Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7HE, UK.
Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK.
Hum Mol Genet. 2023 May 18;32(11):1932-1942. doi: 10.1093/hmg/ddad023.
Orofacial cleft (OC) is a common congenital anomaly in humans, which has lifelong implications for affected individuals. This disorder can be classified as syndromic or non-syndromic depending on the presence or absence of additional physical or neurodevelopmental abnormalities, respectively. Non-syndromic cleft is often non-familial in nature and has a complex aetiology, whereas syndromic forms tend to be monogenic. Although individual OC-related syndromes have been frequently described in the medical literature, there has not been a comprehensive review across syndromes, thereby leaving a gap in our knowledge, which this paper aims to address. Six hundred and three patients with cleft-related human phenotype ontology terms were identified within the Deciphering Developmental Disorders study. Genes carrying pathogenic/likely pathogenic variants were identified and reviewed enabling a diagnostic yield of 36.5%. In total, 124 candidate genes for syndromic OC were identified, including 34 new genes that should be considered for inclusion in clinical clefting panels. Functional enrichment and gene expression analyses identified three key processes that were significantly overrepresented in syndromic OC gene lists: embryonic morphogenesis, protein stability and chromatin organization. Comparison with non-syndromic OC gene networks led us to propose that chromatin remodelling specifically contributes to the aetiology of syndromic OC. Disease-driven gene discovery is a valid approach to gene identification and curation of gene panels. Through this approach, we have started to unravel common molecular pathways contributing to syndromic orofacial clefting.
口腔颌面裂（OC）是人类常见的先天性畸形，对受影响的个体有终身影响。根据是否存在其他身体或神经发育异常，这种疾病可分为综合征或非综合征。非综合征性裂隙通常是非家族性的，其病因复杂，而综合征形式往往是单基因的。尽管在医学文献中经常描述了个别与 OC 相关的综合征，但尚未对综合征进行全面综述，从而导致我们的知识存在空白，本文旨在解决这一问题。在“解析发育障碍”研究中，从 603 名具有裂隙相关人类表型本体论术语的患者中确定了与裂隙相关的患者。确定并审查了携带致病性/可能致病性变异的基因，从而使诊断率达到 36.5%。总共确定了 124 个与综合征 OC 相关的候选基因，包括 34 个应考虑纳入临床裂隙面板的新基因。功能富集和基因表达分析确定了三个在综合征 OC 基因列表中显著过表达的关键过程：胚胎形态发生、蛋白质稳定性和染色质组织。与非综合征 OC 基因网络的比较使我们提出染色质重塑特别有助于综合征 OC 的发病机制。疾病驱动的基因发现是基因鉴定和基因面板 curated 的有效方法。通过这种方法，我们已经开始揭示导致综合征性口腔颌面裂的常见分子途径。
