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

Paulet A, Bennett-Ness C, Ageorges F, Trost D, Green A, Goudie D, Jewell R, Kraatari-Tiri M, PIARD J, Coubes C, Lam W, Lynch SA, Groeschel S, Ramond F, Fluss J, Fagerberg C, Brasch Andersen C, Varvagiannis K, Kleefstra T, Gérard B, Fradin M, Vitobello A, Tenconi R, Denommé-Pichon AS, Vincent-Devulder A, Haack T, Marsh JA, Laulund LW, Grimmel M, Riess A, de Boer E, Padilla-Lopez S, Bakhtiari S, Ostendorf A, Zweier C, Smol T, Willems M, Faivre L, Scala M, Striano P, Bagnasco I, Koboldt D, Iascone M, Suerink M, Kruer MC, Levy J, Verloes A, Abbott CM, Ruaud L (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Book Volume: 32

Pages Range: 1144-1149

Journal Issue: 9

DOI: 10.1038/s41431-024-01560-8

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.

Involved external institutions

Hôpital Universitaire Robert-Debré France (FR) University of Edinburgh United Kingdom (GB) Laboratoire CERBA France (FR) Geneva University Hospitals / Hôpitaux universitaires de Genève (HUG) Switzerland (CH) Odense Universitetshospital (OUH) Denmark (DK) University of Southern Denmark / Syddansk Universitet Denmark (DK) A.S.L. Napoli 1 Centro Italy (IT) Erasmus University Medical Center (MC) Netherlands (NL) Leiden University Medical Center Netherlands (NL) NHS Tayside United Kingdom (GB) Barrow Neurological Institute United States (USA) (US) Université de Strasbourg (UDS) France (FR) Leeds Teaching Hospitals NHS Trust United Kingdom (GB) Centre hospitalier universitaire de Rennes / CHU Rennes France (FR) Oulun Yliopisto / University of Oulo Finland (FI) University College Dublin (UCD) Ireland (IE) Nationwide Children's Hospital United States (USA) (US) Eberhard Karls Universität Tübingen Germany (DE) Inselspital, Universitätsspital Bern Switzerland (CH) Université Bourgogne Franche-Comté France (FR) Centre Hospitalier Universitaire de Montpellier (CHU/CHRU MTP) France (FR) NHS Lothian United Kingdom (GB) Temple Street Children's University Hospital / Children's Health Ireland (CHI) Ireland (IE) Centre hospitalier universitaire (CHU) de Dijon Bourgogne France (FR) Universitätsklinikum Tübingen Germany (DE) CHU de Caen Normandie France (FR) Centre Hospitalier Universitaire de Saint-Étienne (CHU) France (FR) Université de Lille (ULille, UDL) France (FR) Institute for Neurosciences of Montpellier (INM) France (FR) Istituto Giannina Gaslini Italy (IT) Martini Ziekenhuis Netherlands (NL) Centre hospitalier régional et universitaire de Besançon (CHRU Besancon) France (FR)

How to cite

APA:

Paulet, A., Bennett-Ness, C., Ageorges, F., Trost, D., Green, A., Goudie, D.,... Ruaud, L. (2024). Expansion of the neurodevelopmental phenotype of individuals with EEF1A2 variants and genotype-phenotype study. European Journal of Human Genetics, 32(9), 1144-1149. https://doi.org/10.1038/s41431-024-01560-8

MLA:

Paulet, Alix, et al. "Expansion of the neurodevelopmental phenotype of individuals with EEF1A2 variants and genotype-phenotype study." European Journal of Human Genetics 32.9 (2024): 1144-1149.

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