Published online before print April 10, 2008

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Journal of Molecular Diagnostics 2008, Vol. 10, No. 3
Copyright © 2008 American Society for Investigative Pathology & Association for Molecular Pathology
DOI: 10.2353/jmoldx.2008.070163

Consultations in Molecular Diagnostics

A Single Nucleotide Variant in the FMR1 CGG Repeat Results in a "Pseudodeletion" and Is Not Associated with the Fragile X Syndrome Phenotype

Massimiliano Cecconi^*, Francesca Forzano^*, Rosanna Rinaldi, Sandra Cappellacci, Paola Grammatico, Francesca Faravelli^*, Franca Dagna Bricarelli^*, Emilio Di Maria^* and Marina Grasso^*

From the Laboratory of Genetics, * Galliera Hospital, Genoa; the Laboratory of Medical Genetics, "La Sapienza" University, "S. Camillo" Hospital, Rome; and the Department of Neuroscience, Ophthalmology and Genetics, University of Genova, Genoa, Italy

Abstract

The molecular diagnosis of fragile X syndrome relies on the detection of the pathogenic CGG repeat expansion in the FMR1 gene. Deletions and point mutations have occasionally been reported. Rare polymorphisms might mimic a deletion by Southern blot analysis, leading to false-positive results. We describe a novel rare nucleotide substitution within the CGG repeat. The proband was a woman with a positive family history of mental retardation. Southern blot analysis showed an additional band consistent with a deletion in the region detected by the StB12.3 probe. Sequencing of this region revealed a G>C transversion that interrupts the CGG repeat and introduces an EagI site. The same variant was observed in both the healthy son and father of the proband, supporting the hypothesis that the nucleotide substitution is a silent polymorphism, the frequency of which we estimated to be less than 1% in the general population. These findings argue for a pathogenic role of nucleotide variants within the CGG repeat and suggest possible consequences of unexpected findings in the molecular diagnostics of fragile X syndrome. Thus, although the sequence context of a single nucleotide substitution may not predict possible effects on mRNA or protein function, a specific change in the higher order structures of DNA or mRNA may be functionally relevant in the pathological phenotype.