Phenotypic variation in Waardenburg syndrome: Mutational heterogeneity, modifier genes or polygenic background?

Arti Pandya, Xia Juan Xia, Barbara L. Landa, Kathleen S. Arnos, Jamie Israel, Joyce Lloyd, Anthony L. James, Scott R. Diehl, Susan H. Blanton, Walter E. Nance

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


We have identified 11 mutational changes in the PAX3 gene in patients with type 1 Waardenburg syndrome (WS1) including three in the paired domain, six within or immediately adjacent to the homeodomain and two previously described polymorphic variants in exons 2 and 6. The affected members of one family carried substitutions involving two base pairs separated by one unaltered codon. Two of the deleterious mutations were identical and three others were identical to previously reported mutations. A comparison of clinical findings in families carrying substitutions in the same codon failed to reveal conspicuous similarities. Although subtle mutation-specific effects may well exist, allelic heterogeneity clearly cannot account for within family variation. However, the striking concordance of a pair of monozygotic twins with Waardenburg syndrome (WS) and previous reports of similar pairs indicate that phenotypic variation in WS has a genetic basis. If the genetic effects are mediated by oligogenic epistasis, as studies in the mouse suggest, it may ultimately be possible to predict clinically relevant aspects of the Waardenburg phenotype.

Original languageEnglish (US)
Pages (from-to)497-502
Number of pages6
JournalHuman molecular genetics
Issue number4
StatePublished - Apr 1996
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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