1. ¹Faculty Division Rikshospitalet, Department of Medical Genetics, University of Oslo, Oslo, Norway
2. ²Division of Molecular Genetics, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, UK
3. ³Department of Psychological Medicine, University of Glasgow, Glasgow, UK
4. ⁴Department of Clinical Genetics, National University Hospital, Copenhagen, Denmark
5. ⁵Department of Biological Science, University of Warwick, Coventry, UK
6. ⁶Department of Medical Genetics, Rikshospitalet-Radiumhospitalet HF, Oslo, Norway

Correspondence: Dr GPS Knudsen, Department of Medical Genetics, Rikshospitalet-Radiumhospitalet HF, Forskningsveien 2B, 0027 Oslo, Norway. Tel: +47 23075586; Fax: +47 23075590; E-mail: gun.peggy.knudsen@rikshospitalet.no

Received 7 February 2006; Revised 4 May 2006; Accepted 23 May 2006; Published online 5 July 2006.

Abstract

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 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.