Phenotypic diversity and genetic complexity of PAX3-related Waardenburg syndrome

Am J Med Genet A. 2020 Dec;182(12):2951-2958. doi: 10.1002/ajmg.a.61893. Epub 2020 Sep 29.


Waardenburg syndrome subtypes 1 and 3 are caused by pathogenic variants in PAX3. We investigated 12 individuals from four unrelated families clinically diagnosed with Waardenburg syndrome type 1/3. Novel pathogenic variants identified in PAX3 included 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 in PAX3 were evaluated for their nuclear localization and ability to activate MITF promoter. The coexistence of two subtypes of Waardenburg syndrome with pathogenic variants in PAX3 and EDNRB was 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 with PAX3-related Waardenburg syndrome reported in the literature.

Keywords: EDNRB; PAX3; Waardenburg syndrome; multiple genetic diagnoses; phenotypic variability.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Male
  • Mutation*
  • PAX3 Transcription Factor / genetics*
  • Pedigree
  • Phenotype
  • Waardenburg Syndrome / genetics*
  • Waardenburg Syndrome / pathology*


  • PAX3 Transcription Factor
  • PAX3 protein, human