This report concerns a newly described neurodevelopmental disorder associated with de novo variants in the CDKL2 gene. CDKL2 encodes a CDC2-related serine/threonine protein kinase. There is a single orthologous gene in Drosophila, Dmel\Cdkl; the fly gene is the single ortholog of 5 paralogous genes in human.
Loss of Drosophila Cdkl causes a semi-lethal phenotype in pupae, killing 90% of the animals just prior to eclosion. The mutant flies that survive show climbing defects, heat-induced seizures, reduced longevity, and hearing loss. Dmel\Cdkl is expressed primarily in the peripheral nervous system.
Multiple UAS constructs of the human Hsap\CDKL2 gene have been introduced into flies, including wild-type and variants implicated in this disease (see 'Disease-Implicated Variants' table below). Functional complementation (heterologous rescue) is observed: expression of wild-type Hsap\CDKL2 rescues the semi-lethality and other phenotypes of a Cdkl loss-of-function mutation.
The disease-implicated variants of Hsap\CDKL2 characterized in flies do not rescue the semi-lethality of a Cdkl loss-of-function allele; thus these alleles do not appear to retain normal functionality. Over-expression of the disease-implicated variants results in reduced longevity; over-expression of wild-type Hsap\CDKL2 does not affect longevity. These results support the hypothesis that the variants act as dominant negative mutations.
[updated May 2025 by FlyBase; FBrf0222196]
The five individuals assessed presented with overlapping clinical manifestations, including global developmental delay, intellectual disability, childhood-onset epilepsy, dyspraxia, growth abnormality, and speech deficits (Bereshneh et al., 2025; pubmed:40088891).
Heterozygous de novo variants in the CDKL2 gene are implicated (Bereshneh et al., 2025; pubmed:40088891).
CDKL2 encodes a member of a large family of CDC2-related serine/threonine protein kinases. It accumulates primarily in the cytoplasm, with lower levels in the nucleus. [GeneCards, CDKL2; 2025.05.14]
Many to one: 5 human genes to 1 Drosophila gene.
High-scoring ortholog of human CDKL1 and CDKL4; low-scoring ortholog of CDKL2, CDKL5, and CDKL3.
