三例Mowat-Wilson综合征患儿的临床特征及基因分析

Clinical characteristics and genetic analysis of 3 children with Mowat-Wilson syndrome

目的探讨3例伴有特殊面容的智力障碍/发育迟缓患儿的遗传学特征。方法采集患儿的外周血样,分别进行G显带染色体核型分析和染色体微阵列分析(chromosomal microarray analysis,CMA),并对患儿3进行全外显子组测序(whole exome sequencing,WES)。结果3例患儿的染色体核型均未见异常。CMA检测患儿1为arr[GRCh37]:2q22.3(145128071-145159029)×1,存在大约31 kb的缺失,为致病性拷贝数变异,涉及ZEB2基因第8~10外显子;患儿2为arr[hg19]:2q22.3(145071457-146881759)×1,存在1.81 Mb的缺失,涉及ZEB2和GTDC1基因;患儿3为arr[GRCh37]:9p23p23(11698261-12106261)×1,存在408 kb的缺失,未涉及相关基因。WES结果显示其ZEB2基因第8外显子存在c.2102C>A(p.Ser701*)的无义变异,该变异已被ClinVar数据库收录,评级为致病性,Sanger测序验证为新发变异。结论Mowat-Wilson综合征的临床表型和遗传异质性较大,对不明原因的发育迟缓/智力障碍患儿,尤其是合并特殊面容和多种先天畸形者,CMA和WES检测将有助于明确病因。

Objective To explore the genetic basis of three children with unexplained mental retardation/developmental delay.Methods Peripheral venous blood samples were collected for routine G-banding karyotyping analysis and chromosomal microarray analysis(CMA).Whole exome sequencing(WES)was also carried out for patient 3.Results The karyotypes of the 3 children were normal.The result of CMA analysis of patient 1 was arr[GRCh37]:2q22/3(145128071-145159029)×1,with a 31 kb deletion,which was predicted to be a pathogenic copy number variation.The deletion has involved exons 8 to 10 of the ZEB2 gene.Patient 2 was arr[hg19]:2q22.3(145071457-146881759)×1,with a 1.81 Mb deletion involving the ZEB2 and GTDC1 genes.Patient 3 was arr[GRCh37]:9p23p23(11698261-12106261)×1,with a 408 kb deletion containing no disease-associated gene.WES has identified a c.2102C>A(p.Ser701*)variant in exon8 of the ZEB2 gene,which was included in ClinVar database and rated as pathogenic,and verified by Sanger sequencing as a de novo variant.Conclusion For the substantial clinical and genetic heterogeneity of Mowat-Wilson syndrome,CMA and WES are helpful to identify the etiology of children with developmental delay/mental retardation of unknown causes,particularly those with peculiar facial features and multiple congenital malformations.