title: Increased skewing of X chromosome inactivation in Rett syndrome patients and their mothers.
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 > 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.
authors.affiliation: Faculty Division Rikshospitalet, Department of Medical Genetics, University of Oslo, Oslo, Norway. gun.peggy.knudsen@rikshospitalet.no
authors.forename: Gun Peggy S
authors.initials: GP
authors.lastname: Knudsen
authors.forename: Tracey C S
authors.initials: TC
authors.lastname: Neilson
authors.forename: June
authors.initials: J
authors.lastname: Pedersen
authors.forename: Alison
authors.initials: A
authors.lastname: Kerr
authors.forename: Marianne
authors.initials: M
authors.lastname: Schwartz
authors.forename: Maj
authors.initials: M
authors.lastname: Hulten
authors.forename: Mark E S
authors.initials: ME
authors.lastname: Bailey
authors.forename: Karen Helene
authors.initials: KH
authors.lastname: Orstavik
mesh_terms: D001773:Blood Cells / Q000648:ultrastructure; D016022:Case-Control Studies; D005220:Fathers; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D009035:Mothers; D009061:Mouth Mucosa / Q000648:ultrastructure; D010641:Phenotype; D015518:Rett Syndrome / Q000235:genetics*; D049951:X Chromosome Inactivation