Identification of a novel mutation of RUNX2 in a family with supernumerary teeth and craniofacial dysplasia by whole-exome sequencing: A case report and literature review.
Identification of a novel mutation of RUNX2 in a family with supernumerary teeth and craniofacial dysplasia by whole-exome sequencing: A case report and literature review.
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DOI：
10.1097/md.0000000000011328
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发表时间：
2018-08
期刊：
影响因子：
1.6
通讯作者：
Cai T
中科院分区：
文献类型：
--
作者：
Ma D;Wang X;Guo J;Zhang J;Cai T
补充数字内容可在文本多余的牙齿是那些牙齿的数量超过正常计数。当大量出现时，通常与遗传综合征有关。已鉴定出APC、NHS、TRPS1、EVC和RUNX2等几个致病基因。然而，多牙的病因仍不清楚。对临床诊断为多牙、身材矮小、颅面发育不良的一家人进行了检查。分子遗传分析发现RUNX2基因发生突变。根据这一发现和临床表现，最终诊断为锁骨颅内发育不良。对DNA样本进行全外显子组测序（WES）以确定致病突变，包括受影响的儿童和母亲以及健康的父亲。在两名患者中发现了RUNX2 （c.473C>A; p.A158E）的新突变，但在正常家庭成员和包含3000名中国汉人WES的内部数据库中没有发现。Sanger测序进一步证实了该突变，并通过几种常用的算法（包括SIFT、PPT-2、MutationTaster和Proven）预测该突变是有害的。此外，对已发表的239例不同RUNX2突变的病例进行表型-基因型相关分析发现，多牙和面部发育不良与编码蛋白的Runt结构域显著相关。这是首个在中国RUNX2突变患者中鉴定遗传原因的WES研究。我们的发现扩大了突变谱和疾病的临床特征，促进了临床诊断和遗传咨询。
Supplemental Digital Content is available in the text Supernumerary teeth are those that teeth in excess number than the normal count. It is usually associated with genetic syndromes when present in more numbers. Several causal genes, such as APC, NHS, TRPS1, EVC and RUNX2, have been identified. However, etiology of supernumerary teeth remains largely unclear. A family with the clinical diagnosis of supernumerary teeth, short stature and craniofacial dysplasia was examined. Molecular genetic analysis found that mutation occurred in the RUNX2 gene. On the basis of this finding and clinical manifestations, the final diagnosis of cleidocranial dysplasia was made. Whole exome sequencing (WES) of DNA samples was performed to identify the disease-causing mutation, including the affected child and mother as well as the healthy father. A novel mutation of RUNX2 (c.473C>A; p.A158E) was identified in both patients, but not in normal family member and in-house database containing 3,000 Chinese Han individuals WES. This mutation was further confirmed by Sanger sequencing and predicted to be deleterious by several commonly used algorithms, including SIFT, PPT-2, MutationTaster and Proven. Furthermore, phenotype-genotype correlation analyses of all published 239 cases with different mutations in RUNX2 revealed significant association of supernumerary teeth and facial dysplasia with the Runt domain of the encoded protein. This is the first WES study to identify genetic cause in Chinese patients with a novel RUNX2 mutation. Our findings expanded the mutation spectrum and clinical features of the disease and facilitated clinic diagnosis and genetic counseling.