title: Cyclin-dependent kinase-like 5 (CDKL5) mutation screening in Rett syndrome and related disorders.
abstract: 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.
authors.affiliation: Western Sydney Genetics Program, Children's Hospital at Westmead, and Discipline of Paediatrics & Child Health, University of Sydney, Australia.
authors.forename: Rose
authors.initials: R
authors.lastname: White
authors.forename: Gladys
authors.initials: G
authors.lastname: Ho
authors.forename: Swetlana
authors.initials: S
authors.lastname: Schmidt
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.forename: Alexandra
authors.initials: A
authors.lastname: Fischer
authors.forename: Simone C
authors.initials: SC
authors.lastname: Yendle
authors.forename: Thierry
authors.initials: T
authors.lastname: Bienvenu
authors.forename: Juliette
authors.initials: J
authors.lastname: Nectoux
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Ellaway
authors.forename: Artur
authors.initials: A
authors.lastname: Darmanian
authors.forename: XingZhang
authors.initials: X
authors.lastname: Tong
authors.forename: Desiree
authors.initials: D
authors.lastname: Cloosterman
authors.forename: Bruce
authors.initials: B
authors.lastname: Bennetts
authors.forename: Veena
authors.initials: V
authors.lastname: Kalra
authors.forename: Tod
authors.initials: T
authors.lastname: Fullston
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Cox
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
mesh_terms: D000595:Amino Acid Sequence; D003072:Cognition Disorders / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D015331:Cohort Studies; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D015518:Rett Syndrome / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics*; D012640:Seizures / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*
chemical_list: D051360:Cyclin-Dependent Kinase 5