© 1995 Oxford University Press
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Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease
Service de Génétique Médicale, Clinique Chirurgicale Infantile, et Unité de Recherches sur les Handicaps Génétiques de I'Enfant, INSERM U-393, Institut Necker, Hôpital des Enfants Malades 149, rue de Sèvres, 75743 Paris, France 1Cancer Research Campaign Human Cancer Genetics Research Group, Department of Pathology, University of Cambridge Cambridge, UK 2Division of Cancer Epidemiology and Control, and Division of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School Boston, USA 3Departments of Paediatrics and Pathology, Queen's University Kingston, Ontario, Canada 4Service de Biochimie Génétique, Hôpital Cochin 27 rue du Faubourg Saint-Jacques, 75014 Paris, France
*To whom correspondence should be addressed
Received March 15, 1995; Revised May 24, 1995; Accepted May 24, 1995
Hirschsprung disease (HSCR) is a common congenital malformation (1 in 5 000 live births) due to the absence of autonomic ganglia in the terminal hindgut, and resulting in intestinal obstruction in neonates. Recently, a dominant gene for familial HSCR has been mapped to chromosome sub-band 10q11.2 and the disease has been ascribed to mutations in a tyrosine kinase receptor gene mapping to this region, the RETproto-oncogene. Studying the 20 exons of the RET gene by a combination of denaturating gradient gel electrophoresis and single strand conformation polymorphism in a large series of HSCR patients (45 sporadic cases and 35 familial forms), we found mutations of the RET gene in 50% of familial HSCR, regardless of the length of the aganglionic segment. The mean penetrance of the mutant allele in familial HSCR was significantly higher in males (72%) than in females (51%). Most interestingly, mutations at the RET locus accounted for at least 1/3 of sporadic HSCR in our series. These mutations were scattered along the length of the gene. Finally, among the mutations identified in sporadic cases (16/45), seven proved to be de novo mutations suggesting that new mutations at the RET locus significantly contribute to sporadic HSCR. Taken together, the low penetrance of the mutant gene, the lack of genotype-phenotype correlation, the sex-dependent effect of RET mutations and the variable clinical expression of the disease support the existence of one or more modifier genes in familial HSCR.
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