Hirschsprung Disease, Susceptibility To, 9
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.
MappingBrooks et al. (2006) described a multigenerational Dutch family with isolated HSCR. Five patients were affected by either short-segment or long-segment HSCR. The family consisted of 2 main branches: 1 with 4 patients (3 sibs and 1 maternal uncle) and 1 with 1 patient. Analysis of the RET gene (164761), the major gene involved in HSCR susceptibility, revealed neither linkage or mutations. A genomewide linkage analysis showed suggestive linkage to 4q31-q32 with a maximum parametric multipoint lod score of 2.7 between markers D4S1585 and D4S3351. Nonparametric linkage (NPL) analysis of the genomewide scan data showed an NPL score of 2.54 (P = 0.003) for the same region on 4q. The minimum linkage interval of 11.7 cM (12.2 Mb) between markers D4S3049 and D4S1566 on 4q31.3-q32.3 contained no genes that had previously been implicated in HSCR. The 3 affected sibs were heterozygous for a common risk haplotype defined by SNPs located in the 5-prime region of the RET locus reported in Dutch patients (Burzynski et al., 2004, Burzynski et al., 2005). However, their affected maternal uncle and cousin did not carry the 5-prime RET common risk haplotype. Brooks et al. (2006) concluded that, considering the low penetrance of the 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.
CytogeneticsIn a mother and 3 sons with delayed development, dysmorphic facial features, and variable expression of Hirschsprung disease, Wang et al. (2009) identified a 4.3-Mb triplication at chromosome 4q32.1-q32.2 (613603), which included the HSCR9 locus mapped within this region.