We report here a de novo missense variant in HIST1H4J resulting in a complex syndrome combining growth delay, microcephaly and intellectual disability. Trio whole exome sequencing (WES) revealed that the proband was heterozygous for a de novo c.274 A > G p.(K91E) variant in HIST1H4J, a gene not yet associated with human disease. The patient presented with profound intellectual disability, microcephaly, and dysmorphic facial features. Functional consequences of the identified de novo missense variant were evaluated in zebrafish embryos, where they affected general development, especially resulting in defective head organs and reduced body axis length. Our results show that the monoallelic p.K91E substitution on HIST1H4J underlies a human syndrome that is genetically and phenotypically akin to the HIST1H4C-associated neurodevelopmental disorder resulting from p.K91A and p.K91Q substitions in HIST1H4C. The highly overlapping patient phenotypes highlight functional similarities between HIST1H4J and HIST1H4C perturbations, establishing the singular importance of K91 across histone H4 genes for vertebrate development.

中文翻译：

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人类HIST1H4J基因的从头变异引起的综合征类似于与HIST1H4C相关的神经发育障碍。

我们在这里报告了HIST1H4J中的从头错义变异，导致复杂的综合症，其中包括生长延迟，小头畸形和智力残疾。三重全外显子组测序（WES）显示，该先证者在HIST1H4J（该基因尚未与人类疾病相关的基因）中从头重新出现c.274 A> G p。（K91E）变异。该患者表现出严重的智力残疾，小头畸形和畸形的面部特征。在斑马鱼胚胎中评估了已确定的从头错义变体的功能后果，在斑马鱼胚胎中它们影响了总体发育，特别是导致头部器官缺陷和体轴长度减少。我们的结果表明，单等位基因p。HIST1H4J上的K91E取代是人类综合症的基础，该综合症在遗传和表型上类似于HIST1H4C中的p.K91A和p.K91Q替代所致的HIST1H4C相关的神经发育障碍。高度重叠的患者表型突显了HIST1H4J和HIST1H4C扰动之间的功能相似性，从而确立了K91在整个组蛋白H4基因对脊椎动物发育中的重要性。