SMAD9 – Pulmonary Arterial Hypertension

SMAD9 encodes a receptor-regulated SMAD transcription factor within the BMP/TGF-β signaling pathway. Heterozygous variants in SMAD9 have been implicated as rare causes of autosomal dominant pulmonary arterial hypertension (PAH). Clinical screening and experimental data converge to establish a definitive gene–disease relationship.

Genetic screening in a cohort of 324 PAH cases identified one missense variant, c.127A>G (p.Lys43Glu), not seen in controls (PMID:21898662). Independent studies found a truncating SMAD9 variant c.606C>A (p.Cys202Ter) segregating with disease in a father–daughter pair (PMID:19211612), as well as additional SMAD9 variants in a Saudi Arabian cohort (one proband among 48 cases) (PMID:34377436) and a Taiwanese cohort (one proband among 45 cases) (PMID:35811711). In total, four unrelated probands and one segregation event support a causative role for SMAD9 in PAH.

The variant spectrum includes both missense (e.g., p.Lys43Glu) and nonsense alleles (e.g., p.Cys202Ter). All identified variants are heterozygous and distributed throughout the MH1 and MH2 domains of SMAD9, with no recurrent or founder alleles reported to date.

Functional assays demonstrate that the p.Cys202Ter protein is not phosphorylated by constitutively active ALK3 or ALK1 and fails to interact with SMAD4, abolishing BMP-induced transcriptional activation (PMID:19211612). The p.Lys43Glu substitution similarly reduces signaling activity in vitro (PMID:21898662). These data indicate a loss-of-function mechanism consistent with haploinsufficiency.

A recent ClinGen expert curation classified SMAD9 as having Definitive clinical validity for PAH based on robust genetic and experimental evidence (PMID:37422716).

Integration of genetic and functional findings confirms that heterozygous SMAD9 variants cause autosomal dominant PAH with reduced penetrance. SMAD9 should be included in diagnostic gene panels for PAH, enabling identification of at-risk individuals and informing family screening.

Key Take-home: SMAD9 mutations exhibit definitive clinical validity for autosomal dominant pulmonary arterial hypertension and should be incorporated into diagnostic testing.

References

• Genetics in medicine : official journal of the American College of Medical Genetics • 2023 • Defining the clinical validity of genes reported to cause pulmonary arterial hypertension PMID:37422716
• Human mutation • 2011 • Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension PMID:21898662
• Journal of medical genetics • 2009 • A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension PMID:19211612
• Pulmonary circulation • 2021 • Genetic basis of pulmonary arterial hypertension: a prospective study from a highly inbred population PMID:34377436
• Frontiers in cardiovascular medicine • 2022 • Whole Exome Sequencing of Patients With Heritable and Idiopathic Pulmonary Arterial Hypertension in Central Taiwan PMID:35811711

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