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

      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 EMBASE 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.

      Key Words

      Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/xfnr-d-20-00015
      • Women with diminished ovarian reserve have an increased risk of mutations in FMR1, FMR2, and variants in BMP15, GDF9, FSHR, and NOBOX genes.
      • Current clinical testing is limited to FMR1 premutation screening in women with diminished ovarian reserve.
      • Research is needed to establish firmly, or refute, the possible association of BRCA1 and BRCA2 with diminished ovarian reserve.
      Ovarian reserve is the term used to describe a woman’s reproductive potential via estimation of number and quality of oocytes. At birth, the human ovary is endowed with a finite number of nongrowing follicles (NGFs) that progressively diminishes over time, either through atresia or recruitment for ovulation. The size of the NGF pool and rate of depletion are thought to be the primary factors in determining the timeline of ovarian aging (
      • Pelosi E.
      • Forabosco A.
      • Schlessinger D.
      Genetics of the ovarian reserve.
      ). At this time, the NGF pool cannot directly be measured. Instead, the functional, or antral, follicle pool is measured using ultrasound and hormonal assays (serum follicle-stimulating hormone [FSH] and antimüllerian hormone [AMH]) with these markers being important in assessing a patient’s predicted chance of conception either spontaneously or through assisted reproductive technologies (ART) (
      • Tal R.
      • Seifer D.
      Ovarian reserve testing: a user’s guide.
      ).
      Diminished ovarian reserve (DOR) is a common reason for referral for fertility treatment, with an estimated 26% of women undergoing ART cycles having DOR (
      • Devine K.
      • Mumford S.
      • Wu M.
      • DeCherney A.
      • Hill M.
      • Propst A.
      Diminished ovarian reserve in the United States assisted reproductive technology population: diagnostic trend among 181,536 cycles from the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System.
      ). A diagnosis is made via a decreased antral follicle count (AFC) on ultrasound and/or abnormal serum testing (i.e., elevated FSH and low AMH levels) in the setting of regular menstrual cycles (
      • Pastore L.M.
      • Christianson M.S.
      • Stelling J.
      • Kearns W.G.
      • Segars J.H.
      Reproductive ovarian testing and the alphabet soup of diagnoses: DOR, POI, POF, POR and FOR.
      ). Of note, there is an expected decrease in ovarian reserve as a woman ages. Therefore, DOR can be thought of in two categories: age-related or physiologic DOR and pathologic DOR in which a woman has abnormal ovarian reserve testing for her age (
      The American College of Obstetricians and Gynecologists Committee on Gynecologic Practice and the Practice Committee of the American Society for Reproductive Medicine
      Female age-related fertility decline.
      ). However, currently, there are no universally accepted stratifications for ovarian reserve testing by age nor does there exist a universal age cutoff or laboratory criteria for DOR. As a result, this can make comparing studies of women with DOR difficult and can cause confusion between DOR and interrelated terms of primary ovarian insufficiency (POI) and poor ovarian response (POR) (
      • Pastore L.M.
      • Christianson M.S.
      • Stelling J.
      • Kearns W.G.
      • Segars J.H.
      Reproductive ovarian testing and the alphabet soup of diagnoses: DOR, POI, POF, POR and FOR.
      ). For the purposes of this review, we have defined DOR as pertaining to women <42 years with regular menstrual cycles and AFC <5, FSH >12 IU/L, and/or AMH <1.0 ng/mL and we focus on pathologic DOR. We will consider POI as a more severe form of DOR wherein menstrual irregularities occur. We have defined POR according to the Bologna criteria and considered POR as a term that may apply to women with DOR when undergoing treatment with ART (
      • Ferraretti A.P.
      • La Marca A.
      • Fauser B.C.
      • Tarlatzis B.
      • Nargund G.
      • Gianaroli L.
      • et al.
      ESHRE consensus on the definition of “poor response” to ovarian stimulation for in vitro fertilization: the Bologna criteria.
      ).
      Regardless of the criteria used, DOR has been shown to be associated with poor fertility outcomes that represent a major challenge in reproductive medicine (
      • Levi A.J.
      • Raynault M.F.
      • Bergh P.A.
      • Drews M.R.
      • Miller B.T.
      • Scott Jr., R.T.
      Reproductive outcome in patients with diminished ovarian reserve.
      ,
      • Cohen J.
      • Mounsambote L.
      • Prier P.
      • Mathieu d’Argent E.
      • Selleret L.
      • Chabbert-Buffet N.
      • et al.
      Outcomes of first IVF/ICSI in young women with diminished ovarian reserve.
      ,
      • Chang Y.
      • Li J.
      • Liu H.
      • Liang X.
      Egg quality and pregnancy outcome in young infertile women with diminished ovarian reserve.
      ,
      • Atasever M.
      • Soyman Z.
      • Demirel E.
      • Gencdel S.
      • Kelekci S.
      Diminished ovarian reserve: is it a neglected cause in the assessment of recurrent miscarriage? A cohort study.
      ,
      • Kumbak B.
      • Oral E.
      • Kahraman S.
      • Karlikaya G.
      • Karaguzoglu H.
      Young patients with diminished ovarian reserve undergoing assisted reproductive treatments: a preliminary report.
      ,
      • Shahine L.K.
      • Marshall L.
      • Lamb J.D.
      • Hickok L.R.
      Higher rates of aneuploidy in blastocysts and higher risk of no embryo transfer in recurrent pregnancy loss patients with diminished ovarian reserve undergoing in vitro fertilization.
      ). The causes of DOR include autoimmune disease, environmental factors, iatrogenic insults (ovarian surgery, chemotherapy, and radiation), and genetic causes, whereas a significant number of cases remain idiopathic (
      • Kaur M.
      • Arora M.
      Diminished ovarian reserve, causes, assessment and management.
      ,
      • Richardson M.C.
      • Guo M.
      • Fauser B.C.
      • Macklon N.S.
      Environmental and developmental origins of ovarian reserve.
      ,
      • Greene A.D.
      • Patounakis G.
      • Segars J.H.
      Genetic associations with diminished ovarian reserve: a systematic review of the literature.
      ). Some genetic causes of DOR are well-established and many other genes are currently under investigation (
      • Man L.
      • Lekovich J.
      • Rosenwaks Z.
      • Gerhardt J.
      Fragile X-associated diminished ovarian reserve and primary ovarian insufficiency from molecular mechanisms to clinical manifestations.
      ,
      • Daum H.
      • Peretz T.
      • Laufer N.
      BRCA mutations and reproduction.
      ,
      • Pashaiasl M.
      • Ebrahimi M.
      • Ebrahimie E.
      Identification of the key regulatory genes of diminished ovarian reserve (DOR) by network and gene ontology analysis.
      ). Discovering underlying genetic causes for DOR is important because this could help to individualize ART protocols. Furthermore, if a genetic mutation is identified prior to conception, such information might improve outcomes for biological offspring of affected women. In addition, it is possible that the same genetic defects that cause DOR also could lead to other health consequences. The objectives of this systematic review and meta-analysis were to summarize the current literature on single-gene mutations identified as causative for pathologic DOR and to attempt to quantify the risk of carrying each of these genetic variants if a woman is diagnosed with DOR.

      Methods

      A search was conducted on November 17, 2019 using PubMed and Embase databases from March 1997 to September 2019 in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines (
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      The PRISMA Group Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement.
      ). Initial search terms included combinations of “genes” or “genetic” and “diminished ovarian reserve.” The search was then widened based on initial search findings to include “fragile X” or “FMR” or “breast cancer associated genes” or “BRCA” or “myotonic dystrophy” or “DM1” or “AMH polymorphisms” or “bone morphogenetic protein” or “growth differentiation factor 9” or “FSHR polymorphisms” or “ESR polymorphisms” in combination with “ovarian reserve” or “diminished ovarian reserve.” Only full-text publications in English were included and articles were excluded that did not relate to single-gene causes of pathologic DOR in humans. We supplemented our search using the references of the included articles. Systematic reviews and meta-analyses were included; case studies and case reports were excluded as were studies with exclusively nonhuman subjects. Titles and abstracts were screened and study quality was assessed by two authors independently with subsequent review by the senior author. Values for prevalence ratio (PR) were calculated using standard equations. Studies included in these calculations were ones in which prevalence in women diagnosed with DOR per the criteria and study controls could be determined. If no such studies were available but data for POI was, PR was calculated for POI. For genetic polymorphisms, if a meta-analysis pooling all variants for a given gene was available, this was used. If not, data for single individual polymorphisms was used.

      Results

      Figure 1 outlines the studies screened and included. A total of 550 articles were screened, with 404 remaining after removal of duplicates. After review of the abstracts, 54 articles were included. After further collection from references, a total of 108 articles covering 12 genes were included for review. Fifteen studies had prevalence data available for quantitative analysis, one of which was a meta-analysis. The remaining 14 studies were observational studies (primarily case control studies). For 5 of the 12 genes, prevalence data was only available for POI and for one gene; no prevalence data was available for either DOR or POI. Table 1 provides details for single-gene mutations associated with DOR with PRs calculated as described. Table 2 provides the same details for genetic polymorphisms associated with DOR. Prevalence data for the general population are included in Tables 1 and 2 for relevant genetic mutations and polymorphisms if available in the literature for reference. Figure 2 presents the aforementioned data in Tables 1 and 2. Table 3 provides details of inheriting these conditions in biological offspring and current recommendations for genetic screening.
      Figure thumbnail gr1
      Figure 1Article identification and screening. DOR = diminished ovarian reserve.
      Table 1Single-gene mutations associated with diminished ovarian reserve.
      GeneMutationPrevalence of general population, %Prevalence of study controls, % (n)Prevalence of women with DOR, % (n)Prevalence risk, PR (95% CI)Reference
      FMR1Premutation (55–200 CGG)0.3–0.70.0 (200)16.0 (188)2.064 (1.863–2.287)
      • Hunter J.
      • Rivero-Arias O.
      • Angelov A.
      • Kim E.
      • Fotheringham I.
      • Leal J.
      Epidemiology of fragile X syndrome: a systematic review and meta-analysis.
      ,
      • Eslami A.
      • Farahmand K.
      • Totonchi M.
      • Madani T.
      • Asadpour U.
      • Zari Moradi S.
      • et al.
      FMR1 pre-mutation: not only important in premature ovarian failure but also in diminished ovarian reserve.
      Intermediate allele (45–55 CGG)2.920.0 (200)13.3 (188)0.794 (0.574–1.098)
      • Seltzer M.M.
      • Baker M.W.
      • Hong J.
      • Maenner M.
      • Greenberg J.
      • Mandel D.
      Prevalence of CGG expansions of the FMR1 gene in a US population-based sample.
      ,
      • Eslami A.
      • Farahmand K.
      • Totonchi M.
      • Madani T.
      • Asadpour U.
      • Zari Moradi S.
      • et al.
      FMR1 pre-mutation: not only important in premature ovarian failure but also in diminished ovarian reserve.
      Low allele (<26 CGG)30.3 (448)35.9 (117)1.218 (0.872–1.699)
      • Pastore L.
      • Young S.
      • Manichaikul A.
      • Baker V.
      • Wang X.
      • Finkelstein J.
      Distribution of the FMR1 gene in females by race/ethnicity: women with diminished ovarian reserve versus women with normal fertility (SWAN study).
      FMR2Low allele
      Data for POI as no DOR data available.
      (<11 CGG)
      0.7 (1,268)4.1 (147)3.972 (2.096–7.527)
      • Cohen J.
      • Mounsambote L.
      • Prier P.
      • Mathieu d’Argent E.
      • Selleret L.
      • Chabbert-Buffet N.
      • et al.
      Outcomes of first IVF/ICSI in young women with diminished ovarian reserve.
      0.9 (4,796)1.5 (400)1.668 (0.785–3.544)
      • Murray A.
      • Webb J.
      • Dennis N.
      • Conway G.
      • Morton N.
      Microdeletions in FMR2 may be a significant cause of premature ovarian failure.
      BRCA1Multiple0.06
      • Malone K.E.
      • Daling J.R.
      • Doody D.R.
      • Hsu L.
      • Bernstein L.
      • Coates R.J.
      • et al.
      Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35-64 years.
      0.3
      Prevalence in population of women with family history of breast or ovarian cancer.
      38.8 (67)47.3 (76)1.093 (0.841–1.419)
      • Malone K.E.
      • Daling J.R.
      • Doody D.R.
      • Hsu L.
      • Bernstein L.
      • Coates R.J.
      • et al.
      Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35-64 years.
      ,
      • Wang E.T.
      • Pisarska M.D.
      • Bresee C.
      • Ida Chen Y.D.
      • Lester J.
      • Afshar Y.
      • et al.
      BRCA1 germline mutations may be associated with reduced ovarian reserve.
      6.3
      Prevalence in population of reproductive-aged women with personal history of breast cancer.
      16.9 (65)20.0 (20)1.133 (0.450–2.851)
      • Malone K.E.
      • Daling J.R.
      • Doody D.R.
      • Hsu L.
      • Bernstein L.
      • Coates R.J.
      • et al.
      Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35-64 years.
      ,
      • Lambertini M.
      • Goldrat O.
      • Ferreira A.
      • Dechene J.
      • Azim H.
      • Desir J.
      • et al.
      Reproductive potential and performance of fertility preservation strategies in BRCA-mutated breast cancer patients.
      BRCA2Multiple0.4
      • Malone K.E.
      • Daling J.R.
      • Doody D.R.
      • Hsu L.
      • Bernstein L.
      • Coates R.J.
      • et al.
      Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35-64 years.
      0.6
      Prevalence in population of women with family history of breast or ovarian cancer.
      23.9 (67)14.4 (76)0.767 (0.474–1.239)
      • Malone K.E.
      • Daling J.R.
      • Doody D.R.
      • Hsu L.
      • Bernstein L.
      • Coates R.J.
      • et al.
      Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35-64 years.
      ,
      • Wang E.T.
      • Pisarska M.D.
      • Bresee C.
      • Ida Chen Y.D.
      • Lester J.
      • Afshar Y.
      • et al.
      BRCA1 germline mutations may be associated with reduced ovarian reserve.
      4.0
      Prevalence in population of reproductive-aged women with personal history of breast cancer.
      9.2 (65)20.0 (20)1.700 (0.726–3.979)
      • Malone K.E.
      • Daling J.R.
      • Doody D.R.
      • Hsu L.
      • Bernstein L.
      • Coates R.J.
      • et al.
      Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35-64 years.
      ,
      • Lambertini M.
      • Goldrat O.
      • Ferreira A.
      • Dechene J.
      • Azim H.
      • Desir J.
      • et al.
      Reproductive potential and performance of fertility preservation strategies in BRCA-mutated breast cancer patients.
      DMPK1CTG repeat expansion (>55 CTG)0.005

      Bird TD. Myotonic Dystrophy Type 1. 1999 Sep 17 [Updated 2019 Oct 3]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1165. Accessed November 17, 2019.

