ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000013.10) (NC_000013.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
8852658 Kusafuka et al. (1996) analyzed 41 patients with HSCR and found two novel heterozygous mutations in EDNRB: TRP275TER and 1-BP INS, 878T, both resulting in premature stop codons. Family studies were not performed. These mutations were not observed in 70 normal control individuals.
10528251 Syrris et al. (1999) analyzed a family with combined Waardenburg syndrome (WS)-HSCR disease for mutations in EDNRB. They found a heterozygous arg253-to-ter (R253X) mutation in all affected relatives. They tested one unaffected family member and 50 unrelated controls, but did not find the mutation.
8001158 Puffenberger et al. (1994) analyzed a large Mennonite kindred with HSCR and found a missense mutation in exon 4 of EDNRB that changed a highly conserved tryptophan residue to a cysteine (W276C). They performed functional studies by introducing W276C EDNRB cDNA into CHO cells, which do not express endogenous endothelia receptors, and examined the ET receptor ligand-induced intracellular calcium response. The mutant receptor showed a partial impairment in this assay. The authors conclude that "the mutation is dosage sensitive, in that W276C homozygotes and heterozygotes have a 74% and a 21% risk, respectively, of developing HSCR."

Haploinsufficiency phenotype comments:

Nonsyndromic HSCR has been associated with mutations in EDNRB with both AD and AR forms of inheritance. The syndromic form is usually associated with homozygous mutations. The HSCR phenotype is highly variable with demonstrated reduced penetrance and variable expressivity.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity