A human model for multigenic inheritance: Phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus

Reduced penetrance in genetic disorders may be either dependent or independ ent of the genetic background of gene carriers. Hirschsprung disease (HSCR) demonstrates a complex pattern of inheritance with approximate to 50% of f amilial cases being heterozygous for mutations in the receptor tyrosine kin ase RET. Even when identified, the penetrance of RET mutations is only 50-7 0%, gender-dependent and varies with the extent of aganglionosis, We search ed for additional susceptibility genes which, in conjunction with RET, lead to phenotypic expression by studying 12 multiplex HSCR families. Haplotype analysis and extensive mutation screening demonstrated three types of fami lies: six families harboring severe RET mutations (group I); and the six re maining families, five of which are RET-linked families with no sequence al terations and one RET-unlinked family (group II). Although the presence of RET mutations in group I families is sufficient to explain HSCR inheritance , a genome scan reveals a new susceptibility locus an 9q31 exclusively in g roup II families. As such, the gene at 9q31 is a modifier of HSCR penetranc e, These observations imply that identification of new susceptibility facto rs in a complex disease may depend on classification of families by mutatio nal type at known susceptibility genes.