FIGLA – Premature Menopause

This summary integrates evidence from multiple case reports, multi‐patient studies, and functional assessments showing a strong association between FIGLA mutations and premature menopause. Several independent studies have identified biallelic, loss‑of‑function mutations in FIGLA in patients presenting with premature ovarian insufficiency and related reproductive phenotypes (PMID:29914564, PMID:30474133). The consistent observation of homozygous mutations in consanguineous families reinforces a genetically recessive mode of inheritance with clear implications for diagnostic evaluation.

Genetic evidence includes findings from at least four unrelated probands where FIGLA variants such as c.2T>C (p.Met1Thr) have been documented. In-depth segregation analyses in these families have confirmed that the variant co‐segregates with the disease phenotype, with additional affected relatives observed in pedigree analyses (PMID:29914564, PMID:18499083). Furthermore, several mutation types have been identified, including missense changes and indels, underscoring the heterogeneous variant spectrum that contributes to the clinical presentation of premature ovarian insufficiency.

In addition to the genetic data, multiple functional studies have demonstrated that the pathogenic FIGLA mutations result in disrupted transcriptional regulation of downstream ovarian target genes such as ZP1, ZP2, and ZP3. Experimental assays, including luciferase reporter activity and chromatin immunoprecipitation, have shown that these mutations impair FIGLA protein function and reduce target gene expression (PMID:18499083, PMID:34778283). These functional findings provide a mechanistic link between the molecular defect and the observed ovarian insufficiency.

The concordance between the genetic data and the functional assessments strengthens the clinical validity of this association. Studies report not only a clear autosomal recessive inheritance pattern but also robust segregation within affected families. The combined evidence from multiple independent cohorts and experimental validation exceeds the standard ClinGen scoring maximum, further establishing the pathogenic role of FIGLA mutations in premature menopause.

Overall, the weight of evidence indicates that biallelic loss‑of‑function mutations in FIGLA are clinically significant in the diagnosis of premature menopause. This association supports the integration of FIGLA sequencing in genetic screening protocols for patients with premature ovarian insufficiency, thereby improving genetic counseling and tailored patient management.

Key Take‑home: FIGLA mutations, particularly in the homozygous state, represent a strong diagnostic marker for premature menopause, justifying their inclusion in clinical genetic testing panels.

References

• Journal of ovarian research • 2018 • Consanguineous familial study revealed biallelic FIGLA mutation associated with premature ovarian insufficiency PMID:29914564
• Clinical genetics • 2019 • Bi-allelic recessive loss-of-function mutations in FIGLA cause premature ovarian insufficiency with short stature PMID:30474133
• American journal of human genetics • 2008 • Transcription factor FIGLA is mutated in patients with premature ovarian failure PMID:18499083
• Frontiers in medicine • 2021 • Mutations in FIGLA Associated With Premature Ovarian Insufficiency in a Chinese Population PMID:34778283
• Menopause (New York, N.Y.) • 2015 • Mutational analysis of the FIGLA gene in women with idiopathic premature ovarian failure PMID:25314148

Evidence Based Scoring (AI generated)