Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients
- H L Archer1,
- S D Whatley2,
- J C Evans1,
- D Ravine3,
- P Huppke4,
- A Kerr5,
- D Bunyan6,
- B Kerr7,
- E Sweeney8,
- S J Davies9,
- W Reardon10,
- J Horn11,
- K D MacDermot12,
- R A Smith13,
- A Magee14,
- A Donaldson15,
- Y Crow16,
- G Hermon17,
- Z Miedzybrodzka18,
- D N Cooper1,
- L Lazarou9,
- R Butler9,
- J Sampson1,
- D T Pilz9,
- F Laccone19,
- A J Clarke1
- 1Cardiff University, Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK
- 2University Hospital of Wales, Department of Medical Biochemistry, Cardiff, UK
- 3University of Western Australia, Department of Human Genetics, Perth, Australia
- 4Universität Göttingen, Department of Neuropaediatrics, Göttingen, Germany
- 5Glasgow University, Department of Psychological Medicine, Glasgow, UK
- 6National Reference Genetics Laboratory (Wessex), Salisbury, UK
- 7St Mary’s Hospital, Department of Medical Genetics, Manchester, UK
- 8Liverpool Children’s Hospital, Department of Clinical Genetics, Liverpool, UK
- 9University Hospital of Wales, Institute of Medical Genetics, Cardiff, UK
- 10Our Lady’s Hospital for Sick Children, National Centre for Medical Genetics, Crumlin, Dublin, Ireland
- 11Bangor University, Department of Paediatrics, Bangor, UK
- 12Imperial College, Kennedy-Galton Centre, London, UK
- 13York District Hospital, Department of Paediatrics, York, UK
- 14Belfast City Hospital, Northern Ireland Regional Genetics Service, Belfast, UK
- 15Bristol Hospital for Sick Children, Department of Clinical Genetics, Bristol, UK
- 16St James’ University Hospital, Department of Medical Genetics, Leeds, UK
- 17The Children’s Trust, St Margaret’s School, Surrey, UK
- 18Aberdeen Medical School, Department of Medicine and Therapeutics, Foresterhill, Aberdeen, UK
- 19Universität Göttingen, Institut für Humangenetik, Göttingen, Germany
- Correspondence to: Dr H Archer Institute of Medical Genetics, Cardiff University, University Hospital of Wales, Heath Park, Cardiff CF14 4XN, UK; archerhl{at}cardiff.ac.uk
- Received 31 March 2005
- Accepted 6 September 2005
- Revised 18 August 2005
Abstract
MECP2 mutations are identifiable in ~80% of classic Rett syndrome (RTT), but less frequently in atypical RTT. We recruited 110 patients who fulfilled the diagnostic criteria for Rett syndrome and were referred to Cardiff for molecular analysis, but in whom an MECP2 mutation was not identifiable. Dosage analysis of MECP2 was carried out using multiplex ligation dependent probe amplification or quantitative fluorescent PCR. Large deletions were identified in 37.8% (14/37) of classic and 7.5% (4/53) of atypical RTT patients. Most large deletions contained a breakpoint in the deletion prone region of exon 4. The clinical phenotype was ascertained in all 18 of the deleted cases and in four further cases with large deletions identified in Goettingen. Five patients with large deletions had additional congenital anomalies, which was significantly more than in RTT patients with other MECP2 mutations (2/193; p<0.0001). Quantitative analysis should be included in molecular diagnostic strategies in both classic and atypical RTT.
- DHPLC, denaturing high performance liquid chromatography
- FISH, fluorescent in situ hybridisation
- MLPA, multiplex ligation dependent probe amplification
- QF-PCR, quantitative fluorescent PCR
- RTT, Rett syndrome
- TRD, transcription repression domain
- UTR, untranslated region
Footnotes
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Published Online First 14 October 2005
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Competing interests: there are no competing interests.
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Ethics approval was granted by MREC (Wales): reference 02/9/33.
