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.
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.
Archer
Hayley
H
Institute of Medical Genetics, Cardiff University, University Hospital of Wales, Cardiff, UK.
Evans
Julie
J
Leonard
Helen
H
Colvin
Lyn
L
Ravine
David
D
Christodoulou
John
J
Williamson
Sarah
S
Charman
Tony
T
Bailey
Mark E S
ME
Sampson
Julian
J
de Klerk
Nicholas
N
Clarke
Angus
A
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
C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2