Phan M, Conte F, Khandelwal K D, Ockeloen C W, Bartzela T, Kleefstra T, van Bokhoven H, Rubini M, Zhou H, Carels C E L
Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
Hum Genet. 2016 Dec;135(12):1299-1327. doi: 10.1007/s00439-016-1733-z. Epub 2016 Oct 3.
Tooth agenesis and orofacial clefts represent the most common developmental anomalies and their co-occurrence is often reported in patients as well in animal models. The aim of the present systematic review is to thoroughly investigate the current literature (PubMed, EMBASE) to identify the genes and genomic loci contributing to syndromic or non-syndromic co-occurrence of tooth agenesis and orofacial clefts, to gain insight into the molecular mechanisms underlying their dual involvement in the development of teeth and facial primordia. Altogether, 84 articles including phenotype and genotype description provided 9 genomic loci and 26 gene candidates underlying the co-occurrence of the two congenital defects: MSX1, PAX9, IRF6, TP63, KMT2D, KDM6A, SATB2, TBX22, TGFα, TGFβ3, TGFβR1, TGFβR2, FGF8, FGFR1, KISS1R, WNT3, WNT5A, CDH1, CHD7, AXIN2, TWIST1, BCOR, OFD1, PTCH1, PITX2, and PVRL1. The molecular pathways, cellular functions, tissue-specific expression and disease association were investigated using publicly accessible databases (EntrezGene, UniProt, OMIM). The Gene Ontology terms of the biological processes mediated by the candidate genes were used to cluster them using the GOTermMapper (Lewis-Sigler Institute, Princeton University), speculating on six super-clusters: (a) anatomical development, (b) cell division, growth and motility, (c) cell metabolism and catabolism, (d) cell transport, (e) cell structure organization and (f) organ/system-specific processes. This review aims to increase the knowledge on the mechanisms underlying the co-occurrence of tooth agenesis and orofacial clefts, to pave the way for improving targeted (prenatal) molecular diagnosis and finally to reflect on therapeutic or ultimately preventive strategies for these disabling conditions in the future.
牙齿发育不全和口腔颌面部裂隙是最常见的发育异常，患者以及动物模型中经常报告两者同时出现的情况。本系统综述的目的是全面研究当前文献（PubMed、EMBASE），以确定导致牙齿发育不全和口腔颌面部裂隙综合征性或非综合征性同时出现的基因和基因组位点，从而深入了解它们在牙齿和面部原基发育中双重作用的分子机制。总共84篇包括表型和基因型描述的文章提供了9个基因组位点和26个基因候选物，这些基因与两种先天性缺陷同时出现有关：MSX1、PAX9、IRF6、TP63、KMT2D、KDM6A、SATB2、TBX22、TGFα、TGFβ3、TGFβR1、TGFβR2、FGF8、FGFR1、KISS1R、WNT3、WNT5A、CDH1、CHD7、AXIN2、TWIST1、BCOR、OFD1、PTCH1、PITX2和PVRL1。使用可公开访问的数据库（EntrezGene、UniProt、OMIM）研究了分子途径、细胞功能、组织特异性表达和疾病关联。利用GOTermMapper（普林斯顿大学刘易斯-西格勒研究所），根据候选基因介导的生物学过程的基因本体术语对它们进行聚类，推测出六个超级聚类：（a）解剖学发育，（b）细胞分裂、生长和运动，（c）细胞代谢和分解代谢，（d）细胞运输，（e）细胞结构组织，以及（f）器官/系统特异性过程。本综述旨在增加对牙齿发育不全和口腔颌面部裂隙同时出现机制的认识，为改进靶向（产前）分子诊断铺平道路，并最终思考未来针对这些致残性疾病的治疗或最终预防策略。
