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ISSN 2070-8718 (Impreso)

2015, Número 2

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Rev Cub Gen 2015; 9 (2)


Diagnóstico molecular del síndrome de X frágil mediante PCR específica de metilación

Esperón ÁAA, Merencio SL, López RI, Reyes NL, García HM, Collazo MT

Idioma: Español
Referencias bibliográficas: 29
Paginas: 17-23
Archivo PDF: 530.38 Kb.


RESUMEN

El síndrome de X frágil (SXF) es causado por el silenciamiento epigenético del gen FMR1, debido al incremento por encima de 200 repeticiones del trinucleótido CGG localizado en su región 5’ no traducida. Las expansiones entre 55 y 200 repeticiones, denominadas premutación (PM), tienden a expandirse a mutación completa (MC) cuando se transmiten por vía materna. Los individuos con PM pueden desarrollar el síndrome de temblor/ataxia asociado a X frágil o insuficiencia ovárica primaria asociada a X frágil (FXPOI). En este trabajo se describen los resultados del análisis molecular del gen FMR1 en 251 individuos con sospecha clínica de SXF o con historia familiar de esta enfermedad, así como en 14 fetos de madres con riesgo de tener hijos afectados. El análisis se realizó empleando PCR específica de metilación. Se identificaron 16 varones y 4 hembras con MC, 3 varones mosaicos, y 4 varones y 21 mujeres con PM, 8 de ellas con un alto riesgo de transmitir la enfermedad. Se confirmó el diagnóstico clínico de FXPOI en dos mujeres y de SXF en 20 pacientes con discapacidad intelectual. La distribución de frecuencias alélicas difiere de la reportada para otras poblaciones.


REFERENCIAS (EN ESTE ARTÍCULO)

  1. Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 1991;65(5):905-14.

  2. Sutcliffe JS, Nelson DL, Zhang F, Pieretti M, Caskey CT, Saxe D, et al. DNA methylation represses FMR-1 transcription in fragile X syndrome. Human molecular genetics 1992;1(6):397-400.

  3. Collins SC, Coffee B, Benke PJ, Berry-Kravis E, Gilbert F, Oostra B, et al. Array-based FMR1 sequencing and deletion analysis in patients with a fragile X syndrome-like phenotype. PLoS One 2010;5:e9476.

  4. Handt M, Epplen A, Hoffjan S, Mese K, Epplen JT, Dekomien G. Point mutation frequency in the FMR1 gene as revealed by fragile X syndrome screening. Mol Cell Probes 2014;28(5-6):279-83.

  5. Hagerman RJ, Hagerman PJ. Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome. Lancet Neurol 2013;12(8):786-98.

  6. Peprah E. Fragile X syndrome: the FMR1 CGG repeat distribution among world populations. Ann Hum Gene 2012;76(2):178-91.

  7. Loesch D, Hagerman R. Unstable mutations in the FMR1 gene and the phenotypes. Adv Exp Med Biol 2012;769:78-114.

  8. Nolin SL, Glicksman A, Ding X, Ersalesi N, Brown WT, Sherman SL, et al. Fragile X analysis of 1112 prenatal samples from 1991 to 2010. Prenat Diagn 2011;31(10):925-31.

  9. Terracciano A, Pomponi MG, Marino GME, Chiurazzi P, Rinaldi MM, Dobosz M, et al. Expansion to full mutation of a FMR1 intermediate allele over two generations. Eur J Hum Genet 2004;12(4):333-6.

  10. Yrigollen CM, Durbin-Johnson B, Gane L, Nelson DL, Hagerman R, Hagerman PJ, et al. AGG interruptions within the maternal FMR1 gene reduce the risk of offspring with fragile X syndrome. Genet Med 2012;14(8):729-36.

  11. Wittenberger MD, Hagerman RJ, Sherman SL, McConkie-Rosell A, Welt CK, Rebar RW, et al. The FMR1 premutation and reproduction. Fertil Steril 2007;87(3):456-65.

  12. Hagerman PJ, Hagerman RJ. Fragile X-associated tremor/ataxia syndrome (FXTAS). Ment Retard Dev Disabil Res Rev 2004;10:25-30.

