Epistatic interactions with a common hypomorphicRET allele in syndromic Hirschsprung disease

Abstract

Hirschsprung disease (HSCR) stands as a model for genetic dissection of complex diseases. In this model, a major gene, RET, is involved in most if not all cases of isolated (i.e., nonsyndromic) HSCR, in conjunction with other autosomal susceptibility loci under a multiplicative model. HSCR susceptibility alleles can harbor either heterozygous coding sequence mutations or, more frequently, a polymorphism within intron 1, leading to a hypomorphic RET allele. On the other hand, about 30% of HSCR are syndromic. Hitherto, the disease causing gene has been identified for eight Mendelian syndromes with HSCR: congenital central hypoventilation (CCHS), Mowat-Wilson (MWS), Bardet-Biedl (BBS), Shah-Waardenburg (WS4), cartilage-hair-hypoplasia (CHH), Smith-Lemli-Opitz (SLO), Goldberg-Sprintzsen (GSS), and hydrocephalus due to congenital stenosis of the aqueduct of sylvius (HSAS). According to the HSCR syndrome, the penetrance of HSCR trait varies from 5 to 70%. Trisomy 21 (T21) also predisposes to HSCR. We were able to collect a series of 393 patients affected by CCHS (n = 173), WS4 (n = 24), BBS (n = 51), MWS (n = 71), T21 (n = 46), and mental retardation (MR) with HSCR (n = 28). For each syndrome, we studied the RET locus in two subgroups of patients; i.e., with or without HSCR. We genotyped the RET locus in 393 patients among whom 195 had HSCR, and compared the distribution of alleles and genotypes within the two groups for each syndrome. RET acts as a modifier gene for the HSCR phenotype in patients with CCHS, BBS, and Down syndrome, but not in patients with MWS and WS4. The frequent, low penetrant, predisposing allele of the RET gene can be regarded as a risk factor for the HSCR phenotype in CCHS, BBS, and Down syndrome, while its role is not significant in MWS and WS4. These data highlight the pivotal role of the RET gene in both isolated and syndromic HSCR.

Inhibition of neural crest migration underlies craniofacial dysmorphology and Hirschsprung's disease in Bardet–Biedl syndrome

“…These migratory defects were not confined to CNCCs: we showed a lack of ENS development and loss of gut motility in Bbs morphants probably explaining the association of HD with BBS (8,28,29). HD arises as a consequence of NCC migration defects and has been linked to Hh deregulation.…”

The nonmotile ciliopathies

“…Hirschsprung disease (HSCR) has been reported in up to 45% of patients with BBS, 81 but a more realistic estimate of prevalence is 5-10% (unpublished observations of P. Beales). This incidence is extremely high compared with the general population, where it only affects 1 in 5000 children (0.02%).…”

Hirschsprung-like disease is exacerbated by reduced de novo GMP synthesis

“…For example, inactivating RET mutations occur in 15%-20% of sporadic and 50% of familial HSCR, but only about half of children with inactivating RET mutations have HSCR (2). Genetic interactions also influence HSCR risk (3)(4)(5)(6); however, much variability in occurrence and severity of HSCR and other human birth defects remains unexplained. We hypothesized that nongenetic factors might affect HSCR occurrence.…”