EDNRB – Waardenburg Syndrome Type 4A

Waardenburg syndrome type 4A (WS4A) is an autosomal recessive neurocristopathy characterised by congenital sensorineural hearing loss, pigmentary abnormalities, and intestinal aganglionosis. Biallelic loss-of-function variants in EDNRB underlie WS4A, with homozygous or compound heterozygous alleles causing the full WS4 phenotype and heterozygotes displaying isolated Hirschsprung disease or mild pigmentary signs.

Genetic case series have described over 15 distinct EDNRB variants in 25 unrelated probands, including nonsense (e.g., c.757C>T (p.Arg253Ter)), missense (c.587G>A (p.Ser196Asn)), frameshift, and splice-site changes segregating in multiple families ([PMID:10528251], [PMID:16237557]). In one large pedigree, all affected relatives were homozygous for c.757C>T and unaffected family members and >50 controls lacked this allele, confirming full segregation with WS4A ([PMID:10528251]).

The variant spectrum spans exon 2–7, with founder or recurrent alleles such as c.553G>A (p.Val185Met) enriched in East Asian cohorts ([PMID:29106856]). Homozygous missense and nonsense mutations uniformly predict truncated or dysfunctional receptor proteins absent from the plasma membrane in vitro.

Functional assays demonstrate that EDNRB missense mutants (W276C) impair ligand-induced Ca2+ transients ([PMID:8001158]), and complete loss of EDNRB in animal models recapitulates aganglionosis and hypopigmentation ([PMID:8570650]). These concordant functional data support a haploinsufficiency mechanism for truncating alleles and dominant-negative or null effects for missense variants.

Integration of genetic and experimental evidence yields a Definitive gene–disease association. Genetic testing for EDNRB variants is indicated in individuals with congenital pigmentary defects and aganglionosis to guide diagnosis, carrier screening, and prenatal counseling.

Key Take-home: Biallelic EDNRB loss-of-function variants are a definitive cause of autosomal recessive Waardenburg syndrome type 4A, supporting targeted molecular diagnostics and family risk assessment.

References

• American journal of medical genetics • 1999 • Novel nonsense mutation of the endothelin-B receptor gene in a family with Waardenburg-Hirschsprung disease PMID:10528251
• Cell • 1994 • A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung's disease PMID:8001158
• Proceedings of the National Academy of Sciences of the United States of America • 1996 • Null mutation of endothelin receptor type B gene in spotting lethal rats causes aganglionic megacolon and white coat color PMID:8570650

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