Utilizing FMR1 Gene Mutations as Predictors of Treatment Success in Human In Vitro Fertilization

Purpose This is a comprehensive review of the literature in this field attempting to put the FMR1 gene and its evaluation into context, both in general and for the reproductive health audience. Methods Online database search of publications with systematic review of all papers relevant to ovarian reserve and assisted reproduction was done. Results Relevant papers were identified and assessed, and an attempt was made to understand, rationalize and explain the divergent views in this field of study. Seminal and original illustrations were employed. Conclusions FMR1 is a highly conserved gene whose interpretation and effect on outcomes remains controversial in the reproductive health setting. Recent re-evaluations of the commonly accepted normal range have yielded interesting tools for possibly explaining unexpected outcomes in assisted reproduction. Fragile X investigations should perhaps become more routinely assessed in the reproductive health setting, particularly following a failed treatment cycle where oocyte quality is thought to be a contributing factor, or in the presence of a surprise finding of diminished ovarian reserve in a young patient.

Section: The Fmr1 Gene and Ivf Outcomementioning

confidence: 77%

Section: The Fmr1 Gene and Ivf Outcomementioning

confidence: 99%

The impact of FMR1 gene mutations on human reproduction and development: a systematic review

Noto

Harrity

Walsh

et al. 2016

“…Their IVF patients, thus, were very favorably selected and to a significant degree excluded women with low FOR. In contrast, the typical patient selected in one of our recent studies was 39.7 years old, had a mean FSH of 11.2 mIU/mL, and mean AMH of only 1.5 ng/mL [10]. Thus, Bank's patient population provided less power to detect a possible association with impaired FOR and for this reason the observed association was weaker than previously reported in a more at-risk population.…”

Section: Recent Studiesmentioning

confidence: 55%

The importance of redundancy of functional ovarian reserve when investigating potential genetic effects on ovarian function

Barad

Kushnir

Gleicher

2016

Self Cite

Until recently, the Fragile X mental retardation 1 (FMR1) gene, located at Xq27.3, received only limited attention in reproductive medicine since known associated medical conditions were mostly neuro-psychiatric. Fragile X syndrome (FXS), due to FMR1 full mutations (CGG n > 200 ), is the most common form of familial mental retardation. In middle aged males, FMR1's premutation range, at approximately CGG n = 55-200 , is characterized by phenotypic expression of a neurodegenerative disease known as the Fragile Xassociated tremor/ataxia syndrome. In females, the premutation range CGG n = 55-200 is associated with an increased risk of primary ovarian insufficiency (POI). Women with premutation range CGG n = 55-200 have a significant onegenerational risk that their offspring may demonstrate full mutation range CGG expansions and, therefore, FXS. For this reason, pre-conception screening for maternal premutations is now commonly offered. The so-called intermediate (or Bgrayẑ one), between approximately CGG n = 45-54 , carries only minimal risk for one-generational expansion to FXS, while the classical normal (or Bcommon^) range of CGG n < 45 carries no such risk at all [1].

“…Patients with <100 CGG repeats have significantly lower milestones of ovarian response and fertilization rates than those with ≥100 CGG repeats [28], and it has even been postulated that distinct FMR1 genotypes might explain differences in IVF outcome between races [29]. Kushnir et al [30] suggested that the FMR1 gene may negatively impact oocyte/ embryo quality and thus IVF pregnancy rates particularly among those patients that have an allele with low repeats independently from ploidy. Therefore, the number of repeats found on the FMR1 gene may have a role not only in the prognosis of IVF success through embryo quality expectations but also in treatment adjustments since some patients may be initially managed as low responders [28][29][30].…”

Section: Outcomes Of Assisted Reproductionmentioning

confidence: 99%

“…Kushnir et al [30] suggested that the FMR1 gene may negatively impact oocyte/ embryo quality and thus IVF pregnancy rates particularly among those patients that have an allele with low repeats independently from ploidy. Therefore, the number of repeats found on the FMR1 gene may have a role not only in the prognosis of IVF success through embryo quality expectations but also in treatment adjustments since some patients may be initially managed as low responders [28][29][30]. In the future, infertility clinics might become one of the main places where affected families are identified.…”

Section: Outcomes Of Assisted Reproductionmentioning

confidence: 99%

Fragile X premutation in women: recognizing the health challenges beyond primary ovarian insufficiency

Hoyos

Thakur

2016

Fragile X premutation carriers have 55-200 CGG repeats in the 5' untranslated region of the FMR1 gene. Women with this premutation face many physical and emotional challenges in their life. Approximately 20% of these women will develop fragile X-associated primary ovarian insufficiency (FXPOI). In addition, they suffer from increased rates of menstrual dysfunction, diminished ovarian reserve, reduction in age of menopause, infertility, dizygotic twinning, and risk of having an offspring with a premutation or full mutation. Consequent chronic hypoestrogenism may result in impaired bone health and increased cardiovascular risk. Neuropsychiatric issues include risk of developing fragile X-associated tremor/ataxia syndrome, neuropathy, musculoskeletal problems, increased prevalence of anxiety, depression, and sleep disturbances independent of the stress of raising an offspring with fragile X syndrome and higher risk of postpartum depression. Some studies have reported a higher prevalence of thyroid abnormalities and hypertension in these women. Reproductive health providers play an important role in the health supervision of women with fragile X premutation. Awareness of these risks and correlation of the various manifestations could help in early diagnosis and coordination of care and services for these women and their families. This paper reviews current evidence regarding the possible conditions that may present in women with premutation-sized repeats beyond FXPOI.