Wide range of phenotypic severity in individuals with late truncations unique to the predominant CDKL5 transcript in the brain

Am J Med Genet A. 2022 Dec;188(12):3516-3524. doi: 10.1002/ajmg.a.62940. Epub 2022 Aug 7.


Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is caused by heterozygous or hemizygous variants in CDKL5 and is characterized by refractory epilepsy, cognitive and motor impairments, and cerebral visual impairment. CDKL5 has multiple transcripts, of which the longest transcripts, NM_003159 and NM_001037343, have been used historically in clinical laboratory testing. However, the transcript NM_001323289 is the most highly expressed in brain and contains 170 nucleotides at the 3' end of its last exon that are noncoding in other transcripts. Two truncating variants in this region have been reported in association with a CDD phenotype. To clarify the significance and range of phenotypes associated with late truncating variants in this region of the predominant transcript in the brain, we report detailed information on two individuals, updated clinical information on a third individual, and a summary of published and unpublished individuals reported in ClinVar. The two new individuals (one male and one female) each had a relatively mild clinical presentation including periods of pharmaco-responsive epilepsy, independent walking and limited purposeful communication skills. A previously reported male continued to have a severe phenotype. Overall, variants in this region demonstrate a range of clinical severity consistent with reports in CDD but with the potential for milder presentation.

Keywords: CDKL5; alternative transcript; epileptic encephalopathy; phenotypic spectrum; transcripts; whole genome sequencing.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Brain
  • Epileptic Syndromes* / genetics
  • Female
  • Humans
  • Male
  • Phenotype
  • Protein Serine-Threonine Kinases / genetics
  • Spasms, Infantile* / complications
  • Spasms, Infantile* / diagnosis
  • Spasms, Infantile* / genetics


  • CDKL5 protein, human
  • Protein Serine-Threonine Kinases

Supplementary concepts

  • CDKL5 deficiency disorder