      Note: CGG = cytosine-guanine-guanine; CI = confidence interval; CTG = cytosine-thymine-guanine; DOR = diminished ovarian reserve; POI = primary ovarian insufficiency; PR = prevalence ratio.
      a Data for POI as no DOR data available.
      b Prevalence in population of women with family history of breast or ovarian cancer.
      c Prevalence in population of reproductive-aged women with personal history of breast cancer.
      Table 2Genetic polymorphisms associated with diminished ovarian reserve.
      GenePolymorphism(s)Prevalence of general populationPrevalence of study controls, % (n)Prevalence of women with DOR, % (n)PR (95% CI)Reference
      AMH

      Ile49Ser
      Data for POI as no DOR data available.
      Ile/Ile47.6 (233)47.4 (211)0.995 (0.818–1.210)
      • Yoon S.H.
      • Choi Y.M.
      • Hong M.A.
      • Kim J.J.
      • Lee G.H.
      • Hwang K.R.
      • et al.
      Association study of anti-Müllerian hormone and anti-Müllerian hormone type II receptor polymorphisms with idiopathic primary ovarian insufficiency.
      Ile/Ser40.8 (233)41.7 (211)1.020 (0.837–1.244)
      Ser/Ser11.6 (233)10.9 (211)0.964 (0.702–1.324)
      AMHR2
      Data for POI as no DOR data available.


      -482(A>G)
      AA60.9 (233)62.1 (211)1.026 (0.838–1.255)
      • Yoon S.H.
      • Choi Y.M.
      • Hong M.A.
      • Kim J.J.
      • Lee G.H.
      • Hwang K.R.
      • et al.
      Association study of anti-Müllerian hormone and anti-Müllerian hormone type II receptor polymorphisms with idiopathic primary ovarian insufficiency.
      GA36.5 (233)34.6 (211)0.958 (0.779–1.177)
      GG2.6 (233)3.3 (211)1.138 (0.681–1.900)
      BMP15Multiple
      Data for POI as no DOR data available.
      0.4 (1399)4.5 (1236)1.969 (1.797–2.159)
      • Persani L.
      • Rossetti R.
      • Di Pasquale E.
      • Cacciatore C.
      • Fabre S.
      The fundamental role of bone morphogenetic protein 15 in ovarian function and its involvement in female fertility disorders.
      GDF9

      G546A
      GA or AA19.5 (123)33.0 (103)1.427 (1.076–1.892)
      • Wang T.T.
      • Wu Y.T.
      • Dong M.Y.
      • Sheng J.Z.
      • Leung P.C.
      • Huang H.F.
      G546A polymorphism of growth differentiation factor-9 contributes to the poor outcome of ovarian stimulation in women with diminished ovarian reserve.
      FSHR

      -29G>A
      GG41.7 (84)60.0 (15)1.219 (0.613–2.424)
      • Ilgaz N.S.
      • Aydos O.S.E.
      • Karadag A.
      • Taspinar M.
      • Eryilmaz O.G.
      • Sunguroglu A.
      Impact of follicle-stimulating hormone receptor variants in female infertility.
      67.5 (80)46.2 (5200.850 (0.582–1.241)
      • Ghezelayagh Z.
      • Totonchi M.
      • Zarej-Moradi S.
      • Asadpour O.
      • Maroufizadeh S.
      • Eftekhari-Yadi P.
      • et al.
      The impact of genetic variation and gene expression level of the follicle-stimulating hormone receptor on ovarian reserve.
      GA50.0 (84)26.7 (15)0.664 (0.238–1.851)
      • Ilgaz N.S.
      • Aydos O.S.E.
      • Karadag A.
      • Taspinar M.
      • Eryilmaz O.G.
      • Sunguroglu A.
      Impact of follicle-stimulating hormone receptor variants in female infertility.
      20.0 (80)46.2 (52)1.358 (1.002–1.840)
      • Ghezelayagh Z.
      • Totonchi M.
      • Zarej-Moradi S.
      • Asadpour O.
      • Maroufizadeh S.
      • Eftekhari-Yadi P.
      • et al.
      The impact of genetic variation and gene expression level of the follicle-stimulating hormone receptor on ovarian reserve.
      AA8.3 (84)13.3 (15)1.412 (0.386–5.169)
      • Ilgaz N.S.
      • Aydos O.S.E.
      • Karadag A.
      • Taspinar M.
      • Eryilmaz O.G.
      • Sunguroglu A.
      Impact of follicle-stimulating hormone receptor variants in female infertility.
      10.0 (80)7.7 (52)0.857 (0.375–1.958)
      • Ghezelayagh Z.
      • Totonchi M.
      • Zarej-Moradi S.
      • Asadpour O.
      • Maroufizadeh S.
      • Eftekhari-Yadi P.
      • et al.
      The impact of genetic variation and gene expression level of the follicle-stimulating hormone receptor on ovarian reserve.
      307 G>AGG35.7 (84)6.7 (15)0.262 (0.036–1.902)
      • Ilgaz N.S.
      • Aydos O.S.E.
      • Karadag A.
      • Taspinar M.
      • Eryilmaz O.G.
      • Sunguroglu A.
      Impact of follicle-stimulating hormone receptor variants in female infertility.
      GA42.9 (84)60.0 (15)1.200 (0.602–2.390)
      AA21.4 (84)33.3 (15)1.326 (0.554–3.174)
      680 G>AGG32.1 (84)6.7 (15)0.283 (0.039–2.050)
      • Ilgaz N.S.
      • Aydos O.S.E.
      • Karadag A.
      • Taspinar M.
      • Eryilmaz O.G.
      • Sunguroglu A.
      Impact of follicle-stimulating hormone receptor variants in female infertility.
      GA45.2 (84)60.0 (15)1.165 (0.583–2.327)
      AA22.6 (84)33.3 (15)1.281 (0.533–3.080)
      919G.AGG35.0 (80)11.5 (52)0.505 (0.237–1.075)
      • Ghezelayagh Z.
      • Totonchi M.
      • Zarej-Moradi S.
      • Asadpour O.
      • Maroufizadeh S.
      • Eftekhari-Yadi P.
      • et al.
      The impact of genetic variation and gene expression level of the follicle-stimulating hormone receptor on ovarian reserve.
      GA60.0 (80)84.6 (52)1.116 (0.859–1.450)
      AA5.0 (80)8.0 (52)0.852 (0.270–2.692)
      ESR

      -397C/T PvuII
      Data for POI as no DOR data available.
      TT21.9 (155)34.5 (113)1.199 (0.938–1.531)
      • Livshyts G.
      • Podlesnaja S.
      • Kravchenko S.
      • Livshits L.
      Association of PvuII polymorphism in ESR1 gene with impaired ovarian reserve in patients from Ukraine.
      26.2 (221)41.3 (126)1.214 (0.966–1.525)
      • Yoon S.H.
      • Choi Y.M.
      • Hong M.A.
      • Lee G.H.
      • Kim J.J.
      • Im H.J.
      • et al.
      Estrogen receptor {alpha} gene polymorphisms in patients with idiopathic premature ovarian failure.
      CT50.3 (155)50.4 (113)1.001 (0.797–1.257)
      • Livshyts G.
      • Podlesnaja S.
      • Kravchenko S.
      • Livshits L.
      Association of PvuII polymorphism in ESR1 gene with impaired ovarian reserve in patients from Ukraine.
      52.9 (221)46.8 (126)0.948 (0.747–1.202)
      • Yoon S.H.
      • Choi Y.M.
      • Hong M.A.
      • Lee G.H.
      • Kim J.J.
      • Im H.J.
      • et al.
      Estrogen receptor {alpha} gene polymorphisms in patients with idiopathic premature ovarian failure.
      CC27.7 (155)15.0 (113)0.715 (0.468–1.092)
      • Livshyts G.
      • Podlesnaja S.
      • Kravchenko S.
      • Livshits L.
      Association of PvuII polymorphism in ESR1 gene with impaired ovarian reserve in patients from Ukraine.
      11.9 (221)20.8 (126)0.712 (0.450–1.126)
      • Yoon S.H.
      • Choi Y.M.
      • Hong M.A.
      • Lee G.H.
      • Kim J.J.
      • Im H.J.
      • et al.
      Estrogen receptor {alpha} gene polymorphisms in patients with idiopathic premature ovarian failure.
      NOBOXMultiple
      Data for POI as no DOR data available.
      (6 missense mutations)
      0.1%–1.7%0.0 (362)6.2 (178)2.915 (2.597–3.272)
      • Bouilly J.
      • Bachelot A.
      • Broutin I.
      • Touraine P.
      • Binart N.
      Novel NOBOX loss-of-function mutations account for 6.2% of cases in a large primary ovarian insufficiency cohort.
      0.0 (764)7.0 (213)4.175 (3.729–4.676)
      • Bouilly J.
      • Roucher-Boulez F.
      • Gompel A.
      • Bry-Gauillard H.
      • Azibi K.
      • Beldjord C.
      • et al.
      New NOBOX mutations identified in a large cohort of women with primary ovarian insufficiency decrease KIT-L expression.
      Note: CI = confidence interval; DOR = diminished ovarian reserve; POI = primary ovarian insufficiency; PR = prevalence ratio.
      a Data for POI as no DOR data available.
      Figure thumbnail gr2
      Figure 2Prevalence ratios of genetic mutations and gene variants in women with diminished ovarian reserve.
      Table 3Consequences for offspring and current screening recommendations.
      GeneMutationConsequences for biological offspringRecommendations for screeningReference
      FMR1Premutation (55–200 CGG)Fragile X tremor-ataxia syndrome; progressive movement disorder, tremor, dementia, behavioral changes, and peripheral neuropathyACOG: any woman who is currently pregnant or planning a pregnancy with family history of fragile X–related disorder or intellectual disability consistent with fragile X–related disorder or any woman with unexplained ovarian insufficiency or an elevated FSH level before age 40.
      • Greene A.D.
      • Patounakis G.
      • Segars J.H.
      Genetic associations with diminished ovarian reserve: a systematic review of the literature.
      ,
      • Noto V.
      • Harrity C.
      • Walsh D.
      • Marron K.
      The impact of FMR1 gene mutations on human reproduction and development: a systematic review.
      ,
      • Lekovich J.
      • Man L.
      • Xu K.
      • Canon C.
      • Lilienthal D.
      • Stewart J.
      • et al.
      CGG repeat length and AGG interruptions as indicators of fragile X-associated diminished ovarian reserve.
      ,
      • Sullivan-Pyke C.
      • Dokras A.
      Preimplantation genetic screening and preimplantation genetic diagnosis.
      Risk of instability of CGG repeats during transmission and inheritance of a full mutation leading to fragile X syndrome; severe intellectual disability, behavioral disorder, and distinctive physical characteristicsACMG: As above plus any reproductive or fertility problems related to an elevated FSH.
      Intermediate allele (45–55 CGG)Unknown
      Low allele (<24–26 CGG)Unknown
      FMR2Low allele (<11 CGG)Unknown
      National Library of Medicine (US)
      Genetics Home Reference [Internet].
      ,
      • Gécz J.
      • Oostra B.
      • Hockey A.
      • Carbonell P.
      • Turner G.
      • Haan E.
      • et al.
      FMR2 expression in families with FRAXE mental retardation.
      BRCA1MultipleHereditary breast and ovarian cancer syndrome; 65%–85% lifetime risk of breast cancer; 39%–46% lifetime risk of ovarian cancerSGO:

      Women affected with high-grade epithelial ovarian/tubal/peritoneal cancer, breast cancer if certain other criteria are met
      Breast cancer at <45 y, with a close relative with breast cancer at <50 y, more than two close relatives with breast cancer, pancreatic cancer, or aggressive prostate cancer, with Ashkenazi Jewish ancestry, or a close relative with ovarian cancer at any age, breast cancer at <50 y with a limited family history, two breast primaries with first diagnosed prior to age 50 y, triple-negative breast cancer at <60 y.
      , or pancreatic cancer if certain other criteria are met.
      Pancreatic cancer with more than two close relatives with breast, ovarian/tubal/peritoneal cancer, pancreatic, or aggressive prostate cancer.


      Women unaffected with cancer but with first degree or several close relatives that meet one of the above criteria, a close relative carrying a known BRCA mutation, or a close relative with male breast cancer.

