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Cyclin-Dependent Kinase-Like 5 (CDKL5) Mutation Screening in Rett Syndrome and Related Disorders

Published online by Cambridge University Press:  21 February 2012

Rose White ,
Gladys Ho ,
Swetlana Schmidt ,
Ingrid E. Scheffer ,
Alexandra Fischer ,
Simone C. Yendle ,
Thierry Bienvenu ,
Juliette Nectoux ,
Carolyn J. Ellaway  and
Artur Darmanian
...Show all authors
Rose White
Affiliation:
Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, Australia; Discipline of Paediatrics & Child Health, University of Sydney, Australia.
Gladys Ho
Affiliation:
Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, Australia; Discipline of Paediatrics & Child Health, University of Sydney, Australia.
Swetlana Schmidt
Affiliation:
Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, Australia; University of Applied Sciences, Mannheim, Germany.
Ingrid E. Scheffer
Affiliation:
Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia.
Alexandra Fischer
Affiliation:
Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia.
Simone C. Yendle
Affiliation:
Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia.
Thierry Bienvenu
Affiliation:
Université Paris Descartes, Institut Cochin, CNRS (UMR8104), Inserm, U567, Paris, France.
Juliette Nectoux
Affiliation:
Université Paris Descartes, Institut Cochin, CNRS (UMR8104), Inserm, U567, Paris, France.
Carolyn J. Ellaway
Affiliation:
Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, Australia; Discipline of Paediatrics & Child Health, University of Sydney, Australia.
Artur Darmanian
Affiliation:
Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, Australia.
XingZhang Tong
Affiliation:
Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, Australia.
Desiree Cloosterman
Affiliation:
Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, Australia.
Bruce Bennetts
Affiliation:
Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, Australia; Discipline of Paediatrics & Child Health, University of Sydney, Australia.
Veena Kalra
Affiliation:
Department of Pediatrics, All-India Institute of Medical Sciences, New Delhi, India.
Tod Fullston
Affiliation:
Department of Genetic Medicine, Women's and Children's Hospital, Adelaide, Australia; Department of Paediatrics, University of Adelaide, Adelaide, Australia.
Jozef Gecz
Affiliation:
Department of Genetic Medicine, Women's and Children's Hospital, Adelaide, Australia; Department of Paediatrics, University of Adelaide, Adelaide, Australia.
Timothy C. Cox
Affiliation:
Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA.
John Christodoulou*
Affiliation:
Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, Australia; Discipline of Paediatrics & Child Health, University of Sydney, Australia. [email protected]
*
*Address for correspondence: Professor John Christodoulou, Western Sydney Genetics Program, Children's Hospital at Westmead, Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia.

Abstract

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Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting females almost exclusively and is characterized by a wide spectrum of clinical manifestations. Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene have been found in up to 95% of classical RTT cases and a lesser proportion of atypical cases. Recently, mutations in another X-linked gene, CDKL5 (cyclin-dependent kinase-like 5) have been found to cause atypical RTT, in particular the early onset seizure (Hanefeld variant) and one female with autism. In this study we screened several cohorts of children for CDKL5 mutations, totaling 316 patients, including individuals with a clinical diagnosis of RTT but who were negative for MECP2 mutations (n = 102), males with X-linked mental retardation (n = 9), patients with West syndrome (n = 52), patients with autism (n = 59), patients with epileptic encephalopathy (n = 33), patients with Aicardi syndrome (n = 7) and other patients with intellectual disability with or without seizures (n = 54). In all, seven polymorphic variations and four de novo mutations (c.586C>T [p.S196L]; c.58G>C [p.G20R]; c.2504delC [p.P835fs]; deletion of exons 1 - 3) were identified, and in all instances of the latter the clinical phenotype was that of an epileptic encephalopathy. These results suggest that pathogenic CDKL5 mutations are unlikely to be identified in the absence of severe early-onset seizures and highlight the importance of screening for large intragenic and whole gene deletions.

Keywords

CDKL5Rett syndromeinfantile spasmsepileptic encephalopathyintellectual disabilitymutation
Type
Articles
Information
Twin Research and Human Genetics , Volume 13 , Issue 2 , 01 April 2010 , pp. 168 - 178
Copyright
Copyright © Cambridge University Press 2010