Expansion of the neurodevelopmental phenotype of individuals with EEF1A2 variants and genotype-phenotype study

Abstract

Translation elongation factor eEF1A2 constitutes the alpha subunit of the elongation factor-1 complex, responsible for the enzymatic binding of aminoacyl-tRNA to the ribosome. Since 2012, 21 pathogenic missense variants affecting EEF1A2 have been described in 42 individuals with a severe neurodevelopmental phenotype including epileptic encephalopathy and moderate to profound intellectual disability (ID), with neurological regression in some patients. Through international collaborative call, we collected 26 patients with EEF1A2 variants and compared them to the literature. Our cohort shows a significantly milder phenotype. 83% of the patients are walking (vs. 29% in the literature), and 84% of the patients have language skills (vs. 15%). Three of our patients do not have ID. Epilepsy is present in 63% (vs. 93%). Neurological examination shows a less severe phenotype with significantly less hypotonia (58% vs. 96%), and pyramidal signs (24% vs. 68%). Cognitive regression was noted in 4% (vs. 56% in the literature). Among individuals over 10 years, 56% disclosed neurocognitive regression, with a mean age of onset at 2 years. We describe 8 novel missense variants of EEF1A2. Modeling of the different amino-acid sites shows that the variants associated with a severe phenotype, and the majority of those associated with a moderate phenotype, cluster within the switch II region of the protein and thus may affect GTP exchange. In contrast, variants associated with milder phenotypes may impact secondary functions such as actin binding. We report the largest cohort of individuals with EEF1A2 variants thus far, allowing us to expand the phenotype spectrum and reveal genotype-phenotype correlations.

Fig. 1. Our series main features compared with the patients from the literature.

The Fig. 1 shows the proportion of our patients (in black) in comparison to those from the literature (featured in gray) according to the main criteria studied. Walking abilities is represented by the motor category. Concerning the speech abilities, “verbal” means the patient can speak and be understandable, “words” means he can express himself in words but not in sentences, “sentences” stands for the ability of the patient to make proper sentences. On the right part of the diagram, the neurological features are shown with the presence of hypotonia, pyramidal syndrome, epilepsy and the presence of regression. *Stands for statistically significance p < 0.05. P-values are framed at the top.

Fig. 2. Distribution of pathogenic EEF1A2 variants.

a Distribution of variants from our cohort (up) and the previously reported ones (down). Novel variants are underlined. Variants are classified by their associated phenotype in terms of ID, classification is as described as above with associated symbols (circle for not deficient, triangle for mild ID, square for moderate ID and star for severe). Blank when the variant is not clearly classified (for example when associated with 2 ID categories). b Variants mapped onto the crystal structure of GDP-bound eEF1A2 (PDB:4C0S). New variants are shown in black, with labels in bold, previously described mutations are in white. T24M and V437F are buried. The binding site of eEF1B is highlighted in white, and the GTP binding site in dark gray.