心脏瓣膜发育不全1型胎儿1例的临床表型及遗传学分析

Clinical phenotype and genetic analysis of a fetus with Cardiac valvular dysplasia type 1

目的分析1例心脏瓣膜发育不全1型(CVDP1)引产胎儿的遗传学病因。方法选取2022年7月7日在宁波市妇女儿童医院就诊的1例CVDP1胎儿为研究对象。收集胎儿的临床资料。应用家系全外显子组测序(trio-WES)技术对胎儿及父母进行致病基因检测,针对可疑致病变异,进行Sanger测序家系验证。结果胎儿表现为全身水肿、心脏复杂畸形、腹腔积液、肠管回声增强及双肾实质回声增强。WES结果显示胎儿携带PLD1基因c.2977C>T(p.R993*)和c.1460G>A(p.W487*)复合杂合变异,分别遗传自其父母。2个变异既往均未见报道。根据美国医学遗传学与基因组学学会遗传变异标准和指南,c.2977C>T(p.R993*)变异评估为可能致病性(PVS1_Moderate+PM2_Supporting+PM3+PP4),c.1460G>A(p.W487*)变异评估为致病性(PVS1+PM2_Supporting+PP4)。结论PLD1基因c.2977C>T(p.R993*)和c.1460G>A(p.W487*)复合杂合变异可能为本研究胎儿的遗传学病因。新变异位点的发现丰富了PLD1基因变异谱,并为该家系的遗传咨询和产前诊断提供了指导。

Objective To explore the genetic basis for a fetus with Cardiac valvular dysplasia type 1(CVDP1).Methods A CVDP1 fetus identified at the Ningbo Women and Children′s Hospital on July 7,2022 was selected as the study subject.Clinical data of the fetus was collected.The fetus and its parents were subjected to trio-whole exome sequencing(trio-WES),and candidate variants were verified by Sanger sequencing.Results The fetus had exhibited generalized edema,complex cardiac malformation,abdominal effusion,and enhanced intestinal and renal parenchymal echoes.Trio-WES revealed that it has harbored compound heterozygous variants of the PLD1 gene,namely c.2977C>T(p.R993*)and c.1460G>A(p.W487*),which were respectively inherited from its father and mother.Neither variant was reported previously.Based on the guidelines from the American College of Medical Genetics and Genomics(ACMG),the c.2977C>T(p.R993*)variant was evaluated to be likely pathogenic(PVS1_Moderate+PM2_Supporting+PM3+PP4),whilst the c.1460G>A(p.W487*)variant was evaluated to be pathogenic(PVS1+PM2_Supporting+PP4).Conclusion The c.2977C>T(p.R993*)and c.1460G>A(p.W487*)compound heterozygous variants of the PLD1 gene probably underlay the CVDP1 in the fetus.Above discovery has enriched the mutational spectrum of the PLD1 gene and provided a guidance for genetic counseling and prenatal diagnosis in this family.