ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000018.9) (NC_000018.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
17873119 Aretz et al., 2007: Mutation and phenotype analysis was used in 80 unrelated patients of whom 65 met the clinical criteria for juvenile polyposis syndrome (typical JPS) and 15 were suspected to have JPS. Of the 17 point mutations identified in SMAD4, 11 were predicted to lead to truncated proteins (5 nonsense, 6 frameshift). Large genomic deletions involving the SMAD4 were found in six (9%) patients with typical JPS. Four exhibited a heterozygous deletion of all SMAD4 probes by MLPA, encompassing the entire SMAD4 gene and the promoter region. One patient had a deletion of coding exons 5-11 and another had a deletion of coding exons 6-11.
20101697 Callione et al., 2010 identified 15 mutations in 19 patients meeting diagnostic criteria for JPS and hereditary hemorrhagic telangiectasia; 3 small insertions/deletions in exons 8, 9, or 11, predicting to lead to frameshift and premature stop codon in the MH2 domain of the protein. Two protein-truncating mutations in exon 2 and exon 5, and 10 missense mutations in exons 8, 9, or 11. Three were found to be de novo and had no family history of HHT or JPS. Eight had reported family history of either HHT or JP and the available parents did not carry the mutation. Four did not have sufficient family history or parents available for testing.
18823382 Calva-Cerqueira 2009: DNA was extracted from 102 JPS probands. By MLPA, one proband had deletion of most of SMAD4 and another deletion of the 5' end of SMAD4. Additionally, there were 13 patients with predicted pathogenic mutations (11 truncating, 1 nonsense and 1 splicing).
  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity