Submission Details

The SMAD4 gene encodes for the SMAD4 protein, belonging to the SMAD family of transcription factor proteins. SMAD4 plays a pivotal role in signal transduction of the transforming growth factor beta superfamily cytokines by mediating transcriptional activation of target genes.

Variants in SMAD4 are linked to 4 different phenotypes: juvenile polyposis with hereditary hemorrhagic telangiectasia (HHT) syndrome, Myhre syndrome, pancreatic cancer (somatic), juvenile intestinal polyposis. We curated SMAD4 for juvenile polyposis with hereditary hemorrhagic telangiectasia syndrome.

SMAD4 was first reported in relation to juvenile polyposis–HHT syndrome in 2004 (Gallione et al, PMID 15031030) in seven unrelated families or individuals displaying both juvenile polyposis and hereditary haemorrhagic telangiectasia phenotypes. Seven different variants, 4 missense, 1 stop and 2 deletions leading to frameshift, were described in the enrolled individuals. Common phenotypes were arteriovenous malformation, juvenile polyposis and telangiectasia. Epistaxis was common as well as anemia and digital clubbing.

At least 17 unique variants have been reported in humans, comprising missense, stop and frameshift variants.

Evidence supporting this gene-disease relationship includes genetic evidences (case-level data) and experimental evidences (non-human model organisms).

Summary of Case Level Data: 12 POINTS Variants in this gene have been reported in at least 24 probands in 7 publications (PMIDs: 9582123, 15235019, 15031030, 16613914, 32944796, 30210120, 22331366) leading to a score of 12 for genetic evidence. More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence has been reached. The mechanism for disease is heterozygous loss of function.

Summary of Experimental Data: 4 POINTS This gene-disease association is supported by evidences of non-human model organisms, indeed two SMAD4 conditional knock out murine models have been described, both recapitulate most of the juvenile polyposis–HHT phenotypes including anemia and arteriovenous malformations in the brain, gastrointestinal tract, and skin (PMID 30571376) and formation of arteriovenous malformations in the neonate retina (PMID 29460088).

In summary, we found definitive association of SMAD4 with juvenile polyposis–HHT syndrome.

This classification was approved by the ClinGen Hemostasis Thrombosis Working Group on 12/16/2020 (SOP Version 8). The curation was updated on 2/22/2023 to include cases of classic Juveline polyposis with guidance from the Hereditary Cancer GCEP (SOP Version 9)