Cyclin-dependent kinase-like 5 (CDKL5) mutation screening in Rett syndrome and related disorders

Rose White, Gladys Ho, Swetlana Schmidt, Ingrid E Scheffer, Alexandra Fischer, Simone C Yendle, Thierry Bienvenu, Juliette Nectoux, Carolyn J Ellaway, Artur Darmanian, XingZhang Tong, Desiree Cloosterman, Bruce Bennetts, Veena Kalra, Tod Fullston, Jozef Gecz, Timothy Chilton Cox, John Christodoulou

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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.
Original languageEnglish
Pages (from-to)168 - 178
Number of pages11
JournalTwin Research and Human Genetics
Issue number2
Publication statusPublished - 2010

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