      USPTF: Similar to SGO.
      • McGowan M.
      • Cho D.
      • Sharp R.
      The changing landscape of carrier screening: expanding technology and options?.
      ,
      • Shapira M.
      • Raanani H.
      • Feldman B.
      • Srebnik N.
      • Derek-Haim S.
      • Manela D.
      • et al.
      BRCA mutation carriers show normal ovarian response in in vitro fertilization cycles.
      ,
      Society for Gynecologic Oncology Clinical Practice Committee
      Society of gynecologic oncology statement on risk assessment for inherited gynecologic cancer predispositions.
      BRCA2MultipleHereditary breast and ovarian cancer syndrome; 45%–85% lifetime risk of breast cancer; 10%–27% lifetime risk of ovarian cancerSame as BRCA1.
      • McGowan M.
      • Cho D.
      • Sharp R.
      The changing landscape of carrier screening: expanding technology and options?.
      ,
      • Shapira M.
      • Raanani H.
      • Feldman B.
      • Srebnik N.
      • Derek-Haim S.
      • Manela D.
      • et al.
      BRCA mutation carriers show normal ovarian response in in vitro fertilization cycles.
      ,
      Society for Gynecologic Oncology Clinical Practice Committee
      Society of gynecologic oncology statement on risk assessment for inherited gynecologic cancer predispositions.
      DMPKCTG repeat expansion (>55 CTG)Myotonic dystrophy type 1; hypotonia, cataracts, and delayed motor and cognitive developmentScreening only recommended if symptoms concerning for disease.
      • Chan J.
      • Johnson L.
      • Sammel M.
      • DiGiovanni L.
      • Voong C.
      • Domchek S.
      • et al.
      Reproductive decision-making in women with BRCA1/2 mutations.
      ,
      • Srebnik N.
      • Margalioth E.
      • Rabinowitz R.
      • Varshaver I.
      • Altarescu G.
      • Renbaum P.
      Ovarian reserve and PGD treatment outcome in women with myotonic dystrophy.
      SNPsMultipleUnknown
      Note: ACMG = American College of Genetics and Genomics; ACOG = American College of Obstetricians and Gynecologists; CGG = cytosine-guanine-guanine; CTG = cytosine-guanine-guanine; FSH = follicle-stimulating hormone; SGO = Society for Gynecologic Oncology; USPTF = United States Preventative Task Force.
      a Breast cancer at <45 y, with a close relative with breast cancer at <50 y, more than two close relatives with breast cancer, pancreatic cancer, or aggressive prostate cancer, with Ashkenazi Jewish ancestry, or a close relative with ovarian cancer at any age, breast cancer at <50 y with a limited family history, two breast primaries with first diagnosed prior to age 50 y, triple-negative breast cancer at <60 y.
      b Pancreatic cancer with more than two close relatives with breast, ovarian/tubal/peritoneal cancer, pancreatic, or aggressive prostate cancer.

       Fragile X Mental Retardation Genes

      The Fragile X Mental Retardation (FMR) gene is located on the X chromosome and codes for an intracellular messenger RNA (mRNA) shuttle in multiple tissues including the brain and gonads. The FMR1 gene contains an area in the 5’ untranslated region with a highly variable number of cytosine-guanine-guanine (CGG) repeats with most humans having 10–45 copies. Four allelic forms have been defined with respect to number of CGG repeats: normal (<45 CGG), full mutation (>200 CGG), which induces gene silencing, premutation (55–200 CGG), which leads to overproduction of FMR1 protein, and intermediate (45–55 CGG) allele (
      • Pastore L.M.
      • Johnson J.
      The FMR1 gene, infertility, and reproductive decision-making: a review.
      ,
      • Noto V.
      • Harrity C.
      • Walsh D.
      • Marron K.
      The impact of FMR1 gene mutations on human reproduction and development: a systematic review.
      ). Almost all cases of fragile X syndrome are caused by the full mutation with sequelae including a spectrum of developmental delay, behavioral disorder, and characteristic physical appearance with severity of symptoms correlating to the amount of FMR1 protein produced. Heterozygous females are generally less affected due to mRNA transcription from the unaffected X chromosome (
      • Hagerman R.J.
      • Berry-Kravis E.
      • Hazlett H.C.
      • Bailey Jr., D.B.
      • Moine H.
      • Kooy R.F.
      • et al.
      Fragile X syndrome.
      ). The premutation is associated with two alternative phenotypes: fragile X (FX)–associated tremor ataxia syndrome characterized by progressive movement disorder, tremor, dementia, behavioral changes, and peripheral neuropathy and FX-associated POI/DOR (FXPOI/FXDOR) (
      • Man L.
      • Lekovich J.
      • Rosenwaks Z.
      • Gerhardt J.
      Fragile X-associated diminished ovarian reserve and primary ovarian insufficiency from molecular mechanisms to clinical manifestations.
      ). In females, the prevalence of the premutation is thought to be 1:150–300 and prevalence of the intermediate allele is 1:35, although this has been found to vary among different ethnic groups (
      • Man L.
      • Lekovich J.
      • Rosenwaks Z.
      • Gerhardt J.
      Fragile X-associated diminished ovarian reserve and primary ovarian insufficiency from molecular mechanisms to clinical manifestations.
      ,
      • Hunter J.
      • Rivero-Arias O.
      • Angelov A.
      • Kim E.
      • Fotheringham I.
      • Leal J.
      Epidemiology of fragile X syndrome: a systematic review and meta-analysis.
      ,
      • Seltzer M.M.
      • Baker M.W.
      • Hong J.
      • Maenner M.
      • Greenberg J.
      • Mandel D.
      Prevalence of CGG expansions of the FMR1 gene in a US population-based sample.
      ,
      • Hantash F.M.
      • Goos D.M.
      • Crossley B.
      • Anderson B.
      • Zhang K.
      • Sun W.
      • et al.
      FMR1 pre-mutation carrier frequency in patients undergoing routine population-based carrier screening: insights into the prevalence of fragile X syndrome, fragile X-associated tremor/ataxia syndrome, and fragile X-associated primary ovarian insufficiency in the United States.
      ,
      • Pastore L.
      • Young S.
      • Manichaikul A.
      • Baker V.
      • Wang X.
      • Finkelstein J.
      Distribution of the FMR1 gene in females by race/ethnicity: women with diminished ovarian reserve versus women with normal fertility (SWAN study).
      ).

       Fragile X mental retardation gene 1 premutation and DOR

      Women carrying a premutation have an increased risk of developing POI (an estimated 20% compared with 1% in the general population) (
      • Allingham-Hawkins D.J.
      • Babul-Hirji R.
      • Chitayat D.
      • Holden J.J.
      • Yang K.T.
      • Lee C.
      • et al.
      Fragile X premutation is a significant risk factor for premature ovarian failure: the international collaborative POF in fragile X study—preliminary data.
      ,
      • Uzielli M.L.
      • Guarducci S.
      • Lapi E.
      • Cecconi A.
      • Ricci U.
      • Ricotti G.
      • et al.
      Premature ovarian failure (POF) and fragile X premutation females: from POF to fragile X carrier identification, from fragile X carrier diagnosis to POF association data.
      ,
      • Sherman S.L.
      Premature ovarian failure in the fragile X syndrome.
      ,
      • Sullivan A.K.
      • Marcus M.
      • Epstein M.P.
      • Allen E.G.
      • Anido A.E.
      • Paquin J.J.
      • et al.
      Association of FMR1 repeat size with ovarian dysfunction.
      ). 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 (
      • Man L.
      • Lekovich J.
      • Rosenwaks Z.
      • Gerhardt J.
      Fragile X-associated diminished ovarian reserve and primary ovarian insufficiency from molecular mechanisms to clinical manifestations.
      ). There also have been several studies regarding abnormal CGG repeat number and DOR (
      • Man L.
      • Lekovich J.
      • Rosenwaks Z.
      • Gerhardt J.
      Fragile X-associated diminished ovarian reserve and primary ovarian insufficiency from molecular mechanisms to clinical manifestations.
      ,
      • Pastore L.
      • Young S.
      • Manichaikul A.
      • Baker V.
      • Wang X.
      • Finkelstein J.
      Distribution of the FMR1 gene in females by race/ethnicity: women with diminished ovarian reserve versus women with normal fertility (SWAN study).
      ,
      • Sullivan A.K.
      • Marcus M.
      • Epstein M.P.
      • Allen E.G.
      • Anido A.E.
      • Paquin J.J.
      • et al.
      Association of FMR1 repeat size with ovarian dysfunction.
      ,
      • Avraham S.
      • Almog B.
      • Reches A.
      • Zakar L.
      • Malcov M.
      • Sokolov A.
      • et al.
      The ovarian response in fragile X patients and premutation carriers undergoing IVF-PGD: a reappraisal.
      ,
      • Welt C.
      • Smith P.
      • Taylor A.
      Evidence of early ovarian aging in fragile X permutation carriers.
      ,
      • Hundscheid R.D.
      • Braat D.D.
      • Kiemeney L.A.
      • Smits A.P.
      • Thomas C.M.
      Increased serum FSH in female fragile X premutation carriers with either regular menstrual cycles or on oral contraceptives.
      ,
      • Gleicher N.
      • Weghofer A.
      • Barad D.H.
      A pilot study of premature ovarian senescence: correlation of triple CGG repeats on the FMR1 gene to ovarian reserve parameters FSH and anti-mullerian hormone.
      ,
      • Gleicher N.
      • Weghofer A.
      • Barad D.
      Ovarian reserve determinations suggest new function of FMR1 (fragile X gene) in regulating ovarian ageing.
      ,
      • Pastore L.
      • McMurry T.
      • Williams C.
      • Baker V.
      • Young S.
      AMH in women with diminished ovarian reserve: potential differences by FMR1 CGG repeat level.
      ,
      • Eslami A.
      • Farahmand K.
      • Totonchi M.
      • Madani T.
      • Asadpour U.
      • Zari Moradi S.
      • et al.
      FMR1 pre-mutation: not only important in premature ovarian failure but also in diminished ovarian reserve.
      ,
      • Streuli I.
      • Fraisse T.
      • Ibecheole V.
      • Moix I.
      • Morris M.
      • Ziegler D.
      Intermediate and premutation FMR1 alleles in women with occult primary ovarian insufficiency.
      ,
      • Barasoain M.
      • Barrenetxea G.
      • Huerta I.
      • Telez M.
      • Carrillo A.
      • Perez C.
      • et al.
      Study of FMR1 gene association with ovarian dysfunction in a sample from the Basque country.
      ). In studies by Welt et al. (
      • Welt C.
      • Smith P.
      • Taylor A.
      Evidence of early ovarian aging in fragile X permutation carriers.
      ) and Hundscheid et al. (
      • Hundscheid R.D.
      • Braat D.D.
      • Kiemeney L.A.
      • Smits A.P.
      • Thomas C.M.
      Increased serum FSH in female fragile X premutation carriers with either regular menstrual cycles or on oral contraceptives.
      ), regularly cycling premutation carriers were found to have increased FSH levels compared with age-matched controls. A subsequent study found similar results and an increased likelihood for AMH levels <1.0 ng/mL in women with >32 CGG repeats (
      • Gleicher N.
      • Weghofer A.
      • Barad D.H.
      A pilot study of premature ovarian senescence: correlation of triple CGG repeats on the FMR1 gene to ovarian reserve parameters FSH and anti-mullerian hormone.
      ). In studies by Gleicher et al. (
      • Gleicher N.
      • Weghofer A.
      • Barad D.
      Ovarian reserve determinations suggest new function of FMR1 (fragile X gene) in regulating ovarian ageing.
      ) and Pastore et al. (
      • Pastore L.
      • McMurry T.
      • Williams C.
      • Baker V.
      • Young S.
      AMH in women with diminished ovarian reserve: potential differences by FMR1 CGG repeat level.
      ), AMH levels were lower at baseline and decreased more rapidly in women carrying a FMR1 premutation than controls. Supporting results were found in a study by Eslami et al. (
      • Eslami A.
      • Farahmand K.
      • Totonchi M.
      • Madani T.
      • Asadpour U.
      • Zari Moradi S.
      • et al.
      FMR1 pre-mutation: not only important in premature ovarian failure but also in diminished ovarian reserve.
      ) in which Iranian women with DOR were shown to have a higher prevalence of FMR1 premutations compared with controls (16.0% vs. 0.0%), a Swedish study with 22% of women with DOR carrying a CGG repeat >40 compared with 3% of controls (
      • Streuli I.
      • Fraisse T.
      • Ibecheole V.
      • Moix I.
      • Morris M.
      • Ziegler D.
      Intermediate and premutation FMR1 alleles in women with occult primary ovarian insufficiency.
      ), and a study by Barasoain et al. (
      • Barasoain M.
      • Barrenetxea G.
      • Huerta I.
      • Telez M.
      • Carrillo A.
      • Perez C.
      • et al.
      Study of FMR1 gene association with ovarian dysfunction in a sample from the Basque country.
      ) in which Spanish women with DOR had a 13.64% prevalence of FMR1 premutation compared with 3.13% of controls. Of these studies, the only one with prevalence data available for both women with DOR and controls was by Eslami et al. from which a prevalence ratio of 2.064 (95% confidence interval [CI] 1.863–2.287) was generated. Controls in this study were 200 women with proven fertility and normal menstrual cycles (Table 1) (
      • Eslami A.
      • Farahmand K.
      • Totonchi M.
      • Madani T.
      • Asadpour U.
      • Zari Moradi S.
      • et al.
      FMR1 pre-mutation: not only important in premature ovarian failure but also in diminished ovarian reserve.
      ).

