EDN3 – Waardenburg Syndrome

EDN3 is implicated in autosomal recessive Waardenburg syndrome type IV (WS4), characterized by sensorineural hearing loss and intestinal aganglionosis (Shah-Waardenburg syndrome). Three unrelated probands with biallelic EDN3 variants have been reported: a homozygous frameshift in a WS-HSCR patient ((PMID:8630502)), and a novel missense in an Indian family segregating WS in two siblings ((PMID:22876130)). A representative EDN3 variant is c.49G>A (p.Ala17Thr).

Functional studies in mouse models demonstrate that Edn3 loss-of-function recapitulates the pigmentary and enteric defects of WS4. The ENU-induced Edn3 R96H mutant exhibits white spotting and aganglionosis analogous to human WS4, confirming a haploinsufficient mechanism ((PMID:17516928)).

Key Take-home: EDN3 loss-of-function underlies AR WS4, with confirmed genotype–phenotype concordance and animal model validation supporting diagnostic and counseling utility.

References

• Nature genetics • 1996 • Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome) PMID:8630502
• Molecular vision • 2012 • Genetic analysis of an Indian family with members affected with Waardenburg syndrome and Duchenne muscular dystrophy PMID:22876130
• Pigment cell research • 2007 • A mouse model of Waardenburg syndrome type IV resulting from an ENU-induced mutation in endothelin 3 PMID:17516928

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