De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias
Katherine Helbig
(1)
,
Robert Lauerer
(2)
,
Jacqueline Bahr
(2)
,
Ivana Souza
(3)
,
Candace Myers
(4)
,
Betül Uysal
(2)
,
Niklas Schwarz
(2)
,
Maria Gandini
(3)
,
Sun Huang
(3)
,
Boris Keren
(5)
,
Cyril Mignot
(5, 6)
,
Alexandra Afenjar
(7)
,
Thierry Billette de Villemeur
(7, 8, 9)
,
Delphine Héron
(10, 6)
,
Caroline Nava
(6, 10)
,
Stéphanie Valence
(10)
,
Julien Buratti
(10)
,
Christina Fagerberg
(11)
,
Kristina Soerensen
(11)
,
Maria Kibaek
(11)
,
Erik-Jan Kamsteeg
(12)
,
David Koolen
(12)
,
Boudewijn Gunning
(13)
,
H Jurgen Schelhaas
(14)
,
Michael Kruer
(15)
,
Jordana Fox
(15)
,
Somayeh Bakhtiari
(15)
,
Randa Jarrar
(15)
,
Sergio Padilla-Lopez
(15)
,
Kristin Lindstrom
,
Sheng Chih Jin
,
Xue Zeng
,
Kaya Bilguvar
,
Antigone Papavasileiou
,
Qinghe Xing
,
Changlian Zhu
,
Katja Boysen
,
Filippo Vairo
,
Brendan Lanpher
,
Eric Klee
,
Jan-Mendelt Tillema
,
Eric Payne
,
Margot Cousin
,
Teresa Kruisselbrink
,
Myra Wick
,
Joshua Baker
,
Eric Haan
,
Nicholas Smith
,
Azita Sadeghpour
,
Azita Sadeghpour
,
Erica Davis
,
Erica Davis
,
Nicholas Katsanis
,
Nicholas Katsanis
,
Mark Corbett
,
Alastair Maclennan
,
Jozef Gecz
,
Saskia Biskup
,
Eva Goldmann
,
Lance Rodan
,
Elizabeth Kichula
,
Eric Segal
,
Kelly Jackson
,
Alexander Asamoah
,
David Dimmock
,
Julie Mccarrier
,
Lorenzo Botto
,
Francis Filloux
,
Tatiana Tvrdik
,
Gregory Cascino
,
Sherry Klingerman
,
Catherine Neumann
,
Raymond Wang
,
Jessie Jacobsen
,
Melinda Nolan
,
Russell Snell
,
Klaus Lehnert
,
Lynette Sadleir
,
Britt-Marie Anderlid
,
Malin Kvarnung
,
Renzo Guerrini
,
Michael Friez
,
Michael Lyons
,
Jennifer Leonhard
,
Gabriel Kringlen
,
Kari Casas
,
Christelle El Achkar
,
Lacey Smith
,
Alexander Rotenberg
,
Annapurna Poduri
,
Alba Sanchis-Juan
,
Keren Carss
,
Julia Rankin
,
Adam Zeman
,
F Lucy Raymond
,
Moira Blyth
,
Bronwyn Kerr
,
Karla Ruiz
,
Jill Urquhart
,
Imelda Hughes
,
Siddharth Banka
,
Ulrike Hedrich
,
Ingrid Scheffer
,
Ingo Helbig
,
Gerald Zamponi
,
Holger Lerche
,
Heather Mefford
,
Alexander Allori
,
Misha Angrist
,
Patricia Ashley
,
Margarita Bidegain
,
Brita Boyd
,
Eileen Chambers
,
Heidi Cope
,
C. Michael Cotten
,
Theresa Curington
,
Sarah Ellestad
,
Kimberley Fisher
,
Amanda French
,
William Gallentine
,
Ronald Goldberg
,
Kevin Hill
,
Sujay Kansagra
,
Sara Katsanis
,
Joanne Kurtzberg
,
Jeffrey Marcus
,
Marie Mcdonald
,
Mohammed Mikati
,
Stephen Miller
,
Amy Murtha
,
Yezmin Perilla
,
Carolyn Pizoli
,
Todd Purves
,
Sherry Ross
,
Edward Smith
,
John Wiener
1
CHOP -
Children’s Hospital of Philadelphia
2 Hertie Institute for Clinical Brain Research [Tubingen]
3 University of Calgary
4 University of Washington [Seattle]
5 GRC 9 - Groupe de Recherche Clinique : Génétique des Déficiences Intellectuelles de Causes Rares (associées ou non aux Troubles du Spectre Autistique)
6 ICM - Institut du Cerveau = Paris Brain Institute
7 GRC 19 ConCer-LD - Pathologies Congénitales du Cervelet-LeucoDystrophies
8 CHU Trousseau [APHP]
9 NeuroDiderot (UMR_S_1141 / U1141) - Maladies neurodéveloppementales et neurovasculaires
10 GRC 9 - Groupe de Recherche Clinique : Génétique des Déficiences Intellectuelles de Causes Rares (associées ou non aux Troubles du Spectre Autistique)
11 OUH - Odense University Hospital
12 Radboud University Medical Center [Nijmegen]
13 SEIN - Stichting Epilepsie Instellingen Nederland
14 Academic Center for Epileptology Kempenhaeghe & Maastricht UMC+ [Heeze]
15 University of Arizona
2 Hertie Institute for Clinical Brain Research [Tubingen]
3 University of Calgary
4 University of Washington [Seattle]
5 GRC 9 - Groupe de Recherche Clinique : Génétique des Déficiences Intellectuelles de Causes Rares (associées ou non aux Troubles du Spectre Autistique)
6 ICM - Institut du Cerveau = Paris Brain Institute
7 GRC 19 ConCer-LD - Pathologies Congénitales du Cervelet-LeucoDystrophies
8 CHU Trousseau [APHP]
9 NeuroDiderot (UMR_S_1141 / U1141) - Maladies neurodéveloppementales et neurovasculaires
10 GRC 9 - Groupe de Recherche Clinique : Génétique des Déficiences Intellectuelles de Causes Rares (associées ou non aux Troubles du Spectre Autistique)
