The ovarian response in fragile X patients and premutation carriers undergoing IVF–PGD: reappraisal

Avraham, Sarit; Almog, Benny; Reches, Adi; Zakar, Liat; Malcov, Mira; Sokolov, Amit; Alpern, Sharon; Azem, Foad

doi:10.1093/humrep/dex090

Cited by 22 publications

(11 citation statements)

References 10 publications

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“…A review of published research on the FMR1 gene and its effect on IVF outcomes yielded 16 articles (Gleicher et al, 2009;2012a;2012b;2013a;2013b;Bibi et al, 2010;Tsafrir et al, 2010;Lledo et al, 2012;Weghofer et al, 2012;Elizur et al, 2014;Kushnir et al, 2014;Banks et al, 2016;Morin et al, 2016;Avraham et al, 2017). Nine of those were from the same research group (Gleicher et al, 2009;2012a;2012b;2013a;2013b;Weghofer et al, 2012;Kushnir et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

“…In three out of four studies, it was suggested that premutation carriers may have reduced success (oocyte yield, pregnancy rate and live birth rate) with IVF treatment compared with women with either a normal CGG repeat or a full mutation (Bibi et al, 2010;Tsafrir et al, 2010;Elizur et al, 2014), with the largest study (n = 51 premutations) finding no relationship between the specific repeat length and the oocyte yield (Avraham et al, 2017). Future studies that provide additional data will be beneficial in helping counsel patients with premutations before moving forward with ovarian stimulation for IVF.…”

Section: Discussionmentioning

confidence: 99%

“…80-120 CGG) than women with normal or intermediate range repeats (n = 15) (Elizur et al, 2014). Further analysis within the premutation range, in addition to a separate evaluation of IVF parameters among women with a full mutation, was reported by Avraham et al (2017). They found premutation carriers (n = 51) had fewer oocytes retrieved after IVF stimulation than full mutation carriers (n = 21; P = 0.005); Full mutation carriers had a normal response to IVF stimulation, and three modelling techniques did not identify any significant relationship between any IVF outcome assessed and the exact CGG repeats within the premutation range.…”

Section: Ivf Cycles In 3290 Patientsmentioning

confidence: 97%

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Does theFMR1 gene affect IVF success?

Pastore

Christianson

McGuinness

et al. 2019

Reproductive BioMedicine Online

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Published research suggests that women who carry the FMR1 premutation (about 55 to 200 CGG) may have reduced success with IVF, e.g. fewer retrieved oocytes after ovulatory stimulation regimens. A meta-analysis has revealed no association within subcategories of normal repeat length (<45 CGG) and IVF pregnancy rates. ABSTRACTFMR1 CGG trinucleotide repeat expansions are associated with Fragile X syndrome (full mutations) and primary ovarian insufficiency (premutation range); the effect of FMR1 on the success of fertility treatment is unclear. The effect of FMR1 CGG repeat lengths on IVF outcomes after ovarian stimulation was reviewed. PubMed was searched for studies on IVF-related outcomes reported by FMR1 trinucleotide repeat length published between 2002 and December 2017. For women with CGG repeats in the normal (<45 CGG), intermediate range (45-54 CGG), or both, research supports a minimal effect on IVF outcomes, including pregnancy rates; although one study reported lower oocyte yields after IVF stimulation in women with lower CGG repeat lengths and normal ovarian reserve. Metaanalysis revealed no association within subcategories of normal repeat length (<45 CGG) and IVF pregnancy rates (summary OR 1.0, 95% CI 0.87 to 1.15). Premutation carriers (CGG 55-200) may have reduced success with IVF treatment (lower oocyte yield) than women with a normal CGG repeat length or a full mutation, although findings are inconsistent. Direct implications of the repeat length on inheritance and the risk of Fragile X syndrome have been observed. Patients may require clinical and psychological counselling, and further preimplantation genetic testing options should be considered. Thus, there are clinical and psychological counseling implications for patients and potential further patient decisions regarding preimplantation genetic testing options.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Ivf Cycles In 3290 Patientsmentioning

confidence: 97%

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Does theFMR1 gene affect IVF success?

