Mutations in the C-terminus of CDKL5: proceed with caution

Diebold, Bertrand; Delépine, Chloé; Gataullina, Svetlana; Delahaye, Andrée; Nectoux, Juliette; Bienvenu, Thierry

doi:10.1038/ejhg.2013.133

Cited by 13 publications

(15 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 2 , 12 , 18 A recent analysis of missense variants in these exons concluded that genetic variation in this C-terminus was likely to have little or no significance to a CDKL5 disorder phenotype. 37 We find further evidence of this in our study. Furthermore, the identification of nonsense variants in these exons in the population is an important observation, consistent with a previous study in which patients with a 136-kb deletion lost only these 3′ CDKL5 exons and the overlapping RS1 gene.…”

Section: Discussionsupporting

confidence: 75%

CDKL5 variants

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 75%

CDKL5 variants

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Furthermore, it becomes clear that mutations in CDKL5 exons 19-21 are unlikely pathogenic, because the isoform of CDKL5 that predominantly expresses in the brain does not include exons 20-21 (Hector et al, 2016). Consistently, mutations in these regions have been identified in both patients, healthy siblings or parents, arguing against the clinical relevance of exons 19-21 (Diebold et al, 2014). …”

Section: Genetic Studiesmentioning

confidence: 84%

Molecular and genetic insights into an infantile epileptic encephalopathy – CDKL5 disorder

2017

View full text Add to dashboard Cite

Background The discovery that mutations in cyclin-dependent kinase-like 5 (CDKL5) gene are associated with infantile epileptic encephalopathy has stimulated world-wide research effort to understand the molecular and genetic basis of CDKL5 disorder. Given the large number of literature published thus far, this review aims to summarize current genetic studies, draw a consensus on proposed molecular functions, and point to gaps of knowledge in CDKL5 research. Methods A systematic review process was conducted using the PubMed search engine focusing on CDKL5 studies in the recent ten years. We analyzed these publications and summarized the findings into four sections: genetic studies, CDKL5 expression patterns, molecular functions, and animal models. We also discussed challenges and future directions in each section. Results On the clinical side, CDKL5 disorder is characterized by early onset epileptic seizures, intellectual disability, and stereotypical behaviors. On the research side, a series of molecular and genetic studies in human patients, cell cultures and animal models have established the causality of CDKL5 to the infantile epileptic encephalopathy, and pointed to a key role for CDKL5 in regulating neuronal function in the brain. Mouse models of CDKL5 disorder have also been developed, and notably, manifest behavioral phenotypes, mimicking numerous clinical symptoms of CDKL5 disorder and advancing CDKL5 research to the preclinical stage. Conclusions Given what we have learned thus far, future identification of robust, quantitative, and sensitive outcome measures would be the key in animal model studies, particularly in heterozygous females. In the meantime, molecular and cellular studies of CDKL5 should focus on mechanism-based investigation and aim to uncover druggable targets that offer the potential to rescue or ameliorate CDKL5 disorder-related phenotypes.

show abstract

“…In terms of a milder phenotype, Archer et al [] described a young woman who could walk and swim independently, feed herself using cutlery, and speak in phrases. More recently, a Spanish study reported on eight females of whom three learned to walk, four had some hand use, and two could speak using phrases [Martínez et al, ], but the pathogenicity of variants affecting two of these cases has not been confirmed [Ho et al, ; Diebold et al, ]. Reports of males with the CDKL5 disorder are rare, but in the largest previous study (n = 8) all boys had markedly impaired gross motor and communication skills [Mirzaa et al, ].…”

Section: Discussionmentioning

confidence: 99%

Functional abilities in children and adults with the CDKL5 disorder

Fehr

Downs

et al. 2016

American J of Med Genetics Pt A

103

View full text Add to dashboard Cite

Functional abilities in the CDKL5 disorder have been described as severely impaired, yet some individuals are able to run and use phrases for speech. Our study investigated gross motor, hand function, and expressive communication abilities in individuals with the CDKL5 disorder. Data for 108 females and 16 males registered with the International CDKL5 disorder database and with a pathogenic CDKL5 mutation were analyzed. Relationships between functional abilities, age, genotype, and gender were analyzed using regression models. Over half of the females could sit on the floor and nearly a quarter could walk 10 steps. Fewer males could complete these tasks although one boy was able to sit, walk, and run. Most females and few males were able to pick up a large object. Females mostly used gestures to communicate while males mostly used other forms of non-verbal communication. Compared to those with no functional CDKL5 protein, individuals with truncating variants after aa 781 were more likely to be able to stand (OR 5.7, 95%CI 1.2, 26.6) or walk independently (4.3, 95%CI 0.9, 20.5), and use more advanced communication methods such as words (OR 6.1, 95%CI 1.5-24.2). Although abilities were markedly impaired for the majority with the CDKL5 disorder, some females and a few males had better functional abilities. This variability may be related to underlying gene variants, with females with a late truncating variant having better levels of ability than those with no functional protein. © 2016 Wiley Periodicals, Inc.

show abstract

Mutations in the C-terminus of CDKL5: proceed with caution

Cited by 13 publications

References 14 publications

CDKL5 variants

CDKL5 variants

Molecular and genetic insights into an infantile epileptic encephalopathy – CDKL5 disorder

Functional abilities in children and adults with the CDKL5 disorder

Contact Info

Product

Resources

About