Damaging de novo missense variants in EEF1A2 lead to a developmental and degenerative epileptic‐dyskinetic encephalopathy
Gemma Carvill
(1)
,
Katherine Helbig
(2)
,
Candace Myers
,
Marcello Scala
(3, 4)
,
Robert Huether
(5)
,
Sara Lewis
(6, 7)
,
Tyler Kruer
(6, 7)
,
Brandon Guida
(6, 7)
,
Somayeh Bakhtiari
(6, 7)
,
Joy Sebe
(8)
,
Sha Tang
(5)
,
Heather Stickney
(8)
,
Sehribani Ulusoy Oktay
(8)
,
Ashwin Bhandiwad
(8)
,
Keri Ramsey
,
Vinodh Narayanan
,
Timothy Feyma
,
Luis Rohena
,
Andrea Accogli
(4, 9)
,
Mariasavina Severino
(10)
,
Georgina Hollingsworth
,
Deepak Gill
,
Christel Depienne
(11)
,
Caroline Nava
(11)
,
Lynette Sadleir
,
Paul Caruso
(12)
,
Angela Lin
,
Floor Jansen
(13)
,
Bobby Koeleman
(13)
,
Eva Brilstra
(14)
,
Marjolein Willemsen
(15)
,
Tjitske Kleefstra
,
Joaquim Sa
(16)
,
Marie‐laure Mathieu
(17)
,
Laurine Perrin
(18)
,
Gaetan Lesca
(17)
,
Pasquale Striano
(3, 4)
,
Giorgio Casari
(3, 4)
,
Ingrid Scheffer
(19)
,
David Raible
,
Evelyn Sattlegger
,
Valeria Capra
(3)
,
Sergio Padilla-Lopez
(6)
,
Heather Mefford
,
Michael Kruer
(6)
1
Northwestern University [Chicago, Ill. USA]
2 CHOP - Children’s Hospital of Philadelphia
3 Istituto Giannina Gaslini, Genova
4 UniGe - Università degli studi di Genova = University of Genoa
5 Ambry Genetics [Aliso Viejo, CA, USA]
6 Phoenix Children's Hospital
7 University of Arizona
8 University of Washington [Seattle]
9 Ospedale Policlinico San Martino [Genoa]
10 IRCCS Istituto Giannina Gaslini [Genoa, Italy]
11 ICM - Institut du Cerveau = Paris Brain Institute
12 Massachusetts General Hospital [Boston]
13 UMCU - University Medical Center [Utrecht]
14 Universiteit Utrecht / Utrecht University [Utrecht]
15 Radboud University Medical Center [Nijmegen]
16 Centro Hospitalar e Universitário [Coimbra]
17 UCBL - Université Claude Bernard Lyon 1
18 CHU ST-E - Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne]
19 Massey University
2 CHOP - Children’s Hospital of Philadelphia
3 Istituto Giannina Gaslini, Genova
4 UniGe - Università degli studi di Genova = University of Genoa
5 Ambry Genetics [Aliso Viejo, CA, USA]
6 Phoenix Children's Hospital
7 University of Arizona
8 University of Washington [Seattle]
9 Ospedale Policlinico San Martino [Genoa]
10 IRCCS Istituto Giannina Gaslini [Genoa, Italy]
11 ICM - Institut du Cerveau = Paris Brain Institute
12 Massachusetts General Hospital [Boston]
13 UMCU - University Medical Center [Utrecht]
14 Universiteit Utrecht / Utrecht University [Utrecht]
15 Radboud University Medical Center [Nijmegen]
16 Centro Hospitalar e Universitário [Coimbra]
17 UCBL - Université Claude Bernard Lyon 1
18 CHU ST-E - Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne]
19 Massey University
Gemma Carvill
- Fonction : Auteur
- PersonId : 1384961
- ORCID : 0000-0003-4945-3628
Katherine Helbig
- Fonction : Auteur
- PersonId : 1384962
- ORCID : 0000-0001-8249-0549
Candace Myers
- Fonction : Auteur
Keri Ramsey
- Fonction : Auteur
Vinodh Narayanan
- Fonction : Auteur
Timothy Feyma
- Fonction : Auteur
Luis Rohena
- Fonction : Auteur
Georgina Hollingsworth
- Fonction : Auteur
Deepak Gill
- Fonction : Auteur
Lynette Sadleir
- Fonction : Auteur
Angela Lin
- Fonction : Auteur
Tjitske Kleefstra
- Fonction : Auteur
Gaetan Lesca
- Fonction : Auteur
- PersonId : 769268
- ORCID : 0000-0001-7691-9492
- IdRef : 124685811
David Raible
- Fonction : Auteur
Evelyn Sattlegger
- Fonction : Auteur
Heather Mefford
- Fonction : Auteur
Résumé
Heterozygous de novo variants in the eukaryotic elongation factor EEF1A2 have previously been described in association with intellectual disability and epilepsy but never functionally validated. Here we report 14 new individuals with heterozygous EEF1A2 variants. We functionally validate multiple variants as protein-damaging using heterologous expression and complementation analysis. Our findings allow us to confirm multiple variants as pathogenic and broaden the phenotypic spectrum to include dystonia/choreoathetosis, and in some cases a degenerative course with cerebral and cerebellar atrophy. Pathogenic variants appear to act via a haploinsufficiency mechanism, disrupting both the protein synthesis and integrated stress response functions of EEF1A2. Our studies provide evidence that EEF1A2 is highly intolerant to variation and that de novo pathogenic variants lead to an epileptic-dyskinetic encephalopathy with both neurodevelopmental and neurodegenerative features. Developmental features may be driven by impaired synaptic protein synthesis during early brain development while progressive symptoms may be linked to an impaired ability to handle cytotoxic stressors.