LOCUS HETEROGENEITY FOR WAARDENBURG SYNDROME IS PREDICTIVE OF CLINICAL SUBTYPES

Waardenburg syndrome (WS) is a dominantly inherited and clinically var iable syndrome of deafness, pigmentary changes, and distinctive facial features. Clinically, WS type I(WS1) is differentiated from WS type I I (WS2) by the high frequency of dystopia canthorum in the family. In some families, WS is caused by mutations in the PAX3 gene on chromosom e 2q. We have typed microsatellite markers within and flanking PAX3 in 41 WS1 kindreds and 26 WS2 kindreds in order to estimate the proporti on of families with probable mutations in PAX3 and to study the relati onship between phenotypic and genotypic heterogeneity. Evaluation of h eterogeneity in location scores obtained by multilocus analysis indica ted that WS is linked to PAX3 in 60% of all WS families and in 100% of WS1 families. None of the WS2 families were linked. In those families in which equivocal lod scores (between -2 and +1) were found, PAX3 mu tations have been identified in 5 of the 15 WS1 families but in none o f the 4 WS2 families. Although preliminary studies do not suggest any association between the phenotype and the molecular pathology in 20 fa milies with known PAX3 mutations and in four patients with chromosomal abnormalities in the vicinity of PAX3, the presence of dystopia in mu ltiple family members is a reliable indicator for identifying families likely to have a defect in PAX3.