  13. Pastore LM, Karns LB, Pinkerton JV, Silverman LM, Williams CD, Camp TR. Acceptance of fragile X premutation genetic screening in women with ovarian dysfunction. Am J Obstet Gynecol 2006;194(3):738-43.

  14. Ennis S, Ward D, Murray A. Nonlinear association between CGG repeat number and age of menopause in FMR1 premutation carriers. Eur J Hum Genet 2006;14(2):253-5.

  15. Rajkiewicz M, Szlendak-Sauer K, Sulek A, Gawlik-Zawislak S, Krysa W, Radowicki S, et al. A molecular and cytogenetic investigation of FMR1 gene premutations in Polish patients with primary ovarian insufficiency. Eur J Obstet Gynecol Reprod Biol 2011;155(2):176-9.

  16. Rifé M, Badenas C, Quintó L, Puigoriol E, Tazón B, Rodriguez-Revenga L, et al. Analysis of CGG variation through 642 meioses in Fragile X families. Mol Hum Reprod 2004;10(10):773-6.

  17. Zhou Y, Law HY, Boehm CD, Yoon CS, Cutting GR, Ng ISL, et al. Robust fragile X (CGG)n genotype classification using a methylation specific triple PCR assay. J Med Genet 2004;41(4):e45.

  18. Zhou Y, Lum JMS, Yeo G-H, Kiing J, Tay SKH, Chong SS. Simplified molecular diagnosis of fragile X syndrome by fluorescent methylation-specific PCR and GeneScan analysis. Clin Chem 2006;52(8):1492-500.

  19. Gatta V, Gennaro E, Franchi S, Cecconi M, Antonucci I, Tommasi M, et al. MS-MLPA analysis for FMR1 gene: evaluation in a routine diagnostic setting. BMC Med Genet 2013;14:79.

  20. Grasso M, Boon EMJ, Filipovic-Sadic S, van Bunderen PA, Gennaro E, Cao R, et al. A Novel Methylation PCR that Offers Standardized Determination of FMR1 Methylation and CGG Repeat Length without Southern Blot Analysis. J Mol Diagn 2014;16(1):23-31.

  21. Tejada MI, Glover G, Martinez F, Guitart M, de Diego-Otero Y, Fernandez-Carvajal I, et al. Molecular testing for fragile X: analysis of 5062 tests from 1105 fragile X families‒–performed in 12 clinical laboratories in Spain. Biomed Res Int 2014;2014:195793.

  22. 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.

  23. MacKenzie JJ, Sumargo I, Taylor SA. A cryptic full mutation in a male with a classical fragile X phenotype. Clin Genet 2006;70(1):39-42.

  24. Tassone F, Iong KP, Tong TH, Lo J, Gane LW, Berry-Kravis E, et al. FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States. Genome Med 2012;4(12):100.

  25. Fernandez-Carvajal I, Walichiewicz P, Xiaosen X, Pan R, Hagerman PJ, Tassone F. Screening for expanded alleles of the FMR1 gene in blood spots from newborn males in a Spanish population. J Mol Diagn 2009;11(4):324-9.

  26. Winarni TI, Utari A, Mundhofir FEP, Tong T, Durbin-Johnson B, Faradz SMH, et al. Identification of expanded alleles of the FMR1 gene among high-risk population in Indonesia by using blood spot screening. Genet Test Mol Biomarkers 2012;16(3):162-6.

  27. Indhumathi N, Singh D, Chong SS, Thelma BK, Arabandi R, Srisailpathy CRS. Fragile X CGG repeat variation in Tamil Nadu, South India: a comparison of radioactive and methylation-specific polymerase chain reaction in CGG repeat sizing. Genet Test Mol Biomarkers 2012;16(2):113-22.

  28. Fatima T, Zaidi SA, Sarfraz N, Perween S, Khurshid F, Imtiaz F. Frequency of FMR1 gene mutation and CGG repeat polymorphism in intellectually disabled children in Pakistan. Am J Med Genet A 2014;164A(5):1151-61.

  29. Rosales-Reynoso MA, Mendoza-Carrera F, Troyo-Sanromán R, Claudina M, Barros-Núñez P. Genetic Diversity at the FMR1 Locus in Mexican Population. Arch Med Res 2005;36:412-7.




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