Increased skewing of X chromosome inactivation in Rett syndrome patients and their mothers

Eur J Hum Genet. 2006 Nov;14(11):1189-94. doi: 10.1038/sj.ejhg.5201682. Epub 2006 Jul 5.


Rett syndrome is a largely sporadic, X-linked neurological disorder with a characteristic phenotype, but which exhibits substantial phenotypic variability. This variability has been partly attributed to an effect of X chromosome inactivation (XCI). There have been conflicting reports regarding incidence of skewed X inactivation in Rett syndrome. In rare familial cases of Rett syndrome, favourably skewed X inactivation has been found in phenotypically normal carrier mothers. We have investigated the X inactivation pattern in DNA from blood and buccal cells of sporadic Rett patients (n=96) and their mothers (n=84). The mean degree of skewing in blood was higher in patients (70.7%) than controls (64.9%). Unexpectedly, the mothers of these patients also had a higher mean degree of skewing in blood (70.8%) than controls. In accordance with these findings, the frequency of skewed (XCI > or =80%) X inactivation in blood was also higher in both patients (25%) and mothers (30%) than in controls (11%). To test whether the Rett patients with skewed X inactivation were daughters of skewed mothers, 49 mother-daughter pairs were analysed. Of 14 patients with skewed X inactivation, only three had a mother with skewed X inactivation. Among patients, mildly affected cases were shown to be more skewed than more severely affected cases, and there was a trend towards preferential inactivation of the paternally inherited X chromosome in skewed cases. These findings, particularly the greater degree of X inactivation skewing in Rett syndrome patients, are of potential significance in the analysis of genotype-phenotype correlations in Rett syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Cells / ultrastructure
  • Case-Control Studies
  • Fathers
  • Female
  • Genotype
  • Humans
  • Male
  • Mothers
  • Mouth Mucosa / ultrastructure
  • Phenotype
  • Rett Syndrome / genetics*
  • X Chromosome Inactivation*