ANALYSIS OF LOCUS HETEROGENEITY IN WAARDENBURG-SYNDROME TYPE-1 AND TYPE-2 USING HIGHLY INFORMATIVE MICROSATELLITE MARKERS

We performed linkage and locus heterogeneity analyses of Waardenburg s yndrome (WS) types 1 and 2 using 9 DNA markers from 2q35-q37, includin g two highly polymorphic microsatellites very closely linked to the PA X3 candidate gene. None of 5 WS type 2 (WS2) families showed linkage t o the PAX3 candidate region. We localized the marker D2S102 to less th an I cM from PAX3 (led = 33.7, theta = 0), but a complete absence of c rossovers 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 homogeneit y. However, we found significant evidence of locus heterogeneity, with one family initially classified as WS1 unlinked to the PAX3 region. R eevaluation of the clinical features of this family revealed atypical morphology of inner canthi. This produced the appearance of dystopia c anthorum and high W-index scores. While our one unlinked WS1 family ex hibits atypical canthal morphology, our type 1 families with classic d ystopia appear to be homogeneously linked to PAX3. These and other fin dings identify precautions that need to be addressed before using PAX3 -linked markers for diagnostic purposes.