SMAD2 – Congenital Heart Disease

Congenital heart disease (CHD) affects approximately 0.8% of live births and is often sporadic, implicating de novo variants in its etiology. SMAD2 encodes an intracellular mediator of TGF-β signaling critical for embryonic left-right organizer function and chromatin regulation. In a trio exome study of 362 severe CHD cases versus 264 controls, two unrelated probands harbored de novo protein-altering SMAD2 variants, c.822G>C (p.Trp274Cys) and c.784+1G>A, absent from controls ([PMID:23665959]). An expanded analysis of 3,684 CHD subjects confirmed SMAD2 among the top genes with damaging de novo variants contributing to neurodevelopmental and cardiac phenotypes ([PMID:32341405]).

Inheritance is autosomal dominant with de novo occurrence; no inherited segregations have been reported to date. Genetic evidence is limited to two unrelated probands without extended familial segregation.

Functionally, SMAD2 regulates H3K27 methylation in the embryonic organizer and transduces TGF-β signals essential for cardiogenesis. Perturbation of SMAD2 leads to altered chromatin states at poised promoters of key developmental genes, supporting a loss-of-function mechanism in CHD.

No conflicting studies have challenged the de novo SMAD2-CHD association, but additional replication is needed. Overall, the evidence meets a Limited ClinGen gene–disease validity classification.

Key Take-home: De novo SMAD2 variants represent a rare autosomal dominant cause of severe CHD, warranting inclusion in diagnostic gene panels for sporadic cases.

References

• Nature • 2013 • De novo mutations in histone-modifying genes in congenital heart disease. PMID:23665959
• Scientific Reports • 2020 • De novo damaging variants associated with congenital heart diseases contribute to the connectome. PMID:32341405

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