The major gene for Hirschsprung disease (HSCR) encodes the receptor tyrosine 
kinase RET. In a study of 690 European- and 192 Chinese-descent probands and 
their parents or controls, we demonstrate the ubiquity of a >4-fold 
susceptibility from a C-->T allele (rs2435357: p = 3.9 x 10(-43) in European 
ancestry; p = 1.1 x 10(-21) in Chinese samples) that probably arose once within 
the intronic RET enhancer MCS+9.7. With in vitro assays, we now show that the T 
variant disrupts a SOX10 binding site within MCS+9.7 that compromises RET 
transactivation. The T allele, with a control frequency of 20%-30%/47% and case 
frequency of 54%-62%/88% in European/Chinese-ancestry individuals, is involved 
in all forms of HSCR. It is marginally associated with proband gender (p = 0.13) 
and significantly so with length of aganglionosis (p = 7.6 x 10(-5)) and 
familiality (p = 6.2 x 10(-4)). The enhancer variant is more frequent in the 
common forms of male, short-segment, and simplex families whereas multiple, 
rare, coding mutations are the norm in the less common and more severe forms of 
female, long-segment, and multiplex families. The T variant also increases 
penetrance in patients with rare RET coding mutations. Thus, both rare and 
common mutations, individually and together, make contributions to the risk of 
HSCR. The distribution of RET variants in diverse HSCR patients suggests a 
"cellular-recessive" genetic model where both RET alleles' function is 
compromised. The RET allelic series, and its genotype-phenotype correlations, 
shows that success in variant identification in complex disorders may strongly 
depend on which patients are studied.