The relationship between PAX3 and autosomal dominant Waardenburg syndrome was evaluated using the ClinGen Clinical Validity Framework as of 10/10/2017. Variants in PAX3 were first reported in humans with this disease as early as 1995 (Hol et al., PMID 7897628). At least 10 unique variants (e.g. missense, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, biochemical function studies and expression in mouse hair follicles as well as several mouse models (PMID: 18983540, 20095975, 28381738, 28043919, 15729346). Variants in this gene have been reported in at least 8 probands in 12 publications (PMIDs 27759048, 7897628, 28690861, 30314436, 25932447). Variants in this gene segregated with disease in 7 additional family members. In summary, PAX3 is definitively associated with autosomal dominant Waardenberg syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 11/15/2017 (SOP Version 5).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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