Genetic analysis of a pregnant woman with moderate intellectual disability due to variant ofDLG4 gene
时盼来 1赵学潮 1刘莉娜 1夏艳洁 1王聪慧 1陈铎 1侯雅勤 1白周现 1孔祥东 1许芯 李岭
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作者信息
1. 郑州大学第一附属医院遗传与产前诊断中心，郑州 450052
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摘要
目的 探讨1例中度智力低下(ID)孕妇的遗传学病因，并为其提供产前诊断。 方法 以2021年4月28日在郑州大学第一附属医院就诊的1例孕18周的ID孕妇作为研究对象，收集孕妇及其胎儿的临床资料，并采集其外周血样以及羊水样本用于检测。通过低深度全基因组测序(CNV-seq)分析孕妇基因组的拷贝数变异(CNVs)，再通过全外显子组测序(WES)及Sanger测序检测和验证候选基因变异。根据基因检测的结果，对胎儿进行Sanger测序验证，并通过CNV-seq及多重连接探针扩增技术(MLPA)检测胎儿的CNVs。 结果 孕妇为23岁，中度智力低下、走路偏向一侧，持物不稳，孕18+3周胎儿发育未见异常。CNV-seq未发现其存在致病CNVs，WES发现其DLG4基因存在c.1675C>T(p.Arg559*)杂合变异，经Sanger测序验证。根据美国医学遗传学与基因组学学会相关指南，上述变异被判定为可能致病性变异(PVS1+PM2_Supporting)。Sanger测序发现胎儿亦携带DLG4基因c.1675C>T(p.Arg559*)杂合变异，同时CNV-seq发现其Xp21.1区存在0.1 Mb杂合缺失，涉及DMD基因，经MLPA检测得到验证。 结论 DLG4基因c.1675C>T杂合变异可能是该孕妇智力低下的遗传学病因，其胎儿携带相同变异以及DMD基因的缺失，发生智力低下62型的风险较高。 Objective To carry out genetic testing and prenatal diagnosis for a woman featuring moderate intellectual disability (ID). Methods The patient had presented at the First Affiliated Hospital of Zhengzhou University on April 28, 2021. With informed consent, peripheral blood and amniotic fluid samples were collected for the extraction of genomic DNA. Pathogenic copy number variation (CNVs) were detected with CNV-seq, and single gene variants were detected by whole exome sequencing (WES) and Sanger sequencing. Candidate varianttions verified by Sanger sequencing, and CNV-seq and multiplex ligation-dependent probe amplification (MLPA) were used to detect fetal CNVs. Results The 23-year-old woman had moderate ID, sideway walking, and unstable holding. Ultrasonography at 18+ 3 weeks′ gestation had revealed no fetal abnormality. No pathogenic CNV was detected in the woman by CNV-seq, while WES revealed that she has harbored a heterozygous c. 1675C>T (p.Arg559*) variant of theDLG4 gene, which was verified by Sanger sequencing. Based on guidelines from the American College of Medical Genetics and Genomics, the variant was predicted to be likely pathogenic (PVS1+ PM2_Supporting). Sanger sequencing has confirmed that the fetus has inherited this variant, and CNV-seq also revealed that that fetus has harbored a 0.1 Mb heterozygous deletion at Xp21.1, which has encompassed the DMD gene, and the result was verified by MLPA. Conclusion The heterozygous c. 1675C>T variant of theDLG4 gene probably underlay the mental retardation in this woman, and her fetus was found to harbor the same variant in addition with deletion of the DMD gene, which may predispose to ID type 62.
Abstract
Objective To carry out genetic testing and prenatal diagnosis for a woman featuring moderate intellectual disability (ID). Methods The patient had presented at the First Affiliated Hospital of Zhengzhou University on April 28, 2021. With informed consent, peripheral blood and amniotic fluid samples were collected for the extraction of genomic DNA. Pathogenic copy number variation (CNVs) were detected with CNV-seq, and single gene variants were detected by whole exome sequencing (WES) and Sanger sequencing. Candidate varianttions verified by Sanger sequencing, and CNV-seq and multiplex ligation-dependent probe amplification (MLPA) were used to detect fetal CNVs. Results The 23-year-old woman had moderate ID, sideway walking, and unstable holding. Ultrasonography at 18+ 3 weeks′ gestation had revealed no fetal abnormality. No pathogenic CNV was detected in the woman by CNV-seq, while WES revealed that she has harbored a heterozygous c. 1675C>T (p.Arg559*) variant of theDLG4 gene, which was verified by Sanger sequencing. Based on guidelines from the American College of Medical Genetics and Genomics, the variant was predicted to be likely pathogenic (PVS1+ PM2_Supporting). Sanger sequencing has confirmed that the fetus has inherited this variant, and CNV-seq also revealed that that fetus has harbored a 0.1 Mb heterozygous deletion at Xp21.1, which has encompassed the DMD gene, and the result was verified by MLPA. Conclusion The heterozygous c. 1675C>T variant of theDLG4 gene probably underlay the mental retardation in this woman, and her fetus was found to harbor the same variant in addition with deletion of the DMD gene, which may predispose to ID type 62.
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