Submission Details

EDNRB was first reported in relation to autosomal recessive Waardenburg Syndrome Type 4A (WS4) in 1994 (Puffenberger et al.; PMID: 8001158). This condition is associated with sensorineural hearing loss; atypical pigmentation of the hair, skin, and eyes; and Hirschsprung’s disease (aganglionic megacolon). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, the following disease entities have been split: autosomal recessive Waardenburg syndrome Type 4A and autosomal dominant Waardenburg syndrome type 4A (OMIM # for both entities: 277580). The split curation for autosomal dominant Waardenburg Syndrome Type 4A has been curated separately. Five variants (missense) that have been reported in five probands in five publications (PMIDs: 16237557, 21373256, 25852447, 28502583, 30394532) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (knockout mouse models; PMIDs: 11773966, 23360229, 21715336). In summary, there is moderate evidence to support this gene-disease relationship. This gene-disease pair was originally evaluated by the Hearing Loss GCEP on 5/8/2018. It was re-evaluated on 6/27/2023. As a result of this reevaluation, the classification did not change, although additional genetic evidence was added (PMID: 30394532). While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Hearing Loss GCEP on the meeting date 6/27/2023 (SOP Version 9).