We report on a multigenerational family with isolated Hirschsprung's disease 
(HSCR). Five patients were affected by either short segment or long segment 
HSCR. The family consists of two main branches: one with four patients (three 
siblings and one maternal uncle) and one with one patient. Analysis of the RET 
gene, the major gene involved in HSCR susceptibility, revealed neither linkage 
nor mutations. A genome wide linkage analysis was performed, revealing 
suggestive linkage to a region on 4q31-q32 with a maximum parametric multipoint 
LOD score of 2.7. Furthermore, non-parametric linkage (NPL) analysis of the 
genome wide scan data revealed a NPL score of 2.54 (p = 0.003) for the same 
region on chromosome 4q (D4S413-D4S3351). The minimum linkage interval spans a 
region of 11.7 cM (12.2 Mb). No genes within this chromosomal interval have 
previously been implicated in HSCR. Considering the low penetrance of disease in 
this family, the 4q locus may be necessary but not sufficient to cause HSCR in 
the absence of modifying loci elsewhere in the genome. Our results suggest the 
existence of a new susceptibility locus for HSCR at 4q31.3-q32.3.