GENOTYPE-PHENOTYPE CORRELATIONS IN TYPE-1 WAARDENBURG SYNDROME

Type 1 Waardenburg syndrome (WS1) is an autosomal dominant disorder ch aracterized by dystopia canthorum, sensorineural deafness, and pigment ary disturbances, Previous work has linked the disease to PAX3, a tran scription factor with two highly conserved DNA binding motifs: a paire d box and a homeobox, Several mutations within the paired box of PAX3 have been reported. We have identified the first two mutations within the homeobox in two different families. Herein, we report the phenotyp ic expression of WS1 in these two families and explore the implication s for possible genotype-phenotype correlations. The phenotypic express ion was variable within and between the families. Sensorineural hearin g loss was present in 71% of affected individuals. Spectrum of hearing loss included unilateral high frequency (>4000 Hz), profound unilater al hearing loss, and bilateral profound hearing loss, The severity of hearing impairment varied significantly within and among families. Phe notypically, these two WS1 families with mutations within the PAX3 hom eobox could not be differentiated from those families with paired box mutations. More precise genotype/phenotype correlation may be possible when additional mutations are described throughout the PAX3 gene.