title: Correlation between clinical severity in patients with Rett syndrome with a p.R168X or p.T158M MECP2 mutation, and the direction and degree of skewing of X-chromosome inactivation.
abstract: BACKGROUND
  Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder that is usually associated with mutations in the MECP2 gene. The most common mutations in the gene are p.R168X and p.T158M. The influence of X-chromosome inactivation (XCI) on clinical severity in patients with RTT with these mutations was investigated, taking into account the extent and direction of skewing.
  
  
  METHODS
  Female patients and their parents were recruited from the UK and Australia. Clinical severity was measured by the Pineda Severity and Kerr profile scores. The degree of XCI and its direction relative to the X chromosome parent of origin were measured in DNA prepared from peripheral blood leucocytes, and allele-specific polymerase chain reaction was used to determine the parental origin of mutation. Combining these, the percentage of cells expected to express the mutant allele was calculated.
  
  
  RESULTS
  Linear regression analysis was undertaken for fully informative cases with p.R168X (n = 23) and p.T158M (n = 20) mutations. A statistically significant increase in clinical severity with increase in the proportion of active mutated allele was shown for both the p.R168X and p.T158M mutations.
  
  
  CONCLUSIONS
  XCI may vary in neurological and haematological tissues. However, these data are the first to show a relationship between the degree and direction of XCI in leucocytes and clinical severity in RTT, although the clinical utility of this in giving a prognosis for individual patients is unclear.
authors.affiliation: Institute of Medical Genetics, Cardiff University, University Hospital of Wales, Cardiff, UK.
authors.forename: Hayley
authors.initials: H
authors.lastname: Archer
authors.forename: Julie
authors.initials: J
authors.lastname: Evans
authors.forename: Helen
authors.initials: H
authors.lastname: Leonard
authors.forename: Lyn
authors.initials: L
authors.lastname: Colvin
authors.forename: David
authors.initials: D
authors.lastname: Ravine
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
authors.forename: Sarah
authors.initials: S
authors.lastname: Williamson
authors.forename: Tony
authors.initials: T
authors.lastname: Charman
authors.forename: Mark E S
authors.initials: ME
authors.lastname: Bailey
authors.forename: Julian
authors.initials: J
authors.lastname: Sampson
authors.forename: Nicholas
authors.initials: N
authors.lastname: de Klerk
authors.forename: Angus
authors.initials: A
authors.lastname: Clarke
mesh_terms: D019943:Amino Acid Substitution; D001315:Australia; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D009154:Mutation; D015518:Rett Syndrome / Q000235:genetics* / Q000503:physiopathology; D012606:Scotland; D012720:Severity of Illness Index; D014852:Wales; D049951:X Chromosome Inactivation
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2