Hirschsprung disease (HSCR) is a condition characterized by hypomotility of the large intestine attributable to the absence of intramural enteric ganglia. The clinical consequences are constipation, intestinal obstruction and life-threatening enterocolitis in newborns. The condition can be divided into a short segment form where lack of innervation only affects the distal large intestine; and a long segment form characterized by absence of ganglia over more extensive regions of the colon. The length of affected intestine is correlated to the sib recurrence risk and inversely proportional to the ratio of affected males to females (Table 13.4; Garver et al., 1985; Badner et al., 1990).
This condition represents a paradigm for the dissection of a complex and relatively common developmental disorder (present in 1 in 4000 livebom infants) for several reasons. Firstly, studies on the heritability (defined as the degree to which genetic factors can explain the phenotypic variance of a condition) using twin data will probably be relatively free of confounding factors induced by the twinning process itself. Secondly, the pheno-type is well described, exhibits familial clustering and has well-established criteria for diagnosis (Badner et al., 1990). Increasing the attractiveness of this disorder as a model system are data indicating that a limited number of genes contribute to the genotype and that its heritability is at least 80%, an exceptionally high figure for a developmental disorder. These factors indicate that environmental influences are at best minor contributors to the well-established observations of variable expressivity and incomplete penetrance (Badner et al., 1990).
A variety of approaches have been utilized to identify the genetic determinants underlying HSCR. Firstly, clinical and epidemiological studies established that long segment disease exhibited higher penetrance and less variable expressivity than short segment disease (Bodian and Carter, 1963; Garver et al., 1985; Badner et al., 1990). The implications for recurrence risk in family members reflect these observations (Table 13.4). The first gene of major effect in both short and long segment HSCR was identified as RET using classical linkage studies to map a deletion encompassing the RET locus in a familial case of the disease and then detection of mutations in isolated cases of HSCR. The characterization of other genes underlying syndromic HSCR has proved more challenging but several others have had mutations identified using similar approaches (Amiel and Lyonnet, 2001). A genome-wide association study in inbred populations with elevated susceptibility to the condition and work using animal models have identified epistatic relationships between some of these loci and still further uncharacterized genes (Carrasquillo et al., 2002). Although studies replicating all of these interactions are awaited, these data indicate the feasibility of using variations of techniques previously utilized in the identification of genes underlying highly penetrant monogenic malformation syndromes. More recently, a genome-wide scan using an outbred population was adopted to study loci implicated in short segment disease which, although implicating the same gene of major effect, RET, identified different, unidentified contributory loci elsewhere in the genome (Bolk-Gabriel et al., 2002).
The use of mouse models and genome-wide linkage screens to exploit the known high herita-bility of HSCR has enabled the definition of loci which may explain much, if not all of the risk for developing HSCR, in combinatorial fashion. Major challenges that remain are to identify the underlying genes and polymorphisms that confer these more minor genetic contributions to the HSCR phenotype and to provide some form of experimental verification that the proposed models of best fit (Bolk-Gabriel et al., 2002) have a biological underpinning.
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