11 OUH - Odense University Hospital
12 Radboud University Medical Center [Nijmegen]
13 SEIN - Stichting Epilepsie Instellingen Nederland
14 Academic Center for Epileptology Kempenhaeghe & Maastricht UMC+ [Heeze]
15 University of Arizona
Kristin Lindstrom
- Function : Author
Sheng Chih Jin
- Function : Author
Xue Zeng
- Function : Author
Kaya Bilguvar
- Function : Author
Antigone Papavasileiou
- Function : Author
Qinghe Xing
- Function : Author
Changlian Zhu
- Function : Author
Katja Boysen
- Function : Author
Filippo Vairo
- Function : Author
Brendan Lanpher
- Function : Author
Eric Klee
- Function : Author
Jan-Mendelt Tillema
- Function : Author
Eric Payne
- Function : Author
Margot Cousin
- Function : Author
Teresa Kruisselbrink
- Function : Author
Myra Wick
- Function : Author
Joshua Baker
- Function : Author
Eric Haan
- Function : Author
Nicholas Smith
- Function : Author
Azita Sadeghpour
- Function : Author
Azita Sadeghpour
- Function : Author
Erica Davis
- Function : Author
Erica Davis
- Function : Author
Nicholas Katsanis
- Function : Author
Nicholas Katsanis
- Function : Author
Mark Corbett
- Function : Author
Alastair Maclennan
- Function : Author
Jozef Gecz
- Function : Author
Saskia Biskup
- Function : Author
Eva Goldmann
- Function : Author
Lance Rodan
- Function : Author
Elizabeth Kichula
- Function : Author
Eric Segal
- Function : Author
Kelly Jackson
- Function : Author
Alexander Asamoah
- Function : Author
David Dimmock
- Function : Author
Julie Mccarrier
- Function : Author
Lorenzo Botto
- Function : Author
Francis Filloux
- Function : Author
Tatiana Tvrdik
- Function : Author
Gregory Cascino
- Function : Author
Sherry Klingerman
- Function : Author
Catherine Neumann
- Function : Author
Raymond Wang
- Function : Author
Jessie Jacobsen
- Function : Author
Melinda Nolan
- Function : Author
Russell Snell
- Function : Author
Klaus Lehnert
- Function : Author
Lynette Sadleir
- Function : Author
Britt-Marie Anderlid
- Function : Author
Malin Kvarnung
- Function : Author
Renzo Guerrini
- Function : Author
Michael Friez
- Function : Author
Michael Lyons
- Function : Author
Jennifer Leonhard
- Function : Author
Gabriel Kringlen
- Function : Author
Kari Casas
- Function : Author
Christelle El Achkar
- Function : Author
Lacey Smith
- Function : Author
Alexander Rotenberg
- Function : Author
Annapurna Poduri
- Function : Author
Alba Sanchis-Juan
- Function : Author
Keren Carss
- Function : Author
Julia Rankin
- Function : Author
Adam Zeman
- Function : Author
F Lucy Raymond
- Function : Author
Moira Blyth
- Function : Author
Bronwyn Kerr
- Function : Author
Karla Ruiz
- Function : Author
Jill Urquhart
- Function : Author
Imelda Hughes
- Function : Author
Siddharth Banka
- Function : Author
Ulrike Hedrich
- Function : Author
Ingrid Scheffer
- Function : Author
Ingo Helbig
- Function : Author
Gerald Zamponi
- Function : Author
Holger Lerche
- Function : Author
Heather Mefford
- Function : Author
Alexander Allori
- Function : Author
Misha Angrist
- Function : Author
Patricia Ashley
- Function : Author
Margarita Bidegain
- Function : Author
Brita Boyd
- Function : Author
Eileen Chambers
- Function : Author
Heidi Cope
- Function : Author
C. Michael Cotten
- Function : Author
Theresa Curington
- Function : Author
Sarah Ellestad
- Function : Author
Kimberley Fisher
- Function : Author
Amanda French
- Function : Author
William Gallentine
- Function : Author
Ronald Goldberg
- Function : Author
Kevin Hill
- Function : Author
Sujay Kansagra
- Function : Author
Sara Katsanis
- Function : Author
Joanne Kurtzberg
- Function : Author
Jeffrey Marcus
- Function : Author
Marie Mcdonald
- Function : Author
Mohammed Mikati
- Function : Author
Stephen Miller
- Function : Author
Amy Murtha
- Function : Author
Yezmin Perilla
- Function : Author
Carolyn Pizoli
- Function : Author
Todd Purves
- Function : Author
Sherry Ross
- Function : Author
Edward Smith
- Function : Author
John Wiener
- Function : Author
Abstract
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.