De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

Katherine L Helbig, Robert J Lauerer, Jacqueline C Bahr, Ivana A Souza, Candace T Myers, Betül Uysal, Niklas Schwarz, Maria A Gandini, Sun Huang, Boris Keren, Cyril Mignot, Alexandra Afenjar, Thierry Billette de Villemeur, Delphine Héron, Caroline Nava, Stéphanie Valence, Julien Buratti, Christina R Fagerberg, Kristina P Soerensen, Maria KibaekErik-Jan Kamsteeg, David A Koolen, Boudewijn Gunning, H Jurgen Schelhaas, Michael C Kruer, Jordana Fox, Somayeh Bakhtiari, Randa Jarrar, Sergio Padilla-Lopez, Kristin Lindstrom, Sheng Chih Jin, Xue Zeng, Kaya Bilguvar, Antigone Papavasileiou, Qinghe Xin, Changlian Zhu, Katja Boysen, Filippo Vairo, Brendan C Lanpher, Eric W Klee, Jan-Mendelt Tillema, Eric T Payne, Margot A Cousin, Teresa M Kruisselbrink, Myra J Wick, Joshua Baker, Eric Haan, Nicholas Smith, Mark A Corbett, Jozef Gecz, Deciphering Developmental Disorders Study

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Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

Original languageEnglish
Pages (from-to)666-678
Number of pages13
JournalAmerican Journal of Human Genetics
Issue number5
Publication statusPublished - 1 Nov 2018


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