Published online before print June 12, 2009

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Journal of Molecular Diagnostics 2009, Vol. 11, No. 4
Copyright © 2009 American Society for Investigative Pathology & Association for Molecular Pathology
DOI: 10.2353/jmoldx.2009.080174

Expansion of an FMR1 Grey-Zone Allele to a Full Mutation in Two Generations

Isabel Fernandez-Carvajal^*, Blanca Lopez Posadas^*, Ruiqin Pan, Christopher Raske, Paul J. Hagerman and Flora Tassone

From the Laboratorio de Genética Humana, * Unidad de Diagnóstico Genético y Perinatal, Instituto de Biología y Genética Molecular, Universidad de Valladolid-CSIC, Valladolid, Spain; the Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, Davis, California; and the Medical Investigation of Neurodevelopmental Disorders Institute, University of California Davis Health System, Sacramento, California

Fragile X Syndrome is caused by the expansion of an unstable CGG-repeat tract in the 5'-UTR of the FMR1 gene, which generally results in transcriptional silencing and consequent absence of the FMR1 protein. To date, the smallest premutation allele reported to expand to a full mutation allele in a single generation is 59 CGG repeats. Here, we report a single-generation expansion to a full mutation allele (male with 538 CCG repeats) from a mother who is a carrier of a premutation allele of 56 CGG repeats. Furthermore, the maternal grandfather was a carrier of a gray (or intermediate)-zone allele (45 to 54 repeats) of 52 CGG repeats. Thus, in this family, a gray-zone allele expanded to the full mutation range in two generations. Interestingly, the two AGG interruptions present in the grandfather’s allele were absent in the mother’s premutation allele. These observations underscore the need to consider carriers of alleles of greater than 55 CGG repeats as being at risk for transmission of a full mutation allele in a single generation, and those with even smaller alleles in the gray zone as being at risk of having grandchildren with full mutation alleles.