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.

翻译延伸因子 eEF1A2 构成延伸因子-1 复合物的 α 亚基，负责氨酰基-tRNA 与核糖体的酶促结合。自 2012 年以来，在 42 名患有严重神经发育表型的个体中描述了影响EEF1A2 的21 种致病性错义变异，包括癫痫性脑病和中度至重度智力障碍 (ID)，部分患者出现神经功能退化。通过国际协作征集，我们收集了 26 名EEF1A2变异患者，并将其与文献进行比较。我们的队列表现出明显较温和的表型。 83% 的患者能够行走（文献中为 29%），84% 的患者具有语言能力（相对于文献中的 15%）。我们的三名患者没有身份证。 63% 的人患有癫痫（对比 93%）。神经系统检查显示表型不太严重，肌张力低下（58% vs. 96%）和锥体征（24% vs. 68%）明显减轻。 4% 的人出现认知退化（文献中为 56%）。在 10 岁以上的个体中，56% 的人出现神经认知退化，平均发病年龄为 2 岁。我们描述了EEF1A2的 8 种新错义变体。不同氨基酸位点的建模表明，与严重表型相关的变体以及大多数与中度表型相关的变体聚集在蛋白质的开关 II 区域内，因此可能影响 GTP 交换。相反，与较温和表型相关的变异可能会影响次要功能，例如肌动蛋白结合。我们报告了迄今为止最大的具有EEF1A2变异的个体群体，使我们能够扩大表型谱并揭示基因型-表型相关性。