SMAD4 – Pulmonary Arterial Hypertension

Heterozygous SMAD4 variants have been identified as rare contributors to pulmonary arterial hypertension (PAH). In a cohort of 324 unrelated PAH patients, two distinct SMAD4 variants (one missense and one splice-region) were each absent from large control populations, consistent with a low‐frequency autosomal dominant mechanism of disease (2 probands) (PMID:21898662). No familial segregation was reported for these SMAD4 alleles, and they were not detected in PAH pedigrees, supporting limited genetic evidence.

The splice-region variant in SMAD4 (c.1448-6T>C) was shown by in vitro transcript analysis to result in moderate loss of normal SMAD4 mRNA due to impaired splicing efficiency, consistent with a loss-of-function mechanism (PMID:21898662). SMAD4 plays a central role in TGF-β/BMP signaling, and partial reduction of SMAD4 activity is biologically plausible to contribute to pulmonary vascular remodeling.

Although BMPR2 mutations account for the majority of hereditary PAH, variation in SMAD family members including SMAD4 represents an infrequent cause of PAH. Additional studies are needed to define segregating pedigrees and broader variant spectrum, but current evidence supports inclusion of SMAD4 in diagnostic gene panels to capture rare cases and guide management.

Key Take-home: SMAD4 loss-of-function variants are an infrequent autosomal dominant cause of PAH and should be considered in targeted genetic testing panels.

References

• Human Mutation | 2011 | Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension. PMID:21898662

Evidence Based Scoring (AI generated)