Expanding the phenotype of the CDKL5 deficiency disorder: Are seizures mandatory?

Conor I. MacKay, David Bick, Jeremy W. Prokop, Ivan Muñoz, John Rouse, Jenny Downs, Helen Leonard (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


Pathogenic variants in the cyclin-dependent kinase-like 5 (CDKL5) gene cause the neurodevelopmental disorder, the CDKL5 deficiency disorder. Reports of individuals with pathogenic variants in CDKL5 without seizures are exceedingly rare, and in-depth analyses of their variants have been lacking. Whole-genome sequencing was performed on a 29-year-old female with mild intellectual disability who, in the absence of overt seizures, presented with multiple episodes of altered mental status over a 24-year period. Clinical history was supplemented by a parent completed questionnaire from the International CDKL5 Disorder Database. We identified a de novo heterozygous variant in CDKL5 (NM_003159.2:c.645T>A;p.Ser215Arg). In-depth computational analysis performed to predict the impact of the variant on protein structure and function demonstrated that the variant was likely pathogenic. In this light, cell-based studies showed that the S215R substitution causes a marked reduction in CDKL5 kinase activity. Similarities between our case and one previously reported case are striking. These cases, both without seizures but with apparent behavioral symptomatology, together question whether seizures are mandatory in this neurodevelopmental disorder.

Original languageEnglish
Pages (from-to)1217-1222
Number of pages6
JournalAmerican Journal of Medical Genetics Part A
Issue number5
Early online date8 Feb 2020
Publication statusPublished - 17 Apr 2020


  • CDKL5
  • epilepsy
  • genotype
  • neurodevelopment
  • phenotype

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


Dive into the research topics of 'Expanding the phenotype of the CDKL5 deficiency disorder: Are seizures mandatory?'. Together they form a unique fingerprint.

Cite this