Journal Article

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 and Walter E. Nance

in Human Molecular Genetics

Volume 5, issue 4, pages 497-502
Published in print April 1996 | ISSN: 0964-6906
e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/5.4.497
Phenotypic Variation in Waardenburg Syndrome: Mutational Heterogeneity, Modifier Genes or Polygenic Background?

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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.

Journal Article.  4746 words.  Illustrated.

Subjects: Genetics and Genomics

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