Main Article Content
Introduction: The frequency of the premutated alleles of the FMR1 gene varies from 1: 100 to 1: 260 Israeli, Canadian, Finnish and American women, but it is unknown in Brazil. Premutation carriers may have reduced reproductive age and are at risk of transmitting the expanded allele to their offspring, and consequently fragile X syndrome. Objective: To observe the distribution range of the FMR1 gene alleles in a population of women with idiopathic infertility, without symptoms of premature ovarian insufficiency. Methods: The presence of premutation in FMR1 was assessed by conventional PCR, agarose and acrylamide gel and analysis of fragments in capillary electrophoresis. From the lymphocyte DNA obtained from 283 women undergoing infertility treatment. Results: It was observed that 169 patients had the normal heterozygous allele (59.7%), 114 had the normal homozygous allele (40.6%) and no patient had the premutation. Premature ovarian insufficiency is seen in 20 to 30% of women with the premutated allele. Thus, the condition can be asymptomatic in a large part of the premutation carriers. Brazil has a diverse population and, therefore, the allele frequencies of many gene variants are unknown. Previous Brazilian studies have shown a low frequency of the premutated allele in different patient cohorts. Corroborating these articles, the results demonstrated that the frequency of the premutated allele is low in the infertile women population studied. Conclusion: Tracking the size of the FMR1 gene alleles allows the expansion of knowledge about the frequency of risk alleles associated to genetic diseases in the Brazilian population.
Authors who publish with this journal agree to the following terms:
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License (CC BY) that allows others to share and adapt the work with an acknowledgement of the work's authorship and initial publication in this journal.Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
Ferreira JFB, Batista JS, Fantin C. Screening for FMR1 expanded alleles in patients with Autism Spectrum Disorders in Manaus, Northern Brazil. An Acad Bras Cienc. 2019;91(3):e20180882. https://doi.org/10.1590/0001-3765201920180882
Villate O, Ibarluzea N, Maortua H, de la Hoz AB, Rodriguez-Revenga L, Izquierdo-Álvarez S, et al. Effect of AGG Interruptions on FMR1 Maternal Transmissions. Front Mol Biosci. 2020;7:135. https://doi.org/10.3389/fmolb.2020.00135
Zhao C, Liu Y, Wang Y, Li H, Zhang B, Yue Y, et al. A Chinese case of fragile X-associated tremor/ataxia syndrome (FXTAS) with orthostatic tremor: case report and literature review on tremor in FXTAS. BMC Neurol. 2020;20(1):145. https://doi.org/10.1186/s12883-020-01726-z
Nolin SL, Glicksman A, Tortora N, Allen E, Macpherson J, Mila M, et al. Expansions and contractions of the FMR1 CGG repeat in 5,508 transmissions of normal, intermediate, and premutation alleles. Am J Med Genet A. 2019;179(7):1148-56. https://doi.org/10.1002/ajmg.a.61165
Mila M, Mora MIA, Madrigal I, Rodriguez-Revenga L Fragile-X syndrome: An Overview and Update of the FMR1 Gene. Clin Genetic. 2018;93(2):197-205. https://doi.org/10.1111/cge.13075
Tseng E, Tang HT, AlOlaby RR, Hickey L, Tassone F. Altered expression of the FMR1 splicing variants landscape in premutation carriers. Biochim Biophys Acta Gene Regul Mech. 2017;1860(11):1117-26. https://doi.org/10.1016/j.bbagrm.2017.08.007
Huang J, Zhang W, Liu Y, Liu Y, Wang J, Jiang H. Association between the FMR1 CGG repeat lengths and the severity of idiopathic primary ovarian insufficiency: a meta analysis. Artif Cells Nanomed Biotechnol. 2019;47(1):3116-22. https://doi.org/10.1080/21691401.2019.1645153
Hwang YT, Aliaga SM, Arpone M, Francis D, Li X, Chong B, et al. Partially methylated alleles, microdeletion, and tissue mosaicism in a fragile X male with tremor and ataxia at 30 years of age: A case report. Am J Med Genet A. 2016;170(12):3327-32. https://doi.org/10.1002/ajmg.a.37954
Hunter JE, Leslie M, Novak G, Hamilton D, Shubeck L, Charen K, et al. Depression and anxiety symptoms among women who carry the FMR1 premutation: impact of raising a child with fragile X syndrome is moderated by CRHR1 polymorphisms. Am J Med Genet B Neuropsychiatr Genet. 2012;159B(5):549-59. https://doi.org/10.1002/ajmg.b.32061
Tassanakijpanich N, Cohen J, Cohen R, Srivatsa UN, Hagerman RJ. Cardiovascular problems in the fragile X premutation. Front Genet. 20208;11:586910. https://doi.org/10.3389/fgene.2020.586910
Welt CK. Primary ovarian insufﬁciency: a more accurate term for premature ovarian failure. Clin. Endocrinol. 2008;68(4):499-509. https://doi.org/10.1111/j.1365-2265.2007.03073.x
Lahiri DK, Nurnberger Jr JI. A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res. 1991;19(19):5444. https://doi.org/10.1093/nar/19.19.5444
Tassone F, Pan R, Amiri K, Taylor AK, Hagerman PJ. A rapid polymerase chain reaction-based screening method for identification of all expanded alleles of the fragile X (FMR1) gene in newborn and high-risk populations. J Mol Diagn. 2008;10(1):439. https://doi.org/10.2353/jmoldx.2008.070073
Goméz MKA, Acosta AX. Estudo dos alelos da região 5´UTR no gene FMR1 (Fragile X Mental Retardation 1) em homens da população geral de Salvador-BA. [master´s thesis]. [Salvador]: Fundação Oswaldo Cruz; 2011.