       Other FMR1 alleles and ovarian reserve

      For intermediate alleles, the results have been mixed. While each woman inherits two alleles, because of X-inactivation, only one allele will be biologically active in a cell. Investigators have examined the effects of CGG repeats in individuals with alleles of <26; 26-34, and 35-55 CGG repeats. In studies by Eslami et al. (
      • Eslami A.
      • Farahmand K.
      • Totonchi M.
      • Madani T.
      • Asadpour U.
      • Zari Moradi S.
      • et al.
      FMR1 pre-mutation: not only important in premature ovarian failure but also in diminished ovarian reserve.
      ), Bennett et al. (
      • Bennett C.
      • Conway G.
      • MacPherson J.
      • Jacobs P.
      • Murray A.
      Intermediate sized CGG repeats are not a common cause of idiopathic premature ovarian failure.
      ), Lledo et al. (
      • Lledo B.
      • Guerrero J.
      • Ortiz J.
      • Morales R.
      • Ten J.
      • Llacer J.
      • et al.
      Intermediate and normal sized CGG repeat on the FMR1 gene does not negatively affect donor ovarian response.
      ), and Schufreider et al. (
      • Schufreider A.
      • McQueen D.B.
      • Lee S.M.
      • Allon R.
      • Uhler M.L.
      • Davie J.
      • et al.
      Diminished ovarian reserve is not observed in infertility patients with high normal CGG repeats on the fragile X mental retardation 1 (FMR1) gene.
      ), no differences were observed between women with an intermediate number of CGG repeats and controls regarding the prevalence of DOR. However, in a study by Pastore et al. (
      • Pastore L.
      • Young S.
      • Baker V.
      • Karns L.
      • Williams C.
      • Silverman L.
      Elevated prevalence of 35-44 FMR1 trinucleotide repeats in women with diminished ovarian reserve.
      ), women with DOR were seen to have a higher prevalence of CGG repeats, ranging from 35–44, than the general population (14.5% vs. 3.9%.). Low numbers of CGG repeats also have been associated with DOR. In a 2015 study by Gleicher et al. (
      • Gleicher N.
      • Yu Y.
      • Himaya E.
      • Barad D.
      • Weghofer A.
      • Wu Y.
      • et al.
      Early decline in functional ovarian reserve in young women with low (CGG n < 26) FMR1 gene alleles.
      ), oocyte donors with <26 CGG repeats were seen to have lower functional ovarian reserve at the start of the study and more rapid decline in ovarian reserve than controls. Similarly, in a study by Maslow et al. (
      • Maslow B.
      • Davis S.
      • Engmann L.
      • Nulsen J.
      • Benadiva C.
      Correlation of normal-range FMR1 repeat length or genotypes and reproductive parameters.
      ), women with bi-allelic low (<26 CGG repeats) alleles had lower AMH levels than women with bi-allelic normal (26-34 CGG repeats) alleles. The study by Eslami et al. (
      • Eslami A.
      • Farahmand K.
      • Totonchi M.
      • Madani T.
      • Asadpour U.
      • Zari Moradi S.
      • et al.
      FMR1 pre-mutation: not only important in premature ovarian failure but also in diminished ovarian reserve.
      ) was the only study with prevalence data for both women with DOR and controls for the intermediate allele. Prevalence data from this study generated a prevalence ratio of 0.794 (95% CI 0.574–1.098). For low alleles, the only study with prevalence data for cases and controls was a study by Pastore et al. (
      • Pastore L.
      • Young S.
      • Manichaikul A.
      • Baker V.
      • Wang X.
      • Finkelstein J.
      Distribution of the FMR1 gene in females by race/ethnicity: women with diminished ovarian reserve versus women with normal fertility (SWAN study).
      ). For those diagnosed with DOR in this study, the prevalence ratio was calculated as 1.218 (95% CI 0.872–1.699). The control group in this study was women with age of natural menopause at >46 years (Table 1).

       Fragile X mental retardation gene 2 and DOR

      The fragile X mental retardation 2 (FMR2) gene is located proximal to the FMR1 gene on the X chromosome. This gene is less well understood but is believed to play a role in alternative mRNA splicing (
      National Library of Medicine (US)
      Genetics Home Reference [Internet].
      ). Similar to FMR1, most individuals have between 4 and 40 CGG repeats in this gene and expansion to >200 repeats is associated with fragile XE syndrome characterized by developmental delay similar to, although milder than, fragile X syndrome (
      National Library of Medicine (US)
      Genetics Home Reference [Internet].
      ,
      • Gécz J.
      • Oostra B.
      • Hockey A.
      • Carbonell P.
      • Turner G.
      • Haan E.
      • et al.
      FMR2 expression in families with FRAXE mental retardation.
      ). A similar POI phenotype is seen with FMR2 mutations, although there have been few studies detailing this (
      • Murray A.
      • Webb J.
      • Grimley S.
      • Conway G.
      • Jacobs P.
      Studies of FRAXA and FRAXE in women with premature ovarian failure.
      ,
      • Murray A.
      • Webb J.
      • Dennis N.
      • Conway G.
      • Morton N.
      Microdeletions in FMR2 may be a significant cause of premature ovarian failure.
      ,
      • Espeche L.
      • Chiauzzi V.
      • Ferder I.
      • Arrar M.
      • Solari A.
      • Bruque C.
      • et al.
      Distribution of FMR1 and FMR2 repeats in Argentinean patients with primary ovarian insufficiency.
      ). In 1998, Murray et al. (
      • Murray A.
      • Webb J.
      • Grimley S.
      • Conway G.
      • Jacobs P.
      Studies of FRAXA and FRAXE in women with premature ovarian failure.
      ) screened women with idiopathic POI for FMR2 mutations and found an excess of alleles with <11 CGG repeats. In a follow-up study, the preponderance of small alleles was found to be caused by cryptic deletions in the gene and researchers described this genotype as compromising 1.5% of women with POI and 0.04% of women in the general population (
      • Murray A.
      • Webb J.
      • Dennis N.
      • Conway G.
      • Morton N.
      Microdeletions in FMR2 may be a significant cause of premature ovarian failure.
      ). Last, in a 2017 study by Espeche et al. (
      • Espeche L.
      • Chiauzzi V.
      • Ferder I.
      • Arrar M.
      • Solari A.
      • Bruque C.
      • et al.
      Distribution of FMR1 and FMR2 repeats in Argentinean patients with primary ovarian insufficiency.
      ) in an Argentinean cohort of women with POI, 2 women of 133 were found to have a thymine to cytosine change (T>C) adjacent to the CGG repeat region, which could represent a single-nucleotide polymorphism (SNP). There have been no studies that investigated an association of FMR2 mutations and DOR and it is also unclear what implications there are for biological offspring who may inherit these small FMR2 alleles. For PR calculations, the two studies by Murray et al. (
      • Murray A.
      • Webb J.
      • Grimley S.
      • Conway G.
      • Jacobs P.
      Studies of FRAXA and FRAXE in women with premature ovarian failure.
      ,
      • Murray A.
      • Webb J.
      • Dennis N.
      • Conway G.
      • Morton N.
      Microdeletions in FMR2 may be a significant cause of premature ovarian failure.
      ) were used and generated a statistically significant value for the earlier study (PR = 3.972; 95% CI 2.096–7.527) and a nonsignificant value for the later study (PR = 1.668; 95% CI 0.785–3.544) (Table 1).

       Adenine-guanine-guanine repeats and implications for ovarian reserve

      Of note, the CGG repeats of the FMR1 gene are interrupted intermittently by adenine-guanine-guanine (AGG) repeats that are thought to stabilize the gene and more recent research has investigated how the number and distribution of these AGG repeats may influence ovarian reserve (
      • Noto V.
      • Harrity C.
      • Walsh D.
      • Marron K.
      The impact of FMR1 gene mutations on human reproduction and development: a systematic review.
      ,
      • Lekovich J.
      • Man L.
      • Xu K.
      • Canon C.
      • Lilienthal D.
      • Stewart J.
      • et al.
      CGG repeat length and AGG interruptions as indicators of fragile X-associated diminished ovarian reserve.
      ). In a study by Lekovich et al. (
      • Lekovich J.
      • Man L.
      • Xu K.
      • Canon C.
      • Lilienthal D.
      • Stewart J.
      • et al.
      CGG repeat length and AGG interruptions as indicators of fragile X-associated diminished ovarian reserve.
      ), women with the FMR1 premutation were found to have decreased AMH levels compared with controls but AMH and AFC values were higher in women with at least 2 AGG interruptions compared with those with one or no AGG interruptions when controlled for age and number of CGG repeats. Unfortunately, for these variants, no studies were available for determination of prevalence of <2 AGG repeats in women with DOR or POI.

       Consequences for fertility and biological offspring

      By identifying a FMR gene variant in a patient who desires future childbearing, counseling can be provided regarding expectations during fertility treatments and the patient can be advised to avoid a delay in childbearing given increased risk of pathologic DOR at a young age (
      • Man L.
      • Lekovich J.
      • Rosenwaks Z.
      • Gerhardt J.
      Fragile X-associated diminished ovarian reserve and primary ovarian insufficiency from molecular mechanisms to clinical manifestations.
      ). In addition, inheriting a FMR1 premutation can impose significant harm to biological offspring because the number of CGG repeats in these individuals is unstable and can progress to a full mutation upon transmission (
      • Hagerman R.J.
      • Berry-Kravis E.
      • Hazlett H.C.
      • Bailey Jr., D.B.
      • Moine H.
      • Kooy R.F.
      • et al.
      Fragile X syndrome.
      ,
      National Library of Medicine (US)
      Genetics Home Reference [Internet].
      ,
      • Gécz J.
      • Oostra B.
      • Hockey A.
      • Carbonell P.
      • Turner G.
      • Haan E.
      • et al.
      FMR2 expression in families with FRAXE mental retardation.
      ). Screening prior to conception could allow for a couple affected by an abnormality in the fragile X gene to have access to the full scope of reproductive options to include preimplantation genetic screening for monogenic disorders (PGT-M), especially if a patient is already undergoing in vitro fertilization (IVF) for the indication of DOR (
      • Sullivan-Pyke C.
      • Dokras A.
      Preimplantation genetic screening and preimplantation genetic diagnosis.
      ).

       Current recommendations and opportunities for genetic screening

      The American College of Obstetricians and Gynecologists (ACOG) recommends screening for an FMR1 premutation if a woman who is currently pregnant or considering becoming pregnant has a family history of a fragile X–related disorder or intellectual disability consistent with a fragile X–related disorder. Also, ACOG recommends screening if there is evidence of “unexplained ovarian insufficiency or failure or an elevated FSH level before age 40” although FSH cutoff or requirement for menstrual irregularities, which generally distinguish POI from DOR, are not explicitly mentioned in the guidelines (Table 3) (
      American College of Obstetricians and Gynecologists Committee on Genetics
      Committee Opinion No 691: carrier screening for genetic conditions.
      ). The American College of Medical Genetics and Genomics (ACMG) states more broadly that women with “any reproductive or fertility problems related to an elevated FSH” should be offered screening, although there is no mention of other DOR parameters to include AFC or AMH (Table 3) (
      • Sherman S.
      • Pletcher B.
      • Driscoll D.
      Fragile X syndrome: diagnostic and carrier testing.
      ). Some experts have expressed that FMR1 premutation screening should be offered in a population-wide fashion similar to cystic fibrosis and spinal muscular atrophy and this is already seen in some countries such as Israel (
      • Man L.
      • Lekovich J.
      • Rosenwaks Z.
      • Gerhardt J.
      Fragile X-associated diminished ovarian reserve and primary ovarian insufficiency from molecular mechanisms to clinical manifestations.
      ,
      • Wittenberger M.
      • Hagerman R.
      • Sherman S.
      • McConkie-Rosell A.
      • Welt C.
      • Rebar R.
      • et al.
      The FMR1 premutation and reproduction.
      ,
      • Haham L.
      • Avrahami I.
      • Domniz N.
      • Ries-Levavi L.
      • Berkenstadt M.
      • Orvieto R.
      • et al.
      Preimplantation genetic diagnosis versus prenatal diagnosis – decision-making among pregnant FMR1 premutation carriers.
      ). In a 2010 review of population-based screening for fragile X premutations, a preconception strategy was favored (
      • Hill M.
      • Archibald A.
      • Cohen J.
      • Metcalfe S.
      A systematic review of population screening for fragile X syndrome.
      ). However, the ACMG recommends against this, stating that there are currently inadequate services to offer the complex pretest and post-test counseling that is needed when testing for FMR variants (
      • Haham L.
      • Avrahami I.
      • Domniz N.
      • Ries-Levavi L.
      • Berkenstadt M.
      • Orvieto R.
      • et al.
      Preimplantation genetic diagnosis versus prenatal diagnosis – decision-making among pregnant FMR1 premutation carriers.
      ). While prior resources were limited, services are more widely available and increasingly, reproductive-age women seek out genetic screening and expanded carrier panels are requested by patients (
      • McGowan M.
      • Cho D.
      • Sharp R.
      The changing landscape of carrier screening: expanding technology and options?.
      ). Regarding fragile X mutations, these mutations meet the criteria to be included in the large panels based on criteria in a joint statement by ACOG, ACMG, and other leading organizations (
      • Edwards J.
      • Feldman G.
      • Goldberg J.
      • Gregg A.
      • Norton M.
      • Rose N.
      • et al.
      Expanded carrier screening in reproductive medicine-points to consider.
      ).

