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Abstract：
Background Variants of ubiquitin-specific protease 7 ( USP7 ) gene in humans are associated with a neurodevelopmental disorder-Hao-Fountain syndrome, its core symptoms including developmental delay, intellectual disability, and speech delay. Other variable symptoms can affect multiple systems. In present study, we report two patients with core features from two unrelated consanguineous families originating from the Tianjin Children\'s Hospital. Methods and Results Genomic DNA was extracted from the peripheral blood samples collected from the probands with their family members and whole-exome sequencing (WES) was used to detect the pathogenic genes in the probands. Suspected variants were subsequently validated by Sanger sequencing. In family 1, WES revealed that the proband carried the de novo variant c.2697A > C (p.Leu899Phe) in USP7 (NM_003470.3). In family 2, WES identified the variant c.3305A > C (p.Asn1102Thr) in USP7 (NM_003470.3) from the proband. Conclusion We reported two cases of Hao-Fountain syndrome caused by novel USP7 variants. In addition, we report the first case of mosaicism with a USP7 variant in Chinese family. Our findings demonstrate the importance of WES in diagnosis of genetic diseases and expands the USP7 variants spectrum in Hao-Fountain syndrome. Moreover, we summarize the cases caused by USP7 variants in the literature. Our study can provide a vital reference for the diagnosis of future cases.
摘要：
背景人类泛素特异性蛋白酶7（USP7）基因的变异与神经发育障碍-Hao-Fountain综合征有关，其核心症状包括发育迟缓,智力残疾,说话延迟。其他可变症状可影响多个系统。在目前的研究中,我们报告了两名具有核心特征的患者，他们来自天津市儿童医院的两个不相关的近亲家庭。方法和结果从先证者及其家族成员的外周血中提取基因组DNA，并采用全外显子组测序（WES）检测先证者的致病基因。随后通过Sanger测序验证可疑变体。在家族1中，WES显示先证者携带从头变体c.2697A>C（p。Leu899Phe)在USP7(NM_003470.3)中。在家族2中，WES鉴定出变体c.3305A>C（p。Asn1102Thr)在USP7(NM_003470.3)中来自先证者。结论我们报告了两例由新型USP7变体引起的Hao-Fountain综合征。此外,我们报道了中国家庭中首例USP7变异的马赛克病。我们的发现证明了WES在遗传病诊断中的重要性，并扩展了Hao-Fountain综合征的USP7变异谱。此外，我们总结了文献中由USP7变异引起的病例.我们的研究可以为未来病例的诊断提供重要的参考。
