Mutations in the C-terminus of CDKL5: proceed with caution

Eur J Hum Genet. 2014 Feb;22(2):270-2. doi: 10.1038/ejhg.2013.133. Epub 2013 Jun 12.


Mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene have been described in girls with Rett-like features and early-onset epileptic encephalopathy including infantile spasms. Milder phenotypes have been associated with sequence variations in the 3'-end of the CDKL5 gene. Identification of novel CDKL5 transcripts coding isoforms characterized by an altered C-terminal region strongly questions the eventual pathogenicity of sequence variations located in the 3'-end of the gene. We investigated a group of 30 female patients with a clinically heterogeneous phenotype ranging from nonspecific intellectual disability to a severe neonatal encephalopathy and identified two heterozygous CDKL5 missense mutations, the previously reported p.Val999Met and the novel mutation p.Pro944Thr. However, these mutations have also been detected in their healthy father. Considering our results and all data from the literature, we suggest that genetic variations beyond the codon 938 in human CDKL5115 protein may have minor or no significance. It is probable that screening of exons 19-21 of the CDKL5 gene is not useful in practical molecular diagnosis of atypical Rett syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Molecular Diagnostic Techniques
  • Mutation, Missense
  • Protein-Serine-Threonine Kinases / genetics*
  • Rett Syndrome / genetics


  • Protein-Serine-Threonine Kinases
  • CDKL5 protein, human

Supplementary concepts

  • Rett Syndrome, Atypical