MOLECULAR AND EPIDEMIOLOGICAL STUDIES OF WAARDENBURG SYNDROME

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We performed linkage analyses and tests of locus heterogeneity of Waardenburg Syndrome (WS) using 9 DNA markers from 2q35-37, including two highly polymorphic microsatellites very closely linked to the candidate PAX3 locus. Analysis of 14 WS Type 1 (WS1) families at PAX3 yielded a maximum LOD score of 27.81, theta = .010, theta m = .007 assuming homogeneity. However, we found significant evidence of heterogeneity in our study, with approximately 90% of our families linked to the PAX3 region. None of five WS Type 2 (WS2) families showed linkage to the PAX3 candidate region, and linkage was excluded (LOD < -2.0) up to a distance of 17.5 cM. We localized the marker D2S102 to less than 1cM from PAX3 locus (theta = 0), and thus were unable to determine whether it mapped distally or proximally due to lack of crossovers between these two markers. Meiotic breakpoint analysis in one of the three families with a crossover between WE1 and PAX3 provides strong evidence that the disease gene in this family is located elsewhere in the genome.