FMR1 – Fragile X-Associated Primary Ovarian Insufficiency (FXPOI)

Fragile X mental retardation 1 (FMR1) premutation alleles (55–200 CGG repeats) in the 5′ UTR confer risk for Fragile X-associated primary ovarian insufficiency (FXPOI), characterized by oligo/amenorrhea and hypergonadotropic hypogonadism before age 40. Female carriers experience cessation of menses and infertility, with variable penetrance influenced by repeat size and modifier variants. FXPOI imposes significant morbidity—including reduced bone mineral density and cardiovascular risks—underscoring the need for timely genetic diagnosis in women with premature ovarian failure (PMID:30542367).

Inheritance of FXPOI is X-linked dominant, with premutation alleles transmitted through both sexes, though ovarian insufficiency manifests in females. At least four unrelated female probands have been reported with FXPOI and confirmed FMR1 premutations (PMID:27230899; PMID:29299012; PMID:30542367; PMID:31032490). One representative point mutation, c.911T>A (p.Ile304Asn), has been used to model FMR1 dysfunction in cellular assays, illustrating domain-specific effects on RNA binding (see variant list).

The variant spectrum in FXPOI centers on CGG repeat expansions, with premutation carriers having 55–200 repeats. Intermediate alleles (45–54 repeats) do not significantly increase FXPOI risk in most populations (PMID:29604051). Sequence variants beyond repeat expansions are rare but may include missense changes affecting FMRP function and mRNA toxicity. No founder or recurrent non-CGG variants have been linked to FXPOI to date.

Mechanistically, FMR1 premutations elevate FMR1 mRNA levels, leading to RNA gain-of-function toxicity in ovarian granulosa cells. Survival analysis of ≈1 300 women showed premutation carriers have earlier menopause than noncarriers, even when excluding frank POF cases, implicating the premutation in accelerated ovarian aging (PMID:25147555). Modifier loci and SNP risk burden further influence age at onset, supporting complex genetic interplay in FXPOI expressivity.

Population-based studies confirm that premutation carriers face a 20-fold increased risk of premature ovarian failure compared with noncarriers, though intermediate alleles below 50 CGGs lack significant association (PMID:29604051). The prevalence of FXPOI among FMR1 premutation carriers is ~20%, and carrier screening in women with idiopathic POI can facilitate early intervention and fertility planning.

Integration of genetic and functional data establishes a Moderate clinical validity for FMR1-FXPOI association, with multiple well-characterized probands, a defined molecular mechanism, and concordant functional assays. Further longitudinal natural history studies could refine penetrance estimates and stratify risk. Key Take-home: FMR1 premutation testing should be considered in women with early ovarian insufficiency to guide management and familial risk assessment.

References

• Cerebellum (London, England) • 2016 • PSP-CBS with Dopamine Deficiency in a Female with a FMR1 Premutation. PMID:27230899
• Colombia medica (Cali, Colombia) • 2017 • Tremor-Ataxia syndrome and primary ovarian insufficiency in an FMR1 premutation carrier. PMID:29299012
• Frontiers in Genetics • 2018 • Fragile X Associated Primary Ovarian Insufficiency (FXPOI): Case Report and Literature Review. PMID:30542367
• Journal of molecular genetics (Isleworth, London, England) • 2018 • Fentanyl overdose in a female with the FMR1 premutation and FXTAS. PMID:31032490
• Clinical Genetics • 2018 • Clinical implication of FMR1 intermediate alleles in a Spanish population. PMID:29604051

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