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Title: Evaluating the influence of four variants detected in the FRAXA and FRAXE loci
Author: Marques, Isabel
Jorge, Paula
Loureiro, Joana
Santos, Rosário
Keywords: Locus FRAXA
Doenças Genéticas
Atraso Mental
Issue Date: Nov-2011
Publisher: Sociedade Portuguesa de Genética Humana
Citation: 15ª Reunião Anual da SPGH : Livro de Resumos, 2011:120
Abstract: Of the seven folate-sensitive fragile sites cloned in the human genome, only two have a proven clinical expression, FRAXA and FRAXE, the former with a well-documented clinical impact. The expansion of over 200 [CGG] triplets in the Fragile Mental Retardation 1 gene (FMR1), FRAXA locus, is associated with the Fragile X Syndrome (FXS), the most common form of familial severe mental retardation/intellectual disability. The prevalence of FRAXE full mutations is much lower, and is frequently associated with non-syndromic X-linked mental retardation (FRAXE-MR). This phenotype is due to the silencing of the Fragile Mental Retardation 2 gene (AFF2), as a consequence of a [CCG] expansion to more than 200 hyper-methylated triplets located upstream of the gene. Molecular diagnosis of FXS and FRAXE-MR typically rely on techniques such as PCR (for pre-screening), Southern blotting and linkage analysis based on microsatellite markers. The latter is of particular interest in atypical or complex cases. Additional molecular tools are also currently available such as fluorescent methylation-specific PCR, Multiplex Methylation-Specific Real-Time PCR and Methylation-specific MLPA (Multiplex Ligation-dependent Probe Amplification). In the course of FXS and FRAXE-MR molecular diagnosis using standard molecular methodologies, four variants were identified. Three of them are in the FRAXA locus, two in the 5’UTR region of the FMR1 gene: NM_002024.5: c.-412G>C and NM_002024.5:c.-68T>G; and one located ~7kb upstream the FMR1 gene: g.146986184_146986185insAAGCAGA in the amplified region of the polymorphic marker FRAXAC1. The remainder is in the FRAXE locus, positioned in AFF2 gene promoter region: NT_011681.16: c.-3101G>A. Herein, we describe the characterization of these four variants and illustrate how, besides increasing genetic diversity, they in fact influence the interpretation of results in the context of FXS or FRAXE-MR diagnosis.
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