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

November 1, 2018

Helbig KL1, Lauerer RJ2, Bahr JC2, Souza IA3, Myers CT4, Uysal B2, Schwarz N2, Gandini MA3, Huang S3, Keren B5, Mignot C5, Afenjar A6, Billette de Villemeur T7, Héron D5, Nava C5, Valence S5, Buratti J5, Fagerberg CR8, Soerensen KP9, Kibaek M9, Kamsteeg EJ10, Koolen DA10, Gunning B11, Schelhaas HJ12, Kruer MC13, Fox J13, Bakhtiari S13, Jarrar R13, Padilla-Lopez S13, Lindstrom K14, Jin SC15, Zeng X15, Bilguvar K15, Papavasileiou A16, Xin Q17, Zhu C18, Boysen K19, Vairo F20, Lanpher BC20, Klee EW20, Tillema JM20, Payne ET21, Cousin MA22, Kruisselbrink TM23, Wick MJ23, Baker J24, Haan E25, Smith N26, Corbett MA27, MacLennan AH27, Gecz J27, Biskup S28, Goldmann E29, Rodan LH30, Kichula E1, Segal E31, Jackson KE32, Asamoah A32, Dimmock D33, McCarrier J33, Botto LD34, Filloux F35, Tvrdik T36, Cascino GD21, Klingerman S21, Neumann C37, Wang R38, Jacobsen JC39, Nolan MA40, Snell RG39, Lehnert K39, Sadleir LG41, Anderlid BM42, Kvarnung M43, Guerrini R44, Friez MJ45, Lyons MJ45, Leonhard J46, Kringlen G47, Casas K47, El Achkar CM48, Smith LA49, Rotenberg A50, Poduri A48, Sanchis-Juan A51, Carss KJ51, Rankin J52, Zeman A53, Raymond FL54, Blyth M55, Kerr B56, Ruiz K57, Urquhart J58, Hughes I57, Banka S56; Deciphering Developmental Disorders Study59, Hedrich UBS2, Scheffer IE60, Helbig I61, Zamponi GW3, Lerche H2, Mefford HC62.


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.