De novo heterozygous variants in the brain‐specific transcription factor Neuronal Differentiation Factor 2 (NEUROD2) have been recently associated with early‐onset epileptic encephalopathy and developmental delay. Here, we report an adolescent with developmental delay without seizures who was found to have a novel de novo heterozygous NEUROD2 missense variant, p.(Leu163Pro). Functional testing using an in vivo assay of neuronal differentiation in Xenopus laevis tadpoles demonstrated that the patient variant of NEUROD2 displays minimal protein activity, strongly suggesting a loss of function effect. In contrast, a second rare NEUROD2 variant, p.(Ala235Thr), identified in an adolescent with developmental delay but lacking parental studies for inheritance, showed normal in vivo NEUROD2 activity. We thus provide clinical, genetic, and functional evidence that NEUROD2 variants can lead to developmental delay without accompanying early‐onset seizures, and demonstrate how functional testing can complement genetic data when determining variant pathogenicity.

中文翻译：

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扩展 NEUROD2 表型以包括无癫痫发作的发育迟缓

大脑特异性转录因子神经元分化因子 2 ( NEUROD2 ) 的从头杂合变异最近与早发性癫痫性脑病和发育迟缓有关。在这里，我们报告了一名发育迟缓但没有癫痫发作的青少年，他发现他有一个新的从头杂合NEUROD2错义变体 p.(Leu163Pro)。使用非洲爪蟾蝌蚪中神经元分化的体内测定进行功能测试表明，患者的 NEUROD2 变体显示出最小的蛋白质活性，强烈表明功能丧失效应。相比之下，第二个罕见的NEUROD2变体 p.(Ala235Thr) 在发育迟缓但缺乏父母遗传研究的青少年中发现，其体内 NEUROD2 活性正常。因此，我们提供了临床、遗传和功能证据，证明NEUROD2变异可导致发育迟缓，而不会伴随早发性癫痫发作，并证明功能测试在确定变异致病性时如何补充遗传数据。