Rett syndrome from quintuple and triple deletions within the MECP2 deletion hotspot region

Rett syndrome results from mutations in the X-linked methyl-CpG-binding pro tein 2 (MECP2) gene, which are nearly always lethal in males and lead to re gression and reduced life expectancy in females. Herein we report one propo situs with five tandem deletions and a second propositus with three tandem deletions within MECP2 exon 4 that encode truncated protein products result ing in classic Rett syndrome. These deletion breakpoints and single deletio ns in 3 other patients were all found within a 185-bp region along with 64 of 69 other reported deletion breakpoints in the MECP2 gene. Illegitimate r ecombination resulting in deletion at a substantial proportion of the share d MECP2 sites is enhanced by repeated guanosine (G)-DNA sequences in the an tisense direction, consistent with reports at other gene loci that polypuri ne (multiple guanosine or adenosine (A)) basepairs enhance sequence deletio n. Multiple deletions at the same poly G recombination sites confirm the ex istence of deletion hotspots in this gene region with numerous repeated ant isense sites that are enriched 26- to 161-fold. Deletion by illegitimate re combination within a single allele can occur during mitotic or meiotic cell cycles. Although prone to disease-causing deletion, this region is unique in humans and highly conserved among mammals for the last 75000000 years to maintain the MECP2 gene's critical function.