Two sisters with Rett syndrome and non-identical paternally-derived microdeletions in the MECP2 gene

Abstract

The unique case of two sisters with symptoms of RTT and two quite distinct, novel, and apparently de novo microdeletions of the MECP2 gene is described. One sister possessed an 18 base-pair (bp) deletion (c.1155_1172del18) within the deletion hotspot region of exon 4, whereas the other sister exhibited a 43 bp deletion at a different location in the same exon (c.1448_1461del14+29). Although these lesions occurred on the same paternally-derived X chromosome, this is probably due to chance co-occurrence owing to the relatively high mutation rate of the MECP2 gene rather than to a constitutional mutator phenotype.

Fig. 1

Pedigree of the affected family; The clinically affected sisters (Cases 1 and 2) are denoted by filled circles. The MECP2 genotypes of the sisters are given. The paternal inheritance of the c.1373G>A transition is indicated

Fig. 2

Sequence of exon 4 of the MECP2 gene showing the locations of the two microdeletions and the missense mutation detected in the reported family

Fig. 3

Repetitive sequence elements in the vicinity of the microdeletion breakpoints and the secondary structures postulated to have been involved in the genesis of the two mutations. Lower case letters denote deleted nucleotides. (a) Repetitive sequence elements (shown in bold) found in the vicinity of the breakpoints of the 1155_1172del18 microdeletion. (b) Repetitive sequence elements (shown in bold) found in the vicinity of the breakpoints of the 1448_1461del14+29 microdeletion. (c) Schematic representation of the postulated non-B DNA slipped structures at the breakpoint of the 1448_1461del14+29 microdeletion. The nucleotides shown in bold type correspond to the direct repeats shown in (b). Nucleotides circled in grey denote the homology between two breakpoint junctions. The arrows indicate the sequences deleted