Epistasis and Hirschsprung disease

Hirschsprung disease or aganglionic megacolon is a congenital disorder characterized by absence of enteric ganglia along a variable length of the intestine [OMIM]. A nice study by Owens et al. published in Human Molecular Genetics documents epistasis in Hirschsprung disease using genome-wide SNP analysis in mice.

Owens SE, Broman KW, Wiltshire T, Elmore JB, Bradley KM, Smith JR, Southard-Smith EM. Genome-wide Linkage Identifies Novel Modifier Loci of Aganglionosis in the Sox10Dom Model of Hirschsprung Disease. Hum Mol Genet. 2005 Apr 20 [PubMed]

Abstract:

Hirschsprung disease (HSCR) is a complex disorder that exhibits incomplete penetrance and variable expressivity due to interactions among multiple susceptibility genes. Studies in HSCR families have identified RET-dependent modifiers for short-segment HSCR (S-HSCR), but epistatic effects in long-segment (L-HSCR) and syndromic cases have not been fully explained. SOX10 mutations contribute to syndromic HSCR cases and Sox10 alleles in mice exhibit aganglionosis and pigmentary anomalies typical of a subset of HSCR patients categorized as Waardenburg-Shah Syndrome (WS4, OMIM 277580). Sox10 mutant alleles in mice exhibit strain dependent variation in penetrance and expressivity of aganglionic megacolon analogous to the variation observed in patients with aganglionosis. In this study we focused on enteric ganglia deficits in Sox10(Dom) mice and defined aganglionosis as a quantitative trait in Sox10(Dom) intercross progeny to investigate the contribution of strain background to variation in enteric nervous system deficits. We observe that the phenotype of Sox10(Dom/+) mutants ranges over a continuum from severe aganglionosis to no detectable phenotype in the gut. To systematically identify genes that modulate Sox10-dependent aganglionosis we performed a SNP-based genome scan in Sox10(Dom/+) F1 intercross progeny. Our analysis reveals modifier loci on mouse chromosomes 3, 5, 8, 11 and 14 with distinct effects on penetrance and severity of aganglionosis. Three of these loci on chromosomes 3, 8, and 11 do not coincide with previously known aganglionosis susceptibility genes or modifier loci and offer new avenues for elucidating the genetic network that modulates this complex neurocristopathy.