CDKL5 variants

Abstract

Objective:To provide new insights into the interpretation of genetic variants in a rare neurologic disorder, CDKL5 deficiency, in the contexts of population sequencing data and an updated characterization of the CDKL5 gene.Methods:We analyzed all known potentially pathogenic CDKL5 variants by combining data from large-scale population sequencing studies with CDKL5 variants from new and all available clinical cohorts and combined this with computational methods to predict pathogenicity.Results:The study has identified several variants that can be reclassified as benign or likely benign. With the addition of novel CDKL5 variants, we confirm that pathogenic missense variants cluster in the catalytic domain of CDKL5 and reclassify a purported missense variant as having a splicing consequence. We provide further evidence that missense variants in the final 3 exons are likely to be benign and not important to disease pathology. We also describe benign splicing and nonsense variants within these exons, suggesting that isoform hCDKL5_5 is likely to have little or no neurologic significance. We also use the available data to make a preliminary estimate of minimum incidence of CDKL5 deficiency.Conclusions:These findings have implications for genetic diagnosis, providing evidence for the reclassification of specific variants previously thought to result in CDKL5 deficiency. Together, these analyses support the view that the predominant brain isoform in humans (hCDKL5_1) is crucial for normal neurodevelopment and that the catalytic domain is the primary functional domain.

Microtubules: A Key to Understand and Correct Neuronal Defects in CDKL5 Deficiency Disorder?

“…This reflects well the current view that CDD is caused by the absence of functional CDKL5 or by the expression of hypomorphic derivatives. Indeed, CDD-causing mutations in CDKL5 include missense mutations, nonsense, frame-shift and splicing variants, and large genomic deletions [84]. The pathogenic missense mutations, which have been identified so far, fall almost exclusively within the catalytic domain of the protein.…”

“…Although these studies have highlighted the impact of missense mutations on CDKL5 functioning, it needs to be underlined that only very few of these mutations have been studied; we therefore cannot exclude that other missense mutations may generate hypermorphic CDKL5 derivatives. Regarding the nonsense and frame-shift variants, nonsense-mediated decay of the mutated mRNA is likely to impede the expression of the encoded protein, thus acting as hypomorphic or null mutations [84,88,89].…”

Altered NMDAR signaling underlies autistic-like features in mouse models of CDKL5 deficiency disorder

“…Therefore, our studies reveal a novel avenue toward treating specific CDD-related symptoms, but also suggest that modulation of E / I balance in CDD may be a double-edged sword. To date, the majority of reported CDD patients have been predicted to carry loss-of-function mutations, such as nonsense, indels, or missense mutations abolishing CDKL5 kinase activity 39 , suggesting that our knockout and R59X knockin mouse models may carry a high translational relevance. In order to develop targeted therapies for CDD, additional studies are needed to elucidate the specific signaling pathways and neural circuits responsible for each of the behavioral symptoms.…”

In Silico Study of Rett Syndrome Treatment-Related Genes, MECP2, CDKL5, and FOXG1, by Evolutionary Classification and Disordered Region Assessment

“…Further, diagnosis may be challenging as many of the clinical features overlap with those of other neurological and neurodevelopmental disorders, and mutation in MECP2 , FOXG1 , and CDKL5 can also cause neurodevelopmental disorders distinct from RTT [10]. As a result, subsequent studies have suggested that alterations in either CDKL5 or FOXG1 should be classified as a distinct disorder from RTT as the majority of cases showed some differences in clinical features [11,12,13] Moreover, recent studies have suggested that RTT is a monogenic disorder caused by mutations that alter the functionality of the methyl-CpG-binding domain (MBD) and the NCoR/SMRT interaction domain (NID) in MECP2 [14,15,16]. This may simplify the complication of developing a treatment strategy.…”