Novel genetic variants associated with premature ovarian insufficiency: A case series

Premature ovarian insufficiency (POI), characterised by the cessation of normal ovarian function before the age of 40 years, is a recognised cause of infertility and long-term metabolic and cardiovascular morbidity, with many non-chromosomal cases remaining unexplained. Increasing evidence implicates genes involved in meiosis and DNA double-strand break repair. We report three adolescent females presenting with primary or secondary amenorrhoea, hypergonadotropic hypogonadism, low oestradiol, undetectable anti-Müllerian hormone and hypoplastic or absent ovaries on imaging, with normal 46,XX karyotypes. Whole-exome sequencing combined with copy number variation analysis uncovers novel homozygous variants in meiosis-related genes: A truncating frameshift in MEIOB (c.1140_1143del; p.Asp381Ter), a missense variant in STAG3 (c.926T>C; p.Phe309Ser) and a homozygous exon 9–10 deletion in SPIDR . These genes are crucial for meiotic recombination and DNA repair. Molecular diagnosis facilitated hormone replacement therapy, genetic counselling and reproductive planning. This series expands the mutational spectrum and supports comprehensive genomic testing in adolescent POI.