SMAD4 SMAD family member 4

Gene info



Previous symbol


External ID

HGNC: 6770
Entrez Gene: 4089
Ensembl: ENSG00000141646
UCSC: uc060pfa.1
OMIM: 600993
UniProtKB: Q13485

Disease info


CHD Phenotype

  • Atrial septal defect
  • Ventricular septal defect
  • Patent ductus arteriosus
  • Pulmonic stenosis
  • Aortic stenosis
  • Coarctation of the aorta

Extra Cardiac Phenotype

Short stature , Obesity , Prenatal growth deficiency , Microcephaly , Incomplete jaw opening , Maxillary hypoplasia , Midface hypoplasia, Prognathism , Short philtrum, Small ears , Anomalous middle ear bones , Low-set ears, Deafness , Blepharophimosis , Narrow palpebral fissures , Hypertelorism , Microphthalmia , Hyperopia , Strabismus , Deep-set eyes , Bushy eyebrows , Prominent nasal root , Broad mid-nose , Narrow alar root, Small mouth , Thin upper lip , Cleft lip/palate, Short neck, Laryngotracheal stenosis, Respiratory failure , Cryptorchidism , menstrual abnormality, Decreased joint mobility , Thickened calvarium , Large, flattened vertebrae with large pedicles , Platyspondyly , Vertebral fusions, Hypoplastic iliac wings, Short long bones , Cone-shaped epiphyses, Brachydactyly , Clinodactyly , Camptodactyly , Dupuytren contractures, Toe syndactyly (2-3), Overlapping toes, Thickened skin , Stiff skin, Sparse, fine hair , Generalized muscle hypertrophy , Mental retardation , Seizures, Cerebellar ataxia, Cerebellar atrophy, Autism or autistic-like condition, Abnormal voice

Incomplete penetrance


Variable expressivity


Animal model

Mouse study

MGI: Mouse with conditional knockout under the ACTA1 promoter has CHD (myocardial deletion)


Variant info


Selected variant

The Clinvar variants presented in the below IGV track were selected based on the following criteria.

  1. Variant types are single nucleotide variant or Indel
  2. Clinical significance for the variant was assessed to be Pathogenic or Likely Pathogenic
  3. ClinVar review status for the variant is criteria provided

Download annotation file for SMAD4: BED file

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Selected References

  1. Le Goff, C., Mahaut, C., Abhyankar, A., Le Goff, W., Serre, V., Afenjar, A., Destrée, A., di Rocco, M., Héron, D., Jacquemont, S., Marlin, S., Simon, M., Tolmie, J., Verloes, A., Casanova, J.-L., Munnich, A., & Cormier-Daire, V. (2011). Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome. Nature Genetics, 44(1), 85–88. DOI:10.1038/ng.1016 PMID:22158539
  2. Lin, A. E., Michot, C., Cormier-Daire, V., L’Ecuyer, T. J., Matherne, G. P., Barnes, B. H., Humberson, J. B., Edmondson, A. C., Zackai, E., O’Connor, M. J., Kaplan, J. D., Ebeid, M. R., Krier, J., Krieg, E., Ghoshhajra, B., & Lindsay, M. E. (2016). Gain-of-function mutations inSMAD4cause a distinctive repertoire of cardiovascular phenotypes in patients with Myhre syndrome. American Journal of Medical Genetics Part A, 170(10), 2617–2631. Portico. DOI:10.1002/ajmg.a.37739 PMID:27302097