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

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dc.contributor.authorRoyer-Bertrand, Beryl
dc.contributor.authorJequier Gygax, Marine
dc.contributor.authorCisarova, Katarina
dc.contributor.authorRosenfeld, Jill A.
dc.contributor.authorBassetti, Jennifer A.
dc.contributor.authorMoldovan, Oana
dc.contributor.authorO’Heir, Emily
dc.contributor.authorBurrage, Lindsay C.
dc.contributor.authorAllen, Jake
dc.contributor.authorEmrick, Lisa T.
dc.contributor.authorEastman, Emma
dc.contributor.authorKumps, Camille
dc.contributor.authorAbbas, Safdar
dc.contributor.authorVan Winckel, Geraldine
dc.contributor.authorChabane, Nadia
dc.contributor.authorZackai, Elaine H.
dc.contributor.authorLebon, Sebastien
dc.contributor.authorKeena, Beth
dc.contributor.authorBhoj, Elizabeth J.
dc.contributor.authorUmair, Muhammad
dc.contributor.authorLi, Dong
dc.contributor.authorDonald, Kirsten A.
dc.contributor.authorSuperti-Furga, Andrea
dc.date.accessioned2021-11-02T09:51:51Z
dc.date.available2021-11-02T09:51:51Z
dc.date.issued2021-10-26
dc.date.updated2021-10-31T04:18:40Z
dc.description.abstractBackground 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.en_US
dc.identifier.apacitationRoyer-Bertrand, B., Jequier Gygax, M., Cisarova, K., Rosenfeld, Jill A., Bassetti, Jennifer A., Moldovan, O., ... Superti-Furga, A. (2021). De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures. <i>Molecular Autism</i>, 12(Article number: 69), http://hdl.handle.net/11427/35297en_ZA
dc.identifier.chicagocitationRoyer-Bertrand, Beryl, Marine Jequier Gygax, Katarina Cisarova, Jill A. Rosenfeld, Jennifer A. Bassetti, Oana Moldovan, , et al "De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures." <i>Molecular Autism</i> 12, Article number: 69. (2021) http://hdl.handle.net/11427/35297en_ZA
dc.identifier.citationRoyer-Bertrand, B., Jequier Gygax, M., Cisarova, K., Rosenfeld, Jill A., Bassetti, Jennifer A., Moldovan, O., & Burrage, Lindsay C. et al. 2021. De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures. <i>Molecular Autism.</i> 12(Article number: 69) http://hdl.handle.net/11427/35297en_ZA
dc.identifier.ris TY - Journal Article AU - Royer-Bertrand, Beryl AU - Jequier Gygax, Marine AU - Cisarova, Katarina AU - Rosenfeld, Jill A. AU - Bassetti, Jennifer A. AU - Moldovan, Oana AU - O’Heir, Emily AU - Burrage, Lindsay C. AU - Allen, Jake AU - Emrick, Lisa T. AU - Eastman, Emma AU - Kumps, Camille AU - Abbas, Safdar AU - Van Winckel, Geraldine AU - Chabane, Nadia AU - Zackai, Elaine H. AU - Lebon, Sebastien AU - Keena, Beth AU - Bhoj, Elizabeth J. AU - Umair, Muhammad AU - Li, Dong AU - Donald, Kirsten A. AU - Superti-Furga, Andrea AB - 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. DA - 2021-10-26 DB - OpenUCT DP - University of Cape Town IS - Article number: 69 J1 - Molecular Autism KW - Autism spectrum disorder KW - CACNA1E KW - Developmental regression KW - Epilepsy KW - Exome sequencing KW - Global developmental delay KW - Intellectual disability KW - Neurodevelopmental disorders KW - Seizures KW - Topiramate LK - https://open.uct.ac.za PY - 2021 T1 - De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures TI - De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures UR - http://hdl.handle.net/11427/35297 ER - en_ZA
dc.identifier.urihttps://doi.org/10.1186/s13229-021-00473-3
dc.identifier.urihttp://hdl.handle.net/11427/35297
dc.identifier.vancouvercitationRoyer-Bertrand B, Jequier Gygax M, Cisarova K, Rosenfeld Jill A, Bassetti Jennifer A, Moldovan O, et al. De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures. Molecular Autism. 2021;12(Article number: 69) http://hdl.handle.net/11427/35297.en_ZA
dc.language.rfc3066en
dc.publisher.departmentDepartment of Paediatrics and Child Healthen_US
dc.publisher.facultyFaculty of Health Sciencesen_US
dc.rights.holderThe Author(s)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.sourceMolecular Autismen_US
dc.source.journalissueArticle number: 69en_US
dc.source.journalvolume12en_US
dc.source.urihttps://molecularautism.biomedcentral.com/
dc.subjectAutism spectrum disorderen_US
dc.subjectCACNA1Een_US
dc.subjectDevelopmental regressionen_US
dc.subjectEpilepsyen_US
dc.subjectExome sequencingen_US
dc.subjectGlobal developmental delayen_US
dc.subjectIntellectual disabilityen_US
dc.subjectNeurodevelopmental disordersen_US
dc.subjectSeizuresen_US
dc.subjectTopiramateen_US
dc.titleDe novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizuresen_US
dc.typeJournal Articleen_US
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