Damaging de novo missense variants in EEF1A2 lead to a developmental and degenerative epileptic-dyskinetic encephalopathy.

2020-07

Carvill, Gemma L

Helbig, Katherine L

Myers, Candace T

Scala, Marcello

Huether, Robert

Lewis, Sara

Kruer, Tyler N

Guida, Brandon S

Bakhtiari, Somayeh

Sebe, Joy

Tang, Sha

Stickney, Heather

Oktay, Sehribani Ulusoy

Bhandiwad, Ashwin A

Ramsey, Keri

Narayanan, Vinodh

Feyma, Timothy

Rohena, Luis O

Accogli, Andrea

Severino, Mariasavina

Hollingsworth, Georgina

Gill, Deepak

Depienne, Christel

Nava, Caroline

Sadleir, Lynette G

Caruso, Paul A

Lin, Angela E

Jansen, Floor E

Koeleman, Bobby

Brilstra, Eva

Willemsen, Marjolein H

Kleefstra, Tjitske

Sa, Joaquim

Mathieu, Marie-Laure

Perrin, Laurine

Lesca, Gaetan

Striano, Pasquale

Casari, Giorgio

Scheffer, Ingrid E

Raible, David

Sattlegger, Evelyn

Capra, Valeria

Padilla-Lopez, Sergio

Mefford, Heather C

Kruer, Michael C

EEF1A2

de novo

dyskinesia

epilepsy

yeast complementation assay

Journal Article

0000-0003-4945-3628

0000-0001-8249-0549

10.1002/humu.24015

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. This article is protected by copyright. All rights reserved.

link

Human mutation 2020; 41(7): 1263-1279

Human mutation