Genotype-phenotype correlations in type 1 Waardenburg syndrome

Type 1 Waardenburg syndrome (WS1) is an autosomal dominant disorder characterized by dystopia canthorum, sensorineural deafness, and pigmentary disturbances. Previous work has linked the disease to PAX3, a transcription factor with two highly conserved DNA binding motifs: a paired 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 phenotypic expression of WS1 in these two families and explore the implications for possible genotype-phenotype correlations. The phenotypic expression was variable within and between the families. Sensorineural hearing loss was present in 71% of affected individuals. Spectrum of hearing loss included unilateral high frequency (>4000 Hz), profound unilateral hearing loss, and bilateral profound hearing loss. The severity of hearing impairment varied significantly within and among families. Phenotypically, these two WS1 families with mutations within the PAX3 homeobox 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.