       Breast Cancer–Associated Genes

      Two Breast Cancer–Associated (BRCA) genes have been identified, BRCA1 and BRCA2, which are located at chromosomes 17 and 13, respectively (
      American College of Obstetricians and Gynecologists Committee on Practice Bulletins – Gynecology
      Committee on Genetics, Society of Gynecologic Oncologists. Practice Bulletin No. 182: hereditary breast and ovarian cancer syndrome.
      ). Both genes are members of the ataxia-telangiectasia mutated kinase family and code for proteins that repair double-strand DNA breaks (
      • Venkitaraman A.R.
      Cancer susceptibility and the functions of BRCA1 and BRCA2.
      ,
      • Oktay K.
      • Turan V.
      • Titus S.
      • Stobezki R.
      • Liu L.
      BRCA mutations, DNA repair deficiency, and ovarian aging.
      ). More than 1,800 mutations have been identified in the BRCA1 gene, with most leading to lack of protein production or production of an abnormally short protein, leading to a build-up of double-strand DNA breaks (
      National Library of Medicine (US)
      Genetics Home Reference [Internet].
      ). The BRCA2 gene has a similarly large number of mutations identified with most causing production of an abnormally small, nonfunctional version of the BRCA2 protein. The BRCA2 gene is thought to play a smaller role in DNA repair than BRCA1 and function is thought to decrease later in life than in those who carry a BRCA1 mutation (
      National Library of Medicine (US)
      Genetics Home Reference [Internet].
      ,
      • de la Noval B.D.
      Potential implications on female fertility and reproductive lifespan in BRCA germline mutation women.
      ). An estimated 0.06% of the general population carries a BRCA1 mutation and 0.4% carries a BRCA2 mutation (
      • Malone K.E.
      • Daling J.R.
      • Doody D.R.
      • Hsu L.
      • Bernstein L.
      • Coates R.J.
      • et al.
      Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35-64 years.
      ). To understand how BRCA gene mutations lead to accelerated ovarian aging, it is important to note that accumulation of damaged DNA has differing consequences for different populations of cells. In rapidly dividing cells, the damage does not typically cause cell death but does cause replication errors, including those that may be carcinogenic. Conversely, in slowly dividing cells, such as primordial follicles, the DNA damage accumulates over time and causes cellular aging and death (
      • Oktay K.
      • Turan V.
      • Titus S.
      • Stobezki R.
      • Liu L.
      BRCA mutations, DNA repair deficiency, and ovarian aging.
      ).

       Breast cancer–associated gene 1 and DOR

      Through the mechanisms stated, it is believed that women who carry BRCA mutations, particularly BRCA1 mutations, undergo ovarian aging earlier and more rapidly than the general population (
      • Oktay K.
      • Moy F.
      • Titus S.
      • Stobezki R.
      • Turan V.
      • Dickler M.
      • et al.
      Age-related decline in DNA repair function explains diminished ovarian reserve, earlier menopause, and possible oocyte vulnerability to chemotherapy in women with BRCA mutations.
      ). Multiple studies (
      • Titus S.
      • Li F.
      • Stobezki R.
      • Akula K.
      • Unsal E.
      • Jeong K.
      • et al.
      Impairment of BRCA1-related DNA double strand break repair leads to ovarian aging in mice and humans.
      ,
      • Phillips K.A.
      • Collins I.M.
      • Milne R.L.
      • McLachlan S.A.
      • Friedlander M.
      • Hickey M.
      • et al.
      Anti-Mullerian hormone serum concentrations of women with germline BRCA1 or BRCA2 mutations.
      ,
      • Wang E.T.
      • Pisarska M.D.
      • Bresee C.
      • Ida Chen Y.D.
      • Lester J.
      • Afshar Y.
      • et al.
      BRCA1 germline mutations may be associated with reduced ovarian reserve.
      ,
      • Son K.
      • Lee D.
      • Choi D.
      Association of BRCA mutations and anti-Müllerian hormone level in young breast cancer patients.
      ) have found lower AMH levels in BRCA mutation carriers than age-matched controls with a study by Wang et al. (
      • Wang E.T.
      • Pisarska M.D.
      • Bresee C.
      • Ida Chen Y.D.
      • Lester J.
      • Afshar Y.
      • et al.
      BRCA1 germline mutations may be associated with reduced ovarian reserve.
      ) showing four-fold increase in prevalence of AMH <1 ng/mL in this population. BRCA mutation carriers also have been seen to undergo menopause at an earlier age (
      • Lin W.
      • Beattie M.
      • Chen L.
      • Oktay K.
      • Crawford S.
      • Gold E.
      • et al.
      Comparison of age at natural menopause in BRCA1/2 mutation carriers with a non-clinic-based sample of women in northern California.
      ,
      • Finch A.
      • Valentini A.
      • Greenblatt E.
      • Lynch H.T.
      • Ghadirian P.
      • Armel S.
      • et al.
      Frequency of premature menopause in women who carry a BRCA1 or BRCA2 mutation.
      ,
      • Lin W.
      • Titus S.
      • Moy F.
      • Ginsburg E.
      • Oktay K.
      Ovarian aging in women with BRCA germline mutations.
      ,
      • Rzepka-Górska I.
      • Tarnowski B.
      • Chudecka-Glaz A.
      • Górski B.
      • Zielińska D.
      • Toloczko-Grabarek A.
      Premature menopause in patients with BRCA1 gene mutation.
      ) and, in a study by Lin et al., cadaveric ovaries from BRCA carriers had a lower NGF density than controls (
      • Lin W.
      • Titus S.
      • Moy F.
      • Ginsburg E.
      • Oktay K.
      Ovarian aging in women with BRCA germline mutations.
      ). The BRCA1 gene carriers also have been observed to have a higher likelihood of poor response during ART cycles (
      • Oktay K.
      • Kim J.Y.
      • Barad D.
      • Babayev S.N.
      Association of BRCA1 mutations with occult primary ovarian insufficiency: a possible explanation for the link between infertility and breast/ovarian cancer risks.
      ,
      • Derks-Smeets I.
      • van Tilborg T.
      • van Montfoort A.
      • Smits L.
      • Torrance H.
      • Meijer-Hoogeveen M.
      • et al.
      BRCA1 mutation carriers have a lower number of mature oocytes after ovarian stimulation for IVF/PGD.
      ,
      • Lambertini M.
      • Goldrat O.
      • Ferreira A.
      • Dechene J.
      • Azim H.
      • Desir J.
      • et al.
      Reproductive potential and performance of fertility preservation strategies in BRCA-mutated breast cancer patients.
      ). There have been some studies with opposing findings including a study by Michaelson-Cohen et al. (
      • Michaelson-Cohen R.
      • Mor P.
      • Srebnik N.
      • Beller U.
      • Levy-Lahad E.
      • Eldar-Geva T.
      BRCA mutation carriers do not have compromised ovarian reserve.
      ) in which BRCA carriers were found to have similar AMH levels to controls, but this was a relatively young cohort and those with polycystic ovary syndrome were not excluded, which may have confounded results. In studies by Collins et al. (
      • Collins I.M.
      • Milne R.L.
      • McLachlan S.A.
      • Friedlander M.
      • Hickey M.
      • Weideman P.C.
      • et al.
      Do BRCA1 and BRCA2 mutation carriers have earlier natural menopause than their non-carrier relatives? Results from the Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer.
      ) and van Tilborg et al. (
      • van Tilborg T.C.
      • Broekmans F.J.
      • Pijpe A.
      • Schrijver L.H.
      • Mooij T.M.
      • Oosterwijk J.C.
      • et al.
      Do BRCA1/2 mutation carriers have an earlier onset of natural menopause?.
      ), BRCA mutation carriers did not display earlier menopause compared with controls but both studies were survey-based and excluded women who had undergone surgical menopause, which comprises a significant portion of BRCA carriers. Finally, in a study by Shapira et al. (
      • Shapira M.
      • Raanani H.
      • Feldman B.
      • Srebnik N.
      • Derek-Haim S.
      • Manela D.
      • et al.
      BRCA mutation carriers show normal ovarian response in in vitro fertilization cycles.
      ), BRCA carriers had comparable controlled ovarian hyperstimulation (COH) outcomes to controls, but this study excluded women with POI, which may have masked an effect.
      The only two studies with prevalence data available for BRCA1 mutations in women with DOR and controls were those by Wang et al. (
      • Wang E.T.
      • Pisarska M.D.
      • Bresee C.
      • Ida Chen Y.D.
      • Lester J.
      • Afshar Y.
      • et al.
      BRCA1 germline mutations may be associated with reduced ovarian reserve.
      ) and Lambertini et al (
      • Lambertini M.
      • Goldrat O.
      • Ferreira A.
      • Dechene J.
      • Azim H.
      • Desir J.
      • et al.
      Reproductive potential and performance of fertility preservation strategies in BRCA-mutated breast cancer patients.
      ). In the study by Wang et al. (
      • Wang E.T.
      • Pisarska M.D.
      • Bresee C.
      • Ida Chen Y.D.
      • Lester J.
      • Afshar Y.
      • et al.
      BRCA1 germline mutations may be associated with reduced ovarian reserve.
      ), of women with a family history of breast cancer with AMH <1.0 ng/mL, 47.4% of women had a BRCA1 mutation compared with 38.8% of controls (PR = 1.093; 95% CI 0.841–1.419) (Table 1). The prevalence of BRCA1 mutations in both groups was much higher than the estimated prevalence in the general population of women with a family history of breast cancer (0.2%) (Table 1) (
      • Malone K.E.
      • Daling J.R.
      • Doody D.R.
      • Hsu L.
      • Bernstein L.
      • Coates R.J.
      • et al.
      Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35-64 years.
      ). Similarly, in the study by Lambertini et al. (
      • Lambertini M.
      • Goldrat O.
      • Ferreira A.
      • Dechene J.
      • Azim H.
      • Desir J.
      • et al.
      Reproductive potential and performance of fertility preservation strategies in BRCA-mutated breast cancer patients.
      ), of women with a personal history of breast cancer undergoing oocyte cryopreservation who had an AMH <1.0 ng/mL, 20.0% were carriers of a BRCA1 mutation compared with 16.9% of controls (PR = 1.133; 95% CI 0.450–2.851). However, again, prevalence in both groups was much higher than the quoted prevalence of BRCA1 mutation in the general population of women with a personal history of breast cancer (Table 1) (
      • Malone K.E.
      • Daling J.R.
      • Doody D.R.
      • Hsu L.
      • Bernstein L.
      • Coates R.J.
      • et al.
      Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35-64 years.
      ).

       Breast cancer–associated gene 2 and DOR

      The impact of BRCA2 gene mutations on ovarian reserve is less clearly understood. Carriers of BRCA2 mutations were seen to have lower AMH levels than controls in studies by Son et al. (
      • Son K.
      • Lee D.
      • Choi D.
      Association of BRCA mutations and anti-Müllerian hormone level in young breast cancer patients.
      ) and Johnson et al. (
      • Johnson L.
      • Sammel M.D.
      • Domchek S.
      • Schanne A.
      • Prewitt M.
      • Gracia C.
      Antimüllerian hormone levels are lower in BRCA2 mutation carriers.
      ). Similarly, in the study by Lin et al. (
      • Lin W.
      • Beattie M.
      • Chen L.
      • Oktay K.
      • Crawford S.
      • Gold E.
      • et al.
      Comparison of age at natural menopause in BRCA1/2 mutation carriers with a non-clinic-based sample of women in northern California.
      ) already mentioned, lower NGF counts also were seen in cadaveric ovaries of BRCA2 mutation carriers. However, in the studies by Titus et al. (
      • Titus S.
      • Li F.
      • Stobezki R.
      • Akula K.
      • Unsal E.
      • Jeong K.
      • et al.
      Impairment of BRCA1-related DNA double strand break repair leads to ovarian aging in mice and humans.
      ), Phillips et al. (
      • Phillips K.A.
      • Collins I.M.
      • Milne R.L.
      • McLachlan S.A.
      • Friedlander M.
      • Hickey M.
      • et al.
      Anti-Mullerian hormone serum concentrations of women with germline BRCA1 or BRCA2 mutations.
      ), and Wang et al. (
      • Wang E.T.
      • Pisarska M.D.
      • Bresee C.
      • Ida Chen Y.D.
      • Lester J.
      • Afshar Y.
      • et al.
      BRCA1 germline mutations may be associated with reduced ovarian reserve.
      ), AMH levels of BRCA2 carriers and controls were similar and, in a study by Derks-Smeets et al. (
      • Derks-Smeets I.
      • van Tilborg T.
      • van Montfoort A.
      • Smits L.
      • Torrance H.
      • Meijer-Hoogeveen M.
      • et al.
      BRCA1 mutation carriers have a lower number of mature oocytes after ovarian stimulation for IVF/PGD.
      ), women with BRCA2 had a similar response during COH to controls. These null results may be explained by the same mechanism by which BRCA2 mutations are associated with lower risk of breast and ovarian cancers compared with BRCA1 mutations (risk of breast and ovarian cancer for BRCA1 65%–85% and 39%–46%, respectively, and for BRCA2 mutation carriers 45%–85% and 10%–27%, respectively) (
      Society for Gynecologic Oncology Clinical Practice Committee
      Society of gynecologic oncology statement on risk assessment for inherited gynecologic cancer predispositions.
      ). Another possibility is that BRCA2 mutations may cause a later onset of sequelae as seen in average ages of breast cancer diagnosis for BRCA1 and 2 carriers (41–50 years for BRCA1 vs. 51–60 years with BRCA2), making them less likely to impact fertility during a woman’s reproductive years (
      American College of Obstetricians and Gynecologists Committee on Practice Bulletins – Gynecology
      Committee on Genetics, Society of Gynecologic Oncologists. Practice Bulletin No. 182: hereditary breast and ovarian cancer syndrome.
      ). Prevalence data was again drawn from the Wang et al. (
      • Wang E.T.
      • Pisarska M.D.
      • Bresee C.
      • Ida Chen Y.D.
      • Lester J.
      • Afshar Y.
      • et al.
      BRCA1 germline mutations may be associated with reduced ovarian reserve.
      ) and Lambertini et al. (
      • Lambertini M.
      • Goldrat O.
      • Ferreira A.
      • Dechene J.
      • Azim H.
      • Desir J.
      • et al.
      Reproductive potential and performance of fertility preservation strategies in BRCA-mutated breast cancer patients.
      ) studies (PR 0.767; 95% CI 0.474–1.239 and PR 1.700; 95% CI 0.726–3.979, respectively). However, again, the prevalence of BRCA2 mutations in both cases and controls was much higher than the general population (Table 1) (
      • Malone K.E.
      • Daling J.R.
      • Doody D.R.
      • Hsu L.
      • Bernstein L.
      • Coates R.J.
      • et al.
      Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35-64 years.
      ,
      • Wang E.T.
      • Pisarska M.D.
      • Bresee C.
      • Ida Chen Y.D.
      • Lester J.
      • Afshar Y.
      • et al.
      BRCA1 germline mutations may be associated with reduced ovarian reserve.
      ,
      • Lambertini M.
      • Goldrat O.
      • Ferreira A.
      • Dechene J.
      • Azim H.
      • Desir J.
      • et al.
      Reproductive potential and performance of fertility preservation strategies in BRCA-mutated breast cancer patients.
      ).

