母源低比例TCF4基因嵌合变异所致Pitt-Hopkins综合征患儿1例的遗传学分析

Genetic analysis of a child with Pitt-Hopkins syndrome due to a novel variant of TCF4 gene derived from low percentage maternal mosaicism

目的探讨l例Pitt-Hopkins综合征患儿的遗传学病因。方法选取2021年2月24日就诊于甘肃省妇幼保健院医学遗传中心遗传门诊的1例Pitt-Hopkins综合征患儿及其一级亲属为研究对象。收集先证者的临床资料,提取先证者及其父母的外周血样基因组DNA进行家系全外显子组测序(trio-WES),针对候选变异进行Sanger测序验证,并对先证者进行染色体核型分析,对其再孕母亲进行超高深度测序和羊水产前诊断。结果先证者表现为特殊面容、通贯掌、精神发育迟滞及智力异常。基因检测提示其携带TCF4基因c.1762C>T(p.Arg588Cys)杂合变异,其父母均为野生型。该变异既往未见报道,根据美国医学遗传学与基因组学学会(ACMG)相关指南评估为可能致病。超高深度测序提示先证者母亲该位点的变异率为2.63%,提示存在低比例嵌合。羊水产前诊断结果提示胎儿未携带同样的致病变异。结论先证者TCF4基因c.1762C>T杂合变异可能是其遗传学病因,其致病变异可能源于母亲的低比例嵌合变异。

Objective To explore the genetic etiology of a child with Pitt-Hopkins syndrome.Methods A child who had presented at the Medical Genetics Center of Gansu Provincial Maternal and Child Health Care Hospital on February 24,2021 and his parents were selected as the study subjects.Clinical data of the child was collected.Genomic DNA was extracted from peripheral blood samples of the child and his parents and subjected to trio-whole exome sequencing(trio-WES).Candidate variant was verified by Sanger sequencing.Karyotype analysis was also carried out for the child,and her mother was subjected to ultra-deep sequencing and prenatal diagnosis upon her subsequent pregnancy.Results The clinical manifestations of the proband included facial dysmorphism,Simian crease,and mental retardation.Genetic testing revealed that he proband has carried a heterozygous c.1762C>T(p.Arg588Cys)variant of the TCF4 gene,for which both parents had a wild-type.The variant was unreported previously and was rated as likely pathogenic based on the guidelines of the American College of Medical Genetics and Genomics(ACMG).Ultra-deep sequencing indicated that the variant has a proportion of 2.63%in the mother,suggesting the presence of low percentage mosaicism.Prenatal diagnosis of amniotic fluid sample suggested that the fetus did not carry the same variant.Conclusion The heterozygous c.1762C>T variant of the TCF4 gene probably underlay the disease in this child and has derived from the low percentage mosaicism in his mother.