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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.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13229-021-00473-3.

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