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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
  1. Hayley Archer1,*,
  2. Julie Evans1,*,
  3. Helen Leonard2,
  4. Lyn Colvin2,
  5. David Ravine3,
  6. John Christodoulou4,
  7. Sarah Williamson4,
  8. Tony Charman5,
  9. Mark E S Bailey6,
  10. Julian Sampson1,
  11. Nicholas de Klerk2,
  12. Angus Clarke1
  1. 1Institute of Medical Genetics, Cardiff University, University Hospital of Wales, Cardiff, UK
  2. 2Telethon Institute of Child Health Research, Centre for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia
  3. 3Western Australian Institute of Medical Research, School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia
  4. 4Western Sydney Genetics Program, The Children’s Hospital at Westmead and Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia
  5. 5Behavioural & Brain Sciences Unit, Institute of Child Health, University College London, London, UK
  6. 6Division of Molecular Genetics, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, UK
  1. Correspondence to:
 Professor A Clarke
 Institute of Medical Genetics, Cardiff University, University Hospital of Wales, Cardiff CF14 4XN, UK; clarkeaj{at}


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.

  • PCR, polymerase chain reaction
  • RTT, Rett syndrome
  • SNP, single-nucleotide polymorphism
  • 3′UTR, 3′ untranslated region
  • XCI, X-chromosome inactivation

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  • * These authors contributed equally to the work.

  • Funding: The work in the UK was supported by The Health Foundation, Jeans for Genes and the Rett Syndrome Association UK, Rett Syndrome Research Foundation, International Rett Syndrome Association, Rett Syndrome Association Scotland, Scottish Hospital Endowments Research Trust (SHERT/Cruden scholarship to MESB), and Institute of Biomedical and Life Sciences Research Committee, University of Glasgow. The Australian Rett Syndrome research was funded by the National Institutes of Health (1 R01 HD43100-01A1). HL and LC are currently funded by NHMRC program grant 353514, and JC by NHMRC project grants 185202 and 346603, the Rett Syndrome Australian Research Fund, the International Rett Syndrome Association and the Rett Syndrome Research Foundation.

  • Competing interests: None declared.

  • Published Online First 11 August 2006

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