DLG3基因p.S434S同义变异致智力障碍家系分析及产前诊断1例  

Pedigree analysis and prenatal diagnosis of intellectual disability caused by synonymous mutations of p.S434S in DLG3 gene

作　　者：黄佳 朱宏杰 何嘉欢 李茜 雷星星 王红丹 李聪敏 王悦 刘红彦 Huang Jia;Zhu Hongjie;He Jiahuan;Li Xi;Lei Xingxing;Wang Hongdan;Li Congmin;Wang Yue;Liu Hongyan(Institute of Medical Genetics,Henan Provincial People's Hospital,People's Hospital of Zhengzhou University,Zhengzhou 450003,China;Department of Gynecology and Obstetrics,Henan Provincial People's Hospital,People's Hospital of Zhengzhou University,Zhengzhou 450003,China)

机构地区：[1]郑州大学人民医院河南省人民医院医学遗传研究所,郑州450003 [2]郑州大学人民医院河南省人民医院妇产科,郑州450003

出　　处：《中华围产医学杂志》2022年第1期42-47,共6页Chinese Journal of Perinatal Medicine

基　　金：河南省科技攻关计划(202102310038)。

摘　　要：目的对1个智力障碍家系进行致病基因鉴定及产前诊断。方法家系3代17人,4例男性罹患智力障碍,2019年10月先证者之姐于孕8周时就诊于河南省人民医院要求遗传咨询。签署知情同意书后,采集家系成员外周血,采用全外显子组测序分析先证者(Ⅱ-9,男)及父母基因编码序列,筛选候选致病变异,运用Sanger测序进行候选变异与表型共分离分析。采用同源重组构建候选变异表达载体,进行体外剪接实验,应用逆转录聚合酶链反应、TA克隆和Sanger测序分析候选致病变异对剪接的影响。明确智力障碍的遗传学病因后,采用goldeneyeTM20A基因分型系统和Sanger测序为先证者之姐(Ⅱ-7)进行产前诊断。结果全外显子组测序结果显示先证者携带DLG3基因c.1302G>A(p.S434S)半合子同义变异,该变异与家系内患者表型共分离,先证者之母(Ⅰ-1)为该变异杂合携带者。体外剪接实验结果显示c.1302G>A变异明显影响RNA的正常剪接,88.24%的转录本剪接异常,导致阅读框移码,蛋白功能受损。产前诊断胎儿(Ⅲ-7)羊水未检测到该变异,男胎活产,现1岁6月龄,精神行为发育未见异常,继续随访中。结论DLG3基因c.1302G>A同义变异是导致该家系X连锁智力障碍的原因。Objective To analyze the pathogenic gene and prenatal diagnosis of a family with intellectual disability.Methods Out of this family consisting of 17 members in three generations,four males had intellectual disability.The proband's elder sister(Ⅱ-7)visited Henan Provincial People's Hospital in Oct 2019 for genetic counseling at 8 weeks of gestation.After informed consent was obtained,peripheral blood samples of the family members were collected.The whole exome sequencing was performed on the genome DNA of the proband(Ⅱ-9,male)and his parents to screen the candidate variants for phenotype co-segregated analysis by Sanger sequencing.The expression vectors were constructed by homologous recombination and the splicing experiments were performed in vitro.Reverse transcription polymerase chain reaction,Sanger sequencing,and TA clone sequencing were used to analyze the effect of candidate variants on splicing.After the pathogenic variant was determined the proband's elder sister underwent prenatal diagnosis(Ⅲ-7)using goldeneyeTM20A genotyping system and Sanger sequencing.Results A hemizygous synonymous variant of c.1302G>A(p.S434S)in DLG3 gene was found in the proband by whole exome sequencing,which was carried by his mother(Ⅰ-1)and co-segregated with the phenotype in other family patients.In vitro splicing experiment showed that c.1302G>A variant led to abnormal splicing of 88.24%transcripts,which further resulted in the reading frame shift and protein function impairment.The mutation was not detected in the fetus(Ⅲ-7),who was born alive later and showed no abnormal mental or behavioral development at the age of one and a half year and is still being followed up.Conclusions The synonymous mutation c.1302G>A in DLG3 gene was the etiopathogenesis of X-linked intellectual disability in this family.

关 键 词：智力障碍 核蛋白质类 转录因子 沉默变异 全外显子组测序 产前诊断 

分 类 号：R714.5[医药卫生—妇产科学]