EDNRB – Waardenburg Syndrome

Waardenburg syndrome (WS; MONDO:0018094) is a genetically heterogeneous neurocristopathy characterized by sensorineural hearing impairment, pigmentary anomalies, and in some subtypes megacolon. EDNRB (Gene Symbol) encodes the endothelin B receptor, a G protein-coupled receptor crucial for neural crest–derived melanocyte and enteric neuron development. Pathogenic variants in EDNRB underlie WS type IV (autosomal recessive) and have also been implicated in WS type II via autosomal dominant inheritance with incomplete penetrance. Functional studies in vitro demonstrate that both missense and truncating EDNRB mutations impair ligand-induced Ca2+ signaling and receptor trafficking, supporting haploinsufficiency as the primary mechanism.

Genetic evidence includes multiple unrelated families: a heterozygous whole-gene deletion segregated with WS type IV across four affected relatives ([PMID:25118007]), a homozygous missense change c.1133A>G (p.Asn378Ser) identified in a consanguineous Moroccan pedigree with Shah-Waardenburg syndrome ([PMID:25852447]), and six heterozygous EDNRB variants in WS2 cohorts demonstrating dominant transmission with incomplete penetrance ([PMID:28236341]). Segregation analysis across these studies reports at least four additional affected relatives with concordant EDNRB changes. The variant spectrum comprises missense, nonsense, splice-site, frameshift, and whole-gene deletions; recurrent and founder alleles have been described in specific populations.

Functional assays in transfected cells show that mutations such as W276C and P383L reduce endothelin-induced Ca2+ mobilization and inhibit downstream signaling ([PMID:8001158]). Some alleles cause receptor mislocalization or accelerated lysosomal degradation, consistent with loss of function. Animal models recapitulate pigmentary and enteric phenotypes, and co-expression studies confirm that defective EDNRB signaling disrupts neural crest migration and survival.

No studies to date have refuted the EDNRB–WS association; variant pathogenicity is supported by segregation, functional concordance, and animal models. Additional rare EDNRB alleles likely remain to be discovered, particularly in underexplored ethnic groups.

Key take-home: EDNRB variants cause both recessive and dominant forms of Waardenburg syndrome, with strong evidence for clinical genetic testing to inform diagnosis, counseling, and management in affected families.

References

• European journal of medical genetics • 2014 • Familial co-segregation of Coffin-Lowry syndrome inherited from the mother and autosomal dominant Waardenburg type IV syndrome due to deletion of EDNRB inherited from the father. PMID:25118007
• Molecular syndromology • 2015 • A novel mutation in the endothelin B receptor gene in a moroccan family with shah-waardenburg syndrome. PMID:25852447
• Human mutation • 2017 • EDNRB mutations cause Waardenburg syndrome type II in the heterozygous state. PMID:28236341
• Cell • 1994 • A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung's disease. PMID:8001158

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