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a Unidad de Genética
Médica y Diagnóstico Prenatal, Hospital Universitario "Virgen del
Rocío", Avda Manuel Suirot s/n, 41013 Sevilla, Spain, b Clinical Cancer Genetics Program, Comprehensive
Cancer Center and Division of Human Genetics, Department of Internal
Medicine, Ohio State University, Columbus, OH, USA, c Human Cancer Genetics Program,
Ohio State University Comprehensive Cancer Center, 420 W 12th Avenue,
Room 690 MRF, Columbus, OH 43210, USA, d Cirugía
Infantil, Hospital Universitario "Virgen del Rocío", Sevilla,
Spain, e Cancer Research Campaign Human Cancer Genetics
Research Group, University of Cambridge, Cambridge, UK
Correspondence to: Dr Borrego, gantinolog{at}sego.es
Revised version received 11 April 2000;
Accepted for publication 17
April 2000
BACKGROUND
Hirschsprung
disease (HSCR), which may be sporadic or familial, occurs in 1:5000
live births and presents with functional intestinal obstruction
secondary to aganglionosis of the hindgut. Germline mutations of the
RET proto-oncogene are believed to account for up to 50% of familial cases and up to 30% of isolated cases in
most series. However, these series are highly selected for the most
obvious and severe cases and large familial aggregations. Population
based studies indicate that germline RET
mutations account for no more than 3% of isolated HSCR cases.
Recently, we and others have noted that specific polymorphic sequence
variants, notably A45A (exon 2), are over-represented in isolated HSCR.
PURPOSEIn order to determine if it
is the variant per se, a combination thereof, or another locus in
linkage disequilibrium which predisposes to HSCR, we looked for
association of RET haplotype(s) and disease
in HSCR cases compared to region matched controls.
METHODSSeven loci across
RET were typed and haplotypes formed for
HSCR cases, their unaffected parents, and region matched controls. Haplotype and genotype frequencies and distributions were compared among these groups using the transmission disequilibrium test and
standard case-control statistic.
RESULTSTwelve unique haplotypes,
labelled A-L, were obtained. The distributions of haplotypes between
cases and controls (
112 =81.4, p<<0.0001)
and between cases and non-transmitted parental haplotypes were
significantly different (211=53.1,
p<0.0001). Genotypes comprising pairs of haplotypes were formed for
cases and controls. There were 38 different genotypes among cases and
controls combined. Inspection of the genotypes in these two groups
showed that the genotype distribution between cases and controls was
distinct (372=93.8, p<<0.0001). For
example, BB, BC, BD, and CD, all of which contain at least one allele
with the polymorphic A45A, are prominently represented among HSCR
cases, together accounting for >35% of the case genotypes, yet these
four genotypes were not represented among the population matched normal
controls. Conversely, AA, AG, DD, GG, and GJ, none of which contains
A45A, are commonly represented in the controls, together accounting for
43% of the control genotypes, and yet they are never seen among the
HSCR cases.
CONCLUSIONSOur data suggest that
genotypes comprising specific pairs of RET
haplotypes are associated with predisposition to HSCR either in a
simple autosomal recessive manner or in an additive, dose dependent fashion.
This article has been cited by other articles:
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  J Amiel, E Sproat-Emison, M Garcia-Barcelo, F Lantieri, G Burzynski, S Borrego, A Pelet, S Arnold, X Miao, P Griseri, et al. Hirschsprung disease, associated syndromes and genetics: a review J. Med. Genet., January 1, 2008; 45(1): 1 - 14. [Abstract] [Full Text] [PDF]
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 F. Weber and C. Eng Editorial: Germline Variants within RET: Clinical Utility or Scientific Playtoy? J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6334 - 6336. [Full Text] [PDF]
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R M Fernandez, G Boru, A Pecina, K Jones, M Lopez-Alonso, G Antinolo, S Borrego, and C Eng Ancestral RET haplotype associated with Hirschsprung's disease shows linkage disequilibrium breakpoint at -1249 J. Med. Genet., April 1, 2005; 42(4): 322 - 327. [Full Text] [PDF]
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A Pelet, L de Pontual, M Clement-Ziza, R Salomon, C Mugnier, F Matsuda, M Lathrop, A Munnich, J Feingold, S Lyonnet, et al. Homozygosity for a frequent and weakly penetrant predisposing allele at the RET locus in sporadic Hirschsprung disease J. Med. Genet., March 1, 2005; 42(3): e18 - e18. [Full Text] [PDF]
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 M. Garcia-Barcelo, R. W. Ganster, V. C.H. Lui, T. Y.Y. Leon, M.-T. So, A. M.F. Lau, M. Fu, M.-H. Sham, J. Knight, M. S. Zannini, et al. TTF-1 and RET promoter SNPs: regulation of RET transcription in Hirschsprung's disease Hum. Mol. Genet., January 15, 2005; 14(2): 191 - 204. [Abstract] [Full Text] [PDF]
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M-M Garcia-Barcelo, M-H Sham, V C-H Lui, B L-S Chen, Y-Q Song, W-S Lee, S-K Yung, G Romeo, and P K-H Tam Chinese patients with sporadic Hirschsprung's disease are predominantly represented by a single RET haplotype J. Med. Genet., November 1, 2003; 40(11): e122 - 122. [Full Text] [PDF]
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S. R. McWhinney, G. Boru, P. K. Binkley, M. Peczkowska, A. A. Januszewicz, H. P. H. Neumann, and C. Eng Intronic Single Nucleotide Polymorphisms in the RET Protooncogene Are Associated with a Subset of Apparently Sporadic Pheochromocytoma and May Modulate Age of Onset J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4911 - 4916. [Abstract] [Full Text] [PDF]
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M Sancandi, P Griseri, B Pesce, G Patrone, F Puppo, M Lerone, G Martucciello, G Romeo, R Ravazzolo, M Devoto, et al. Single nucleotide polymorphic alleles in the 5' region of the RET proto-oncogene define a risk haplotype in Hirschsprung's disease J. Med. Genet., September 1, 2003; 40(9): 714 - 718. [Full Text] [PDF]
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S Borrego, R M Fernandez, H Dziema, A Niess, M Lopez-Alonso, G Antinolo, and C Eng Investigation of germline GFRA4 mutations and evaluation of the involvement of GFRA1, GFRA2, GFRA3, and GFRA4 sequence variants in Hirschsprung disease J. Med. Genet., March 1, 2003; 40(3): e18 - 18. [Full Text] [PDF]
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F Lesueur, M Corbex, J D McKay, J Lima, P Soares, P Griseri, J Burgess, I Ceccherini, S Landolfi, M Papotti, et al. Specific haplotypes of the RET proto-oncogene are over-represented in patients with sporadic papillary thyroid carcinoma J. Med. Genet., April 1, 2002; 39(4): 260 - 265. [Abstract] [Full Text] [PDF]
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J. Amiel and S. Lyonnet Hirschsprung disease, associated syndromes, and genetics: a review J. Med. Genet., November 1, 2001; 38(11): 729 - 739. [Abstract] [Full Text] [PDF]
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O. Gimm, H. Chi, P. L. M. Dahia, A. Perren, R. Hinze, P. Komminoth, H. Dralle, P. R. Reynolds, and C. Eng Somatic Mutation and Germline Variants of MINPP1, a Phosphatase Gene Located in Proximity to PTEN on 10q23.3, in Follicular Thyroid Carcinomas J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1801 - 1805. [Abstract] [Full Text]
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