Mosaicism for the full mutation and a microdeletion involving the CGG repeat and flanking sequences in the FMR1 gene in eight fragile X patients

The molecular mechanism of the fragile X syndrome is based on the expansion of an unstable CGG repeat in the 5' untranslated region of the FMR1 gene i n most patients. This expansion is associated with an abnormal DNA methylat ion leading to the absence of production of FMR1 protein (FMRP). Such expan sion apparently predisposes the repeat and flanking regions to further inst ability that may lead to mosaic conditions with a fall mutation and a premu tation or, rarely, with normal or reduced alleles that can sometimes be tra nscriptionally active. In this study we describe eight unrelated fragile X patients who are mosaic for both a full mutation and an allele of normal (f our cases) or reduced size (four cases). Sequencing analysis of the deletio n breakpoints in 6 patients demonstrated an internal deletion confined to t he CGG repeat in four of them, which represents the most likely explanation for the regression of the full mutation to a normal sized allele. In two p atients with a reduced allele, the deletion encompassed the entire CGG repe at and part of the flanking regions. Analysis of FMRP by Western blot was p erformed in one of the mosaics with a normal sized allele and in three of t hose with a reduced allele. In the first patient's lymphocytes FMRP was det ected, whereas in the three other patients the deletion is likely to impair transcription as no FMRP was present in their lymphocytes. Am. J. Med. Gen et. 85:311-316, 1999. (C) 1999 Wiley-Liss, Inc.