Tang R, Chen R, Luo M, Lin S, Yu Q. Chinese women with 29-30 FMR1 CGG repeats have an earlier menopause. Climacteric. 2020;23(3):298-305. https://doi.org/10.1080/13697137.2020.1727877
Asadi R, Omrani MD, Ghaedi H, Mirfakhraie R, Azargashb E, Habibi M, et al. Premutations of FMR1 CGG repeats are not related to idiopathic premature ovarian failure in Iranian patients: A case control study. Gene. 2018;676:189-94. https://doi.org/10.1016/j.gene.2018.07.034
Murray A, Schoemaker MJ, Bennett CE, Ennis S, Macpherson JN, Jones M, et al. Population-based estimates of the prevalence of FMR1 expansion mutations in women with early menopause and primary ovarian insufﬁciency. Genet Med. 2014;16(1):19-24. https://doi.org/10.1038/gim.2013.64
Bussani C, Papi L, Sestini R, Baldinotti F, Bucciantini S, Bruni V, et al. Premature ovarian failure and fragile X premutation: a study on 45 women. Eur J Obstet Gynecol Reprod Biol. 2004;112(2):189-91.
Allen EG, Sullivan AK, Marcus M, Small C, Dominguez C, Epstein MP, et al. Examination of reproductive aging milestones among women who carry the FMR1 premutation. Hum Reprod. 2007;22(8):2142-52.
Streuli I, Fraisse T, Ibecheole V, Moix I, Morris MA, Ziegler D. Intermediate and premutation FMR1 alleles in women with occult primary ovarian insufﬁciency. Fertil Steril. 2009;92(2):464-70. https://doi.org/ 10.1016/j.fertnstert.2008.07.007
Karimov CB, Moragianni VA, Cronister A, Srouji S, Petrozza J, Racowsky C, et al. Increased frequency of occult fragile X-associated primary ovarian insufﬁciency in infertile women with evidence of impaired ovarian function. Hum Reprod. 2011;26(8):2077-83. https://doi.org/10.1093/humrep/der168
Pastore LM, Johnson J. The FMR1 gene, infertility, and reproductive decision-making: a review. Genet. 2014;5:195. https://doi.org/10.3389/fgene.2014.00195
Dean DD, Agarwal S, Kapoor D, Singh K, Vati C. Molecular Characterization of FMR1 Gene by TP-PCR in Women of Reproductive Age and Women With Premature Ovarian Insufficiency. Mol Diagn Ther. 2018;22(1):91-100. https://doi.org/10.1007/s40291-017-0305-9
Filipovic-Sadic S, Sah S, Chen L, Krosting J, Sekinger E, Zhang W, et al. A novel FMR1 PCR method for the routine detection of low abundance expanded alleles and full mutations in fragile X syndrome. Clin Chem. 2010;56(3):399-408. https://doi.org/10.1373/clinchem.2009.136101
Silva RG, Silva LM. Detecção de expansões CGG na população do estado de Pernambuco e verificação de sua relação com a síndrome do x-frágil. [dissertation]. [Recife]: Universidade de Pernambuco; 2004.
Sucharov CC, Silva R, Rondinelli E, Moura-Neto RS. Fragile X trinucleotide repeats from a normal population in Rio de Janeiro, Brazil. Hereditas. 1999;130(2):189-90. https://doi.org/10.1111/j.1601-5223.1999.00189.x
Mingroni-Neto RC, Rosemberg C, Vianna-Morgante AM, Pavanello RC. Fragile X frequency in a mentally retarded population in Brazil. Am J Med Genet. 1990;(35):22-7. https://doi.org/10.1002/ajmg.1320350106
Queiroz MA. Avaliação de Pré-mutação por PCR na Síndrome do X Frágil, 2006. [master´s thesis]. [Florianópolis]: Universidade Federal de Santa Catarina; 2006.
Rosot N, Franco VDF, Riechi TIJS. A Síndrome do X Frágil e o estabelecimento de fenótipos cognitivo-comportamentais: uma revisão sistemática de literatura. Cienc Cognição. 2017;22(1):30-40.