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a Unidad de Genética
Médica y Diagnóstico Prenatal, Hospitales Universitarios Virgen del
Rocío, Avenida Manuel Siurot s/n, 41013 Sevilla, Spain, b Cirugía Infantil, Hospitales Universitarios
Virgen del Rocío, Sevilla, Spain, c Clinical
Cancer Genetics and Human Cancer Genetics Programs, Ohio State
University Comprehensive Cancer Center, 420 W 12th Avenue, Suite 690, Columbus, OH 43210, USA, d CRC Human Cancer Genetics Research Group,
University of Cambridge, Cambridge, UK
Correspondence to: Dr Borrego.
Revised version received 19 July 1999;
Accepted for publication 22 July
1999
Hirschsprung disease (HSCR) is a common genetic disorder
presenting with functional intestinal obstruction secondary to enteric aganglionosis. HSCR can be familial or sporadic. Although five putative
susceptibility genes have been identified, only germline mutations in
the RET proto-oncogene account for a
significant minority (up to 50%) of familial HSCR; 3% of sporadic
HSCR in a population based series carry RET
mutations. From 1998 to February 1999, we prospectively ascertained 64 cases of sporadic HSCR from the western Andalusia region. To determine
if polymorphic sequence variants within RET
could act as low penetrance predisposing alleles, we examined allelic
frequencies at seven polymorphic loci in this population based series.
Whether allele frequencies differed from those in the control
population were determined by either chi-squared analysis or Fisher's
exact test. For two sequence variants, A45A (c 135G
A) (exon 2) and
L769L (c 2307TG) (exon 13), the rarer polymorphic allele was
over-represented among HSCR cases versus controls (p<0.0006). In
contrast, two other polymorphisms, G691S (c 2071CA) (exon 11) and
S904S (c 2712CG) (exon 15), were under-represented in the HSCR
patients compared to controls (p=0.02). Polymorphisms in the
RET proto-oncogene appear to predispose to
HSCR in a complex, low penetrance fashion and may also modify
phenotypic expression.
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