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Mutation analysis in the MECP2 gene and genetic counselling for Rett syndrome
  1. H Gill1,
  2. J P Cheadle1,
  3. J Maynard1,
  4. N Fleming1,
  5. S Whatley2,
  6. T Cranston3,
  7. E M Thompson4,
  8. H Leonard6,
  9. M Davis7,
  10. J Christodoulou5,
  11. O Skjeldal8,
  12. F Hanefeld9,
  13. A Kerr10,
  14. A Tandy11,
  15. D Ravine1,
  16. A Clarke1
  1. 1Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK
  2. 2Department of Medical Biochemistry, University Hospital of Wales, Heath Park, Cardiff CF14 4W, UK
  3. 3Clinical Molecular Genetics, Level 5, Camelia Botnar Laboratories, Great Ormond Street, London WC1N 3JH, UK
  4. 4South Australia Clinical Genetics Service, Women’s and Children’s Hospital, 72 King William Road, North Adelaide 5006, South Australia
  5. 5Western Sydney Genetics Programme, Children’s Hospital at Westmead and Department of Paediatrics and Child Health, University of Sydney, Sydney, Australia
  6. 6TVW Telethon Institute for Child Health Research, West Perth, Australia WA6872
  7. 7Department of Neuropathology, Royal Perth Hospital, Perth, Australia
  8. 8Department of Paediatrics, Nordland Central Hospital, N-8017 Bodo, Norway
  9. 9Abteilung Kinderheilkunde, Scheuerpunk, Neuropaeditre, Georg-August-Universital, Göttingen, Germany
  10. 10University of Glasgow, Department of Psychological Medicine, Gartnaval Royal Hospital, 1055 Great Western Road, Glasgow G12 OXH, UK
  11. 11Department of Paediatrics, Taunton and Somerset Hospital, Musgrove Park, Taunton, Somerset TA1 5DA, UK
  1. Correspondence to:
 Professor A Clarke, Department of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK; 
 clarkeaj{at}cardiff.ac.uk

https://doi.org/10.1136/jmg.40.5.380

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    We looked for pathogenic MECP2 mutations in 11 families with an index case affected by Rett syndrome (RTT), together with a sib or other relative affected by RTT or a less specific developmental disturbance. In one family, we detected the same MECP2 mutation in two affected sisters and their unaffected mother, who was subsequently shown to have skewed X chromosome inactivation. In five families, one affected subject was found to have a MECP2 mutation, but the other relative in whom a diagnosis of RTT was suspected, did not carry this or any other detectable MECP2 mutation. In the remaining five families, no MECP2 mutation was detected in any subject. These results suggest that familial RTT is rare and may be overdiagnosed. Furthermore, and despite the small probability of recurrence, many relatives of females with the usual, sporadic RTT may seek genetic testing to clarify their situation.

    Rett syndrome (RTT) is a neurodevelopmental disorder that mostly affects females and is usually sporadic. It has therefore often been considered to be an X linked dominant condition with male lethality, although it is now recognised that de novo mutations in RTT occur predominantly on the paternally derived X chromosome and this could lead to similar observations.1–4 It is an important cause of profound mental handicap in girls, accounting for up to 10% of all cases. The diagnosis is currently based upon the clinical criteria proposed by the Rett Syndrome Working Group in 1988.5 The major criteria are: (1) normal pre- and perinatal period and apparently normal development for the first 6 months of life, (2) a period of regression occurring at 6 months to 3 years of age, (3) deceleration in head growth, (4) acquisition of stereotypical hand movements, and (5) eventual profound developmental delay. In addition, there are a …

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