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RET-associated Hirschsprung disease
Wednesday 7 May 2008
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. RET gene has a pivotal role in both isolated and syndromic HSCR.
HSCR susceptibility alleles can harbor either heterozygous coding sequence mutations or, more frequently, a polymorphism within intron 1, leading to a hypomorphic RET allele.
Epistatic interactions with a common hypomorphic RET allele in syndromic Hirschsprung disease
About 30% of HSCR are syndromic. The disease causing gene has been identified for eight Mendelian syndromes with HSCR:
congenital central hypoventilation syndrome (CCHS)
Mowat-Wilson syndrome (MWS)
Bardet-Biedl syndrome (BBS)
Shah-Waardenburg syndrome (WS4)
cartilage-hair-hypoplasia syndrome (CHH)
Smith-Lemli-Opitz syndrome (SLO)
Goldberg-Sprintzsen syndrome (GSS)
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.
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.
References
Amiel J, Sproat-Emison E, Garcia-Barcelo M, Lantieri F, Burzynski G, Borrego S, Pelet A, Arnold S, Miao X, Griseri P, Brooks AS, Antinolo G, de Pontual L, Clement-Ziza M, Munnich A, Kashuk C, West K, Wong KK, Lyonnet S, Chakravarti A, Tam PK, Ceccherini I, Hofstra RM, Fernandez R; Hirschsprung Disease Consortium. Hirschsprung disease, associated syndromes and genetics: a review. J Med Genet. 2008 Jan;45(1):1-14. PMID: 17965226
de Pontual L, Pelet A, Clement-Ziza M, Trochet D, Antonarakis SE, Attie-Bitach T, Beales PL, Blouin JL, Dastot-Le Moal F, Dollfus H, Goossens M, Katsanis N, Touraine R, Feingold J, Munnich A, Lyonnet S, Amiel J. Epistatic interactions with a common hypomorphic RET allele in syndromic Hirschsprung disease. Hum Mutat. 2007 Aug;28(8):790-6.PMID: 17397038
