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.