Submission Details

The CDKL5 gene is associated with CDKL5 disorder, a disorder sometimes referred to as a Rett syndrome variant, but which can be considered a distinct condition. Individuals with CDKL5 disorder lack some of the distinctive clinical features of classical Rett syndrome such as the clear period of regression and the characteristic intense eye-gaze (PMID:21154482). Of note, normal development during the first 6 months of life commonly seen in Rett syndrome is rare in individuals with CDKL5 disorder. Heterozygous truncating as well as missense variants of CDKL5 cause CDKL5 disorder, almost exclusively arising de novo. Two mouse models of CDKL5 disorder have been characterized (Wang 2012, Amendola 2014), which recaputulate many of the autism-associated phenotypes of CDKL5 disorder. Notably, however, neither mouse model exhibited spontaneous seizures, challenging the usefulness of Cdkl5 KO mice in modeling the human phenotype. Most mice studied have also been hemizygous males, while CDKL5 disorder primarily affects heterozygous females. In summary, CDKL5 is definitively associated with CDKL5 disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Approved by the ClinGen Rett/Angelman Expert Panel 4/30/2018.