Submission Details

SMAD4 has been implicated in autosomal dominant Myhre syndrome (MONDO:0007688), generalized juvenile polyposis/juvenile polyposis coli (MONDO:0008276), and juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (MONDO:0008278). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in molecular mechanisms and phenotypic variability among these disorders. Therefore, each of the disease entities listed above was curated separately. The current curation is for Myhre syndrome.

SMAD4 was first reported in relation to autosomal dominant Myhre syndrome in 2011 (Le Goff et al., PMID: 22158539). Individuals with Myhre syndrome present with short stature, typical facial appearance, hearing loss, laryngotracheal stenosis, skeletal abnormalities, cardiovascular abnormalities, developmental delay, mild-to-moderate intellectual disability, and autistic behavior in a minority of patients (PMIDs: 22158539, 27302097). Congenital hearts defects are reported in 40-60% of affected individuals, with persistent ductus arteriosus, mitral/aortic valve defects, tetralogy of Fallot and ventricular septal defects being the most common (PMIDs: 27302097, 38779990). Myhre syndrome is caused by one of four SMAD4 missense variants [c.1498A>G (p.Ile500Val); c.1499T>C (p.Ile500Thr); c.1500A>G (p.Ile500Met); and c.1486C>T (p.Arg496Cys)] (PMIDs: 22158539, 27302097, 28406602). Over 55 Myhre syndrome patients with a de novo SMAD4 pathogenic variant have been reported in the literature (PMIDs: 22158539, 26636501, 27302097, 31654632); only 9 probands were scored in this curation because the maximum score for genetic evidence (12 points) has been reached. Only one inherited variant has been reported in a patient with Myhre syndrome (PMID: 31595668). The mechanism of pathogenicity is gain of function (PMID: 22158539).

SMAD4 encodes a transcription factor that regulates bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFβ) signaling. Experimental evidence supporting this gene-disease relationship includes functional assays in patient fibroblasts and cell culture models, expression studies, and model organisms (PMIDs: 16023633, 22158539, 29695415).

In summary, SMAD4 is definitively associated with autosomal dominant Myhre syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel (GCEP) on December 1, 2021 (SOP Version 8). This curation was re-evaluated by the ClinGen Congenital Heart Disease GCEP on October 29, 2025. The classification and SOP did not change, but additional information about congenital heart defects was added to the evidence summary.

SMAD4 has been implicated in autosomal dominant Myhre syndrome (MONDO:0007688), generalized juvenile polyposis/juvenile polyposis coli (MONDO:0008276), and juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (MONDO:0008278). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms and phenotypic variability among these disorders. Therefore, each of the disease entities listed above was curated separately. The current curation is for Myhre syndrome.

SMAD4 was first reported in relation to autosomal dominant Myhre syndrome in 2011 (Le Goff et al., PMID: 22158539). Individuals with Myhre syndrome present with short stature, typical facial appearance, hearing loss, laryngotracheal stenosis, skeletal abnormalities, cardiovascular abnormalities, developmental delay, mild-to-moderate intellectual disability, and autistic behavior in a minority of patients (PMIDs: 22158539, 27302097). Myhre syndrome is caused by one of four SMAD4 missense variants [c.1498A>G (p.Ile500Val); c.1499T>C (p.Ile500Thr); c.1500A>G (p.Ile500Met), and c.1486C>T (p.Arg496Cys)] (PMIDs: 22158539, 27302097, 28406602). Over 55 Myhre syndrome patients with a de novo SMAD4 pathogenic variant have been reported in the literature (PMIDs: 22158539, 26636501, 27302097, 31654632); only 9 probands were scored in this curation because the maximum score for genetic evidence has been reached. Only one inherited variant has been reported in a patient with Myhre syndrome (PMID: 31595668). SMAD4 encodes a transcription factor that regulates bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFβ) signaling. The mechanism of pathogenicity is gain-of-function (PMID: 22158539). Experimental evidence supporting this gene-disease relationship includes functional assays in patient fibroblasts and cell culture models, expression studies, and model organisms (PMIDs: 16023633, 22158539, 29695415).

In summary, SMAD4 is definitively associated with autosomal dominant Myhre syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 12/01/2021 (SOP Version 8).