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

Gemma L. Carvill, Katherine L. Helbig, Candace T. Myers, Marcello Scala, Robert Huether, Sara Lewis, Tyler N. Kruer, Brandon S. Guida, Somayeh Bakhtiari, Joy Sebe, Sha Tang, Heather Stickney, Sehribani Ulusoy Oktay, Ashwin A. Bhandiwad, Keri Ramsey, Vinodh Narayanan, Timothy Feyma, Luis O. Rohena, Andrea Accogli, Mariasavina SeverinoGeorgina Hollingsworth, Deepak Gill, Christel Depienne, Caroline Nava, Lynette G. Sadleir, Paul A. Caruso, Angela E. Lin, Floor E. Jansen, Bobby Koeleman, Eva Brilstra, Marjolein H. Willemsen, Tjitske Kleefstra, Joaquim Sa, Marie Laure Mathieu, Laurine Perrin, Gaetan Lesca, Pasquale Striano, Giorgio Casari, Ingrid E. Scheffer, David Raible, Evelyn Sattlegger, Valeria Capra, Sergio Padilla-Lopez, Heather C. Mefford*, Michael C. Kruer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1263-1279
Number of pages17
JournalHuman mutation
Issue number7
StatePublished - Jul 1 2020


  • EEF1A2
  • de novo
  • dyskinesia
  • epilepsy
  • yeast complementation assay

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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