Abstract：
OBJECTIVE: To explore the genetic etiology of a fetus with cryptophthalmos detected by prenatal ultrasonography.
METHODS: A fetus undergoing induced labor at 32nd gestational week due to absence of bilateral eye fissures detected by prenatal ultrasonography in January 2017 was selected as the study subject. Umbilical cord blood sample from the fetus and peripheral blood samples from its parents were collected for the extraction of genomic DNA. Pathogenic variants were screened through whole exome sequencing (WES) and verified by Sanger sequencing. Pathogenicity of candidate variants was verified by bioinformatic analysis and protein structure simulation. Based on the results of genetic testing, prenatal diagnosis was provided to the couple upon their subsequent pregnancy.
RESULTS: The couple had four adverse pregnancies previously. The aborted fetus was the fifth, with fused bilateral upper and lower eyelids, poorly developed eyeballs, adhesion of the cornea with the upper eyelid, low-set ears, and abnormal plantar creases, and was diagnosed with cryptophthalmos. WES and Sanger sequencing revealed that the fetus has harbored compound heterozygous variants of the FREM2 gene, namely c.4537G>A (p.D1513N) and c.7292C>T (p.T2431M). Both variants were unreported associated with cryptophthalmos previously. Protein structure simulation showed that they may lead to loss of hydrogen bonds in the protein product. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be likely pathogenic (PM1_Supporting+PM2_Supporting+PM5+PP3+PP4; PM2_Supporting+PM3+PP3+PP4). The mother was performed prenatal diagnosis in her sixth pregnancy based on the variants detected in this family, and delivered a daughter with normal phenotype.
CONCLUSIONS: The FREM2: c.4537G>A and c.7292C>T compound heterozygous variants probably underlay the pathogenesis of cryptophthalmos in this fetus. Above finding has enriched the mutational spectrum of the FREM2 gene.
METHODS: A fetus undergoing induced labor at 32nd gestational week due to absence of bilateral eye fissures detected by prenatal ultrasonography in January 2017 was selected as the study subject. Umbilical cord blood sample from the fetus and peripheral blood samples from its parents were collected for the extraction of genomic DNA. Pathogenic variants were screened through whole exome sequencing (WES) and verified by Sanger sequencing. Pathogenicity of candidate variants was verified by bioinformatic analysis and protein structure simulation. Based on the results of genetic testing, prenatal diagnosis was provided to the couple upon their subsequent pregnancy.
RESULTS: The couple had four adverse pregnancies previously. The aborted fetus was the fifth, with fused bilateral upper and lower eyelids, poorly developed eyeballs, adhesion of the cornea with the upper eyelid, low-set ears, and abnormal plantar creases, and was diagnosed with cryptophthalmos. WES and Sanger sequencing revealed that the fetus has harbored compound heterozygous variants of the FREM2 gene, namely c.4537G>A (p.D1513N) and c.7292C>T (p.T2431M). Both variants were unreported associated with cryptophthalmos previously. Protein structure simulation showed that they may lead to loss of hydrogen bonds in the protein product. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be likely pathogenic (PM1_Supporting+PM2_Supporting+PM5+PP3+PP4; PM2_Supporting+PM3+PP3+PP4). The mother was performed prenatal diagnosis in her sixth pregnancy based on the variants detected in this family, and delivered a daughter with normal phenotype.
CONCLUSIONS: The FREM2: c.4537G>A and c.7292C>T compound heterozygous variants probably underlay the pathogenesis of cryptophthalmos in this fetus. Above finding has enriched the mutational spectrum of the FREM2 gene.
摘要：
目的：探讨产前超声检查发现隐胸胎儿的遗传学病因。
方法：选择2017年1月因产前超声检查发现双侧眼裂而在第32孕周进行引产的胎儿作为研究对象。收集来自胎儿的脐带血样品和来自其父母的外周血样品用于提取基因组DNA。通过全外显子组测序(WES)筛选致病变体,并通过Sanger测序进行验证。通过生物信息学分析和蛋白质结构模拟验证了候选变体的致病性。根据基因检测的结果,这对夫妇在随后怀孕时提供了产前诊断。
结果：这对夫妇之前有过四次不良妊娠。流产的胎儿是第五个，双侧上下眼睑融合，发育不良的眼球，角膜与上眼睑的粘连，低设定的耳朵，和不正常的足底折痕,并被诊断出患有隐脑症.WES和Sanger测序显示，胎儿具有FREM2基因的复合杂合变体，即c.4537G>A（p。D1513N）和c.7292C>T（p。T2431M)。这两种变体以前都未报道过与隐thalmos相关。蛋白质结构模拟表明，它们可能导致蛋白质产物中氢键的丧失。根据美国医学遗传学和基因组学学院（ACMG）的指南，预测这两种变体可能是致病性的(PM1_支持+PM2_支持+PM5+PP3+PP4;PM2_支持+PM3+PP3+PP4)。根据该家族中检测到的变异，母亲在第六次怀孕时进行了产前诊断，产下一个表型正常的女儿.
结论：FREM2：c.4537G>A和c.7292C>T复合杂合变体可能是该胎儿隐丘脑的发病机理的基础。以上发现丰富了FREM2基因的突变谱。
方法：选择2017年1月因产前超声检查发现双侧眼裂而在第32孕周进行引产的胎儿作为研究对象。收集来自胎儿的脐带血样品和来自其父母的外周血样品用于提取基因组DNA。通过全外显子组测序(WES)筛选致病变体,并通过Sanger测序进行验证。通过生物信息学分析和蛋白质结构模拟验证了候选变体的致病性。根据基因检测的结果,这对夫妇在随后怀孕时提供了产前诊断。
结果：这对夫妇之前有过四次不良妊娠。流产的胎儿是第五个，双侧上下眼睑融合，发育不良的眼球，角膜与上眼睑的粘连，低设定的耳朵，和不正常的足底折痕,并被诊断出患有隐脑症.WES和Sanger测序显示，胎儿具有FREM2基因的复合杂合变体，即c.4537G>A（p。D1513N）和c.7292C>T（p。T2431M)。这两种变体以前都未报道过与隐thalmos相关。蛋白质结构模拟表明，它们可能导致蛋白质产物中氢键的丧失。根据美国医学遗传学和基因组学学院（ACMG）的指南，预测这两种变体可能是致病性的(PM1_支持+PM2_支持+PM5+PP3+PP4;PM2_支持+PM3+PP3+PP4)。根据该家族中检测到的变异，母亲在第六次怀孕时进行了产前诊断，产下一个表型正常的女儿.
结论：FREM2：c.4537G>A和c.7292C>T复合杂合变体可能是该胎儿隐丘脑的发病机理的基础。以上发现丰富了FREM2基因的突变谱。
