ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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."

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.