MUTATIONS IN PAX3 THAT CAUSE WAARDENBURG SYNDROME TYPE-I - 10 NEW MUTATIONS AND REVIEW OF THE LITERATURE

Waardenburg syndrome (WS) is an autosomal-dominant disorder characteri zed by sensorineural hearing loss, dystopia canthorum, and pigmentary disturbances, and it represents the most common form of inherited deaf ness in infants. WS type Il is characterized by the presence of dystop ia canthorum, while individuals with WS type II have normally-located canthi. WS type III is similar to WS type I but is also characterized by musculoskeletal abnormalities. Defects in the PAX3 gene, a transcri ption factor expressed during embryonic development, have been shown t o cause WS types I and III in several families. In contrast, mutations in PAX3 do not cause WS type II, and linkage of the disease to other chromosomal regions has been demonstrated. We describe 10 additional m utations in the PAX3 gene in families with WS type I. Eight of these m utations are in the region of PAX3, where only one mutation has been p reviously described. These mutations, together with those previously r eported, cover essentially the entire PAX3 gene and represent a wide s pectrum of mutations that can cause WS type I. Thus far, all but one o f the mutations are private; only one mutation has been reported in tw o apparently unrelated families. Our analysis thus far demonstrates li ttle correlation between genotype and phenotype; deletions of the enti re PAX3 gene result in phenotypes indistinguishable from those associa ted with single-base substitutions in the paired domain or homeodomain of PAX3. Moreover, two similar mutations in close proximity can resul t in significantly different phenotypes, WS type I in one family and W S type III in another. (C) 1995 Wiley-Liss, Inc.