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Decoding cell fate: human models reveal how SMAD2 variants shape development

Nature Reviews Genetics volume 26, page 586 (2025)Cite this article

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The ability to sequence genomes at scale has revealed a vast landscape of rare and de novo variants in patients with congenital heart disease (CHD) and other complex disorders. Yet how do we decode the functional impact of these variants, especially when animal models fall short? SMAD2, a co-regulator that binds a variety of transcription factors during human development, is a case in point. Heterozygous SMAD2 loss-of-function and missense variants have been identified in patients with CHD and arterial aneurysms, but the mechanisms by which these variants cause distinct cardiovascular phenotypes remain elusive. As a stem cell biologist and bioengineer fascinated by the intersection of developmental biology and human disease, I found that a recent paper by Ward et al. captivated my attention and broadened my perspective on the challenge of connecting genetic variants to their functional consequences in human cells, tissues and organs.

Ward et al. used genome engineering to construct isogenic human induced pluripotent stem cell (iPSC) lines carrying heterozygous or homozygous loss-of-function and missense SMAD2 variants identified in probands with CHD. This approach enabled them to delineate the transcriptional and epigenetic effects of SMAD2 mutations in a human context, a challenge that is often difficult to address in animal models.

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References

Original article

  • Ward, T. et al. Modeling SMAD2 mutations in induced pluripotent stem cells provides insights into cardiovascular disease pathogenesis. J. Am. Heart Assoc. 14, e036860 (2025)

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Related article

  • Bhattacharya, R. et al. Engineered human iPS cell models reveal altered podocytogenesis and glomerular capillary wall in CHD-associated SMAD2 mutations. Preprint at bioRxiv https://doi.org/10.1101/2024.08.02.606108 (2024)

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Authors and Affiliations

  1. Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, USA

    Samira Musah

  2. Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA

    Samira Musah

  3. Center for Biomolecular and Tissue Engineering, Duke University, Durham, NC, USA

    Samira Musah

  4. Developmental and Stem Cell Biology Program, Duke University, Durham, North Carolina, USA

    Samira Musah

  5. Department of Cell Biology, Duke University, Durham, NC, USA

    Samira Musah

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  1. Samira Musah
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Correspondence to Samira Musah.

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Musah, S. Decoding cell fate: human models reveal how SMAD2 variants shape development. Nat Rev Genet 26, 586 (2025). https://doi.org/10.1038/s41576-025-00881-8

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