Fragile X premutation is a significant risk factor for premature ovarian failure: The international collaborative POF in fragile X study—preliminary data

Allingham-Hawkins, Diane; Babul‐Hirji, Riyana; Chitayat, David; Holden, Jeanette J. A.; Yang, Kathy T.; Lee, C.; Hudson, R.; Gorwill, H.; Nolin, Sarah L.; Jenkins, Edmund C.; Brown, W. Ted; Howard‐Peebles, Patricia N.; Becchi, Cindy; Cummings, Emilie; Fallon, Lee; Seitz, Suzanne; Black, Susan H.; Vianna‐Morgante, Angela Maria; Costa, Silvia Souza da; Otto, Paulo Alberto; Mingroni‐Netto, Regina Célia; Webb, J.; MacSwinney, F.; Dennis, N.; Jacobs, Patricia A.; Syrrou, Maria; Georgiou, Ioannis; Patsalis, Phillipos C.; Uzielli, Maria Luisa Giovannucci; Guarducci, S.; Lapi, E.; Cecconi, A.; Ricci, U.; Ricotti, G.; Biondi, C.; Scarselli, B.; Vieri, F.

doi:10.1002/(sici)1096-8628(19990402)83:4<322::aid-ajmg17>3.3.co;2-2

Cited by 120 publications

(150 citation statements)

References 5 publications

(10 reference statements)

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“…32 This may indicate the dosage-sensitive character of the FMR1 gene. However, we cannot state that excess mRNA is the cause of our patient's phenotype, as the levels of FMR1 expression were found to be normal.…”

Section: Discussionmentioning

confidence: 99%

De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity

et al. 2012

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Loss-of-function due to expansion of a CGG repeat located in the 5'UTR of the FMR1 gene is the most frequent cause of fragile X syndrome. Less than 1% of individuals with fragile X syndrome have been reported to have a partial or full deletion or point mutation of the FMR1 gene. However, whether a copy number gain of the FMR1 gene could result in certain clinical phenotypes has not been fully investigated. Here, we report the case of a child who presented with developmental delay starting at 9 months of age, fine motor and speech delay, progressive seizures since 18 months of age and hyperactivity. Molecular workup identified a de novo microduplication in the Xq27.3 region, including the FMR1 gene and the ASFMR1 gene. The expression level of the FMR1 gene in peripheral blood did not differ from that of the controls. In addition, an inherited 363-kb duplication on the chromosome 1q44 region and an inherited deletion of 168 kb on the chromosome 4p15.31 region were detected. It is not clear whether these inherited copy number variations (CNVs) also have a modifying role in the clinical phenotype of this patient.

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Section: Discussionmentioning

confidence: 99%

De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity

et al. 2012

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“…Because of the high incidence rates of POI among relatives suffering from fragile X syndrome 13,14 and as POI may be preceded by reduced ovarian reserve, 15 an increasing number of women presenting with infertility with or without POI are now being offered a FMR1 gene diagnostic test. Several medical organizations dealing with reproduction and obstetrics including the American College of Obstetricians and Gynecologists and the European Society of Human Reproduction and Embryology have decided to recommend FMR1 carrier testing in infertile women with signs of early onset of ovarian insufficiency 16 or to counsel women diagnosed with POI about their risk of carrying the premutation.…”

Section: Original Research Articlementioning

confidence: 99%

Similar prevalence of expanded CGG repeat lengths in the fragile X mental retardation I gene among infertile women and among women with proven fertility: a prospective study

Geyter

M’Rabet

Geyter

et al. 2014

Genetics in Medicine

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“…In fact, because of the increased numbers of CGG repeats, these patients exhibit abnormally high levels of FMR1 gene transcripts, which have been suggested to have a Bgain of toxicity^effect at the level of the ovaries, leading to an increased risk of POI [1,3]. With a peak risk for Fragile Xassociated POI (FXPOI), between 80 and 100 CGG repeats [4], 16-24 % of PM carriers will experience POI in some severity [5,6].…”

Section: Introductionmentioning

confidence: 99%

Evidence of an age-related correlation of ovarian reserve and FMR1 repeat number among women with “normal” CGG repeat status

Gustin

Ding

Desai

et al. 2015

J Assist Reprod Genet

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Purpose The objective of this analysis is to examine the relationship between Fragile X Mental Retardation 1 gene (FMR1) cytosine-guanine-guanine (CGG) repeat number and ovarian reserve, with a particular focus exclusively on the range of CGG repeat number below the premutation (PM) range (<55 CGG repeats). Methods Our study included female patients who underwent assessment of FMR1 CGG repeat number and serum antiMullerian hormone (AMH) in 2009-2014. To examine the association between FMR1 repeat number and serum AMH, we created three summary measures of CGG repeat number for the two alleles-BSum,^BMax,^and BGap^(absolute difference). Using multivariable regression models, controlling for age, we then analyzed the impact of these summary measures on AMH.Results A total of 566 patients were included in our study. Using multivariable regression models, we found that the relationship between CGG repeat number and AMH differed depending on age. Specifically, in younger women, AMH increased by 7-8 % (Sum p<0.01, Max p=0.04) for every 1 unit increase in CGG repeat number. In contrast, starting at age 40, there was a 3 to 5 % decline in AMH for every 1 unit increase in CGG repeat number (Sum p<0.01, Max p=0.04). Conclusions This is the first study to report a statistically significant correlation of ovarian reserve and CGG repeat number in women with <55 CGG repeats. Although these women are generally considered to have a normal phenotype, our data suggest that increasing CGG repeat number within this normal range is associated with a more rapid decline in ovarian reserve.

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Fragile X premutation is a significant risk factor for premature ovarian failure: The international collaborative POF in fragile X study—preliminary data

Cited by 120 publications

References 5 publications

De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity

De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity

Similar prevalence of expanded CGG repeat lengths in the fragile X mental retardation I gene among infertile women and among women with proven fertility: a prospective study

Evidence of an age-related correlation of ovarian reserve and FMR1 repeat number among women with “normal” CGG repeat status

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