Abstract
The term “Fragile X” can be used for either of two conditions resulting from trinucleotide repeat expansions at neighboring loci, FRAXA or FRAXE, in the Xq27–28 region; however, FRAXA is by far the more common condition, and only mutations at this locus cause the classical phenotype of “Fragile X syndrome,” those at FRAXE are responsible for a variable, milder phenotype of nonspecific mental impairment. For this reason, many laboratories consider it cost-effective to test only for FRAXA mutations. However, a brief description of PCR techniques for FRAXE testing are also given (see Note 1).
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References
Verkerk, A. J. M. H., Pieretti, M., Sutcliffe, J. S., Fu, Y. H., Kuhl, D., Pizzuti, A., et al. (1991) Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905–914.
Fu, Y.-H., Kuhl, D. P. A., Pizzuti, A., Pieretti, M., Sutcliffe, J. S., Richards, S., et al. (1991) Variation of the p(CGG)n repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 67, 1047–1058.
Eichler, E. E., Holden, J. J. A., Popovich, B. W., Reiss, A. L., Snow, K., Thibodeau, S. N., et al. (1994) Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nat. Genet. 8, 88–93.
Kunst, C. B. and Warren, S. T (1994) Cryptic and polar variation of the fragile X repeat could result in predisposing normal alleles. Cell 77, 853–861.
Heitz, D., Devys, D., Imbert, G., Kretz, C, and Mandel, J. L. (1992) Inheritance of the fragile X syndrome: size of the fragile X premutation is a major determinant of the transition to full mutation. J. Med. Genet. 29, 794–801.
Fisch, G. S., Snow, K., Thibodeau, S.N., Chalifaux, M., Holden, J. J. A., Nelson, D. L., et al. (1995) The fragile X premutation in carriers and its effect on mutation size in offspring. Am. J. Med. Genet. 56, 1147–1155.
Nolin, S. L., Rousseau, F, Houck, G. E., Gargano, A., Biancalana, V., Hinkle, L., et al. (2001) FMR1 CGG expansion to full mutation: what is the lower limit in premutation females? Am. J. Hum. Genet. 67(Suppl. 2), Abstract 2041.
Pieretti, M., Zhang, F, Fu, Y.-H., Warren, S. T, Oostra, B. A., Caskey, C. T, et al. (1991) Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 66, 817–822.
Oberlé, I., Rousseau, F., Heitz, D., Kretz, C, Devys, D., Hanauer, A., et al. (1991) Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science 252, 1097–1102.
Rousseau, F., Heitz, D., Biancalana, V., Blumenfeld, S., Kretz, C, Boué, J., et al. (1991) Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation. N. Engl. J. Med. 325, 1673–1681.
Willemsen, R., Los, F., Mohkamsing, S., van den Ouweland, A., Deelen, W., Galjaard, H., et al. (1997) Rapid antibody test for prenatal diagnosis of fragile X syndrome on amniotic fluid cells: a new appraisal. J. Med. Genet. 34, 250–251.
Devys, D., Biancalana, V., Rousseau, F., Boué, J., Mandel, J. L., and Oberlé, I. (1992) Analysis of full Fragile X mutation in fetal tissues and monozygotic twins indicate that abnormal methylation and somatic heterogeneity are established early in development. Am. J. Med. Genet. 43, 208–216.
Rousseau, F., Heitz, D., Biancalana, V., Oberlé, I., and Mandel, J. L. (1992) On some technical aspects of direct DNA diagnosis of the Fragile X syndrome. Am. J. Med. Genet. 43, 197–207.
Rousseau, F, Heitz, D., Tarleton, J., MacPherson, J., Mamlgren, H., Dahl, N, et al. (1994) A multicenter study on genotype-phenotype correlations in the fragile X syndrome, using direct diagnosis with probe StB12.3: the first 2,253 cases. Am. J. Med. Genet. 55, 225–237.
Larsen, L. A., Gronskov, K., Norgaard-Pedersen, B., Brondum-Nielsen, K., Hasholt, L., and Vuust, J. (1997) High-throughput analysis of fragile X (CGG)n alleles in the normal and premutation range by PCR amplification and automated capillary electrophoresis. Hum. Genet. 100, 564–568.
Wang, Q., Green, E., Bobrow, M., and Mathew, C. G. (1995) A rapid, nonradioactive screening test for fragile X mutations at the FRAXA and FRAXE loci. J. Med. Genet. 32, 170–173.
Warner, J. P., Barron, L. H., Goudie, D., Kelly, K., Dow, D., Fitzpatrick, D. R., et al. (1996) A general method for the detection of large CAG repeat expansions by fluorescent PCR. J. Med. Genet. 33, 1022–1026.
Biancalana, V., Taine, L., Bouix, J. C., Finck, S., Chauvin, A., De Verneuil, H., et al. (1996) Expansion and methylation status at FRAXE can be detected on EcoRI blots used for FRAXA diagnosis: analysis of four FRAXE families with mild mental retardation in males. Am. J. Hum. Genet. 59, 847–854.
Van den Ouweland, A. M. W., Deele, W. H., Kunst, C. B., Giovannucci Uzielli, M. L., Nelson, D. L., Warren, S. T., et al. (1994) Loss of mutation at the FMR1 locus through multiple exchanges between maternal X chromosomes. Hum. Mol. Genet. 3, 1823–1827.
Vits, L., De Boulle, K., Reyniers, E., Handig, I., Darby, J. K, Oostra, B., et al. (1994) Apparent regression of the CGG repeat in FMR1 to an allele of normal size. Hum. Genet. 94, 523–526.
Malzac, P., Biancalana, V., Volckel, M. A., Moncla, A., Pellissier, M. C., Boccaccio, I., et al. (1996) Unexpected inheritance of the (CGG)n trinucleotide expansion in a Fragile X syndrome family. Eur. J. Hum. Genet. 4, 8–12.
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Biancalana, V., Macpherson, J. (2004). Fragile X Disease. In: Elles, R., Mountford, R. (eds) Molecular Diagnosis of Genetic Diseases. Methods in Molecular Medicine™, vol 92. Humana Press, Totowa, NJ. https://doi.org/10.1385/1-59259-432-8:157
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DOI: https://doi.org/10.1385/1-59259-432-8:157
Publisher Name: Humana Press, Totowa, NJ
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