       Breast cancer–associated gene mutations and implications for fertility

      Identifying a BRCA mutation in a young woman is invaluable, not only in terms of providing her with information regarding future cancer risk, but also in helping guide procreative management. Women with recognized BRCA mutations are urged not to delay childbearing given increased risk for pathologic DOR but also because risk-reducing bilateral salpingo-oophorectomy is recommended at a relatively young age (35–40 years for BRCA1 carriers and 40–45 years for BRCA2 carriers) (
      American College of Obstetricians and Gynecologists Committee on Genetics
      Committee Opinion No 691: carrier screening for genetic conditions.
      ,
      • Santoro N.
      BRCA mutations and fertility: do not push the envelope!.
      ). Additionally, increased risks to fertility are incurred if a cancer diagnosis is made prior to completion of childbearing and chemotherapy is required (
      • Santoro N.
      BRCA mutations and fertility: do not push the envelope!.
      ).

       Current screening guidelines for BRCA gene mutations

      Currently, the Society for Gynecologic Oncology and the United States Preventative Task Force recommend screening women for BRCA mutations if they have a known family history of a BRCA mutation or history of certain personal and/or family cancer diagnoses. These organizations do not recommend routinely screening women diagnosed with DOR for BRCA mutations (Table 3) (
      Society for Gynecologic Oncology Clinical Practice Committee
      Society of gynecologic oncology statement on risk assessment for inherited gynecologic cancer predispositions.
      ,
      US Preventative Task Force
      Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer.
      ). Additionally, it is recommended that adult-onset conditions such as BRCA be excluded from expanded carrier screening panels (
      • Edwards J.
      • Feldman G.
      • Goldberg J.
      • Gregg A.
      • Norton M.
      • Rose N.
      • et al.
      Expanded carrier screening in reproductive medicine-points to consider.
      ). However, direct-to-consumer services such as 23andMe include testing for BRCA, but only the three most common allelic variants in those of Ashkenazi Jewish descent, which may lead to false-negative results (
      American Association for Cancer Research
      Direct-to-consumer test for BRCA mutations authorized.
      ).

       Implications for biological offspring of BRCA gene mutation carriers

      Identifying a BRCA mutation in a potential parent has significant consequences for potential offspring, especially because these mutations are inherited in an autosomal-dominant fashion. Although BRCA mutations cause sequelae largely in adulthood, many couples seek to build their families using IVF with PGT-M if a member of the couple has a known BRCA mutation. These decisions are complicated, however, in that not all BRCA mutation carriers will develop cancer in their lifetime and there are strategies to minimize cancer risk in individuals with BRCA mutations. This may be an especially difficult decision in women affected by BRCA-related DOR who have a low embryo yield with IVF and the choice then becomes having biological children affected by a BRCA mutation or no biological children at all. All this considered, the majority of BRCA mutation carriers do feel that PGT-M should be offered to those carrying a mutation (
      • Chan J.
      • Johnson L.
      • Sammel M.
      • DiGiovanni L.
      • Voong C.
      • Domchek S.
      • et al.
      Reproductive decision-making in women with BRCA1/2 mutations.
      ). In support of these couples, the American Society for Reproductive Medicine issued a Committee Opinion in 2018 stating that PGT-M for adult-onset conditions is ethically justifiable and significant research supports that COH protocols do not increase the risk of cancer in these individuals (
      • Pastore L.M.
      • Johnson J.
      The FMR1 gene, infertility, and reproductive decision-making: a review.
      ,
      The Ethics Committee of the American Society of Reproductive Medicine
      Use of preimplantation genetic testing for monogenic defects (PGT-M) for adult-onset conditions: an Ethics Committee opinion.
      ).

       Myotonic Dystrophy

      The myotonic dystrophy protein kinase gene (DMPK) gene is located on chromosome 19 and has a cytosine-thymine-guanine (CTG) repeat of variable length in its 3’ untranslated region similar to the one seen in the FMR genes. The normal variant has 5–37 repeats, however, variants with up to thousands of repeats have been identified. An elevated number of repeats is associated with myotonic dystrophy type 1 (DM1), which is characterized by hypotonia, cataracts, and delayed motor and cognitive development (
      • Dechanet C.
      • Castelli C.
      • Reyftmann L.
      • Coubes C.
      • Hamamah S.
      • Hedon B.
      Myotonic dystrophy type 1 and PGD: ovarian stimulation response and correlation analysis between ovarian reserve and genotype.
      ). The prevalence of this condition in the general population is estimated to be 1:20,000 (

      Bird TD. Myotonic Dystrophy Type 1. 1999 Sep 17 [Updated 2019 Oct 3]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1165. Accessed November 17, 2019.

      ). Three studies have shown an association of DM1 with DOR (
      • Dechanet C.
      • Castelli C.
      • Reyftmann L.
      • Coubes C.
      • Hamamah S.
      • Hedon B.
      Myotonic dystrophy type 1 and PGD: ovarian stimulation response and correlation analysis between ovarian reserve and genotype.
      ,
      • Feyereisen E.
      • Amar A.
      • Kerbrat V.
      • Steffann J.
      • Munnich A.
      • Vekemans M.
      • et al.
      Myotonic dystrophy: does it affect ovarian follicular status and responsiveness to controlled ovarian stimulation?.
      ,
      • Srebnik N.
      • Margalioth E.
      • Rabinowitz R.
      • Varshaver I.
      • Altarescu G.
      • Renbaum P.
      Ovarian reserve and PGD treatment outcome in women with myotonic dystrophy.
      ). Initially, a study by Feyereisen et al. (
      • Feyereisen E.
      • Amar A.
      • Kerbrat V.
      • Steffann J.
      • Munnich A.
      • Vekemans M.
      • et al.
      Myotonic dystrophy: does it affect ovarian follicular status and responsiveness to controlled ovarian stimulation?.
      ) demonstrated a lower number of mature oocytes retrieved with COH in women with DM1 compared with controls. In a subsequent study, women with DM1 were seen to have higher FSH levels, lower AMH levels, and lower AFC than controls and were found to require higher doses of exogenous FSH while having a lower number of oocytes retrieved during COH (
      • Srebnik N.
      • Margalioth E.
      • Rabinowitz R.
      • Varshaver I.
      • Altarescu G.
      • Renbaum P.
      Ovarian reserve and PGD treatment outcome in women with myotonic dystrophy.
      ). In a study by Dechanet et al. (
      • Dechanet C.
      • Castelli C.
      • Reyftmann L.
      • Coubes C.
      • Hamamah S.
      • Hedon B.
      Myotonic dystrophy type 1 and PGD: ovarian stimulation response and correlation analysis between ovarian reserve and genotype.
      ), patients with DM1 also were seen to require higher levels of exogenous FSH than controls to achieve collection of a similar number of oocytes. However, Verpoest et al. (
      • Verpoest W.
      • De Rademaeker M.
      • Sermon K.
      • De Rycke M.
      • Seneca S.
      • Papanikolau E.
      • et al.
      Real and expected delivery rates of patients of patients with myotonic dystrophy undergoing intracytoplasmic sperm injection and preimplantation genetic diagnosis.
      ) did not find a difference between reproductive outcomes of patients with DM1 and controls. This disorder also is inherited in an autosomal-dominant fashion, therefore, if a prospective parent is a carrier, there is a 50% chance their biological child will inherit the disease. Currently, there are no recommendations for screening beyond clinical suspicion for the disorder in an individual or known family history (Table 3) (
      • Turner C.
      • Hilton-Jones D.
      Myotonic dystrophy: diagnosis, management, and new therapies.
      ). None of these four studies had data amenable to calculating the prevalence of a DMPK mutation in those with DOR or POI.

       Single-Nucleotide Polymorphisms

      In addition to genetic mutations, there have been several polymorphisms that may be associated with DOR. SNPs are similar to mutations in that they are a variation in genetic code, however, they are much more prevalent than mutations and are used as genetic signatures in populations (
      • Karki R.
      • Pandya D.
      • Elston R.C.
      • Ferlini C.
      Defining “mutation” and “polymorphism” in the era of personal genomics.
      ). SNPs in multiple genes have been found to be associated with an increased risk for DOR to include genes coding for AMH and AMH receptor 2 (AMHR2), growth differentiation factor 9 (GDF9), bone morphogenic protein 15 (BMP15), follicle-stimulating hormone receptor (FSHR), luteinizing hormone/choriogonadotropin receptor (LHCGR), estrogen receptor 1 (ESR1), and others.

       Antimüllerian hormone and AMHR2 genes

      The AMH gene is located on chromosome 19 and codes for a protein involved in sex differentiation, which is secreted by the granulosa cells of small growing follicles (
      • Tal R.
      • Seifer D.
      Ovarian reserve testing: a user’s guide.
      ,
      • Pabalan N.
      • Montagna E.
      • Singian E.
      • Tabangay L.
      • Jarianazi H.
      • Barbosa C.
      • et al.
      Associations of polymorphisms in anti-Müllerian hormone (AMH Ile49Ser) and its type II receptor (AMHR – 482 A>G) on reproductive outcomes and polycystic ovarian syndrome: a systemic review and meta-analysis.
      ). The AMHR2 gene is located on chromosome 13 and codes for a protein located on the membrane of the fetal müllerian ducts (
      • Pabalan N.
      • Montagna E.
      • Singian E.
      • Tabangay L.
      • Jarianazi H.
      • Barbosa C.
      • et al.
      Associations of polymorphisms in anti-Müllerian hormone (AMH Ile49Ser) and its type II receptor (AMHR – 482 A>G) on reproductive outcomes and polycystic ovarian syndrome: a systemic review and meta-analysis.
      ). One of the earliest studies examining SNPs in the AMHR2 gene was by Kevenaar et al. (
      • Kevenaar M.
      • Themmen A.
      • Rivadeneira F.
      • Uitterlinden A.
      • Laven J.
      • van Schoor N.
      • et al.
      A polymorphism in the AMH type II receptor gene is associated with age at menopause in interaction with parity.
      ) in which the 482 A>G SNP was associated with age of menopause in interaction with parity. These results were replicated in a study by Voorhuis et al. (
      • Voorhuis M.
      • Broekmans F.J.
      • Fauser B.C.
      • Onland-Moret N.C.
      • van der Schouw Y.T.
      Genes involved in initial follicle recruitment may be associated with age at menopause.
      ) in 2011. A 2013 study by Braem et al. (
      • Braem M.
      • Voorhuis M.
      • van der Schouw Y.
      • Peeters P.
      • Schouten L.
      • Eijkemans M.
      • et al.
      Interactions between genetic variants in AMH and AMHR2 may modify age at natural menopause.
      ) found a similar association for the Ile49Ser SNP on the AMH gene, however, results were not statistically significant. There have been numerous studies to date showing differences in ovarian reserve testing parameters as well as number and quality of oocytes in women with polymorphisms of the AMH and AMHR2 genes (
      • Braem M.
      • Voorhuis M.
      • van der Schouw Y.
      • Peeters P.
      • Schouten L.
      • Eijkemans M.
      • et al.
      Interactions between genetic variants in AMH and AMHR2 may modify age at natural menopause.
      ,
      • Peluso C.
      • Fonseca F.L.
      • Gastaldo G.G.
      • Christofolini D.M.
      • Cordts E.B.
      • Barbosa C.P.
      • et al.
      AMH and AMHR2 polymorphisms and AMH serum level can predict assisted reproduction outcomes: a cross sectional study.
      ,
      • Lazaros L.
      • Fotaki A.
      • Pamporaki C.
      • Hatzi E.
      • Kitsou C.
      • Zikopoulos A.
      • et al.
      The ovarian response to standard gonadotropin stimulation is influenced by AMHRII genotypes.
      ,
      • Yoshida Y.
      • Yamashita Y.
      • Saito N.
      • Ono Y.
      • Yamamoto H.
      • Nakamura Y.
      • et al.
      Analyzing the possible involvement of anti-Müllerian hormone and anti-Müllerian hormone receptor II single nucleotide polymorphism in infertility.
      ). However, others have not found differences in age at natural menopause, prevalence of POI, and ART outcomes in women with and without these polymorphisms (
      • Karagiorga I.
      • Partsinevelos G.
      • Mavrogianni D.
      • Anagnostou E.
      • Zervomanolakis I.
      • Kallianidis K.
      • et al.
      Single nucleotide polymorphisms in the anti-Müllerian hormone (AMH) and anti-Müllerian hormone type II receptor (AMHRII – 482 A>G) as genetic markers in assisted reproduction technology.
      ,
      • Yu E.
      • Zhu H.
      • Li Y.
      • Chua S.
      • Indran I.
      • Li J.
      • et al.
      Polymorphisms of anti-Müllerian signaling pathway in healthy Singapore women: population differences, endocrine effects, and reproductive outcomes.
      ,
      • Jurczak A.
      • Szkup M.
      • Grzywacz A.
      • Safranow K.
      • Grochans E.
      The relationship between AMH and AMHR2 polymorphisms and the follicular phase in late reproductive stage women.
      ,
      • Hanevik H.
      • Hilmarsen H.
      • Skjelbred C.
      • Tanbo T.
      • Kahn J.
      Single nucleotide polymorphisms in the anti-Müllerian hormone signaling pathway do not determine high or low response to ovarian stimulation.
      ,
      • Yoon S.H.
      • Choi Y.M.
      • Hong M.A.
      • Kim J.J.
      • Lee G.H.
      • Hwang K.R.
      • et al.
      Association study of anti-Müllerian hormone and anti-Müllerian hormone type II receptor polymorphisms with idiopathic primary ovarian insufficiency.
      ,
      • Cerra C.
      • Newman W.G.
      • Tohlob D.
      • Byers H.
      • Horne G.
      • Roberts S.A.
      • et al.
      AMH type II receptor and AMH gene polymorphisms are not associated with ovarian reserve, response, or outcomes in ovarian stimulation.
      ). In a meta-analysis by Pabalan et al. (
      • Pabalan N.
      • Montagna E.
      • Singian E.
      • Tabangay L.
      • Jarianazi H.
      • Barbosa C.
      • et al.
      Associations of polymorphisms in anti-Müllerian hormone (AMH Ile49Ser) and its type II receptor (AMHR – 482 A>G) on reproductive outcomes and polycystic ovarian syndrome: a systemic review and meta-analysis.
      ) performed in 2016, the associations of the AMH Ile49Ser variant and AMHR2 482A>G variant on reproductive outcomes initially appeared null, however, after subgroup analysis, pooled effects were found in differing ethnic groups with polymorphisms appearing to be protective in whites and variable in those of Asian descent. However, a subsequent 2019 meta-analysis did not find a difference in measures of ovarian reserve in women with differing variants of the AMHR2 -482A>G gene (
      • Cheng R.
      • Xiong W.
      • Luo X.
      • Ma Y.
      • Nie Y.
      • Qiao X.
      • et al.
      Association of gene polymorphisms in the anti-Müllerian hormone signaling pathway with ovarian function: a systematic review and meta-analysis.
      ). There were no studies available in our search with prevalence data available for both women with DOR and controls for variants in either AMH or AMHR2 genes. Prevalence ratios were able to be calculated for Ile49Ser variants of the AMH gene and the -482(A>G) variants of the AMHR2 gene in women with POI and those with age of natural menopause >45 years from a study by Yoon et al. (
      • Yoon S.H.
      • Choi Y.M.
      • Hong M.A.
      • Kim J.J.
      • Lee G.H.
      • Hwang K.R.
      • et al.
      Association study of anti-Müllerian hormone and anti-Müllerian hormone type II receptor polymorphisms with idiopathic primary ovarian insufficiency.
      ) (Table 2).

