Systematic mapping and <i>in silico</i> re-evaluation of genomic copy number variations in Primary Ovarian Insufficiency

Primary Ovarian Insufficiency (POI) is a highly heterogeneous condition characterized by the cessation of ovarian function before age 40. While genetic factors play a substantial role, the contribution of structural variants remains incompletely mapped. We conducted a systematic review and in silico genomic re-analysis of published copy number variations (CNVs) in individuals with POI. Following PRISMA guidelines, we aggregated 382 CNVs from 25 studies, standardized genomic coordinates, and filtered variants against population databases. Pathogenicity was re-evaluated using ACMG/ClinGen guidelines, yielding 42 pathogenic/likely pathogenic variants and 25 large CNVs (>3.5 Mb). Consistent with previous findings, the X chromosome exhibited the highest CNV burden, emphasizing its central role in structural genomic instability and POI pathogenesis. Beyond canonical POI-associated genes, gene ontology and GTEx expression profiling identified several biologically plausible, highly ovary-expressed candidate genes within disrupted loci-notably ATF3, GAS5, PPP4R1, and PRKAA1. Despite their established roles in cellular stress responses, DNA repair, and meiotic progression, these genes remain absent from most commercial POI diagnostic panels. This comprehensive re-analysis highlights the complex structural genomic landscape of POI and suggests that expanding current clinical testing panels to include these under-recognized genes could improve diagnostic yields for genetically unexplained cases.