De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures

Abstract

Background De novo variants in the voltage-gated calcium channel subunit α1 E gene (CACNA1E) have been described as causative of epileptic encephalopathy with contractures, macrocephaly and dyskinesias. Methods Following the observation of an index patient with developmental delay and autism spectrum disorder (ASD) without seizures who had a de novo deleterious CACNA1E variant, we screened GeneMatcher for other individuals with CACNA1E variants and neurodevelopmental phenotypes without epilepsy. The spectrum of pathogenic CACNA1E variants was compared to the mutational landscape of variants in the gnomAD control population database. Results We identified seven unrelated individuals with intellectual disability, developmental regression and ASD-like behavioral profile, and notably without epilepsy, who had de novo heterozygous putatively pathogenic variants in CACNA1E. Age of onset of clinical manifestation, presence or absence of regression and degree of severity were variable, and no clear-cut genotype–phenotype association could be recognized. The analysis of disease-associated variants and their comparison to benign variants from the control population allowed for the identification of regions in the CACNA1E protein that seem to be intolerant to substitutions and thus more likely to harbor pathogenic variants. As in a few reported cases with CACNA1E variants and epilepsy, one patient showed a positive clinical behavioral response to topiramate, a specific calcium channel modulator. Limitations The significance of our study is limited by the absence of functional experiments of the effect of identified variants, the small sample size and the lack of systematic ASD assessment in all participants. Moreover, topiramate was given to one patient only and for a short period of time. Conclusions Our results indicate that CACNA1E variants may result in neurodevelopmental disorders without epilepsy and expand the mutational and phenotypic spectrum of this gene. CACNA1E deserves to be included in gene panels for non-specific developmental disorders, including ASD, and not limited to patients with seizures, to improve diagnostic recognition and explore the possible efficacy of topiramate.

The Cannabis-Induced Epigenetic Regulation of Genes Associated with Major Depressive Disorder

“…VGCCs are transmembrane proteins activated in response to the depolarization of the cell membrane, and they mediate the flux of calcium ions into excitable cells [ 71 , 72 ]. These genes are highly associated with various mental disorder phenotypes, such as neurodevelopmental disorders, intellectual disability, bipolar disorder, anxiety, and depression [ 73 , 74 ], and there is increasing evidence that CACNA1C expression in the brain directly regulates depression-related behaviors [ 72 ]. Interestingly, the genetic risk variants of mental disorders in CACNA1C act as both mQTLs and eQTLs; therefore, the genotype at these risk SNPs is associated with a variation in DNAm and expression levels of the gene [ 56 , 75 ].…”

Network-Based Data Analysis Reveals Ion Channel-Related Gene Features in COVID-19: A Bioinformatic Approach

“…The CACNA1A gene encodes a subunit of the voltage-dependent P/Q-type calcium channel α-1A (Zhang et al 2020b ), and the CACNA1E gene encodes a subunit of the voltage-dependent R-type calcium channel α-1E (Helbig et al 2018 ). These genes are widely expressed throughout the central nervous system and are strongly associated with epilepsy and intellectual developmental disorders (Hommersom et al 2021 ; Royer-Bertrand et al 2021 ). In addition, CACNA1E is of potential therapeutic value in non-small cell lung cancer (Gao et al 2022 ).…”

Phenotype and genetic analysis of data collected within the first year of NeuroDev

“…To date, case studies on three of the newly identified genes -AGO1, CACNA1C, and CACNA1E -have been published. [25][26][27] NeuroDev participants comprised the only geographic African cases in any of the case series reports, and NeuroDev will be the first African NDD cohort to contribute, at scale, to rare disease discovery activities. As described by the NHGRI Atlas of Human Malformations initiative, syndromic NDDs often vary in their phenotypic presentation between ancestral groups 28 , a phenomenon particularly well documented with regard to canonical facial features.…”

“…To date, case studies on three of these genes -AGO1, CACNA1C, and CACNA1Ehave been published. [28][29][30] These variants may potentially be reclassified after re-evaluation over time.…”