       Growth differentiation factor 9 and BMP15 genes

      The GDF9 and BMP15 genes are both part of the transforming growth factor-β superfamily located on chromosome 5 and the X chromosome, respectively (
      • Sanfins A.
      • Rodrigues P.
      • Albertini D.
      GDF-9 and BMP-15 direct the follicle symphony.
      ). These genes are thought to play a role in folliculogenesis and SNPs in these genes have been associated with premature ovarian aging (
      • Greene A.D.
      • Patounakis G.
      • Segars J.H.
      Genetic associations with diminished ovarian reserve: a systematic review of the literature.
      ,
      • Sanfins A.
      • Rodrigues P.
      • Albertini D.
      GDF-9 and BMP-15 direct the follicle symphony.
      ,
      • Santos M.
      • Cordts E.
      • Peluso C.
      • Dornas M.
      • Neto F.
      Association of BMP15 and GDF9 variants to premature ovarian insufficiency.
      ). The first identified BMP15 mutation associated with DOR was a heterozygous Y235C missense mutation (
      • Di Pasquale E.
      • Beck-Peccoz P.
      • Persani L.
      Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene.
      ). Since that time, multiple polymorphisms have been identified and, in a 2014 study by Persani et al. (
      • Persani L.
      • Rossetti R.
      • Di Pasquale E.
      • Cacciatore C.
      • Fabre S.
      The fundamental role of bone morphogenetic protein 15 in ovarian function and its involvement in female fertility disorders.
      ), all known variants of BMP15 at the time were pooled and found to have a 10-fold higher prevalence in patients with POI than in controls. This was again seen in a 2018 article by Belli et al. (
      • Belli M.
      • Shimasaki S.
      Molecular aspects and clinical relevance of GDF9 and BMP15 in ovarian function.
      ). Multiple polymorphisms in the GDF9 gene have been associated with POR and POI and, interestingly, in a study by Patino et al. where gene expression and activity in those with 10 BMP15 SNPs were assessed, it was found that three of the variants led to a significantly reduced ability to synergize with the GDF9 protein, indicating a possible relationship between the two proteins in determining reproductive potential (
      • Wang T.T.
      • Wu Y.T.
      • Dong M.Y.
      • Sheng J.Z.
      • Leung P.C.
      • Huang H.F.
      G546A polymorphism of growth differentiation factor-9 contributes to the poor outcome of ovarian stimulation in women with diminished ovarian reserve.
      ,
      • Wang T.T.
      • Ke Z.H.
      • Song Y.
      • Chen L.T.
      • Chen X.J.
      • Feng C.
      • et al.
      Identification of a mutation in GDF9 as a novel cause of diminished ovarian reserve in young women.
      ,
      • Serdyńska-Szuster M.
      • Jędrzejczak P.
      • Ożegowska K.E.
      • Hołysz H.
      • Pawelczyk L.
      • Jagodziński P.P.
      Effect of growth differentiation factor-9 C447T and G546A polymorphisms on the outcomes of in vitro fertilization.
      ,
      • Ma L.
      • Chen Y.
      • Mei S.
      • Liu C.
      • Ma X.
      • Li Y.
      • et al.
      Single nucleotide polymorphisms in premature ovarian failure-associated genes in a Chinese Hui population.
      ,
      • Laissue P.
      • Christin-Maitra S.
      • Touraine P.
      • Kuttenn F.
      • Ritvos O.
      • Aittomaki K.
      • et al.
      Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure.
      ,
      • Dixit H.
      • Rao L.
      • Padmalatha V.
      • Kanakavalli M.
      • Deenadayal M.
      • Gupta N.
      • et al.
      Mutational screening of the coding region of growth differentiation factor 9 gene in Indian women with ovarian failure.
      ,
      • Zhao H.
      • Qin Y.
      • Kovanci E.
      • Simpson J.
      • Chen Z.
      • Rajkovic A.
      Analyses of GDF9 mutation in 100 Chinese women with premature ovarian failure.
      ,
      • Patino L.
      • Walton K.
      • Mueller T.
      • Johnson K.
      • Stocker W.
      • Richani D.
      • et al.
      BMP15 mutations associated with primary ovarian insufficiency reduce expression, activity, or synergy with gdf9.
      ). The PR for BMP15 was calculated using data from the Persani et al. (
      • Persani L.
      • Rossetti R.
      • Di Pasquale E.
      • Cacciatore C.
      • Fabre S.
      The fundamental role of bone morphogenetic protein 15 in ovarian function and its involvement in female fertility disorders.
      ) meta-analysis of women with POI (PR = 1.969; 95% CI 1.797–2.159) and PR for GDF9 variants was calculated using data from the Wang et al. (
      • Wang T.T.
      • Wu Y.T.
      • Dong M.Y.
      • Sheng J.Z.
      • Leung P.C.
      • Huang H.F.
      G546A polymorphism of growth differentiation factor-9 contributes to the poor outcome of ovarian stimulation in women with diminished ovarian reserve.
      ) study that compared women with DOR undergoing IVF with women undergoing IVF for other indications (PR = 1.427; 95% CI 1.076–1.892) (Table 2).

       Follicle-stimulating hormone receptor gene

      The FSHR gene is located on chromosome 2 and codes for a G-protein–coupled receptor located on granulosa cells in the ovary. The receptor binds FSH, a glycoprotein that is largely responsible for folliculogenesis and recruitment of a dominant follicle prior to ovulation. Most studies to date investigating an association between FSHR polymorphisms and DOR have focused on three loci on exon 10: 680, 307, and 189 (
      • Riccetti L.
      • De Pascali F.
      • Gilioli L.
      • Santi D.
      • Brigante G.
      • Simoni M.
      • et al.
      Genetics of gonadotropins and their receptors as markers of ovarian reserve and response in controlled ovarian stimulation.
      ). Women carrying the Ser homozygous variant at the 680 locus have been seen to have higher basal FSH than heterozygous or Asn homozygous women and require higher doses of FSH during COH (
      • Yao Y.
      • Ma C.H.
      • Tang H.L.
      • Hu Y.F.
      Influence of follicle-stimulating hormone receptor (FSHR) Ser680Asn polymorphism on ovarian function and in vitro fertilization outcome: a meta-analysis.
      ,
      • Pabalan N.
      • Trevisan C.
      • Peluso C.
      • Jarjanazi H.
      • Christofolini D.
      • Barbosa C.
      • et al.
      Evaluating influence of genotypes in the follicle-stimulating hormone receptor (FSHR) Ser680Asn (rs6166) polymorphism on poor and hyper-responders to ovarian stimulation: a meta-analysis.
      ). However, other studies have not found this association (
      • Binder H.
      • Strick R.
      • Zaherdoust O.
      • Dittrich R.
      • Hamori M.
      • Beckmann M.
      • et al.
      Assessment of FSHR variants and anti-müllerian hormone in infertility patients with a reduced ovarian response to gonadotropin stimulation.
      ,
      • Laisk-Podar T.
      • Kaart T.
      • Peters M.
      • Salumets A.
      Genetic variants with female reproductive aging – potential markers for assessing ovarian function and ovarian stimulation outcome.
      ,
      • Mohiyiddeen L.
      • Newman W.
      • McBurney H.
      • Mulugeta B.
      • Roberts S.
      • Nardo L.
      Follicle-stimulating hormone receptor gene polymorphisms are not associated with ovarian reserve markers.
      ,
      • Zerbetto I.
      • Gromoll J.
      • Luisi S.
      • Reis F.M.
      • Nieschlag E.
      • Simoni M.
      • et al.
      Follicle-stimulating hormone receptor and DAZL gene polymorphisms do not affect the age of menopause.
      ). Polymorphisms at the 307 locus are associated with earlier onset of POI and higher incidence of POR than in controls (
      • Vilodre L.C.
      • Kohek M.B.F.
      • Spritzer P.M.
      Screening of follicle-stimulating hormone receptor gene in women with premature ovarian failure in southern Brazil and associations with phenotype.
      ,
      • Motawi T.
      • Rizk S.
      • Maurice N.
      • Maged A.
      • Raslan A.
      • Sawaf A.
      The role of gene polymorphisms and AMH level in prediction of poor ovarian response in Egyptian women undergoing IVF procedure.
      ). However, another study showed the same variants to be protective from DOR (
      • Achrekar S.K.
      • Modi D.N.
      • Desai S.K.
      • Mangoli V.S.
      • Mangoli R.V.
      • Mahale S.D.
      Follicle-stimulating hormone receptor polymorphism (Thr307Ala) is associated with variable ovarian response and ovarian hyperstimulation syndrome in Indian women.
      ). Finally, a polymorphism at the 189 locus has been associated with elevated basal serum FSH levels and the -29G>A polymorphism was seen more frequently in patients with DOR than controls in one study (
      • Desai S.S.
      • Roy B.S.
      • Mahale S.D.
      Mutations and polymorphisms in FSH receptor: functional implications in human reproduction.
      ,
      • Ilgaz N.S.
      • Aydos O.S.E.
      • Karadag A.
      • Taspinar M.
      • Eryilmaz O.G.
      • Sunguroglu A.
      Impact of follicle-stimulating hormone receptor variants in female infertility.
      ,
      • Ghezelayagh Z.
      • Totonchi M.
      • Zarej-Moradi S.
      • Asadpour O.
      • Maroufizadeh S.
      • Eftekhari-Yadi P.
      • et al.
      The impact of genetic variation and gene expression level of the follicle-stimulating hormone receptor on ovarian reserve.
      ). At this time, some strategies to incorporate knowledge of FSHR SNPs into COH protocols have been underway with interesting findings regarding intraovarian injection of adenovirus expressing a copy of FSHR restoring folliculogenesis in mice with a knockout for the FSHR gene (
      • Ghadami M.
      • El-Demerdash E.
      • Salama S.A.
      • Binhazim A.A.
      • Archibong A.E.
      • Chen X.
      • et al.
      Toward gene therapy of premature ovarian failure: intraovarian injection of adenovirus expressing human FSH receptor restores folliculogenesis in FSHR (-/-)FORKO mice.
      ). There were no studies available with data on pooled effects of all FSHR polymorphisms but prevalence data was available for polymorphisms at site -29, 307, 680, and 919 from studies by Ilgaz et al. (
      • Ilgaz N.S.
      • Aydos O.S.E.
      • Karadag A.
      • Taspinar M.
      • Eryilmaz O.G.
      • Sunguroglu A.
      Impact of follicle-stimulating hormone receptor variants in female infertility.
      ) and Ghezelayagh et al. (
      • Ghezelayagh Z.
      • Totonchi M.
      • Zarej-Moradi S.
      • Asadpour O.
      • Maroufizadeh S.
      • Eftekhari-Yadi P.
      • et al.
      The impact of genetic variation and gene expression level of the follicle-stimulating hormone receptor on ovarian reserve.
      ) (Table 1). Using these data, there were no statistically significant PRs identified with the exception of increased prevalence of the GA variant of -29G>A in women with DOR in the study by Ghezelayagh et al. (
      • Ghezelayagh Z.
      • Totonchi M.
      • Zarej-Moradi S.
      • Asadpour O.
      • Maroufizadeh S.
      • Eftekhari-Yadi P.
      • et al.
      The impact of genetic variation and gene expression level of the follicle-stimulating hormone receptor on ovarian reserve.
      ) (PR = 1.358; 95% CI 1.002–1.840). However, this was not seen with the same variant in the Ilgaz et al. study (
      • Ilgaz N.S.
      • Aydos O.S.E.
      • Karadag A.
      • Taspinar M.
      • Eryilmaz O.G.
      • Sunguroglu A.
      Impact of follicle-stimulating hormone receptor variants in female infertility.
      ). Both studies used women with proven fertility as controls.

