To assess the consequences of patient-specific CDKL5 variants in the pathophysiology of CDD and to obtain a model that could potentially be suitable for gene therapy testing, we generated a Cdkl5E364X KI mouse model humanized for the presence of a nonsense mutation described in a patient [23] (Supplementary Fig. S1A). Here, CDKL5 is linked to craniodiaphyseal dysplasia.