRNA profile in female patients with CPP. The coordinated alteration of freely circulating and EV-associated miRNAs highlight the potential contribution of miRNA-mediated regulation to premature HPG axis activation and provides a framework for further investigation of the molecular mechanisms underlying pubertal disorders.
Maria Morrou, V. Neocleous, M. Toumba et al.· Frontiers in Endocrinology· 0 citations
Background/Objectives: Congenital anomalies and neurodevelopmental disorders frequently co-occur and exhibit substantial genetic and phenotypic heterogeneity, posing a persistent diagnostic challenge. Exome sequencing has become an important first- or second-tier diagnostic tool for these conditions, yet diagnostic yields vary considerably depending on phenotype, ancestry, sequencing strategy, and interpretation, with over half of referrals remaining without a definitive genetic diagnosis. Methods: We analyzed data from 692 patients referred to the Department of Cytogenetics and Genomics at the Cyprus Institute of Neurology and Genetics between January 2021 and December 2025 for clinical exome sequencing or whole-exome sequencing as part of the diagnostic work-up for congenital disorders and/or syndromic or non-syndromic neurodevelopmental disorders. Results: A total of 134 distinct variants were identified, corresponding to an overall diagnostic yield of 17.9% out of which 52 (38.8%) were novel, and 50 variants (37.3%) were de novo, as expected from the high proportion of severe neurodevelopmental presentations. Missense variants were the most prevalent within our cohort, while chromatin and transcriptional regulator genes constituted the largest functional gene category, followed by variants in collagen-encoding genes. Conclusions: This study provides the first systematic, mutational-level characterization of a Cypriot Mendelian disease cohort, establishing a local baseline diagnostic yield and revealing a high proportion of novel variants that reflect the underrepresentation of Eastern Mediterranean populations in global databases. These findings underscore the value of submitting population-specific variants to public repositories and of phenotype-driven reanalysis targeting recurrent gene families, supporting more efficient diagnostics and future precision medicine initiatives in Cyprus.
A. Theodosiou, L. Kousoulidou, Ioannis Papaevripidou et al.· Genes· 0 citations