目的 对1例Meckel综合征(MKS)胎儿进行产前诊断，明确其致病原因。 方法 选取2018年2月就诊于苏州市立医院的1例孕妇作为研究对象，收集其临床信息。采集引产胎儿肌肉组织标本以及孕妇夫妇的外周血样，进行染色体微阵列分析(CMA)和全外显子组测序，并用Sanger测序对候选变异进行验证。 结果 孕18周超声提示胎儿存在小头畸形、小脑香蕉征、多囊肾和羊水过少。引产后观察到胎儿脑膨出、多指和肾脏囊形结构。胎儿CMA检测未见异常。基因测序提示引产胎儿TMEM67基因存在母源c.296delA(p.Lys99SerfsTer6)和父源c.1243G>A(p.Val415Met)变异。根据美国医学遗传学与基因组学学会变异相关指南，c.296del被评级为致病性变异(PVS1＋PM2_Supporting＋PP4)，c.1243G>A被评级为可能致病性变异(PM2_Supporting＋PM3＋PP3_Moderate＋PP4)。 结论 TMEM67基因c.296delA和c.1243G>A变异可能是该MKS胎儿的遗传学病因。 Objective To carry out prenatal diagnosis for a fetus with Meckel syndrome(MKS) and explore its genetic basis. Methods A pregnant woman presented at Suzhou Municipal Hospital in February 2018 was selected as the study subject. Clinical data was collected. Muscle tissue sample from the abortus and peripheral blood samples from the couple were collected. Genomic DNA was extracted and subjected to chromosomal microarray analysis (CMA) and whole exome sequencing. Candidate variant was verified by Sanger sequencing. Results The fetus was found to have microcephaly, oligohydramnios, polycystic kidneys and banana-shaped cerebellum at 18 weeks of gestation. After induction of labor, it was found to have encephalocele, renal cysts and polydactyly. CMA has found no abnormality. Whole exome sequencing revealed novel compound heterozygous variants c. 296delA (p.Lys99SerfsTer6) and c. 1243G>A (p.Val415Met) in theTMEM67 gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c. 296delA variant was predicted to be pathogenic (PVS1+ PM2_Supporting+ PP4), whilst the c. 1243G>A variant was predicted to be likely pathogenic (PM2_Supporting+ PM3+ PP3_Moderate+ PP4). Conclusion The c. 296delA and c. 1243G>A compound heterozygous variants of theTMEM67 gene probably underlay the MKS in this fetus.
Genetic analysis of a fetus with Meckel syndrome due to variants ofTMEM67 gene
Objective To carry out prenatal diagnosis for a fetus with Meckel syndrome(MKS) and explore its genetic basis. Methods A pregnant woman presented at Suzhou Municipal Hospital in February 2018 was selected as the study subject. Clinical data was collected. Muscle tissue sample from the abortus and peripheral blood samples from the couple were collected. Genomic DNA was extracted and subjected to chromosomal microarray analysis (CMA) and whole exome sequencing. Candidate variant was verified by Sanger sequencing. Results The fetus was found to have microcephaly, oligohydramnios, polycystic kidneys and banana-shaped cerebellum at 18 weeks of gestation. After induction of labor, it was found to have encephalocele, renal cysts and polydactyly. CMA has found no abnormality. Whole exome sequencing revealed novel compound heterozygous variants c. 296delA (p.Lys99SerfsTer6) and c. 1243G>A (p.Val415Met) in theTMEM67 gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c. 296delA variant was predicted to be pathogenic (PVS1+ PM2_Supporting+ PP4), whilst the c. 1243G>A variant was predicted to be likely pathogenic (PM2_Supporting+ PM3+ PP3_Moderate+ PP4). Conclusion The c. 296delA and c. 1243G>A compound heterozygous variants of theTMEM67 gene probably underlay the MKS in this fetus.
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