SMAD5 as a novel susceptibility gene for congenital patent ductus arteriosus
7 affiliations
- 1Department of Obstetrics, Shanghai East Hospital, Tongji University School of Medicine
- 2Community Health Service Center, General Practice of Western Medicine
- 3Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
- 4Department of Pediatrics, Huashan Hospital, Fudan University
- 5Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University
- 6Department of Cardiology, Shanghai Fifth People′s Hospital, Fudan University
- 7Department of Cardiology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine
Abstract
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.
Related
- Quantitative CT Geometry of the Patent Ductus Arteriosus in Infants with Congenital Heart Disease: Association with Aortic Arch Obstruction or Hypoplasia
- Absent right pulmonary artery with patent ductus arteriosus and Eisenmenger syndrome
- Pharmacological treatment of patent ductus arteriosus: lessons from recent randomized trials.
- Anomalous Origin of the Right Pulmonary Artery from the Ascending Aorta in an Adult After Prior Patent Ductus Arteriosus Surgery
- Associations Between Longitudinal Antenatal Hematological Indicators and Risk of Patent Ductus Arteriosus in Newborns — Beijing, China, 2011–2025
BibTeX
@article{zhang2026smad5,
title = {{SMAD5 as a novel susceptibility gene for congenital patent ductus arteriosus}},
author = {Hong Zhang and Xiao-Qing Hu and Yan-Jie Li and Bin-Bin Dong and Ri-Tai Huang and Yi-Qing Yang and Juan Wang},
journal = {Scientific Reports},
year = {2026},
month = jul,
doi = {10.1038/s41598-026-63062-5},
url = {https://doi.org/10.1038/s41598-026-63062-5},
note = {CC BY},
}
RIS
TY - JOUR
TI - SMAD5 as a novel susceptibility gene for congenital patent ductus arteriosus
AU - Hong Zhang
AU - Xiao-Qing Hu
AU - Yan-Jie Li
AU - Bin-Bin Dong
AU - Ri-Tai Huang
AU - Yi-Qing Yang
AU - Juan Wang
PY - 2026
DA - 2026/07/01
JO - Scientific Reports
DO - 10.1038/s41598-026-63062-5
UR - https://doi.org/10.1038/s41598-026-63062-5
AB - 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.
SN - 2045-2322
ER -