Heterozygous de novo variants in the eukaryotic elongation factor EEF1A2 have previously been described in association with intellectual disability and epilepsy but never functionally validated. Here we report 14 new individuals with heterozygous EEF1A2 variants. 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 that EEF1A2 is 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.

中文翻译：

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EEF1A2 中破坏性的从头错义变异导致发育性和退行性癫痫-运动障碍性脑病。

真核细胞延伸因子EEF1A2中的杂合子 de novo 变体先前已被描述为与智力障碍和癫痫有关，但从未在功能上得到验证。在这里，我们报告了 14 位具有EEF1A2杂合子的新个体变种。我们使用异源表达和互补分析在功能上验证多个变体为蛋白质损伤。我们的发现使我们能够确认多种变异为致病性，并拓宽了表型谱，包括肌张力障碍/舞蹈手足徐动症，以及在某些情况下伴有大脑和小脑萎缩的退行性病程。致病变异似乎通过单倍剂量不足机制起作用，破坏了 EEF1A2 的蛋白质合成和综合应激反应功能。我们的研究提供证据表明EEF1A2对变异高度不耐受，并且从头致病变异导致具有神经发育和神经退行性特征的癫痫-运动障碍性脑病。发育特征可能是由早期大脑发育过程中突触蛋白合成受损所驱动，而渐进性症状可能与处理细胞毒性压力源的能力受损有关。