       Estrogen receptor 1

      The ESR1 gene is located on chromosome 6 and codes for a protein primarily located on the ovarian theca cells, which is thought to be essential in regulation of granulosa cell proliferation and folliculogenesis (
      • Greene A.D.
      • Patounakis G.
      • Segars J.H.
      Genetic associations with diminished ovarian reserve: a systematic review of the literature.
      ,
      • Altmäe S.
      • Haller K.
      • Peters M.
      • Hovatta O.
      • Stavreus-Evers A.
      • Karro H.
      • et al.
      Allelic estrogen receptor 1 (ESR1) gene variants predict the outcome of ovarian simulation in in vitro fertilization.
      ). Multiple ESR1 polymorphisms have been identified and found to be associated with POI, with the most extensively researched polymorphism being at the -397C/T (PvuII) locus. Studies in both Ukranian (
      • Livshyts G.
      • Podlesnaja S.
      • Kravchenko S.
      • Livshits L.
      Association of PvuII polymorphism in ESR1 gene with impaired ovarian reserve in patients from Ukraine.
      ) and Korean (
      • Yoon S.H.
      • Choi Y.M.
      • Hong M.A.
      • Lee G.H.
      • Kim J.J.
      • Im H.J.
      • et al.
      Estrogen receptor {alpha} gene polymorphisms in patients with idiopathic premature ovarian failure.
      ) populations found an increased prevalence of homozygous Thymine-Thymine (TT) at this site in women with POI compared with controls and, in a study by de Mattos et al. (
      • de Mattos C.
      • Trevisan C.
      • Peluso C.
      • Adami F.
      • Cordts E.
      • Christofolini D.
      • et al.
      ESR1 and ESR2 gene polymorphisms are associated with human reproduction outcomes in Brazilian women.
      ), women with the TT genotype had longer induction times in COH cycles and required higher doses of exogenous FSH than controls (
      • Yoon S.H.
      • Choi Y.M.
      • Hong M.A.
      • Lee G.H.
      • Kim J.J.
      • Im H.J.
      • et al.
      Estrogen receptor {alpha} gene polymorphisms in patients with idiopathic premature ovarian failure.
      ,
      • de Mattos C.
      • Trevisan C.
      • Peluso C.
      • Adami F.
      • Cordts E.
      • Christofolini D.
      • et al.
      ESR1 and ESR2 gene polymorphisms are associated with human reproduction outcomes in Brazilian women.
      ,
      • Bretherick K.L.
      • Hanna C.W.
      • Curie L.M.
      • Fluker M.R.
      • Hammond G.L.
      • Robinson W.P.
      Estrogen receptor a gene polymorphisms are associated with idiopathic premature ovarian failure.
      ). However, these results were not replicated in Serbian (
      • Li J.
      • Vujovic S.
      • Dalgleish R.
      • Thompson J.
      • Dragojevic-Dikic S.
      • Al-Azzawi F.
      Lack of association between ESR1 gene polymorphisms and premature ovarian failure in Serbian women.
      ) and Canadian (
      • Bouilly J.
      • Bachelot A.
      • Broutin I.
      • Touraine P.
      • Binart N.
      Novel NOBOX loss-of-function mutations account for 6.2% of cases in a large primary ovarian insufficiency cohort.
      ) populations, implying that there may be ethnic differences with varying effects on ovarian reserve. No meta-analyses exist to date, which could pool the effects of these polymorphisms in different populations and no studies were found with prevalence data for women with DOR and controls. Prevalence ratios were calculated using data from studies by Livshyts et al. (
      • Livshyts G.
      • Podlesnaja S.
      • Kravchenko S.
      • Livshits L.
      Association of PvuII polymorphism in ESR1 gene with impaired ovarian reserve in patients from Ukraine.
      ) and Yoon et al. (
      • Yoon S.H.
      • Choi Y.M.
      • Hong M.A.
      • Lee G.H.
      • Kim J.J.
      • Im H.J.
      • et al.
      Estrogen receptor {alpha} gene polymorphisms in patients with idiopathic premature ovarian failure.
      ), which had prevalence data available for women with POI and used fertile women and women with age of natural menopause >45 years as controls, respectively. Using these data, there were no increased prevalence risks identified in women with POI carrying variants at the PvuII locus of the ESR1 gene (Table 1).

       Other polymorphisms associated with DOR

      Polymorphisms in a number of other genes have been found to be associated with DOR. One such gene is the luteinizing hormone/choriogonadotropin receptor (LHCGR) gene that resides on chromosome 2 and codes for a transmembrane protein with two ligands: luteinizing hormone, which is important for ovulation, and chorionic gonadotropin, which is important in maintaining an early pregnancy. Mutations in this gene have been seen in cases of familial infertility and “empty follicle syndrome” in which no oocytes could be retrieved during a COH cycle (
      • Pabalan N.
      • Trevisan C.
      • Peluso C.
      • Jarjanazi H.
      • Christofolini D.
      • Barbosa C.
      • et al.
      Evaluating influence of genotypes in the follicle-stimulating hormone receptor (FSHR) Ser680Asn (rs6166) polymorphism on poor and hyper-responders to ovarian stimulation: a meta-analysis.
      ). Another gene of interest is the newborn ovary homeobox (NOBOX) gene, which is thought to play a role in early folliculogenesis. Mutations of NOBOX have been found to be associated with POI in two separate populations (
      • Bouilly J.
      • Bachelot A.
      • Broutin I.
      • Touraine P.
      • Binart N.
      Novel NOBOX loss-of-function mutations account for 6.2% of cases in a large primary ovarian insufficiency cohort.
      ,
      • Bouilly J.
      • Roucher-Boulez F.
      • Gompel A.
      • Bry-Gauillard H.
      • Azibi K.
      • Beldjord C.
      • et al.
      New NOBOX mutations identified in a large cohort of women with primary ovarian insufficiency decrease KIT-L expression.
      ). Others include a polymorphism in the synaptonemal complex protein 2-like (SYCP2L) gene, which has been associated with both age at natural menopause and dosage of exogenous FSH required during COH and a polymorphism in the tumor protein 73 (TP73) gene associated with lower levels of AMH and lower AFC (
      • Vagnini L.D.
      • Renzi A.
      • Oliveira-Pelegrin G.R.
      • Canas Mdo C.
      • Petersen C.G.
      • Mauri A.L.
      • et al.
      The TP73 gene polymorphism (rs4648551, A>G) is associated with diminished ovarian reserve.
      ). Last, polymorphisms in several other genes have been found in small series of isolated and familial cases of DOR and POI but need validation in larger studies (
      • Pabalan N.
      • Trevisan C.
      • Peluso C.
      • Jarjanazi H.
      • Christofolini D.
      • Barbosa C.
      • et al.
      Evaluating influence of genotypes in the follicle-stimulating hormone receptor (FSHR) Ser680Asn (rs6166) polymorphism on poor and hyper-responders to ovarian stimulation: a meta-analysis.
      ,
      • Jaillard S.
      • Sreenivasan R.
      • Beaumont M.
      • Robevska G.
      • Dubourg C.
      • Knarston I.M.
      • et al.
      Analysis of NR5A1 in 142 patients with premature ovarian insufficiency, diminished ovarian reserve, or unexplained infertility.
      ). The only one of these polymorphisms with prevalence data available was for NOBOX in individuals with POI from the Bouilly et al. (
      • Bouilly J.
      • Bachelot A.
      • Broutin I.
      • Touraine P.
      • Binart N.
      Novel NOBOX loss-of-function mutations account for 6.2% of cases in a large primary ovarian insufficiency cohort.
      ,
      • Bouilly J.
      • Roucher-Boulez F.
      • Gompel A.
      • Bry-Gauillard H.
      • Azibi K.
      • Beldjord C.
      • et al.
      New NOBOX mutations identified in a large cohort of women with primary ovarian insufficiency decrease KIT-L expression.
      ) studies, however, they did cite population-level data on frequency of missense mutations, which were used for calculations (PR = 2.915; CI 2.597–3.272 and PR = 4.175; CI 3.729–4.676 for the two studies, respectively) (Table 2).

      Discussion

      Pathologic DOR is a common reason for seeking fertility consultation and is defined as abnormal ovarian reserve testing for a woman’s age in the setting of regular menstrual cycles. Treatment options for women diagnosed with DOR include ovulation induction with intrauterine insemination, IVF, or, if severe, use of alternative family-building modalities to include donor oocyte IVF or adoption. Although there are many causes of DOR, many cases remain idiopathic although underlying genetic causes are suspected. Early diagnosis of DOR is critical to maximizing reproductive potential and identifying genetic causes and implementing appropriate genetic screening could not only help to identify cases of genetic DOR earlier but also to minimize effects on offspring if the same mutation causing DOR also causes other deleterious effects.
      In this systematic review and meta-analysis, mutations and polymorphisms in 12 genes thought to be associated with DOR were reviewed. To our knowledge, this is the first review to attempt to quantify the PR of carrying an abnormality in these genes if a woman is diagnosed with DOR. Elevated PRs were found for the FMR1 premutation and FMR2 mutations as well as SNPs in the BMP15, GDF9, FSHR, and NOBOX genes. However, PRs were not seen to be elevated in the other six genes investigated. However, for some genes with population-level data available, prevalence in both cases and controls was much higher than the rate of the mutation in the general population (Table 1 and Table 2). This may be because the features of the control group predispose them to having a higher risk of carrying a mutation, making them an inaccurate representation of the general population and, therefore, a poor comparison group. This is particularly notable for BRCA1 and BRCA2 mutations in which the prevalence of mutations in the control groups range from modestly above the general population in the Lambertini et al. (
      • Lambertini M.
      • Goldrat O.
      • Ferreira A.
      • Dechene J.
      • Azim H.
      • Desir J.
      • et al.
      Reproductive potential and performance of fertility preservation strategies in BRCA-mutated breast cancer patients.
      ) study (factor of 2.3–2.7) to significantly above the estimated rate in the general population in the Wang et al. (
      • Wang E.T.
      • Pisarska M.D.
      • Bresee C.
      • Ida Chen Y.D.
      • Lester J.
      • Afshar Y.
      • et al.
      BRCA1 germline mutations may be associated with reduced ovarian reserve.
      ) study (factor of 39.8–129.0). This also was seen for the intermediate allele of FMR1 with the control population having a 20.0% prevalence rate of the mutation compared with the estimated prevalence rate in the population of 2.9% (
      • Seltzer M.M.
      • Baker M.W.
      • Hong J.
      • Maenner M.
      • Greenberg J.
      • Mandel D.
      Prevalence of CGG expansions of the FMR1 gene in a US population-based sample.
      ,
      • Eslami A.
      • Farahmand K.
      • Totonchi M.
      • Madani T.
      • Asadpour U.
      • Zari Moradi S.
      • et al.
      FMR1 pre-mutation: not only important in premature ovarian failure but also in diminished ovarian reserve.
      ).
      Our findings of an elevated PR for FMR1 premutations support current screening guidelines given expansion of the CGG repeat region of the gene can be unstable on transmission and lead to development of fragile X syndrome in offspring (Table 1). However, we recommend altering guidelines to include other indicators of DOR to include AFC and AMH because guidelines by ACOG and ACMG only comment on FSH levels (Table 3). Although elevated PR values also were found for FMR2 mutations and multiple SNPs, it makes sense that screening for these mutations is not recommended at this time because the low allele for FMR2 and other genetic variants investigated have no known deleterious effects on offspring. However, this information may be useful in developing genetic screening panels to help predict a patient’s risk of developing DOR or predicting response to COH to help inform treatment protocols.
      We did not detect an elevated PR for BRCA1 and BRCA2 based on review of current evidence. Notably, a few studies have found an association between BRCA mutations and DOR. Our inability to detect an elevated PR for BRCA1 and BRCA2 mutations likely is explained by limitations of available studies from which to draw prevalence data and/or limitations of published study control groups. Although our findings support the lack of current guidelines recommending screening women diagnosed with DOR for BRCA mutations, further studies are critical given the potential risk reduction for malignancy if women with BRCA mutations are diagnosed early.
      There are multiple limitations of this study. First, there was a small number of studies available where it was possible to calculate PRs for each gene and often these studies had small sample sizes. Additionally, for some genes, the only available data was for patients with POI, which, although similar to DOR, represents a different and much more limited patient population. Other limitations in these calculations was heterogeneity of definitions of DOR in the included studies, making the calculated PRs difficult to compare with one another. In terms of the review itself, one limitation is that we did not review the other types of genetic changes associated with DOR to include aneuploidy, translocations, epigenetics, and alterations in gene expression that either are already known to be or are under investigation as potential genetic causes of DOR.
      In conclusion, based on the available literature, we found a significantly increased risk of carrying a FMR1 premutation, FMR2 mutations, or SNPs in BMP15, GDF9, FSHR, and NOBOX genes in a patient who is diagnosed with DOR. Further studies detailing prevalence of mutations in these genes in both fertile and infertile populations are needed to determine PRs with greater accuracy, particularly in regard to BRCA1 and BRCA2 mutations because both women and their offspring have a high risk of morbidity and mortality due to malignancy if carrying a mutation in one of these genes.

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