Major-locus contributions to variability of the craniofacial feature dystopia canthorum in Waardenburg syndrome.

We used segregation analysis to investigate the genetic basis of variation in dystopia canthorum, one of the key diagnostic features of Waardenburg syndrome type 1 (WS1). We sought to determine whether the W-index, a quantitative measure of this craniofacial feature, is influenced primarily either by allelic variation in the PAX3 disease gene or other major loci, by polygenic background effects, or by all of these potential sources of genetic variation. We studied both WS1-affected individuals and their WS1-unaffected relatives. After adjustment of the W-index for WS1 disease status, segregation analyses by the regression approach indicated major-locus control of this variation, although residual parent-offspring and sib-sib correlations are consistent with additional (possibly polygenic) effects. Separate analyses of WS1-affected and WS1-unaffected individuals suggest that epistatic interactions between disease alleles at the PAX3 WS1 locus and a second major locus influence variation in dystopia canthorum. Our approach should be applicable for assessing the genetic architecture of variation associated with other genetic diseases.