EDNRB

Gene Facts

• HGNC Symbol: EDNRB (HGNC:3180)
• HGNC Name: endothelin receptor type B
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: HSCR2, HSCR
• Alias symbols: ETB
• %HI: 5.87
• pLI: 0.49
• LOEUF: 0.59
• Cytoband: 13q22.3
• Genomic Coordinates:

  GRCh37/hg19:	chr13:78469616-78549662
  GRCh38/hg38:	chr13:77895481-77975527

• MANE Select Transcript: NM_001122659.3 ENST00000646607.2
• Function: Non-specific receptor for endothelin 1, 2, and 3. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. {ECO:0000269|PubMed:7536888}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-24269
• ClinGen Curation ID: CCID:007050
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Little Evidence for Haploinsufficiency (1)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 02/07/2022

Haploinsufficiency (HI) Score Details

• HI Score: 1
• HI Evidence Strength: Little Evidence for Haploinsufficiency

HI Disease

• Waardenburg Syndrome type 4A

HI Evidence

• PUBMED: 10528251
  Syrris P et al., (1999) reported a family of Afro-Caribbean origin with a combined Waardenburg syndrome (WS)-Hirschsprung disease (HSCR) phenotype and a nonsense variant (Arg253Ter) in EDNRB. This variant leads to a premature end of translation of EDNRB at exon 3, and is predicted to produce a truncated and nonfunctional endothelin‐B receptor. All seven affected relatives were heterozygous for this variant and it was not observed in over 50 unrelated individuals used as controls.
• PUBMED: 30394532
  Samasherkar PH et al., (2019) reported a heterozygous EDNRB variant, c.327C>A [p.(Cys109Ter)] in a subject with Waardenburg syndrome without HSCR that was inherited from the patient's unaffected father. A homozygous variant in EDNRB, c.673G>A [p.(Gly225Ser)] was identified in a proband with Waardenburg syndrome without HSCR. This individual's heterozygous parents are both asymptomatic.
• PUBMED: 28236341
  Issa S et al., (2017) described heterozygous EDNRB variants in six individuals with Waardenburg syndrome. A heterozygous nonsense variant, 678G>A (p.Trp226*), was identified in family 5. The family has two affected daughters and an affected mother with Waardenburg syndrome 2. Of note, a variant in MITF (c.559G>A) was identified in the father and both affected daughters of this family. This MITF variant is predicted to disrupt the donor splice site of exon 5. Both daughters had a more severe phenotype than the parents and the unaffected sibling did not have either variant. The proband in family 6 was also identified to have a frameshift variant in EDNRB (c.1163del). This variant was found in the affected sibling and mother as well. The other variants identified in EDNRB were c.409A>T(p.Asn137Tyr), c.50T>C (p.Leu17Pro), c.467C>G (p.Pro156Arg), and c.484-5T>G.
• PUBMED: 32990402
  Somashekar PH et al., (2020) reported a clinically diagnosed family with WS1 and pathogenic variants in PAX3 and/or EDNRB. The proband had pathogenic variants in PAX3 (c.166C>T) and EDNRB (c.1047delC). Three other family members (proband’s mother, father and maternal grandmother) had either PAX3 or EDNRB variants showing subtle clinical features when compared to the proband. The proband’s brother, despite having pathogenic variants in PAX3, was nonpenetrant. None of the individuals with the variants in EDNRB had HSCR. This EDNRB variant was inherited from the proband's paternal grandmother.
• PUBMED: 31427586
  Ideura M et al., (2019) reported an heterozygous deletion, c.223delG (p.D75fs) in EDNRB gene in the proband of a Waardenburg syndrome 2 (WS2) family from a cohort of 23 probands with Waardenburg syndrome patients in Japan. This variant is inherited from the affected mother.