Pastore

Christianson

McGuinness

et al. 2019

Reproductive BioMedicine Online

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“…This is thought to occur via overproduction of abnormal FMR1 mRNA, which may lead to either a reduced NGF pool and/or abnormally rapid depletion of oocytes (16). There also have been several studies regarding abnormal CGG repeat number and DOR (16,26,(30)(31)(32)(33)(34)(35)(36)(37)(38)(39). In studies by Welt et al (32) and Hundscheid et al (33), regularly cycling premutation carriers were found to have increased FSH levels compared with age-matched controls.…”

Section: Fragile X Mental Retardation Genesmentioning

confidence: 99%

New perspectives on the genetic causes of diminished ovarian reserve and opportunities for genetic screening: systematic review and meta-analysis

Nesbit

Jia

Singh³

et al. 2020

F&S Reviews

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Objective: To provide an update on single-gene mutations identified as causative for pathologic diminished ovarian reserve (DOR) to inform clinical screening recommendations. Evidence Review: A systematic review of the literature was performed in accordance with PRISMA guidelines using PubMed and EM-BASE databases. Only full-text articles in English were included and articles were excluded that did not relate to single-gene causes of pathologic DOR in humans. The search was supplemented using references of the included articles. Primary outcomes included prevalence ratios (PRs) for 12 genes associated with pathologic DOR. Result(s): A total of 550 articles were screened, with 108 articles included for review. Fifteen observational studies had prevalence data available for quantitative analysis. Elevated prevalence ratios were found in women with DOR for the FMR1 premutation and FMR2 mutations as well as single-nucleotide polymorphisms in the BMP15, GDF9, FSHR, and NOBOX genes. Although some studies have suggested an increased prevalence of BRCA1 and BRCA2 mutations in women with DOR, the prevalence in the controls in the included studies was elevated and PRs did not achieve statistical significance. Conclusion(s): Women diagnosed with DOR are at an increased risk of carrying mutations in FMR1, FMR2, and variants in BMP15, GDF9, FSHR, and NOBOX genes. Of these, the only gene identified as having the potential to cause significant deleterious effects in offspring is the FMR1 premutation, which supports current national screening guidelines. Further studies of BRCA1 and BRCA2 are needed to determine whether pathologic DOR might be associated with mutations in those genes.

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“…While some authors considered PGT-M for FRAX patients as an "unrealistic option" due to its inefficiency [10], various PGT centers nowadays offer this strategy for FRAX mutation or premutation carriers and several reports have been published with contradictory results. On the one hand, Platteau and colleagues as well as Avraham and his team showed that premutation carriers required a higher dose of FSH for ovarian stimulation and were at higher risk of cancellation for low ovarian response [20,21]; on the other hand, Tsafrir and colleagues reported that premutation carriers necessitated less FSH and had more retrieved oocytes than mutation carriers [22]. Moreover, some studies suggested that the number of CGG repeats is correlated with ovarian response [23] and that the lowest response is observed in women with mid-size CGG repeats (80-120) [24].…”

Section: Introductionmentioning

confidence: 99%

Are ovarian response and pregnancy rates similar in selected FMR1 premutated and mutated patients undergoing preimplantation genetic testing?

Ranisavljevic

Hess

Castelli³

et al. 2020

J Assist Reprod Genet

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Purpose To assess if the ovarian response of FMR1 premutated women undergoing preimplantation genetic testing (PGT) for Fragile X syndrome is lower compared with fully mutated patients, due to their frequent premature ovarian failure. Methods In a retrospective cohort study from January 2009 to March 2019, we compared PGT outcomes in 18 FMR1 premutated women and 12 fully mutated women and aimed to identify predictive factors of stimulation outcomes. Results Eighty-six IVF/PGT-M cycles for FMR1 PGT were analyzed. Premutation and full mutation patients were comparable in terms of age, body mass index (BMI), basal FSH, antral follicular count, and cycle length. However, premutation carriers had significantly lower AMH (1.9 versus 4.0 ng/mL, p = 0.0167). Premutated patients required higher doses of FSH (2740 versus 1944 IU, p = 0.0069) but had similar numbers of metaphase II oocytes (7.1 versus 6.6, p = 0.871) and embryos (5.6 versus 4.9, p = 0. 554). Pregnancy rates (37.1% versus 13.3%, p = 0.1076) were not statistically different in both groups. Conclusion In spite of lower ovarian reserve and thanks to an increased total dose of FSH, FMR1 premutated selected patients seem to have similar ovarian response as fully mutated patients. Neither the number of CGG repeats in FMR1 gene nor FMR1 mutation status was good predictors of the number of retrieved oocytes.

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The ovarian response in fragile X patients and premutation carriers undergoing IVF–PGD: reappraisal

Abstract: None.

Cited by 22 publications

References 10 publications

Does theFMR1 gene affect IVF success?

Does theFMR1 gene affect IVF success?

New perspectives on the genetic causes of diminished ovarian reserve and opportunities for genetic screening: systematic review and meta-analysis

Are ovarian response and pregnancy rates similar in selected FMR1 premutated and mutated patients undergoing preimplantation genetic testing?

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