Biallelic variants in PAX3 cause Klein syndrome

Clin Genet. 2022 Sep;102(3):223-227. doi: 10.1111/cge.14167. Epub 2022 Jun 5.


Waardenburg syndrome is a group of genetic conditions that can cause hearing loss and pigmentation deficiency of the hair, skin, and eyes. Klein-Waardenburg syndrome (Waardenburg syndrome type 3) represents a distinct presentation of Waardenburg syndrome type 1 and includes musculoskeletal abnormalities in addition to dystopia canthorum hearing loss and pigmentary changes. Heterozygous or homozygous variants in the PAX3 gene cause Klein-Waardenburg syndrome. Here we report on a new severely affected child, with a homozygous PAX3 variant (c.251C>T; p.Ser84Phe), review the features of the syndrome, and propose a new classification. The designation of Waardenburg syndrome should be given only to patients with monoallelic pathogenic variants in PAX3 whether or not musculoskeletal abnormalities are present. Patients with biallelic PAX3 variants should be outlined as a distinct group and designated Klein syndrome.

Keywords: Klein syndrome; Waardenburg syndrome; deafness; joint limitations; pigmentary defects.

Publication types

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

MeSH terms

  • Child
  • Heterozygote
  • Humans
  • PAX3 Transcription Factor* / genetics
  • Pedigree
  • Waardenburg Syndrome* / diagnosis
  • Waardenburg Syndrome* / genetics


  • PAX3 Transcription Factor
  • PAX3 protein, human