Analysis of a Chinese pedigree affected with Meckel syndrome due to variants ofTMEM67 gene
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目的 探讨1个疑似麦克尔综合征家系的遗传学病因。 方法 选取2017年8月31日因"连续3次不良妊娠史"就诊于郑州大学第一附属医院的1个家系作为研究对象，收集家系相关临床资料。对该家系第3个引产胎儿组织通过高通量测序进行纤毛病相关致病基因变异筛选并用Sanger测序进行家系验证。 结果 该家系第1个胎儿妊娠过程中出现胚胎停育，第2个胎儿临床疑诊为纤毛病，后引产但未行进一步的病因检测，第3个胎儿疑诊为纤毛病且经高通量测序及Sanger测序检测，结果提示胎儿TMEM67基因存在父源的c.978＋1G>A和母源的c.1288G>C(p.D430H)复合杂合变异。依据美国医学遗传学与基因组学学会相关变异指南与标准，c.978＋1G>A评级为致病性变异(PVS1＋PM2_Supporting＋PP5)，c.1288G>C(p.D430H)评级为可能致病性变异(PM2_Supporting＋PM3＋PM5＋PP3)。 结论 TMEM67基因c.978＋1G>A和c.1288G>C(p.D430H)复合杂合变异应为该家系3次疑似纤毛病不良妊娠的遗传学病因。TMEM67基因c.1288G>C(p.D430H)变异的发现拓宽了TMEM67基因致病变异谱。 Objective To explore the genetic etiology for a Chinese pedigree affected with Meckel syndrome. Methods A pedigree with a history of three consecutive adverse pregnancies which presented at the First Affiliated Hospital of Zhengzhou University on August 31, 2017 was selected as the study subject. Clinical data of the pedigree were collected. High-throughput sequencing was carried out to screen for variants of ciliopathy-related genes in the third fetus following induced abortion, and candidate variant was verified by Sanger sequencing. Results The first pregnancy of the couple had ended as spontaneous abortion, whilst the fetus of the second pregnancy was suspected for having ciliopathy, though no genetic testing was carried out following elected abortion. The fetus of the third pregnancy was suspected for having ciliopathy, and high-throughput sequencing and Sanger sequencing had shown that the fetus had harbored compound heterozygous variants of the TMEM67 gene, including c. 978+ 1G>A from the father and c. 1288G>C (p.D430H) from the mother. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c. 978+ 1G>A was classified as a pathogenic variant (PVS1+ PM2_Supporting+ PP5), whilst the newly discovered c. 1288G>C (p.D430H) was classified as a likely pathogenic variant (PM2_Supporting+ PM3+ PM5+ PP3). Conclusion The c. 978+ 1G>A and c. 1288G>C (p.D430H) compound heterozygous variants of theTMEM67 gene probably underlay the three consecutive adverse pregnancies suspected for ciliopathy in this pedigree. The discovery of c. 1288G>C (p.D430H) has also expanded the mutational spectrum of theTMEM67 gene.
Objective To explore the genetic etiology for a Chinese pedigree affected with Meckel syndrome. Methods A pedigree with a history of three consecutive adverse pregnancies which presented at the First Affiliated Hospital of Zhengzhou University on August 31, 2017 was selected as the study subject. Clinical data of the pedigree were collected. High-throughput sequencing was carried out to screen for variants of ciliopathy-related genes in the third fetus following induced abortion, and candidate variant was verified by Sanger sequencing. Results The first pregnancy of the couple had ended as spontaneous abortion, whilst the fetus of the second pregnancy was suspected for having ciliopathy, though no genetic testing was carried out following elected abortion. The fetus of the third pregnancy was suspected for having ciliopathy, and high-throughput sequencing and Sanger sequencing had shown that the fetus had harbored compound heterozygous variants of the TMEM67 gene, including c. 978+ 1G>A from the father and c. 1288G>C (p.D430H) from the mother. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c. 978+ 1G>A was classified as a pathogenic variant (PVS1+ PM2_Supporting+ PP5), whilst the newly discovered c. 1288G>C (p.D430H) was classified as a likely pathogenic variant (PM2_Supporting+ PM3+ PM5+ PP3). Conclusion The c. 978+ 1G>A and c. 1288G>C (p.D430H) compound heterozygous variants of theTMEM67 gene probably underlay the three consecutive adverse pregnancies suspected for ciliopathy in this pedigree. The discovery of c. 1288G>C (p.D430H) has also expanded the mutational spectrum of theTMEM67 gene.
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