PDF(Pubmed)
Abstract：
BACKGROUND: Congenital heart diseases (CHD) are the most common congenital malformations in newborns and remain the leading cause of mortality among infants under one year old. Molecular diagnosis is crucial to evaluate the recurrence risk and to address future prenatal diagnosis. Here, we describe two families with various forms of inherited non-syndromic CHD and the genetic work-up and resultant findings.
METHODS: Next-generation sequencing (NGS) was employed in both families to uncover the genetic cause. In addition, we performed functional analysis to investigate the consequences of the identified variants in vitro.
RESULTS: NGS identified possible causative variants in both families in the protein kinase domain of the TGFBR1 gene. These variants occurred on the same amino acid, but resulted in differently substituted amino acids (p.R398C/p.R398H). Both variants co-segregate with the disease, are extremely rare or unique, and occur in an evolutionary highly conserved domain of the protein. Furthermore, both variants demonstrated a significantly altered TGFBR1-smad signaling activity. Clinical investigation revealed that none of the carriers had (signs of) aortopathy.
CONCLUSIONS: In conclusion, we describe two families, with various forms of inherited non-syndromic CHD without aortopathies, associated with unique/rare variants in TGFBR1 that display altered TGF-beta signaling. These findings highlight involvement of TGFBR1 in CHD, and warrant consideration of potential causative TGFBR1 variants also in CHD patients without aortopathies.
METHODS: Next-generation sequencing (NGS) was employed in both families to uncover the genetic cause. In addition, we performed functional analysis to investigate the consequences of the identified variants in vitro.
RESULTS: NGS identified possible causative variants in both families in the protein kinase domain of the TGFBR1 gene. These variants occurred on the same amino acid, but resulted in differently substituted amino acids (p.R398C/p.R398H). Both variants co-segregate with the disease, are extremely rare or unique, and occur in an evolutionary highly conserved domain of the protein. Furthermore, both variants demonstrated a significantly altered TGFBR1-smad signaling activity. Clinical investigation revealed that none of the carriers had (signs of) aortopathy.
CONCLUSIONS: In conclusion, we describe two families, with various forms of inherited non-syndromic CHD without aortopathies, associated with unique/rare variants in TGFBR1 that display altered TGF-beta signaling. These findings highlight involvement of TGFBR1 in CHD, and warrant consideration of potential causative TGFBR1 variants also in CHD patients without aortopathies.
摘要：
背景：先天性心脏病（CHD）是新生儿最常见的先天性畸形，仍然是一岁以下婴儿死亡的主要原因。分子诊断对于评估复发风险和解决未来的产前诊断至关重要。这里,我们描述了两个患有各种形式的遗传性非综合征性CHD的家庭,以及遗传研究和结果发现.
方法：在两个家庭中都采用了下一代测序（NGS）来揭示遗传原因。此外,我们进行了功能分析,以研究体外鉴定的变异体的后果.
结果：NGS在TGFBR1基因蛋白激酶域的两个家族中鉴定出可能的致病变异。这些变异发生在相同的氨基酸上，但导致不同的氨基酸取代(p.R398C/p。R398H)。两种变体都与疾病分离，非常罕见或独特，并发生在蛋白质的进化高度保守的结构域中。此外，两种变体均显示TGFBR1-smad信号活性显著改变.临床调查显示，没有携带者有主动脉病（迹象）。
结论：结论：我们描述了两个家庭，患有各种形式的遗传性非综合征性冠心病，没有主动脉病变，与显示改变的TGF-β信号的TGFBR1中的独特/罕见变体相关。这些发现强调了TGFBR1在CHD中的参与，并且在没有主动脉病变的CHD患者中也需要考虑潜在的致病性TGFBR1变异。
方法：在两个家庭中都采用了下一代测序（NGS）来揭示遗传原因。此外,我们进行了功能分析,以研究体外鉴定的变异体的后果.
结果：NGS在TGFBR1基因蛋白激酶域的两个家族中鉴定出可能的致病变异。这些变异发生在相同的氨基酸上，但导致不同的氨基酸取代(p.R398C/p。R398H)。两种变体都与疾病分离，非常罕见或独特，并发生在蛋白质的进化高度保守的结构域中。此外，两种变体均显示TGFBR1-smad信号活性显著改变.临床调查显示，没有携带者有主动脉病（迹象）。
结论：结论：我们描述了两个家庭，患有各种形式的遗传性非综合征性冠心病，没有主动脉病变，与显示改变的TGF-β信号的TGFBR1中的独特/罕见变体相关。这些发现强调了TGFBR1在CHD中的参与，并且在没有主动脉病变的CHD患者中也需要考虑潜在的致病性TGFBR1变异。
