UNSW Embryology
DEVELOPMENT OF THE GASTROINTESTINAL SYSTEM
HIRSCHSPRUNG DISEASE 2
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#600155 HIRSCHSPRUNG DISEASE 2; HSCR2table OF CONTENTSDatabase LinksGene Map Locus: 13q22
TEXTA number sign (#) is used with this entry because of evidence that the mutation resides in the gene encoding the endothelin B receptor (EDNRB; 131244). Hirschsprung disease (HSCR; 142623),
or aganglionic megacolon, is a congenital disorder
characterized by absence of enteric ganglia along a
variable length of the intestine. Dominant
mutations in the RET oncogene (164761)
can give rise to the disorder; see 164761.0014.
There is also evidence for a recessive gene on
chromosome 13 as a cause of this disorder.
Tentatively, the Hirschsprung disease related to
chromosome 13 will be referred to here as
Hirschsprung disease-2 (HSCR2). See also HSCR3
(600156),
a putative chromosome 21-linked HSCR modifier
locus.
Puffenberger et al.
(1992) found a high frequency of Hirschsprung
disease in an extended inbred Mennonite kindred. In
49 nuclear families, 56 affected persons were
found. In one of these individuals, one or more of
the following characteristics was found: white
forelock, hearing deficit, and heterochromia
iridis. However, further studies suggested that
this triad of traits segregated independently of
Hirschsprung disease in several of the families
within the kindred. A couple who immigrated to the
United States about 1717 was ancestral to both
parents of all affected individuals. Segregation
analysis yielded a segregation ratio of 12.0% for
males and 6.2% for females.
Lamont et al. (1989)
described 3 cases of interstitial deletion of
chromosome 13 involving the common segment
13q22.1-q32.1. In addition to the recognized
clinical features of this deletion, such as
prominent upper incisors, 2 had short segment
Hirschsprung disease with aganglionosis confirmed
histologically. Bottani et
al. (1991) also described an interstitial
deletion of 13q in approximately the same region in
a boy who, in addition to having Hirschsprung
disease, was mentally retarded and autistic. They
concluded that the 13q33.1 band was missing in all
cells. Sparkes et al.
(1984) and Kiss and
Osztovics (1989) had also reported Hirschsprung
disease in association with deletions of 13q.
In further studies of the large and extensively
affected Mennonite kindred, Puffenberger
et al. (1994) found that segregation analysis
indicated a segregation ratio of 10.67% for males
and 5.45% for females. They searched for locations
of the genes responsible for HSCR in this kindred
by genotyping 3 small multicase families and
locating genomic regions demonstrating
identity-by-descent followed by linkage
disequilibrium analysis of 28 additional nuclear
families. Based on this novel strategy, Puffenberger
et al. (1994) identified a new locus for HSCR
on 13q22. They genotyped 9 microsatellite markers
spanning 10 cM in this region on 31 nuclear
families. Significant nonrandom association was
detected with alleles at 4 markers. In addition,
their studies in this kindred revealed preliminary
evidence for a genetic modifier of HSCR located on
21q22 (600156).
Cohen and Gadd (1982)
had suggested a dominant inheritance pattern for
HSCR in the Mennonite kindred. However, arguing
against this was the high degree of inbreeding and
the identification of a single common ancestral
couple for all 122 parents. In the series of 61
nuclear families, only 3 contained a parent with
documented HSCR. Although this disorder was
effectively lethal 1 or 2 generations ago, some
affected persons had undergone surgical treatment,
survived to adulthood, and reproduced. A total of
13 affected parents had a total of 6 affected and
52 unaffected offspring (segregation ratio, 10.3%).
These data were considered consistent with a
recessive mode of inheritance with a relatively
high carrier frequency in this population
(Puffenberger et al.,
1994). If the susceptibility gene on chromosome
13 is recessive, then the segregation analysis
suggests that penetrance is about 32%. Puffenberger
et al. (1994) reported association studies
indicating that 36% of homozygotes for a
235-basepair allele at locus D13S160 were affected
and 27% of heterozygotes were affected, giving an
overall penetrance of 31%, which accords well with
the 33% value estimated by Badner
et al. (1990). In studies of 2 patients with
HSCR and interstitial deletions of chromosome 13
analyzed with microsatellite markers, they found
that the 13q22 region was included and was bounded
distally by D13S160.
Badner et al. (1990) suggested that recessive inheritance might account for up to 80% of cases of Hirschsprung disease. As detailed in entry 131244, Puffenberger et al. (1994) studied the endothelin-B receptor gene which maps to the same area of chromosome 13 as does the Mennonite Hirschsprung disease and found point mutations. The locus in the mouse that is homologous to the chromosome 13 locus for Hirschsprung disease in the human may be 'piebald lethal' (s-l), which is located on chromosome 14; this chromosome in the mouse carries several other loci that are homologous to chromosome 13 loci.
REFERENCES
CLINICAL SYNOPSIS
CREATION DATEVictor A. McKusick : 10/19/1994 EDIT HISTORYdkim : 7/2/1998 |
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