Hirschsprung Disease, Susceptibility To, 5
Description
The disorder described by Hirschsprung (1888) and known as Hirschsprung disease or aganglionic megacolon is characterized by congenital absence of intrinsic ganglion cells in the myenteric (Auerbach) and submucosal (Meissner) plexuses of the gastrointestinal tract. Patients are diagnosed with the short-segment form (S-HSCR, approximately 80% of cases) when the aganglionic segment does not extend beyond the upper sigmoid, and with the long-segment form (L-HSCR) when aganglionosis extends proximal to the sigmoid. Total colonic aganglionosis and total intestinal HSCR also occur (Amiel et al., 2008).
Isolated HSCR appears to be of complex nonmendelian inheritance with low sex-dependent penetrance and variable expression according to the length of the aganglionic segment, suggestive of the involvement of one or more genes with low penetrance (Amiel et al., 2008).
For a general description and a discussion of genetic heterogeneity of Hirschsprung disease (HSCR), see 142623.
MappingWhile approximately 50% of familial cases of Hirschsprung disease (142623) are heterozygous for mutations in RET (164761), the penetrance of these mutations is only 50 to 70%, gender-dependent, and varies according to the extent of aganglionosis. In 12 multiplex Hirschsprung disease families, Bolk et al. (2000) searched for additional susceptibility genes which, in conjunction with the gene encoding the receptor tyrosine kinase RET (164761), lead to phenotypic expression. Haplotype analysis and extensive mutation screening demonstrated 3 types of families: 6 families harbored 'severe' RET mutations (group I); 5 families were RET-linked with no sequence alterations, and 1 family was RET-unlinked (group II). Although the presence of RET mutations in group I families was sufficient to explain HSCR inheritance, a genome scan revealed a new susceptibility locus on 9q31 exclusively in group II families. A nonparametic lod score of 3.8 (P = 0.002) was obtained between markers D9S1677 and D9S1828. Bolk et al. (2000) concluded that the degree of RET expression is critical for development of the HSCR phenotype: severe alleles lead to HSCR directly, while weak alleles require the additional effects of a 9q31 gene.
Tang et al. (2010) provided evidence for 2 different putative loci within the HSCR 9q31 region that differed according to population. After stratification of 137 Dutch trios by RET mutation status, they identified a strong association with HSCR in those without RET mutations for rs10816998 in the intronic region of the SVEP1 (611691) gene (odds ratio (OR) of 2.38; p = 5.33 x 10(-5)). However, the findings were not replicated in a second cohort of 107 Dutch patients without RET mutations. In an independent Chinese population, after stratification of 173 patients and 436 controls by RET mutation status, there was a significant association between those with RET mutations and 2 SNPs in the IKBKAP gene (603722) (rs10979596 and rs10979597) (OR of 3.32; p = 5.10 x 10(-6)). These findings were replicated in another Chinese cohort of 21 patients with RET mutations. Tang et al. (2010) noted that HSCR association found for IKBKAP in Chinese suggested population specificity and implied that RET mutation carriers may have an additional risk for the disorder.