Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications

Abstract

Point mutations and genomic deletions of the CDKL5 (STK9) gene on chromosome Xp22 have been reported in patients with severe neurodevelopmental abnormalities, including Rett-like disorders. To date, only larger-sized (8-21 Mb) duplications harboring CDKL5 have been described. We report seven females and four males from seven unrelated families with CDKL5 duplications 540-935 kb in size. Three families of different ethnicities had identical 667 kb duplications containing only the shorter CDKL5 isoform. Four affected boys, 8-14 years of age, and three affected girls, 6-8 years of age, manifested autistic behavior, developmental delay, language impairment, and hyperactivity. Of note, two boys and one girl had macrocephaly. Two carrier mothers of the affected boys reported a history of problems with learning and mathematics while at school. None of the patients had epilepsy. Similarly to CDKL5 mutations and deletions, the X-inactivation pattern in all six studied females was random. We hypothesize that the increased dosage of CDKL5 might have affected interactions of this kinase with its substrates, leading to perturbation of synaptic plasticity and learning, and resulting in autistic behavior, developmental and speech delay, hyperactivity, and macrocephaly.

Genetic Counselling Pitfall: Co-Occurrence of an 11.8-Mb Xp22 Duplication and an Xp21.2 Duplication Disrupting IL1RAPL1

“…Considering the 59 genes duplicated, it is difficult to obtain a precise genotype/phenotype correlation for each phenotypic trait as it has already been the case in similar findings of large Xp functional disomies [Lintas et al, 2016]. However, among others, we could note the presence of a single CDKL5 gene, while CDKL5 duplications have already been reported as being responsible for autistic behaviour and development and speech delay in both males and females in case of random X-chromosme inactivation [Szafranski et al, 2015]. We observed complete skewed X-chromosome inactivation in both female carriers of this duplication (patients I.1 and II.1).…”

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

“…Mutations of CDKL5 have been associated with several X-linked neurodevelopmental disorders, as well as ASD (Weaving et al, 2004; Scala et al, 2005; Archer et al, 2006; Russo et al, 2009; Sprovieri et al, 2009; Schaaf et al, 2011; Bahi-Buisson and Bienvenu, 2012; Bartnik et al, 2012; Maortua et al, 2012; Carvill et al, 2013; Epi et al, 2013; Piton et al, 2013; Zhao et al, 2014; Codina-Sola et al, 2015; Szafranski et al, 2015). Expression of CDKL5 is enriched in the brain and increases gradually following development (Lin et al, 2005; Rusconi et al, 2008).…”

Synaptic Synthesis, Dephosphorylation, and Degradation

“…This suggests that CDKL5 levels need to be tightly regulated and that both gain and loss of functions might be detrimental for proper brain development. Accordingly, duplications in CDKL5 have very recently been identified in patients with neurologic deficits (22). The developmental regulation of the response of CDKL5 to neuronal activation is further supported by the fact that the KCl-mediated depolarization induces the dephosphorylation of CDKL5 only beyond a certain developmental stage.…”