Abstract：
OBJECTIVE: Coffin-Siris Syndrome (CSS) is a congenital disorder characterized by delayed growth, dysmorphic facial features, hypoplastic nails and phalanges of the fifth digit, and dental abnormalities. Tooth agenesis has been reported in CSS patients, but the mechanisms regulating this syndromic tooth agenesis remain largely unknown. This study aims to identify the pathogenic mutation of CSS presenting tooth genesis and explore potential regulatory mechanisms.
METHODS: We utilized whole-exome sequencing to identify variants in a CSS patient, followed by Sanger validation. In silico analysis including conservation analysis, pathogenicity predictions, and 3D structural assessments were carried out. Additionally, single-cell RNA sequencing and fluorescence in situ hybridization (FISH) were applied to explore the spatio-temporal expression of Sox4 expression during murine tooth development. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to examine the functional role of SOX4.
RESULTS: A novel de novo SOX4 missense mutation (c.1255C > G, p.Leu419Val) was identified in a Chinese CSS patient exhibiting tooth agenesis. Single-cell RNA sequencing and FISH further verified high expression of Sox4 during murine tooth development, and WGCNA confirmed its central role in tooth development pathways. Enriched functions included cell-substrate junctions, focal adhesion, and RNA splicing.
CONCLUSIONS: Our findings link a novel SOX4 mutation to syndromic tooth agenesis in CSS. This is the first report of SOX4 missense mutation causing syndromic tooth agenesis.
CONCLUSIONS: This study not only enhances our understanding of the pathogenic mutation for syndromic tooth agenesis but also provides genetic diagnosis and potential therapeutic insights for syndromic tooth agenesis.
METHODS: We utilized whole-exome sequencing to identify variants in a CSS patient, followed by Sanger validation. In silico analysis including conservation analysis, pathogenicity predictions, and 3D structural assessments were carried out. Additionally, single-cell RNA sequencing and fluorescence in situ hybridization (FISH) were applied to explore the spatio-temporal expression of Sox4 expression during murine tooth development. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to examine the functional role of SOX4.
RESULTS: A novel de novo SOX4 missense mutation (c.1255C > G, p.Leu419Val) was identified in a Chinese CSS patient exhibiting tooth agenesis. Single-cell RNA sequencing and FISH further verified high expression of Sox4 during murine tooth development, and WGCNA confirmed its central role in tooth development pathways. Enriched functions included cell-substrate junctions, focal adhesion, and RNA splicing.
CONCLUSIONS: Our findings link a novel SOX4 mutation to syndromic tooth agenesis in CSS. This is the first report of SOX4 missense mutation causing syndromic tooth agenesis.
CONCLUSIONS: This study not only enhances our understanding of the pathogenic mutation for syndromic tooth agenesis but also provides genetic diagnosis and potential therapeutic insights for syndromic tooth agenesis.
摘要：
目的：Coffin-Siris综合征（CSS）是一种以生长迟缓为特征的先天性疾病，畸形面部特征，发育不良的指甲和第五位指骨，和牙齿异常。已经报道了CSS患者的牙齿发育不全，但是调节这种综合征性牙齿发育不全的机制仍然未知。本研究旨在确定CSS牙齿起源的致病突变，并探索潜在的调控机制。
方法：我们利用全外显子组测序来鉴定CSS患者的变异，其次是桑格验证。在硅分析中，包括保守分析，致病性预测，并进行了3D结构评估。此外,应用单细胞RNA测序和荧光原位杂交(FISH)技术探讨小鼠牙齿发育过程中Sox4表达的时空表达。采用加权基因共表达网络分析(WGCNA)来检查SOX4的功能作用。
结果：一种新的从头SOX4错义突变（c.1255C>G，p.Leu419Val）在一名中国CSS患者中发现牙齿发育不全。单细胞RNA测序和FISH进一步验证了小鼠牙齿发育过程中Sox4的高表达，WGCNA证实了其在牙齿发育途径中的重要作用。丰富的功能包括细胞-底物连接，病灶粘连,和RNA剪接。
结论：我们的发现将一个新的SOX4突变与CSS中的综合征性牙齿发育不全联系起来。这是SOX4错义突变导致综合征性牙齿发育不全的首次报道。
结论：这项研究不仅增强了我们对综合征性牙齿发育不全致病突变的理解，而且为综合征性牙齿发育不全提供了基因诊断和潜在的治疗见解。
方法：我们利用全外显子组测序来鉴定CSS患者的变异，其次是桑格验证。在硅分析中，包括保守分析，致病性预测，并进行了3D结构评估。此外,应用单细胞RNA测序和荧光原位杂交(FISH)技术探讨小鼠牙齿发育过程中Sox4表达的时空表达。采用加权基因共表达网络分析(WGCNA)来检查SOX4的功能作用。
结果：一种新的从头SOX4错义突变（c.1255C>G，p.Leu419Val）在一名中国CSS患者中发现牙齿发育不全。单细胞RNA测序和FISH进一步验证了小鼠牙齿发育过程中Sox4的高表达，WGCNA证实了其在牙齿发育途径中的重要作用。丰富的功能包括细胞-底物连接，病灶粘连,和RNA剪接。
结论：我们的发现将一个新的SOX4突变与CSS中的综合征性牙齿发育不全联系起来。这是SOX4错义突变导致综合征性牙齿发育不全的首次报道。
结论：这项研究不仅增强了我们对综合征性牙齿发育不全致病突变的理解，而且为综合征性牙齿发育不全提供了基因诊断和潜在的治疗见解。
