RT Journal Article SR Electronic T1 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 JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 148 OP 152 DO 10.1136/jmg.2006.045260 VO 44 IS 2 A1 Hayley Archer A1 Julie Evans A1 Helen Leonard A1 Lyn Colvin A1 David Ravine A1 John Christodoulou A1 Sarah Williamson A1 Tony Charman A1 Mark E S Bailey A1 Julian Sampson A1 Nicholas de Klerk A1 Angus Clarke YR 2007 UL http://jmg.bmj.com/content/44/2/148.abstract AB Introduction: 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.