Based on the current evidence, we concluded that intermediate-sized FMR1 CGG repeat alleles should not be considered as a high-risk factor for POF and DOR.
Women who carry a fragile X premutation, defined as having 55-200 unmethylated CGG repeats in the 5' UTR of the X-linked FMR1 gene, have a 20-fold increased risk for primary ovarian insufficiency (FXPOI).
Women who develop primary ovarian insufficiency related to a premutation in FMR1 are at risk of having a child with fragile X syndrome, the most common cause of inherited intellectual disability.
Previous studies have demonstrated that transplantation of hAECs effectively alleviate chemotherapy-induced ovarian damage via inhibiting granulose cells apoptosis in animal models of premature ovarian failure/insufficiency (POF/POI).
Their inability to sustain gene expression, together with their likely aberrant effects on protein stability and degradation, make the identified NOBOX mutations a plausible cause of POI onset.
Mutations in NR5A1 in 46,XX women are associated with primary ovarian insufficiency, which includes a lack of ovary formation, primary and secondary amenorrhoea as well as early menopause.
Premutations in the fragile X mental retardation 1 (FMR1) gene cause fragile X-associated tremor/ataxia syndrome (FXTAS) and FMR1-related primary ovarian insufficiency (POI).
Conversely, 6.4% of the cases present a NOBOX mutations; this high prevalence strengthens the consideration of NOBOX gene as strong autosomal candidate for POI.
In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels.
In the four SNPs identified across the GDF9 loci, D57Y (169G>T), rs1049127 (546G>A), rs254286 (447C>T) and rs254285 (969C>G), the frequencies of the 546G>A genotype and allele A were significantly higher in the POF group, compared with the normal control group (34.92, vs. 6.90%; P<0.05 and 19.05, vs. 3.23%; P<0.05, respectively), while no significant differences were observed in the occurrence of the c.447C>T and c.969C>G mutations between the two groups (60.32, vs. 50% and 50.79, vs. 55.17%, respectively).
The diagnosis of POI was made on pubertal delay or primary amenorrhea in these five patients, whilst the others presented with clitoral hypertrophy at birth or short stature and pubertal delay in two cases with NR5A1 mutation or with short stature and learning difficulties in one case with mitochondrial disease.