• HI Evidence Comments: Waardenburg syndrome (WS) is a genetic disorder characterized by sensorineural hearing loss (SNHL) and pigmentation anomalies including depigmented areas of skin and hair and vivid blue eyes or iris heterochromia. There are four clinically classified subtypes, Types 1 to 4. Types 1 and 2 are most frequently associated with congenital SNHL and pigmentary abnormalities of the hair, skin, and eyes. Type 1 also has the additional phenotypic feature of dystopia canthorum. Individuals with type 3 show both dystopia canthorum and musculoskeletal abnormalities of the limbs, while individuals with type 4 also have Hirschsprung disease (HSRC/HD). Both heterozygous and biallelic variants in EDNRB have been reported in individuals with Waardenburg syndrome (with or without Hirschsprung), and heterozygous variants in EDNRB have been reported in individuals with Hirschsprung disease without apparent features of Waardenburg syndrome. Reported variants in EDNRB are often missense and not localized to one region. A few deletions and truncating variants have been reported in heterozygous EDNRB individuals. Additional evidence is needed to clarify the role of haploinsufficiency of EDNRB in both Waardenburg syndrome and Hirschsprung disease. Additional evidence: PMID: 31581539 Wu CC et al., (2019) reported one variant c.754-2A>G, in EDNRB in one affected individual from a cohort of 5314 unrelated families with sensorineural hearing impairment. The pathogenicity of this variant was not clearly described. PMID: 31544051 Cheng HH eta l., (2019) reported a Chinese family with Waardenburg syndrome type I (WS1) an a heterozygous missense variant, c.469A>G (p.Ile157Val). Three affected individuals (proband, his elder sister and paternal aunt) all had this variant. PMID: 33234331 Varga L et al., (2021) described a missense c.521G>A (p.Cys174Tyr) variant in exon 3 of the EDNRB gene in a 4 generation family. 4 individuals in the family carried this variant but only the proband had WS2. Probands’ sister and father carried the same EDNRB variant, both had signs of skin hypopigmentation of the chest and upper abdomen area. They had normal hearing thresholds as well as normal eye and hair pigmentation. The paternal grandma, aged of 68 yrs old, had this variant and bilateral high-frequency SNHL. PMID:8852658 Kusafuka et al. (1996) analyzed 41 patients with Hirschsprung disease (HSCR) and found two novel heterozygous variants: a G to A transition at nucleotide 824 [NM_001122659.3(EDNRB):c.824G>A (p.Trp275Ter)] and an insertion of T at nucleotide 878 [NM_001122659.3(EDNRB):c.877dup (p.Tyr293fs)]. Both variants resulted in stop codons, predicted to produce a truncated and non-functional endothelin-B receptor. Dysfunction or loss of function of endothelin-B receptor may be involved in the etiology of some isolated patients with HSCR. PMID:14633923 Garcia-Barcelo M et al., (2004) screened for variants and polymorphisms in the coding regions and intron/exon boundaries of the RET, GDNF, EDNRB, and EDN3 genes of 84 HSCR patients and 96 ethnically matched controls. This study reported one novel deletion, p.P383_L386delinsP, in the EDNRB gene. This 9-bp deletion (nucleotides c1149–1157) in exon 6 affects the codons for proline-383, isoleucine-384, alanine-385, and lysine-386, substituting them for a proline, which results in a shorter protein lacking highly conserved residues of the seventh transmembrane domain of the receptor. PMID:30217742 Tang CSM et al., (2018) performed genome sequence analyses of 443 patients with short-segment disease from hospitals in China and Vietnam, and 493 ethnically matched individuals without Hirschsprung disease (controls) to identify genetic factors that contribute to disease development and analyzed the functional effects of these variants. This study showed the patients had a significant excess of rare protein-altering variants in genes previously associated with Hirschsprung disease including the EDNRB gene. A 245kb deletion of the EDNRB gene was detected in addition to 12 other variants. None of these 13 variants were detected in control individuals. This study concluded rare and common variants in these genes are associated with disease risk. PMID:20009762 Sanchez-Meijias A et al., (2010) performed a genetic screening of EDNRB and END3 genes in a total of 196 patients with HSCR and 150 controls. They found two heterozygous stop gain variants in the EDNRB gene, one paternal origin (c.43A>T,p.K15X) and the other maternal origin (c.42_45del, p.L15PfsX29). Both are sporadic cases without any family history of HSCR. Neither the mother or the father had Hirschsprung disease. PMID:8001158 Puffenberger et al. (1994) analyzed a large Mennonite kindred with HSCR and found a missense variant 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."

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity