Submission Details

The relationship between EDNRB and autosomal dominant Waardenburg syndrome was evaluated using the ClinGen Clinical Validity Framework as of 12/14/2017. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, the relationship between EDNRB and autosomal recessive Waardenburg syndrome has been assessed separately. Variants in EDNRB were first reported in humans with this disease as early as 2009 (Tuysuz et al., PMID 19764031). At least 6 missense, nonsense and frameshift variants have been reported in humans (Issa et al. 2017, PMID 28236341). Variants in this gene segregate with disease in multiple family members, however phenotypes vary among family members. A mouse model from Matsushima et al. 2002 shows a heterozygous Ednrb variant mouse without Waardenburg phenotypes, and a mouse model by Ida-Eto et al. 2011 shows recovered hearing in a heterozygous Ednrb variant mouse (PMIDs 11773966, 21715336). In summary, there is limited evidence to support this gene-disease association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. This classification was approved by the ClinGen Hearing Loss Working Group on 5/8/2018.