Mutation analysis of the FOXL2 and BMP15 genes in patients with premature ovarian insufficiency

Premature ovarian insufficiency (POI) is defined by irregular menstrual cycles or amenorrhea before age 40 with elevated follicle-stimulating hormone (FSH) levels. We evaluated FOXL2 and BMP15 variants in Turkish women with POI and assessed the distribution of the BMP15 promoter variant c.-9C>G in a case-control setting.

Seventy-five women younger than 40 years with hypergonadotropic hypogonadism, primary/secondary amenorrhea, serum FSH ≥25 mIU/mL on two occasions at least four weeks apart, a normal 46,XX karyotype, and negative FMR1 CGG repeat testing were included. Women with prior ovarian surgery, pelvic chemotherapy/radiotherapy, or endocrine or autoimmune disease were excluded. FOXL2 and BMP15 coding regions and intron-exon junctions were analyzed by Sanger sequencing. BMP15 c.-9C>G genotype frequencies were compared with 80 ethnically matched controls with normal ovarian function. Genotype-specific analyses compared CG versus CC + GG using Fisher's exact test, with odds ratios (ORs) and 95% confidence intervals (CIs).

No pathogenic POI-associated variants were detected in FOXL2 or BMP15. The heterozygous BMP15 c.-9C>G variant was identified in 34/75 patients; it occurred alone in 21, with c.308A>G in 12, and with c.352G>A in 1 patient. In the case-control comparison, the CG genotype was more frequent in POI than in controls (34/75, 45.3% vs. 15/80, 18.8%) and was associated with increased POI risk (OR=3.59, 95% CI: 1.74-7.40; p=0.0005).

No pathogenic BMP15 or FOXL2 variant was identified. The BMP15 c.-9C>G variant may be associated with susceptibility to POI in this Turkish cohort, but this finding requires confirmation in larger, unrelated, well-matched populations and functional studies.