Submission Details

The EDN3 gene has been associated with autosomal recessive Waardenburg syndrome using the ClinGen Clinical Validity Framework as of 12/8/2017. This association was made using case-level data only. At least 7 variants (missense and frameshift) have been reported in humans. EDN3 was first associated with this disease in humans as early as 1996 (Edery et al.). Association is seen in at least 8 probands in 8 publications (8630502, 19764030, 22876130, 20583152, 30394532, 33713422, 8630503, 12189494). Variants in this gene segregated with disease in one additional family member. This gene-disease association is supported by two mouse models with homozygous missense EDN3 variants, which display white spotting, aganglionic megacolon, and early death. In summary, there is moderate evidence to support this gene-disease association. While more evidence is needed to establish this association definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the ClinGen Hearing Loss GCEP on 5/8/2018. It was reevaluated on 5/17/2023. As a result of this reevaluation, the classification did not change. However additional genetic evidence has been included and scoring adjusted to the current Gene Clinical Validity SOP Version 9. The new genetic evidence included these publications (PMID: 20583152, 30394532, 33713422, 8630503, 12189494) and an additional proband was identified in Moghadam et al 2020 and scored 1.1 (http://repozytorium.ur.edu.pl/handle/item/5791). As the paper did not have a pubmed ID the relevant information was entered under non-scorable evidence. Therefore, the actual score for genetic evidence is 3.9 (including the score from Moghadam et al 2020 (1.1) and score for consanguineous probands (-0.4)). The final total points are 8.4 (MODERATE).