EDNRB – Hirschsprung disease

EDNRB encodes the endothelin-B receptor, a G protein–coupled receptor essential for migration and differentiation of neural crest–derived enteric neurons. Mutations in EDNRB disrupt endothelin-3/EDNRB signaling, leading to aganglionosis of the distal colon and variable penetrance of Hirschsprung disease (PMID:8852660). Genetic testing of EDNRB is therefore critical in infants presenting with congenital intestinal obstruction.

Clinical Validity (ClinGen: Strong)

• Multiple cohorts comprising 58 probands (41 isolated HSCR patients in Japan [PMID:8852658] and 17 Italian probands [PMID:8852659]) harbor heterozygous or homozygous EDNRB variants.
• Segregation of variants (e.g., p.Trp276Cys) in Mennonite and other pedigrees demonstrates incomplete penetrance but clear co-segregation with HSCR features ([PMID:8852660]); familial analysis supports dosage sensitivity.
• Functional concordance across studies (cell-based Ca²⁺ assays, receptor trafficking, animal models) is consistent and reproducible.

Genetic Evidence (ClinGen: Strong)

Inheritance is autosomal recessive with haploinsufficiency and dosage sensitivity. Case reports and series identify 58 probands with EDNRB variants including five loss-of-function alleles (nonsense, frameshift, splice) and numerous missense changes in transmembrane and exoplasmic domains. Segregation in >1 family confirms pathogenicity; heterozygotes often display isolated HSCR while homozygotes develop syndromic Waardenburg-Hirschsprung (WS4).

Functional / Experimental Evidence (ClinGen: Moderate)

• The p.Trp276Cys (c.828G>T (p.Trp276Cys)) variant reduces ligand-induced Ca²⁺ transients in transfected cells, indicating loss of G protein coupling ([PMID:8001158]).
• Truncating mutations (e.g., p.Trp275Ter) abolish receptor function in vitro ([PMID:8852658]).
• Spotting lethal rats with a null EDNRB allele exhibit aganglionic megacolon and pigment defects, confirming the receptor’s role in enteric neuron development ([PMID:8570650]).

Conflicting Evidence

The EDNRB p.Asn104Ile variant shows wild-type binding and signaling properties, suggesting it may be a benign polymorphism rather than pathogenic ([PMID:9556633]).

Integration & Take-Home

EDNRB variants, particularly loss-of-function and critical missense changes, have a strong and reproducible association with Hirschsprung disease via impaired endothelin signaling and neural crest migration. Genetic testing for EDNRB should be incorporated into diagnostic panels for congenital aganglionosis. Accurate interpretation of variant pathogenicity requires integration of segregation, population frequency, and functional assay data.

References

• Human molecular genetics • 1996 • Novel mutations of the endothelin-B receptor gene in isolated patients with Hirschsprung's disease. PMID:8852658
• Human molecular genetics • 1996 • Endothelin-B receptor mutations in patients with isolated Hirschsprung disease from a non-inbred population. PMID:8852659
• Human molecular genetics • 1996 • Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease. PMID:8852660
• Cell • 1994 • A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung's disease. PMID:8001158
• The Journal of biological chemistry • 1998 • Novel mutations of the endothelin B receptor gene in patients with Hirschsprung's disease and their characterization. PMID:9556633
• Proceedings of the National Academy of Sciences • 1996 • Null mutation of endothelin receptor type B gene in spotting lethal rats causes aganglionic megacolon and white coat color. PMID:8570650

Evidence Based Scoring (AI generated)