Fragile X premutations are associated with primary ovarian insufficiency when the patient presents with amenorrhea, but the fragile X mental retardation 1 (FMR1) CGG repeat count among cycling women with low ovarian reserve (diminished ovarian reserve [DOR]) is not yet established.
Patients and Methods:
Sixty-two infertile DOR patients were recruited from 4 US private and academic fertility centers. Results: The prevalence of 35-44 FMR1 CGG repeats was 14.5%. Compared with the general female population estimate from the literature, infertile women with DOR were more likely to have 35-44 FMR1 CGG repeats (14.5% and 3.9%, respectively, P = .0003). Similar findings were noted by 5-repeat bandwidth: 35-39 CGG repeats (9.7% DOR vs 3.2% comparison, P = .012) or 40-44 CGG repeats (4.8% DOR vs 0.7% comparison, P = .024).
Conclusions:
These data suggest that CGG repeats of 35-44 may be markedly overrepresented in women with DOR, whereas the current FMR1 reference range indicates that there is no clinical phenotype with <45 CGG repeats.
McConkie-RosellAAbramsLFinucaneBRecommendations from multi-disciplinary focus groups on cascade testing and genetic counseling for fragile X-associated disorders. J Genet Couns. 2007;16(5):593–606.
2.
NelsonLMBakalovVK. Mechanisms of follicular dysfunction in 46, XX spontaneous premature ovarian failure. Endocrinol Metab Clin North Am. 2003;32(3):613–637.
3.
SperoffLFritzMA. Clinical Gynecologic Endocrinology and Infertility. 7 ed. Philadelphia: Lippincott Williams & Wilkins; 2005.
4.
ScottRTJr, HofmannGE. Prognostic assessment of ovarian reserve. Fertil Steril. 1995;63(1):1–11.
5.
LeviAJRaynaultMFBerghPADrewsMRMillerBTScottRTJr. Reproductive outcome in patients with diminished ovarian reserve. Fertil Steril. 2001;76(4):666–669.
6.
SpectorEKronquistK. Fragile X: Technical standards and guidelines: ACMG Standards and Guidelines for Clinical Genetics Laboratories; 2005.
7.
ShermanSL. Premature ovarian failure in the fragile X syndrome. Am J Med Genet. 2000;97(3):189–194.
8.
Garcia-ArocenaDHagermanPJ. Advances in understanding the molecular basis of FXTAS. Hum Mol Genet. 2010;19(R1):R83–R89.
9.
ShermanSPletcherBADriscollDA. Fragile X syndrome: diagnostic and carrier testing. Genet Med. 2005;7(8):584–587.
10.
ACOG Committee of Genetics. Carrier Screening for Fragile X Syndrome. Obstet Gynecol. 2010;116(4):1008–1010.
11.
NolinSLBrownWTGlicksmanAExpansion of the fragile X CGG repeat in females with premutation or intermediate alleles. Am J Hum Genet. 2003;72(2):454–464.
12.
ZunigaAJuanJMilaMGuerreroA. Expansion of an intermediate allele of the FMR1 gene in only two generations. Clin Genet. 2005;68(5):471–473.
13.
FuYHKuhlDPAPizzutiAVariation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell. 1991;67(6):1047–1058.
14.
PeprahE. Fragile X syndrome: the FMR1 CGG repeat distribution among world populations. Ann Hum Genet. 2012;76(2):178–191.
15.
StreuliIFraisseTIbecheoleVMoixIMorrisMAde ZieglerD. Intermediate and premutation FMR1 alleles in women with occult primary ovarian insufficiency. Fertil Steril. 2009;92(2):464–470.
16.
BretherickKLFlukerMRRobinsonWP. FMR1 repeat sizes in the gray zone and high end of the normal range are associated with premature ovarian failure. Hum Genet. 2005;117(4):376–382.
17.
OtsukaSSakamotoYSiomiHFragile X carrier screening and FMR1 allele distribution in the Japanese population. Brain Dev. 2010;32(2):110–114.
18.
BodegaBBioneSDalpraLInfluence of intermediate and uninterrupted FMR1 CGG expansions in premature ovarian failure manifestation. Hum Reprod. 2006;21(4):952–957.
19.
TaiebJOlivennesFBirrASComparison of day 3 FSH serum values as determined by six different immunoassays. Hum Reprod. 2002;17(4):926–928.
20.
ScriverJBakerVYoungSBehrBPastoreL. Inter-laboratory validation of the measurement of follicle stimulating hormone (FSH) after various lengths of frozen storage. Reprod Biol Endocrinol. 2010;8(1):145.
21.
LarsenLAGrønskovKNørgaard-PedersenBBrøndum-NielsenKHasholtLVuustJ. High-throughput analysis of Fragile X (CGG)n alleles in the normal and premutation range by PCR amplification and automated capillary electrophoresis. Hum Genet. 1997;100(5-6):564–568.
22.
GleicherNWeghoferAOktayKBaradD. Relevance of triple CGG repeats in the FMR1 gene to ovarian reserve. Reprod Biomed Online. 2009;19(3):385–390.
23.
GleicherNWeghoferABaradDH. Effects of race/ethnicity on triple CGG counts in the FMR1 gene in infertile women and egg donors. Reprod Biomed Online. 2010;20(4):485–491.
24.
GleicherNWeghoferALeeIHBaradDH. Association of FMR1 genotypes with in vitro fertilization (IVF) outcomes based on ethnicity/race. PLoS One. 2011;6(4):e18781.
25.
MaddalenaARichardsCSMcGinnissMJTechnical standards and guidelines for fragile X: the first of a series of disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics. Quality Assurance Subcommittee of the Laboratory Practice Committee. Genet Med. 2001;3(3):200–205.
26.
GleicherNWeghoferABaradDH. A pilot study of premature ovarian senescence: I. Correlation of triple CGG repeats on the FMR1 gene to ovarian reserve parameters FSH and anti-Müllerian hormone. Fertil Steril. 2009;91(5):1700–1706.
27.
FiciciogluCYildirimGAttarRKumbakBYesildaglarN. The significance of the number of CGG repeats and autoantibodies in premature ovarian failure. Reprod Biomed Online. 2010;20(6):776–782.
28.
GleicherNWeghoferAOktayKBaradDH. Correlation of triple repeats on the FMR1 (fragile X) gene to ovarian reserve: a new infertility test?Acta Obstet Gynecol Scand. 2009;88(9):1024–1030.
29.
GleicherNWeghoferABaradD. Ovarian reserve determinations suggest new finction of FMR1 (fragile X gene) in regulating ovarian ageing. Reprod Biomed Online. 2010;20(6):768–775.
30.
CronisterATeicherJRohlfsEMDonnenfeldAHallamS. Prevalence and instability of fragile X alleles: implications for offering fragile X prenatal diagnosis. Obstet Gynecol. 2008;111(3):596–601.
