PDF(Pubmed)
Abstract：
BACKGROUND: TBX6, a member of the T-box gene family, encodes the transcription factor box 6 that is critical for somite segmentation in vertebrates. It is known that the compound heterozygosity of disruptive variants in trans with a common hypomorphic risk haplotype (T-C-A) in the TBX6 gene contribute to 10% of congenital scoliosis (CS) cases. The deletion of chromosome 17q12 is a rare cytogenetic abnormality, which often leads to renal cysts and diabetes mellitus. However, the affected individuals often exhibit clinical heterogeneity and incomplete penetrance.
METHODS: We here present a Chinese fetus who was shown to have CS by ultrasound examination at 17 weeks of gestation. Trio whole-exome sequencing (WES) was performed to investigate the underlying genetic defects of the fetus. In vitro functional experiments, including western-blotting and luciferase transactivation assay, were performed to determine the pathogenicity of the novel variant of TBX6.
RESULTS: WES revealed the fetus harbored a compound heterozygous variant of c.338_340del (p.Ile113del) and the common hypomorphic risk haplotype of the TBX6 gene. In vitro functional study showed the p.Ile113del variant had no impact on TBX6 expression, but almost led to complete loss of its transcriptional activity. In addition, we identified a 1.85 Mb deletion on 17q12 region in the fetus and the mother. Though there is currently no clinical phenotype associated with this copy number variation in the fetus, it can explain multiple renal cysts in the pregnant woman.
CONCLUSIONS: This study is the first to report a Chinese fetus with a single amino acid deletion variant and a T-C-A haplotype of TBX6. The clinical heterogeneity of 17q12 microdeletion poses significant challenges for prenatal genetic counseling. Our results once again suggest the complexity of prenatal genetic diagnosis.
METHODS: We here present a Chinese fetus who was shown to have CS by ultrasound examination at 17 weeks of gestation. Trio whole-exome sequencing (WES) was performed to investigate the underlying genetic defects of the fetus. In vitro functional experiments, including western-blotting and luciferase transactivation assay, were performed to determine the pathogenicity of the novel variant of TBX6.
RESULTS: WES revealed the fetus harbored a compound heterozygous variant of c.338_340del (p.Ile113del) and the common hypomorphic risk haplotype of the TBX6 gene. In vitro functional study showed the p.Ile113del variant had no impact on TBX6 expression, but almost led to complete loss of its transcriptional activity. In addition, we identified a 1.85 Mb deletion on 17q12 region in the fetus and the mother. Though there is currently no clinical phenotype associated with this copy number variation in the fetus, it can explain multiple renal cysts in the pregnant woman.
CONCLUSIONS: This study is the first to report a Chinese fetus with a single amino acid deletion variant and a T-C-A haplotype of TBX6. The clinical heterogeneity of 17q12 microdeletion poses significant challenges for prenatal genetic counseling. Our results once again suggest the complexity of prenatal genetic diagnosis.
摘要：
背景：TBX6，T-box基因家族的成员，编码转录因子盒6，该因子盒6对脊椎动物的体节分割至关重要。众所周知，TBX6基因中具有常见低态风险单倍型（T-C-A）的反式破坏性变体的复合杂合性导致10％的先天性脊柱侧凸（CS）病例。染色体17q12的缺失是一种罕见的细胞遗传学异常，这通常会导致肾囊肿和糖尿病。然而,受影响的个体通常表现出临床异质性和不完全外显率。
方法：我们在此介绍一名中国胎儿，该胎儿在妊娠17周时通过超声检查显示患有CS。进行三全外显子组测序（WES）以调查胎儿的潜在遗传缺陷。体外功能实验，包括蛋白质印迹和荧光素酶反式激活测定，进行以确定TBX6的新变体的致病性。
结果：WES显示胎儿具有c.338_340del的复合杂合变体（p。Ile113del）和TBX6基因的常见低态风险单倍型。体外功能研究表明，p.Ile113del变体对TBX6的表达没有影响，但几乎导致其转录活性的完全丧失。此外,我们在胎儿和母亲的17q12区域发现了1.85Mb缺失。尽管目前没有与胎儿拷贝数变异相关的临床表型，它可以解释孕妇的多发性肾囊肿。
结论：本研究首次报道了具有单个氨基酸缺失变体和TBX6T-C-A单倍型的中国胎儿。17q12微缺失的临床异质性对产前遗传咨询提出了重大挑战。我们的结果再次表明了产前遗传诊断的复杂性。
方法：我们在此介绍一名中国胎儿，该胎儿在妊娠17周时通过超声检查显示患有CS。进行三全外显子组测序（WES）以调查胎儿的潜在遗传缺陷。体外功能实验，包括蛋白质印迹和荧光素酶反式激活测定，进行以确定TBX6的新变体的致病性。
结果：WES显示胎儿具有c.338_340del的复合杂合变体（p。Ile113del）和TBX6基因的常见低态风险单倍型。体外功能研究表明，p.Ile113del变体对TBX6的表达没有影响，但几乎导致其转录活性的完全丧失。此外,我们在胎儿和母亲的17q12区域发现了1.85Mb缺失。尽管目前没有与胎儿拷贝数变异相关的临床表型，它可以解释孕妇的多发性肾囊肿。
结论：本研究首次报道了具有单个氨基酸缺失变体和TBX6T-C-A单倍型的中国胎儿。17q12微缺失的临床异质性对产前遗传咨询提出了重大挑战。我们的结果再次表明了产前遗传诊断的复杂性。
