HECT And RLD Domain-Containing E3 Ubiquitin Protein Ligase 2, or HERC2, codes an ubiquitin ligase that has an important role in key cellular processes including cell cycle regulation, DNA repair, mitochondrial functions, and spindle formation during mitosis. While HERC2 Neurodevelopmental Disorder in Old Order Amish is a well characterized human disorder involving HERC2, bi-allelic HERC2 loss of function has only been described in three families and results in a more severe neurodevelopmental disorder. Herein, we delineate the HERC2 loss of function phenotype by describing three previously unreported patients, and by summarizing the molecular and phenotypic information of all known HERC2 missense variants and biallelic loss of function patients. Collectively, these twelve individuals present with recurring features that define a syndrome with varying combinations of severe neurodevelopmental delay, structural brain anomalies, seizures, hypotonia, feeding difficulties, hearing and vision issues, and renal anomalies. This study describes a distinct neurodevelopmental disorder, emphasizing the importance of further characterization of HERC2-related disorders, as well as highlighting the importance of ongoing work into understanding these critical neurodevelopmental pathways.

中文翻译：

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描绘 HERC2 相关疾病的扩展表型：双等位基因功能丧失与错义变异的影响

包含 HECT 和 RLD 结构域的 E3 泛素蛋白连接酶 2 或HERC2编码一种泛素连接酶，该酶在细胞周期调节、DNA 修复、线粒体功能和有丝分裂期间纺锤体形成等关键细胞过程中发挥重要作用。虽然旧秩序阿米什人中的HERC2神经发育障碍是一种特征明确的人类疾病，涉及HERC2，但仅在三个家族中描述了双等位基因HERC2功能丧失，并导致更严重的神经发育障碍。在这里，我们通过描述三个以前未报告的患者，并通过总结所有已知HERC2的分子和表型信息来描述HERC2功能丧失表型错义变异和双等位基因功能丧失患者。总的来说，这 12 个人表现出反复出现的特征，这些特征定义了一种具有严重神经发育迟缓、结构性脑异常、癫痫发作、张力减退、喂养困难、听力和视力问题以及肾脏异常的各种组合的综合征。本研究描述了一种独特的神经发育障碍，强调了进一步表征HERC2相关疾病的重要性，并强调了正在进行的工作以了解这些关键的神经发育途径的重要性。