title: Analysis of locus heterogeneity in Waardenburg syndrome types 1 and 2 using highly informative microsatellite markers.
abstract: We performed linkage and locus heterogeneity analyses of Waardenburg syndrome (WS) types 1 and 2 using 9 DNA markers from 2q35-q37, including two highly polymorphic microsatellites very closely linked to the PAX3 candidate gene. None of 5 WS type 2 (WS2) families showed linkage to the PAX3 candidate region. We localized the marker D2S102 to less than 1 cM from PAX3 (lod = 33.7, theta = 0), but a complete absence of crossovers prevented determining whether it maps distal or proximal to PAX3. Study of 14 WS type 1 (WS1) families yielded a maximum lod score of 27.81 at PAX3, theta f = 0.010, theta = 0.007 assuming homogeneity. However, we found significant evidence of locus heterogeneity, with one family initially classified as WS1 unlinked to the PAX3 region. Reevaluation of the clinical features of this family revealed atypical morphology of inner canthi. This produced the appearance of dystopia canthorum and high W-index scores. While our one unlinked WS1 family exhibits atypical canthal morphology, our type 1 families with classic dystopia appear to be homogeneously linked to PAX3. These and other findings identify precautions that need to be addressed before using PAX3-linked markers for diagnostic purposes.
authors.affiliation: Department of Human Genetics, Medical College of Virginia, Virginia Commonwealth University, Richmond, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Reynolds
authors.forename: K S
authors.initials: KS
authors.lastname: Arnos
authors.forename: B
authors.initials: B
authors.lastname: Landa
authors.forename: C A
authors.initials: CA
authors.lastname: Stevens
authors.forename: B A
authors.initials: BA
authors.lastname: Salbert
authors.forename: L
authors.initials: L
authors.lastname: Wright
authors.forename: B
authors.initials: B
authors.lastname: Duke
authors.forename: W
authors.initials: W
authors.lastname: Hunt
authors.forename: M L
authors.initials: ML
authors.lastname: Marazita
authors.forename: L
authors.initials: L
authors.lastname: Ploughman
mesh_terms: D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2; D003434:Crossing Over, Genetic; D017931:DNA Primers; D004276:DNA, Satellite / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005190:Family; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D007621:Karyotyping; D008126:Lod Score; D008297:Male; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D016133:Polymerase Chain Reaction / Q000379:methods; D011110:Polymorphism, Genetic; D011995:Recombination, Genetic; D014157:Transcription Factors; D014849:Waardenburg Syndrome / Q000235:genetics*
chemical_list: D017931:DNA Primers; D004276:DNA, Satellite; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D014157:Transcription Factors; C068686:Pax3 protein, mouse