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<p> Congenital heart disease (CHD), which represents the most common type of human birth defect affecting approximately 1% of all live births globally, is a leading cause of substantial infant mortality and morbidity worldwide. Although aggregating evidence has convincingly suggested a strong genetic basis underpinning CHD, the inherited components underlying CHD in most cases remain indefinite. Hence, the current investigation aimed to identify and characterize novel genetic variations underlying CHD. A five-generation pedigree with patent ductus arteriosus (PDA) and another group of 174 index patients with CHD were enrolled. In addition, 218 unrelated non-CHD people were employed as controls. Clinical assessments, along with exome-sequencing and Sanger-sequencing examinations, were performed in the study participants. The functional effects of the detected variations in the <i>SMAD5</i> gene, which encodes a transcription factor required for proper cardiovascular morphogenesis, were measured by dual-luciferase reporter assays. Two new <i>SMAD5</i> variants, NM_005903.7: c.244&#xa0;A &gt; T; p.(Lys82*) and NM_005903.7: c.209G &gt; T; p.(Arg70Ile), were detected in a heterozygous status in the PDA pedigree and one PDA case out of the 174 index patients affected with CHD, respectively. Neither of the two <i>SMAD5</i> variations was observed in the 436 control chromosomes. Quantitative biochemical assays using dual-reporter genes revealed that the Lys82*- or Arg70Ile-mutant SMAD5 possessed diminished transactivation of <i>NKX2.5</i>, an established CHD-causative gene. Furthermore, the Lys82* or Arg70Ile variation nullified or significantly reduced the synergistic transactivation of <i>ID2</i> between SMAD5 and BMP4, and both <i>ID2</i> and <i>BMP4</i> had been causally implicated in the pathogenesis underpinning CHD. The present findings indicate that <i>SMAD5</i> haplo-insufficient variants contribute to PDA in humans, which sheds more light on the genetic architecture of PDA and implies a potential target for genetic counseling and individualized medicine of PDA in a subgroup of patients.</p>

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SMAD5 as a novel susceptibility gene for congenital patent ductus arteriosus

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月21日

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  • Hong Zhang,
  • Xiao-Qing Hu,
  • Yan-Jie Li,
  • Bin-Bin Dong,
  • Ri-Tai Huang,
  • Yi-Qing Yang,
  • Juan Wang

摘要

Congenital heart disease (CHD), which represents the most common type of human birth defect affecting approximately 1% of all live births globally, is a leading cause of substantial infant mortality and morbidity worldwide. Although aggregating evidence has convincingly suggested a strong genetic basis underpinning CHD, the inherited components underlying CHD in most cases remain indefinite. Hence, the current investigation aimed to identify and characterize novel genetic variations underlying CHD. A five-generation pedigree with patent ductus arteriosus (PDA) and another group of 174 index patients with CHD were enrolled. In addition, 218 unrelated non-CHD people were employed as controls. Clinical assessments, along with exome-sequencing and Sanger-sequencing examinations, were performed in the study participants. The functional effects of the detected variations in the SMAD5 gene, which encodes a transcription factor required for proper cardiovascular morphogenesis, were measured by dual-luciferase reporter assays. Two new SMAD5 variants, NM_005903.7: c.244 A > T; p.(Lys82*) and NM_005903.7: c.209G > T; p.(Arg70Ile), were detected in a heterozygous status in the PDA pedigree and one PDA case out of the 174 index patients affected with CHD, respectively. Neither of the two SMAD5 variations was observed in the 436 control chromosomes. Quantitative biochemical assays using dual-reporter genes revealed that the Lys82*- or Arg70Ile-mutant SMAD5 possessed diminished transactivation of NKX2.5, an established CHD-causative gene. Furthermore, the Lys82* or Arg70Ile variation nullified or significantly reduced the synergistic transactivation of ID2 between SMAD5 and BMP4, and both ID2 and BMP4 had been causally implicated in the pathogenesis underpinning CHD. The present findings indicate that SMAD5 haplo-insufficient variants contribute to PDA in humans, which sheds more light on the genetic architecture of PDA and implies a potential target for genetic counseling and individualized medicine of PDA in a subgroup of patients.