Epistatic interactions with a common hypomorphic RET allele in syndromic Hirschsprung disease†
L. de Pontual
Université Paris-René Descartes, Faculté de Médecine, INSERM U-781, AP-HP, Hôpital Necker-Enfant Malades, Paris, France
Search for more papers by this authorA. Pelet
Université Paris-René Descartes, Faculté de Médecine, INSERM U-781, AP-HP, Hôpital Necker-Enfant Malades, Paris, France
Search for more papers by this authorM. Clement-Ziza
Université Paris-René Descartes, Faculté de Médecine, INSERM U-781, AP-HP, Hôpital Necker-Enfant Malades, Paris, France
Search for more papers by this authorD. Trochet
Université Paris-René Descartes, Faculté de Médecine, INSERM U-781, AP-HP, Hôpital Necker-Enfant Malades, Paris, France
Search for more papers by this authorS.E. Antonarakis
Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals of Geneva, Geneva, Switzerland
Search for more papers by this authorT. Attie-Bitach
Université Paris-René Descartes, Faculté de Médecine, INSERM U-781, AP-HP, Hôpital Necker-Enfant Malades, Paris, France
Search for more papers by this authorP.L. Beales
Molecular Medicine Unit, Institute of Child Health, University College London, London, United Kingdom
Search for more papers by this authorJ.-L. Blouin
Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals of Geneva, Geneva, Switzerland
Search for more papers by this authorF. Dastot-Le Moal
INSERM U-654, Bases Moléculaires et Cellulaires des Maladies Génétiques, Créteil, France
Search for more papers by this authorH. Dollfus
Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
Search for more papers by this authorM. Goossens
INSERM U-654, Bases Moléculaires et Cellulaires des Maladies Génétiques, Créteil, France
Search for more papers by this authorN. Katsanis
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
Search for more papers by this authorR. Touraine
Service de Génétique, Hôpital Nord, CHU Saint-Etienne, Saint-Etienne, France
Search for more papers by this authorJ. Feingold
Université Paris-René Descartes, Faculté de Médecine, INSERM U-781, AP-HP, Hôpital Necker-Enfant Malades, Paris, France
Search for more papers by this authorA. Munnich
Université Paris-René Descartes, Faculté de Médecine, INSERM U-781, AP-HP, Hôpital Necker-Enfant Malades, Paris, France
Search for more papers by this authorS. Lyonnet
Université Paris-René Descartes, Faculté de Médecine, INSERM U-781, AP-HP, Hôpital Necker-Enfant Malades, Paris, France
Search for more papers by this authorCorresponding Author
J. Amiel
Université Paris-René Descartes, Faculté de Médecine, INSERM U-781, AP-HP, Hôpital Necker-Enfant Malades, Paris, France
Département de Génétique, Hôpital Necker-Enfants Malades, 149, rue de Sèvres, 75743 Paris Cedex 15, FranceSearch for more papers by this authorL. de Pontual
Université Paris-René Descartes, Faculté de Médecine, INSERM U-781, AP-HP, Hôpital Necker-Enfant Malades, Paris, France
Search for more papers by this authorA. Pelet
Université Paris-René Descartes, Faculté de Médecine, INSERM U-781, AP-HP, Hôpital Necker-Enfant Malades, Paris, France
Search for more papers by this authorM. Clement-Ziza
Université Paris-René Descartes, Faculté de Médecine, INSERM U-781, AP-HP, Hôpital Necker-Enfant Malades, Paris, France
Search for more papers by this authorD. Trochet
Université Paris-René Descartes, Faculté de Médecine, INSERM U-781, AP-HP, Hôpital Necker-Enfant Malades, Paris, France
Search for more papers by this authorS.E. Antonarakis
Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals of Geneva, Geneva, Switzerland
Search for more papers by this authorT. Attie-Bitach
Université Paris-René Descartes, Faculté de Médecine, INSERM U-781, AP-HP, Hôpital Necker-Enfant Malades, Paris, France
