A unique case of reversion to normal size of a maternal premutation FMR1 allele in a normal boy

Abstract

Fragile X syndrome (FXS) is caused mostly by expansion and subsequent methylation of the CGG repeat in the 5′UTR of the FMR1 gene, resulting in silencing of the gene, absence of FMRP and development of the FXS phenotype. The expansion also predisposes the CGG repeat and the flanking regions to further instability that may lead to mosaics between a full mutation and a premutation or, rarely, a normal or deleted allele. Here, we report on a 10-year-old boy with no FXS phenotype, who has a normal CGG tract, although he inherited the maternal expanded allele that causes FXS in his two brothers. Southern blotting demonstrated that the mother carries a premutation allele (∼190CGG), whereas the propositus shows a normal 5.2kb fragment after HindIII digestion and a smaller 2.2kb fragment after double HindIII-EagI digestion, without any apparent mosaicism in peripheral blood leukocytes. PCR and sequence analysis of the FMR1 5′UTR revealed an allele of 43 repeats, with two interspersed AGG triplets in position 10 and 25 and an exceptional CCG triplet in position 17. This latter creates an abnormal EagI site compatible with the smaller 2.2kb fragment observed with Southern blotting. Haplotype analysis proved that the rearranged allele originated from the maternal expanded allele. To the best of our knowledge, this is the first non-mosaic case of reduction in the CGG tract of the FMR1 gene, resulting in a normal allele.