Phenotypic diversity and genetic complexity ofPAX3-related Waardenburg syndrome

Waardenburg syndrome subtypes 1 and 3 are caused by pathogenic variants inPAX3. We investigated 12 individuals from four unrelated families clinically diagnosed with Waardenburg syndrome type 1/3. Novel pathogenic variants identified inPAX3included single nucleotide variants (c.166C>T, c.829C>T), a 2-base pair deletion (c.366_367delAA) and a multi-exonic deletion. Two novel variants, c.166C>T and c.829C>T and a previously reported variant, c.256A>T inPAX3were evaluated for their nuclear localization and ability to activateMITFpromoter. The coexistence of two subtypes of Waardenburg syndrome with pathogenic variants inPAX3andEDNRBwas seen in one of the affected individuals. Multiple genetic diagnoses of Waardenburg syndrome type 3 and autosomal recessive deafness 1A was identified in an individual. We also review the phenotypic and genomic spectrum of individuals withPAX3-related Waardenburg syndrome reported in the literature.