Damaging de novo missense variants inEEF1A2lead to a developmental and degenerative epileptic-dyskinetic encephalopathy

• Type: Article in International Scientific Journal
• Date: 2020

Authors

Carvill, GL (Author) Other; Helbig, KL (Author) Other; Myers, CT (Author) Other; Scala, M (Author) Other; Huether, R (Author) Other; Lewis, S (Author) Other; Kruer, TN (Author) Other; Guida, BS (Author) Other; Bakhtiari, S (Author) Other; Sebe, J (Author) Other; Tang, S (Author) Other; Stickney, H (Author) Other; Oktay, SU (Author) Other; Bhandiwad, AA (Author) Other; Ramsey, K (Author) Other; Narayanan, V (Author) Other; Feyma, T (Author) Other; Rohena, LO (Author) Other; Accogli, A (Author) Other; Severino, M (Author) Other; Hollingsworth, G (Author) Other; Gill, D (Author) Other; Depienne, C (Author) Other; Nava, C (Author) Other; Sadleir, LG (Author) Other; Caruso, PA (Author) Other; Jansen, FE (Author) Other; Koeleman, B (Author) Other; Brilstra, E (Author) Other; Willemsen, MH (Author) Other; Kleefstra, T (Author) Other; Sa, J (Author) Other; Mathieu, ML (Author) Other; Perrin, L (Author) Other; Lesca, G (Author) Other; Striano, P (Author) Other; Casari, G (Author) Other; Scheffer, IE (Author) Other; Raible, D (Author) Other; Sattlegger, E (Author) Other; Capra, V (Author) Other; Padilla Lopez, S (Author) Other; Mefford, HC (Author) Other; Kruer, MC (Author) Other

Journal

Title: Human Mutation

Vol. 41

Pages: 1263-1279

ISSN: 1059-7794

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 7 Citations

Scopus - 7 Citations

Other information

Authenticus ID: P-00R-ZNZ

DOI: 10.1002/humu.24015

Abstract (EN): Heterozygous de novo variants in the eukaryotic elongation factorEEF1A2have previously been described in association with intellectual disability and epilepsy but never functionally validated. Here we report 14 new individuals with heterozygousEEF1A2variants. 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 thatEEF1A2is 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 17