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

• Published in: Twin research and human genetics Vol. 13; no. 2; pp. 168 - 178
• Main Authors: White, Rose, Ho, Gladys, Schmidt, Swetlana, Scheffer, Ingrid E., Fischer, Alexandra, Yendle, Simone C., Bienvenu, Thierry, Nectoux, Juliette, Ellaway, Carolyn J., Darmanian, Artur, Tong, XingZhang, Cloosterman, Desiree, Bennetts, Bruce, Kalra, Veena, Fullston, Tod, Gecz, Jozef, Cox, Timothy C., Christodoulou, John
• Format: Journal Article
• Language: English
• Published: Cambridge, UK Cambridge University Press 01.04.2010
• Subjects: Age; Amino Acid Sequence; Autism; CDKL5; Cognition Disorders - diagnosis; Cognition Disorders - enzymology; Cognition Disorders - genetics; Cohort Studies; Convulsions & seizures; Cyclin-dependent kinase; Cyclin-Dependent Kinase 5 - genetics; Cyclin-Dependent Kinase 5 - metabolism; Cyclin-dependent kinases; Diseases; Encephalopathy; Epilepsy; epileptic encephalopathy; Exons; Female; Genetic aspects; Genetic Testing; Humans; infantile spasms; Intellectual disabilities; intellectual disability; Male; MeCP2 protein; Mental illness; Methyl-CpG binding protein; Molecular Sequence Data; Mutation; Nervous system; Neurodevelopmental disorders; Phenotypes; Protein kinases; Rett syndrome; Rett Syndrome - diagnosis; Rett Syndrome - enzymology; Rett Syndrome - genetics; Seizures; Seizures - diagnosis; Seizures - enzymology; Seizures - genetics; mutation; CDKL5; infantile spasms; epileptic encephalopathy; intellectual disability; Rett syndrome
• ISSN: 1832-4274; 1839-2628
• DOI: 10.1375/twin.13.2.168

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.