1. ¹Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
2. ²Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin-Dahlem, Germany
3. ³Service de Génétique, CHRU de Tours, Tours, France
4. ⁴Department of Paediatric Neurology, University Children's Hospital, Heidelberg, Germany
5. ⁵CH de Vannes, Génétique Médicale, Vannes, France
6. ⁶Institut Cochin (IC), Département de Génétique et Pathologie Moléculaire GDPM, Equipe de Génétique et Physiopathologie du Retard Mental GPRM, Paris, France
7. ⁷Service de Génétique Médicale, Hôpital Pellegrin-Enfants, CHU de Bordeaux, France
8. ⁸Service de Neuropédiatrie Hôpital Saint-Eloi, CHU de Montpellier, France
9. ⁹Institute for Human Genetics, University Heidelberg, Heidelberg, Germany
10. ¹⁰Children's University Hospital, Limited Liability Company (Limited by Shares), Dublin, Ireland
11. ¹¹Our Lady's Hospital, Crumlin and The Children's University Hospital, Dublin, Ireland
12. ¹²Department of Paediatrics and Child Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand
13. ¹³Center for Human Genetics, University Hospital Leuven, Leuven, Belgium
14. ¹⁴Department of Genetic Medicine, Women's and Children's Hospital and Department of Paediatrics, University of Adelaide, Adelaide, Australia

Correspondence: Dr T Kleefstra, Department of Human Genetics, Radboud University Nijmegen Medical Centre, PO Box 9101, Nijmegen 6500 HB, The Netherlands. Tel: +31 24 361 3946; Fax:+31 24 366 8753; E-mail: T.Kleefstra@antrg.umcn.nl

Received 2 May 2008; Revised 25 July 2008; Accepted 12 September 2008; Published online 5 November 2008.

Abstract

Duplications in Xq28 involving MECP2 have been described in patients with severe mental retardation, infantile hypotonia, progressive spasticity, and recurrent infections. However, it is not yet clear to what extent these and accompanying symptoms may vary. In addition, the frequency of Xq28 duplications including MECP2 has yet to be determined in patients with unexplained X-linked mental retardation and (fe)males with severe encephalopathy. In this study, we used multiplex ligation-dependent probe amplification to screen Xq28 including MECP2 for deletions and duplications in these patient cohorts. In the group of 283 patients with X-linked mental retardation, we identified three Xq28 duplications including MECP2, which suggests that approximately 1% of unexplained X-linked mental retardation may be caused by MECP2 duplications. In addition, we found three additional MECP2 duplications in 134 male patients with mental retardation and severe, mostly progressive, neurological symptoms, indicating that the mutation frequency could be as high as 2% in this group of patients. In 329 female patients, no Xq28 duplications were detected. In total, we assessed 13 male patients with a MECP2 duplication from six unrelated families. Moderate to severe mental retardation and childhood hypotonia was noted in all patients. The majority of the patients also presented with absent speech, seizures, and progressive spasticity as well as ataxia or an ataxic gait and cerebral atrophy, two previously unreported symptoms. We propose to implement DNA copy number testing for MECP2 in the current diagnostic testing in all males with moderate to severe mental retardation accompanied by (progressive) neurological symptoms.