| Gene (HGNC symbol) | Typical inheritance pattern (AR/AD/X-linked or reported) | Molecular mechanism | Key clinical features | Key study evidence | Key quantitative data | URL |
|---|---|---|---|---|---|---|
| NUP107 | Autosomal recessive / recessive reported | Missense loss of function affecting nucleoporin function; ovarian development defect supported by functional model data | 46,XX gonadal dysgenesis with lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, hypergonadotropic hypogonadism; ovaries not visualized on imaging in reported cases (pqac-00000005) | Weinberg-Shukron 2015, *J Clin Invest* (pqac-00000005) | Example values reported: LH 38–60 IU/L, FSH 50–92 IU/L; variant absent from databases and 150 ethnically matched controls (pqac-00000005) | https://doi.org/10.1172/JCI83553 |
| PSMC3IP (HOP2) | Often autosomal recessive / often AR in unexplained XX-GD families | Loss of function; meiotic recombination defect and abolished coactivation of estrogen-driven transcription | Rare 46,XX gonadal dysgenesis with absent spontaneous puberty, primary amenorrhea, uterine hypoplasia, streak gonads, hypergonadotropic hypogonadism (pqac-00000006) | Zangen 2011, *Am J Hum Genet* (pqac-00000006) | Homozygous 3-bp deletion p.Glu201del identified in consanguineous family; functional assay showed mutation abolished estrogen-driven transcriptional coactivation (pqac-00000006) | https://doi.org/10.1016/j.ajhg.2011.09.006 |
| FSHR | Autosomal recessive / AR reported | Receptor resistance / inactivating loss of function in FSH signaling | Primary amenorrhea due to hypergonadotropic ovarian failure; 46,XX gonadal dysgenesis / ovarian dysgenesis phenotype with absent puberty or delayed puberty and high gonadotropins (pqac-00000005, pqac-00000007) | Bramble 2016, *Hum Reprod*; cited in reviews of XX-GD/amenorrhea (pqac-00000005, pqac-00000007) | Described as an “extremely rare” cause; novel p.Asp408Tyr showed ~48% reduction in cell-surface signal and ~50% reduction in FSH-stimulated cAMP (pqac-00000007) | https://doi.org/10.1093/humrep/dew025 |
| BMP15 | X-linked recessive reported; heterozygous and homozygous variants reported | Oocyte-derived growth factor dysfunction / impaired ovarian growth and maturation | Hypergonadotropic ovarian failure; ovarian dysgenesis/POI with primary amenorrhea possible, including severe ovarian dysgenesis phenotypes (pqac-00000005, pqac-00000010) | Di Pasquale 2004, *Am J Hum Genet*; summarized in later reviews (pqac-00000005, pqac-00000010) | Ovarian dysgenesis accounts for about half of primary amenorrhea cases in older review context; BMP15 variants reported in 1.5%–15% of POI in review summary (pqac-00000010) | https://doi.org/10.1086/422103 |
| NR5A1 | Heterozygous variants reported; AD/reported | Loss of function affecting ovarian steroidogenic/gonadal developmental transcriptional regulation | POI or 46,XX DSD with primary or secondary amenorrhea, estrogen deficiency, elevated gonadotropins, infertility; can overlap with ovarian dysgenesis spectrum (pqac-00000009) | Luppino 2024, *Curr Issues Mol Biol*; Jaillard 2020, *Maturitas* summarized therein (pqac-00000009) | NR5A1 variants found in 2.8% of 142 women with ovarian deficiency/DOR/unexplained infertility; pathogenic variants reported in 0.26%–8% of sporadic POI (pqac-00000009) | https://doi.org/10.3390/cimb46050274 |
| FIGLA | Reported; autosomal recessive possible in some families, but not specified here | Transcription factor defect in ovarian maturation / folliculogenesis | Ovarian dysgenesis or POI spectrum with primary amenorrhea and reduced/absent ovarian function (pqac-00000007, pqac-00000008, pqac-00000010) | Cattoni 2020, *Front Endocrinol*; review summaries (pqac-00000007, pqac-00000008, pqac-00000010) | FIGLA variants found in 4% of one Chinese sporadic POI series (pqac-00000007) | https://doi.org/10.3389/fendo.2020.540683 |
| NOBOX | Reported; autosomal recessive possible in some families, but not specified here | Loss of function in ovarian developmental transcription factor | Ovarian dysgenesis/POI with primary amenorrhea possible; impaired ovarian function spectrum (pqac-00000007, pqac-00000008, pqac-00000010) | Cattoni 2020, *Front Endocrinol*; review summaries (pqac-00000007, pqac-00000008, pqac-00000010) | Loss-of-function NOBOX variants accounted for 6.2%, 6.5%, and 5.6% in three POI cohorts (pqac-00000007) | https://doi.org/10.3389/fendo.2020.540683 |
| FOXL2 | Autosomal dominant in BPES syndromic context; heterozygous and homozygous variants reported in ovarian dysgenesis/POI | Transcription factor dysfunction affecting granulosa/overy maintenance | Ovarian dysgenesis/POI with delayed puberty, primary amenorrhea, or POI; can be syndromic (BPES) or isolated ovarian insufficiency (pqac-00000010) | Yatsenko 2024, *Endocrinol Metab Clin N Am*; Luo 2023, *J Ovarian Res* summarized in gathered evidence (pqac-00000010) | In 500 POI patients, FOXL2 had the highest occurrence frequency at 3.2% (16/500); p.R349G accounted for 2.6% in that cohort (pqac-00000010) | https://doi.org/10.1016/j.ecl.2024.01.009 |
| WNT4 | Not specified in gathered evidence | Pro-ovarian developmental pathway defect / ovarian determination | Included among known causes or candidate genes for XX-GD/ovarian development disorders; detailed XX-GD phenotype specifics not provided in gathered evidence (pqac-00000005, pqac-00000006) | Summarized in Weinberg-Shukron 2015, *J Clin Invest* and Zangen 2011, *Am J Hum Genet* (pqac-00000005, pqac-00000006) | Not specified | https://doi.org/10.1172/JCI83553 |
| RSPO1 | Not specified in gathered evidence | Pro-ovarian developmental pathway defect / ovarian determination | Included among genes implicated in ovarian development disorders and 46,XX gonadal development pathways; detailed pure XX-GD quantitative data not specified here (pqac-00000005, pqac-00000006) | Summarized in Weinberg-Shukron 2015, *J Clin Invest* and Zangen 2011, *Am J Hum Genet* (pqac-00000005, pqac-00000006) | Not specified | https://doi.org/10.1172/JCI83553 |


*Table: This table summarizes evidence-supported genes implicated in 46,XX gonadal dysgenesis / XX ovarian dysgenesis and closely related primary ovarian insufficiency presenting with primary amenorrhea. It highlights inheritance, mechanisms, hallmark phenotypes, and key quantitative findings to support disease knowledge base curation.*