GCDH基因新变异致戊二酸血症Ⅰ型的遗传学分析及产前诊断

Genetic analysis and prenatal diagnosis of novel GCDH variant responsible for glutaric aciduria typeⅠ

目的寻找戊二酸血症Ⅰ型(GAⅠ)致病基因,为相关疾病的产前诊断提供依据。方法对1例疑似GAⅠ家系先证者的DNA进行全外显子组测序,并对先证者及其父母进行DNA Sanger测序验证,确定变异位点,分析变异的致病性;随后对先证者孕18周母亲进行羊膜腔穿刺,获取胎儿羊水DNA进行戊二酰辅酶A脱氢酶(GCDH)基因测序分析。以“戊二酸血症Ⅰ型/Glutarate disease typeⅠ”“GCDH”以及“产前诊断/Prenatal diagnosis”为检索词,检索PubMed、CNKI、万方数据知识服务平台、维普中文科技期刊数据库,收集并分析GAⅠ产前诊断的文献资料。结果先证者外周血DNA中检测到GCDH基因(NM_000159.3)的2个变异:父源性c.206_207delAC(p.Thr70Leufs^(*)117)和母源性c.892G>A(p.Ala298Thr)。父源的c.206_207delAC变异为未见报道的新变异,母源的c.892G>A变异为已知突变,致病性分析均判定为致病变异。先证者母亲羊水的基因检测提示GCDH基因复合杂合变异:c.206_207delAC和c.892G>A。先证者父母选择终止妊娠。文献共检索到GCDH基因测序分析产前诊断GAⅠ的9例家系,其中4例家系中5例胎儿的产前诊断为GAⅠ,4例胎儿家属选择终止妊娠,仅有1例胎儿家属要求继续妊娠并足月分娩。结论在GAⅠ家系中发现了GCDH基因一个新的变异c.206_207delAC,明确了GAⅠ家系先证者的GCDH基因致病变异位点。

Objective To identify pathogenic gene variants of glutaric aciduria typeⅠ(GAⅠ)and provide reference for prenatal diagnosis of this disease.Methods Genomic DNA was extracted from the family members of a suspected case of GAⅠ.Whole exome sequencing was performed on the proband,and DNA Sanger sequencing was performed on the parents to verify the variants and analyze their pathogenicity.Amniotic fluid fetal cells were extracted by amniocentesis at 18 weeks of gestation to detect GCDH gene.Literature review was conducted from PubMed,CNKI,Wanfang Data and Ch ongqing VIP databases using the keywords of“glutaric aciduria typeⅠ”,“GCDH”and prenatal diagnosis in both Chinese and English.Results Two variants of GCDH gene were detected in the proband:c.206_207delAC(p.Thr70Leufs^(*)117)and c.892G>A(p.Ala298Thr),from the father and mother,respectively.The paternal variant was a novel variant,and the maternal variant was a known variant.And two variants were both pathogenic.GCDH gene variant analysis of amniotic fluid fetal cells showed compound heterozygous c.206_207delAC and c.892G>A variants.The couple decided to terminate the pregnancy thereafter.A total of 9 families with prenatal diagnosis of GAⅠwere retrieved by GCDH g ene sequencing analysis.Among them,5 fetuses from 4 families had prenatal diagnosis of GAⅠ.Four families decided to terminate the pregnancy,and only 1 family insisted o n continuing pregnancy until full-term delivery.Conclusions The novel variant of GCDH gene(c.206_207delAC)is detected in this family of GAⅠ.The pathogenic variant sites of GCDH gene are identified in the proband of this GAⅠfamily.