title: Phenotypic variation in Waardenburg syndrome: mutational heterogeneity, modifier genes or polygenic background?
abstract: 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.
authors.affiliation: Department of Human Genetics, Medical College of Virginia, Richmond 23298, USA.
authors.forename: A
authors.initials: A
authors.lastname: Pandya
authors.forename: X J
authors.initials: XJ
authors.lastname: Xia
authors.forename: B L
authors.initials: BL
authors.lastname: Landa
authors.forename: K S
authors.initials: KS
authors.lastname: Arnos
authors.forename: J
authors.initials: J
authors.lastname: Israel
authors.forename: J
authors.initials: J
authors.lastname: Lloyd
authors.forename: A L
authors.initials: AL
authors.lastname: James
authors.forename: S R
authors.initials: SR
authors.lastname: Diehl
authors.forename: S H
authors.initials: SH
authors.lastname: Blanton
authors.forename: W E
authors.initials: WE
authors.lastname: Nance
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D004252:DNA Mutational Analysis; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D018740:Genetic Heterogeneity; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D014157:Transcription Factors; D014849:Waardenburg Syndrome / Q000235:genetics*
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D014157:Transcription Factors; C068686:Pax3 protein, mouse