Search for more papers by this authorP.L. Beales
Molecular Medicine Unit, Institute of Child Health, University College London, London, United Kingdom
Search for more papers by this authorJ.-L. Blouin
Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals of Geneva, Geneva, Switzerland
Search for more papers by this authorF. Dastot-Le Moal
INSERM U-654, Bases Moléculaires et Cellulaires des Maladies Génétiques, Créteil, France
Search for more papers by this authorH. Dollfus
Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
Search for more papers by this authorM. Goossens
INSERM U-654, Bases Moléculaires et Cellulaires des Maladies Génétiques, Créteil, France
Search for more papers by this authorN. Katsanis
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
Search for more papers by this authorR. Touraine
Service de Génétique, Hôpital Nord, CHU Saint-Etienne, Saint-Etienne, France
Search for more papers by this authorJ. Feingold
Université Paris-René Descartes, Faculté de Médecine, INSERM U-781, AP-HP, Hôpital Necker-Enfant Malades, Paris, France
Search for more papers by this authorA. Munnich
Université Paris-René Descartes, Faculté de Médecine, INSERM U-781, AP-HP, Hôpital Necker-Enfant Malades, Paris, France
Search for more papers by this authorS. Lyonnet
Université Paris-René Descartes, Faculté de Médecine, INSERM U-781, AP-HP, Hôpital Necker-Enfant Malades, Paris, France
Search for more papers by this authorCorresponding Author
J. Amiel
Université Paris-René Descartes, Faculté de Médecine, INSERM U-781, AP-HP, Hôpital Necker-Enfant Malades, Paris, France
Département de Génétique, Hôpital Necker-Enfants Malades, 149, rue de Sèvres, 75743 Paris Cedex 15, FranceSearch for more papers by this authorCommunicated by Daniel Schorderet
Abstract
Hirschsprung disease (HSCR) stands as a model for genetic dissection of complex diseases. In this model, a major gene, RET, is involved in most if not all cases of isolated (i.e., nonsyndromic) HSCR, in conjunction with other autosomal susceptibility loci under a multiplicative model. HSCR susceptibility alleles can harbor either heterozygous coding sequence mutations or, more frequently, a polymorphism within intron 1, leading to a hypomorphic RET allele. On the other hand, about 30% of HSCR are syndromic. Hitherto, the disease causing gene has been identified for eight Mendelian syndromes with HSCR: congenital central hypoventilation (CCHS), Mowat-Wilson (MWS), Bardet-Biedl (BBS), Shah-Waardenburg (WS4), cartilage-hair-hypoplasia (CHH), Smith-Lemli-Opitz (SLO), Goldberg-Sprintzsen (GSS), and hydrocephalus due to congenital stenosis of the aqueduct of sylvius (HSAS). According to the HSCR syndrome, the penetrance of HSCR trait varies from 5 to 70%. Trisomy 21 (T21) also predisposes to HSCR. We were able to collect a series of 393 patients affected by CCHS (n = 173), WS4 (n = 24), BBS (n = 51), MWS (n = 71), T21 (n = 46), and mental retardation (MR) with HSCR (n = 28). For each syndrome, we studied the RET locus in two subgroups of patients; i.e., with or without HSCR. We genotyped the RET locus in 393 patients among whom 195 had HSCR, and compared the distribution of alleles and genotypes within the two groups for each syndrome. RET acts as a modifier gene for the HSCR phenotype in patients with CCHS, BBS, and Down syndrome, but not in patients with MWS and WS4. The frequent, low penetrant, predisposing allele of the RET gene can be regarded as a risk factor for the HSCR phenotype in CCHS, BBS, and Down syndrome, while its role is not significant in MWS and WS4. These data highlight the pivotal role of the RET gene in both isolated and syndromic HSCR. Hum Mutat 28(8), 790–796, 2007. © 2007 Wiley-Liss, Inc.
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