KMT2D基因突变所致的Kabuki综合征6例报告并文献复习

目的：探讨KMT2D突变引起的Kabuki综合征（KS）的临床、遗传学特点及其在新生儿期的临床特征。方法：采用全外显子组测序（WES）和临床panel的二代测序技术，结合复旦大学附属儿科医院分子诊断中心建立的数据分析流程，行相关基因测序和数据分析，对6例KMT2D基因突变患儿的临床及分子生物学特征进行总结。计算机检索 PubMed、中国知网、维普、中国生物医学文献和万方数据库，收集KS相关文献，检索时间从2012年4月至 2017年4月，对描述新生儿期临床特征的文献进行提取、归纳和总结。结果：6例KS患儿，男4例，女2例。其中3例在婴儿期均因KS相关临床表现，家属要求行家系WES确诊，1例新生儿经临床panel检测后确诊，2例因家属要求对患儿进行WES测序确诊。6例KS患儿共检测到7个KMT2D基因的杂合突变，分别位于11、39、51和53号外显子，包括1个终止、4个错义和2个移码突变。其中c.12697C>T（p.Q4233X）、c.16498C>T（p.R5500W）、c.16273G>A（p.E5425K）为人类基因突变数据库(HGMD)已收录的致病突变位点。c.12696G>T(p.Q4232H)、c.3495delC (p.Pro1165LeufsTer47)、c.10881delT（p.Leu3627ArgfsTer31）、c.12560G>A（p.G418E）为新发突变位点。经SIFT、Polyphen 2和MutationTaster 软件预测为有害突变。纳入18篇KS新生儿期起病文献加上本文2例（34例），新生儿期表现为喂养困难（19例），心脏发育异常（20例），特殊容貌（17例），骨骼发育异常（15例），低血糖（10例）和肌张力低下（9例）等。结论：KS的典型临床表型在新生儿期还未完全呈现，当新生儿有喂养困难、心脏发育异常、特殊容貌等临床特征时需考虑KS，并尽早完善相关基因检测，实现早诊断、早干预。

Report of 6 Kabuki syndrome cases caused by KMT2D gene mutation and literature review

Objective To investigate the clinical and genetic features of Kabuki syndrome caused by KMT2D mutation and summarize the clinical features in neonate.Methods Using Whole-Exome Sequencing(WES)and Clinical panel deep sequencing,combined with data analysis pipeline established by molecular diagnostic center of Children's Hospital of Fudan University,the clinical and molecular features of 6 children with KMT2D mutations were summarized.Databases including PubMed,CNKI,WanFang Database and VIP were searched to collect literature of KS,which describe the clinical features of neonatal period from April 2012 to April 2017.Results Four males and two females were diagnosed as KS.Three cases were diagnosed by WES due to KS related manifestations were present and the families came to order trio-WES.One case was diagnosed by clinical neonatal panel screening.Another two cases were diagnosed by WES.Seven heterozygous mutations were detected in six patients with KS,mutations were located in exon 11,exon 39,exon 51 and exon 53 respectively.The types of mutations were one stop gained,four missenses and two frameshifts.Mutation of c.12697C>T(p.Q4233X)、c.16498C>T(p.R5500W)、c.16273G>A(p.E5425K)were reported as pathogenic mutations and had recorded in Human Gene Mutation Database(HGMD).Mutation of c.12696G>T(p.Q4232H),c.3495delC(p.Pro1165LeufsTer47),c.10881delT(p.Leu3627Argfs Ter31)and c.12560G>A(p.G418E)were novel,which predicted as harmful variants by SIFT,polyphen 2 and MutationTaster software.In a total of 18 literatures,together with the 2 cases in this study,there were 34 neonates were included.The most common clinical features were as follows: feeding problem was in 19cases,cardiac dysplasia in 20 cases,special appearance in 17 cases,skeletal dysplasia in 15 cases,hypoglycemia in 10 cases and hypotonia in 9 cases.Conclusion The typical clinical features of KS are not shown in the neonatal period.This disease should be considered when the newborn has feeding problem,abnormal cardiac morphololy,special appearance and other clinical features.Genetic test can help to diagnose earlier in clinical.Early diagnosis can provide accurate information to clinic,may help patients to acquire appropriate treatment and family genetic counseling.