1例Pitt-Hopkins综合征患儿的临床及遗传学分析

Clinical and genetic analysis of a child with Pitt-Hopkins syndrome

目的探讨1例智力障碍、特殊面容、语言发育迟缓及行为异常患儿的遗传学病因,为遗传咨询及产前诊断提供依据。方法选取2022年11月17日在临沂市人民医院遗传咨询门诊就诊的1例智力障碍、特殊面容、语言发育迟缓及行为异常患儿为研究对象,对患儿及其父母进行全外显子测序(WES),应用生物信息学分析筛选致病性变异,通过Sanger测序对先证者及其父母进行变异位点验证并对胎儿进行产前诊断。结果基因检测发现患儿的TCF4基因存在c.1486+1G>T杂合变异,为新生变异(de novo mutation),在受检者父母中均未检出此变异。TCF4基因与Pitt-Hopkins综合征(OMIM#610954)相关,为常染色体显性遗传。经检索HGMD、PubMed、1000 Genomes等数据库,该变异位点未被收录,根据ACMG指南,该变异判读为致病性变异(PVS1+PS2+PM2_P)。经产前诊断提示腹中胎儿未携带该变异。结论TCF4基因的c.1486+1G>T变异是该患儿的致病原因,该患儿为1例Pitt-Hopkins综合征患儿。

Objective To explore the clinical features and genetic etiology of one child with Mental retardation,special facial features,language retardation and abnormal behavior,so as to provide references for clinical genetic counseling and prenatal diagnosis.Methods A child with Mental retardation,special facial features,language retardation and abnormal behavior was selected as research subject of this study.The child and her parents visited Genetic counseling Clinic,Linyi People's Hospital on 17 November 2022.Peripheral blood samples were taken from the child and her parents and subjected for whole exome sequencing(WES).Candidate variants were verified by Sanger sequencing.Bioinformatic software was used to analyze the pathogenicity of the protein model for the variant loci,and prenatal diagnosis was performed on the fetus.Results WES revealed that the propositus has a heterozygous splicing variant of TCF4 gene,namely c.1486+1G>T,for which both of her parents were of wild-type.Pitt-Hopkins syndrome(PTHS)(OMIM#610954)is a group of autosomal recessive disorder,caused by deletions of or variants in the TCF4 gene.Above mutation was not found in HGMD,PubMed,1000 Genomes.Based on the guidelines from the American College of Medical Genetics and Genomics(ACMG),the c.1486+1G>T variant was graded as pathogenic(PVS1+PS2+PM2_P).The fetus does not carry the same variation by prenatal diagnosis.Conclusion The c.1486+1G>T mutation in the TCF4 gene underlay the pathogenesis of Pitt-Hopkins syndrome in this child,respectively.