Neurodevelopmental disorders are major indications for genetic referral and have been linked to more than 1,500 loci including genes encoding transcriptional regulators. The dysfunction of transcription factors often results in characteristic syndromic presentations, however, at least half of these patients lack a genetic diagnosis. The implementation of machine learning approaches has the potential to aid in the identification of new disease genes and delineate associated phenotypes. Next generation sequencing was performed in seven affected individuals with neurodevelopmental delay and dysmorphic features. Clinical characterization included reanalysis of available neuroimaging datasets and 2D portrait image analysis with GestaltMatcher. The functional consequences of ZSCAN10 loss were modelled in mouse embryonic stem cells (mESC), including a knock-out and a representative ZSCAN10 protein truncating variant. These models were characterized by gene expression and Western blot analyses, chromatin immunoprecipitation and quantitative PCR (ChIP-qPCR), and immunofluorescence staining. Zscan10 knockout mouse embryos were generated and phenotyped. We prioritized bi-allelic ZSCAN10 loss-of-function variants in seven affected individuals from five unrelated families as the underlying molecular cause. RNA-Seq analyses in Zscan10-/- mESCs indicated dysregulation of genes related to stem cell pluripotency. In addition, we established in mESCs the loss-of-function mechanism for a representative human ZSCAN10 protein truncating variant by showing alteration of its expression levels and subcellular localization, interfering with its binding to DNA enhancer targets. Deep phenotyping revealed global developmental delay, facial asymmetry, and malformations of the outer ear as consistent clinical features. Cerebral MRI showed dysplasia of the semicircular canals as an anatomical correlate of sensorineural hearing loss. Facial asymmetry was confirmed as a clinical feature by GestaltMatcher and was recapitulated in the Zscan10 mouse model along with inner and outer ear malformations. Our findings provide evidence of a novel syndromic neurodevelopmental disorder caused by bi-allelic loss-of-function variants in ZSCAN10.

中文翻译：

---

ZSCAN10 缺陷会导致神经发育障碍，并伴有特征性耳面部畸形

神经发育障碍是遗传转诊的主要适应症，与 1,500 多个基因座相关，包括编码转录调节因子的基因。转录因子的功能障碍通常会导致特征性的综合征表现，然而，这些患者中至少一半缺乏基因诊断。机器学习方法的实施有可能帮助识别新的疾病基因并描绘相关的表型。对七名患有神经发育迟缓和畸形特征的受影响个体进行了下一代测序。临床表征包括对可用神经影像数据集的重新分析以及使用 GestaltMatcher 进行 2D 肖像图像分析。ZSCAN10 缺失的功能后果在小鼠胚胎干细胞 (mESC) 中建模，包括敲除和代表性的 ZSCAN10 蛋白截短变体。这些模型通过基因表达和蛋白质印迹分析、染色质免疫沉淀和定量 PCR (ChIP-qPCR) 以及免疫荧光染色进行表征。生成 Zscan10 敲除小鼠胚胎并进行表型分析。我们优先考虑来自 5 个无关家族的 7 名受影响个体的双等位基因 ZSCAN10 功能丧失变异作为潜在的分子原因。Zscan10-/- mESC 中的 RNA 测序分析表明与干细胞多能性相关的基因失调。此外，我们通过显示其表达水平和亚细胞定位的改变，干扰其与 DNA 增强子靶标的结合，在 mESC 中建立了代表性人类 ZSCAN10 蛋白截短变体的功能丧失机制。深度表型分析显示整体发育迟缓、面部不对称和外耳畸形是一致的临床特征。脑 MRI 显示半规管发育不良与感音神经性听力损失存在解剖相关性。GestaltMatcher 证实面部不对称是一种临床特征，并在 Zscan10 小鼠模型中与内耳和外耳畸形一起重现。我们的研究结果提供了由 ZSCAN10 中双等位基因功能丧失变异引起的新型综合征性神经发育障碍的证据。