Haploinsufficient variants in SMAD5 are associated with isolated congenital heart disease

Mothers against decapentaplegic homolog 5 (SMAD5) is a transcriptional regulator that functions within the TGF-β signaling cascade. Evidence from animal studies show that it is crucial for dorsoventral patterning, left-right asymmetry, cardiac looping, and other embryonic processes. However, its role in human development has not been explored, and the contribution of SMAD5 variants to congenital disease is unknown. Here, we report SMAD5 variants identified in six unrelated families with seven individuals presenting with congenital heart disease (CHD). Isolated congenital heart defects are observed in six individuals who carry de novo or inherited missense, nonsense, frameshift, or copy-number variants in SMAD5. A multi-organ phenotype is observed in one individual with a de novo SMAD5 variant that alters an amino acid crucial for SMAD5 multimerization. Septal defects, identified in four individuals, are the most common cardiac lesion in our cohort, with hypoplastic left heart also observed in two individuals. In silico assessment of SMAD5 missense variants predicts disrupted binding to co-factors, and in vitro functional assessment shows changes in SMAD5 gene and protein expression, as well as impaired activation of a BMP4-responsive promoter by the variants. Our findings suggest haploinsufficiency as the underlying molecular mechanism in five of the six families, resulting in isolated CHD, with a SMAD5 dominant-negative variant identified in one family leading to multiple congenital defects. Here, we provide evidence that SMAD5 variants lead to CHD and offer a basis for future exploration of SMAD5 variants in both CHD and post-natal disease.

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Publication Details

Journal
Human Genetics and Genomics Advances
Published
2025-07-05
DOI
https://doi.org/10.1016/j.xhgg.2025.100478
Primary Topic
Congenital heart defects research
Type
article
Field-Weighted Citation Impact
0.00

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article

Haploinsufficient variants in SMAD5 are associated with isolated congenital heart disease

David S. Winlaw, Victoria C. O׳Reilly, Eleni Giannoulatou, Annabelle Enriquez et al.
Human Genetics and Genomics Advances
Congenital heart defects research
article

Haploinsufficient variants in SMAD5 are associated with isolated congenital heart disease

David S. Winlaw, Victoria C. O׳Reilly, Eleni Giannoulatou, Annabelle Enriquez, Dimuthu Alankarage, Wendy K. Chung, Sally L. Dunwoodie, Bert Callewaert, David T. Humphreys, Gillian M. Blue, Nicola Poplawski, Anja Sipka, Edwin Philip Kirk, Maxim Verlee, Richard P. Harvey, Emma M. Rath, Stephanie Portelli, Miriam Fine, Gavin Chapman, Michael Troup, David B. Ascher, Debjani Das, Iryna Leshchynska
article en

Abstract

Mothers against decapentaplegic homolog 5 (SMAD5) is a transcriptional regulator that functions within the TGF-β signaling cascade. Evidence from animal studies show that it is crucial for dorsoventral patterning, left-right asymmetry, cardiac looping, and other embryonic processes. However, its role in human development has not been explored, and the contribution of SMAD5 variants to congenital disease is unknown. Here, we report SMAD5 variants identified in six unrelated families with seven individuals presenting with congenital heart disease (CHD). Isolated congenital heart defects are observed in six individuals who carry de novo or inherited missense, nonsense, frameshift, or copy-number variants in SMAD5. A multi-organ phenotype is observed in one individual with a de novo SMAD5 variant that alters an amino acid crucial for SMAD5 multimerization. Septal defects, identified in four individuals, are the most common cardiac lesion in our cohort, with hypoplastic left heart also observed in two individuals. In silico assessment of SMAD5 missense variants predicts disrupted binding to co-factors, and in vitro functional assessment shows changes in SMAD5 gene and protein expression, as well as impaired activation of a BMP4-responsive promoter by the variants. Our findings suggest haploinsufficiency as the underlying molecular mechanism in five of the six families, resulting in isolated CHD, with a SMAD5 dominant-negative variant identified in one family leading to multiple congenital defects. Here, we provide evidence that SMAD5 variants lead to CHD and offer a basis for future exploration of SMAD5 variants in both CHD and post-natal disease.

Human Genetics and Genomics AdvancesVol. 6(4)
Boston Children's Hospital (US), Royal Adelaide Hospital (AU), Harvard University (US), The University of Queensland (AU), The University of Melbourne (AU), Victor Chang Cardiac Research Institute (AU), Ghent University Hospital (BE), UNSW Sydney (AU), Sydney Children's Hospital (AU), Lurie Children's Hospital (US), Sydney Children’s Hospitals Network (AU)
NSW Ministry of Health, New South Wales Government, Australian Research Council, National Health and Medical Research Council
Good health and well-being
Openalex Percentile: Top 85%
Congenital heart defects research
DOIOpen Access PDFOpenAlex
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