The SET domain containing 2, histone lysine methyltransferase encoded by SETD2 is a dual‐function methyltransferase for histones and microtubules and plays an important role for transcriptional regulation, genomic stability, and cytoskeletal functions. Specifically, SETD2 is associated with trimethylation of histone H3 at lysine 36 (H3K36me3) and methylation of α‐tubulin at lysine 40. Heterozygous loss of function and missense variants have previously been described with Luscan‐Lumish syndrome (LLS), which is characterized by overgrowth, neurodevelopmental features, and absence of overt congenital anomalies. We have identified 15 individuals with de novo variants in codon 1740 of SETD2 whose features differ from those with LLS. Group 1 consists of 12 individuals with heterozygous variant c.5218C>T p.(Arg1740Trp) and Group 2 consists of 3 individuals with heterozygous variant c.5219G>A p.(Arg1740Gln). The phenotype of Group 1 includes microcephaly, profound intellectual disability, congenital anomalies affecting several organ systems, and similar facial features. Individuals in Group 2 had moderate to severe intellectual disability, low normal head circumference, and absence of additional major congenital anomalies. While LLS is likely due to loss of function of SETD2, the clinical features seen in individuals with variants affecting codon 1740 are more severe suggesting an alternative mechanism, such as gain of function, effects on epigenetic regulation, or posttranslational modification of the cytoskeleton. Our report is a prime example of different mutations in the same gene causing diverging phenotypes and the features observed in Group 1 suggest a new clinically recognizable syndrome uniquely associated with the heterozygous variant c.5218C>T p.(Arg1740Trp) in SETD2.

中文翻译：

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SETD2 密码子 1740 处的基因型-表型相关性。

SET 结构域包含 2，由SETD2编码的组蛋白赖氨酸甲基转移酶是组蛋白和微管的双功能甲基转移酶，对转录调控、基因组稳定性和细胞骨架功能起着重要作用。具体而言，SETD2与组蛋白 H3 在赖氨酸 36 (H3K36me3) 的三甲基化和 α-微管蛋白在赖氨酸 40 的甲基化有关。杂合子功能丧失和错义变异先前已被描述为 Luscan-Lumish 综合征 (LLS)，其特征是过度生长、神经发育特征和没有明显的先天性异常。我们已经确定了 15 个在SETD2的密码子 1740 中具有新生变异的个体其特征与 LLS 不同。第 1 组由 12 个具有杂合变体 c.5218C>T p.(Arg1740Trp) 的个体组成，第 2 组由 3 个具有杂合变体 c.5219G>A p.(Arg1740Gln) 的个体组成。第 1 组的表型包括小头畸形、严重智力障碍、影响多个器官系统的先天性异常以及相似的面部特征。第 2 组中的个体具有中度至重度智力障碍、正常低头围并且没有其他主要先天性异常。虽然 LLS 可能是由于SETD2功能丧失, 在具有影响密码子 1740 的变体的个体中看到的临床特征更严重，表明存在替代机制，例如功能获得、对表观遗传调控的影响或细胞骨架的翻译后修饰。我们的报告是同一基因中不同突变导致不同表型的主要示例，在第 1 组中观察到的特征表明一种新的临床可识别综合征与 SETD2 中的杂合变体 c.5218C>T p.(Arg1740Trp) 独特相关。