HOMOZYGOSITY FOR WAARDENBURG SYNDROME

In a large kindred including many individuals affected with Waardenbur g (WS) type 1 (WS1) syndrome, a child affected with a very severe form of WS type 3 was born. This child presented with dystopia canthorum, partial albinism, and very severe upper-limb defects. His parents were first cousins, both affected with a mild form of WSI. Molecular analy sis of PAX3, the gene that was determined by linkage to cause the diso rder in the family, demonstrated a novel missense mutation (S84F) in e xon 2 of PAX3 within the paired box. While individuals affected with W S1 were heterozygous for the mutation, the child with WS3 was homozygo us for S84F. The observation that the PAX3 homozygote in humans may al low life at least in early infancy and does not cause neural tube defe cts was unexpected, since, in all the mutations known in mice (splotch ), homozygosity has led to severe neural tube defects and intrauterine or neonatal death.