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.
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Data availability
All anonymized data and related documentation from this study are available on reasonable request. Declaration to public database: All variants are reported and annotated in ClinVar website (accession number SCV004171535- SCV004171551): https://www.ncbi.nlm.nih.gov/clinvar/.
Change history
03 April 2024
A Correction to this paper has been published: https://doi.org/10.1038/s41431-024-01606-x
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Acknowledgements
We want to acknowledge AnDDI-Rares and the families for their participation. In addition, the collaboration in this study were facilitated by ERN ITHACA, one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States, cofounded by European Commission. [EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516].
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The aims of this study contribute to the Solve-RD project, which has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 779257.
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Conceptualization: AP, LR, CA, AV. Formal Analysis: AP. Investigation: AP, FA, LR, MCK, SB, JL, DT, SB, MCK, AV, RT, CBA, MG, BG, SP, AO, CZ, TS, MW, LF, MS, PS, IB, DK, MI, MS. Supervision: LR, AV, CA. Visualization: AP, CA, CBN. Writing - Original Draft: AP, LR, CA, CBN. Writing - Review & Editing: AP, LR, CA, CBN, AV, FM, CC, RF, JP, SJ, CF, LW, JF, AV, ASDP, TH, JM, SAL, WL, RJ, MK, DG, AG, EDB, JL, DT, SB, MCK, AV, RT, CBA, MG, BG, SP, DK.
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Ethical approval was not required because it was a retrospective observational study and patients have already signed consent for genetics analyses for diagnosis. Every patient has been anonymized by the clinician before collecting data (a number has been assigned to each patient).
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The original online version of this article was revised: In the original version of this article, the given and family names of Samuel Groeschel were incorrectly structured. The name was displayed correctly in all versions at the time of publication. The authors, Adam Ostendorf, Christiane Zweier, Thomas Smol, Marjolaine Willems, Laurence Faivre, Marcello Scala, Pasquale Striano, Irene Bagnasco, Daniel Koboldt, Maria Iascone, Manon Suerink were missing from the author list. Moreover, the author contribution texts have been updated in accordance with addition of authors.
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Paulet, A., Bennett-Ness, C., Ageorges, F. et al. Expansion of the neurodevelopmental phenotype of individuals with EEF1A2 variants and genotype-phenotype study. Eur J Hum Genet (2024). https://doi.org/10.1038/s41431-024-01560-8
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DOI: https://doi.org/10.1038/s41431-024-01560-8
