目的 对1例具有手部畸形的引产胎儿进行高通量测序，以明确其遗传学病因。 方法 选取2018年10月20日在湖北省妇幼保健院经超声确诊的1例手部发育异常的胎儿作为研究对象。收集孕妇的基本资料及影像学检查结果，采集引产胎儿的脐带组织以及孕妇夫妇的外周静脉血样，提取基因组DNA，进行拷贝数变异测序(CNV-seq)与家系全外显子组测序(trio-WES)，对检出的候选变异进行家系验证。 结果 孕30＋2周超声提示胎儿右手小，大拇指可显示，其余四指短缺，左手未见异常。CNV-seq未检出大于100 kb的拷贝数变异；trio-WES检测结果显示胎儿携带SMC3基因c.3298G>A(p.Val1100Met)杂合变异。该变异位点在正常人群数据库中未见收录，多个生物信息软件均预测为有害变异。多序列比对发现该位点在不同物种中高度保守。Sanger测序结果显示孕妇夫妇均未携带该变异，提示其为新发变异。根据美国医学遗传学与基因组学学会(ACMG)相关指南，判定该变异为可能致病性变异(PS2＋PM2_Supporting＋PP3)。 结论 SMC3基因c.3298G>A变异可能是上述胎儿具有手部畸形的遗传学病因，胎儿被诊断为德朗热综合征。 Objective To explore the genetic basis for a fetus featuring oligodactyly. Methods A fetus with hand deformity identified by ultrasound at the Maternal and Child Health Care Hospital of Hubei Province on October 20, 2018 was selected as the study subject. Clinical information and ultrasonographic finding of the pregnant woman were collected. Following elected abortion, umbilical cord and peripheral venous blood samples of the couple were collected for the extraction of genomic DNA. Copy number variation sequencing (CNV-seq) and trio-whole exome sequencing (trio-WES) were carried out. Candidate variants were verified by Sanger sequencing. Results Ultrasonographic examination at 30+ 2 weeks of gestation revealed that the fetus had small right hand with absence of 2nd ~ 5th fingers, whilst its left hand had appeared to be normal. By CNV-seq, no pathogenic or likely pathogenic copy number variation (CNV) (> 100 kb) was detected in the fetus. Trio-WES revealed that the fetus had harbored a novel heterozygous c.3298G>A (p.Val1100Met) variant of theSMC3 gene. The variant has not been recorded in the population databases, and was predicted to be deleterious by several bioinformatics software and evolutionarily conserved based on multiple sequence alignment analysis. Sanger sequencing showed that neither parent has carried the same variant. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be likely pathogenic (PS2+ PM2_Supporting+ PP3). Conclusion The fetus was diagnosed with Cornelia de Lange syndrome, for which the novel heterozygous c.3298G>A variant of theSMC3 gene may be accountable.
Genetic analysis of a fetus with Cornelia de Lange syndrome due to variant ofSMC3 gene
Objective To explore the genetic basis for a fetus featuring oligodactyly. Methods A fetus with hand deformity identified by ultrasound at the Maternal and Child Health Care Hospital of Hubei Province on October 20, 2018 was selected as the study subject. Clinical information and ultrasonographic finding of the pregnant woman were collected. Following elected abortion, umbilical cord and peripheral venous blood samples of the couple were collected for the extraction of genomic DNA. Copy number variation sequencing (CNV-seq) and trio-whole exome sequencing (trio-WES) were carried out. Candidate variants were verified by Sanger sequencing. Results Ultrasonographic examination at 30+ 2 weeks of gestation revealed that the fetus had small right hand with absence of 2nd ~ 5th fingers, whilst its left hand had appeared to be normal. By CNV-seq, no pathogenic or likely pathogenic copy number variation (CNV) (> 100 kb) was detected in the fetus. Trio-WES revealed that the fetus had harbored a novel heterozygous c.3298G>A (p.Val1100Met) variant of theSMC3 gene. The variant has not been recorded in the population databases, and was predicted to be deleterious by several bioinformatics software and evolutionarily conserved based on multiple sequence alignment analysis. Sanger sequencing showed that neither parent has carried the same variant. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be likely pathogenic (PS2+ PM2_Supporting+ PP3). Conclusion The fetus was diagnosed with Cornelia de Lange syndrome, for which the novel heterozygous c.3298G>A variant of theSMC3 gene may be accountable.
Cornelia de Lange syndromeSMC3 geneWhole exome sequencingSanger sequencing
万方数据
