title: Mutations of the Imprinted CDKN1C Gene as a Cause of the Overgrowth Beckwith-Wiedemann Syndrome: Clinical Spectrum and Functional Characterization.
abstract: Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder associating macroglossia, abdominal wall defects, visceromegaly, and a high risk of childhood tumor. Molecular anomalies are mostly epigenetic; however, mutations of CDKN1C are implicated in 8% of cases, including both sporadic and familial forms. We aimed to describe the phenotype of BWS patients with CDKN1C mutations and develop a functional test for CDKN1C mutations. For each propositus, we sequenced the three exons and intron-exon boundaries of CDKN1C in patients presenting a BWS phenotype, including abdominal wall defects, without 11p15 methylation defects. We developed a functional test based on flow cytometry. We identified 37 mutations in 38 pedigrees (50 patients and seven fetuses). Analysis of parental samples when available showed that all mutations tested but one was inherited from the mother. The four missense mutations led to a less severe phenotype (lower frequency of exomphalos) than the other 33 mutations. The following four tumors occurred: one neuroblastoma, one ganglioneuroblastoma, one melanoma, and one acute lymphoid leukemia. Cases of BWS caused by CDKN1C mutations are not rare. CDKN1C sequencing should be performed for BWS patients presenting with abdominal wall defects or cleft palate without 11p15 methylation defects or body asymmetry, or in familial cases of BWS.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, F-75005, Paris, France.|AP-HP, Hôpital Armand Trousseau, Explorations Fonctionnelles Endocriniennes, F-75012, Paris, France.|INSERM, UMR_S 938, Centre de recherche Saint-Antoine, F-75012, Paris, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Brioude
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, F-75005, Paris, France.|AP-HP, Hôpital Armand Trousseau, Explorations Fonctionnelles Endocriniennes, F-75012, Paris, France.|INSERM, UMR_S 938, Centre de recherche Saint-Antoine, F-75012, Paris, France.
authors.forename: Irène
authors.initials: I
authors.lastname: Netchine
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, F-75005, Paris, France.|INSERM, UMR_S 938, Centre de recherche Saint-Antoine, F-75012, Paris, France.
authors.forename: Francoise
authors.initials: F
authors.lastname: Praz
authors.affiliation: AP-HP, Hôpital Armand Trousseau, Explorations Fonctionnelles Endocriniennes, F-75012, Paris, France.
authors.forename: Marilyne
authors.initials: M
authors.lastname: Le Jule
authors.affiliation: INSERM, UMR_S 938, Centre de recherche Saint-Antoine, F-75012, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Calmel
authors.affiliation: CHU Bordeaux, Service de Génétique Médicale, Bordeaux, France.|Laboratoire Maladies Rares: Génétique et Métabolisme (MRGM), Université de Bordeaux, EA4576, Bordeaux, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.affiliation: Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Service de Génétique, Bron, France.|Centre de Recherche en Neurosciences de Lyon, Inserm 1028, CNRS 5292 UMR UCBL, Lyon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Edery
authors.affiliation: Fédération de Neurologie Groupe Hospitalier Pitié-Salpêtrière, F-75651, Paris, France.|Laboratoire de Biologie du Développement UMR 7622, CNRS and Université Pierre et Marie Curie, F-75252, Paris, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Catala
authors.affiliation: CHU de Rennes, Hôpital Sud, Service de Génétique clinique, F-35203, Rennes, France.|Université de Rennes 1, Rennes, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Odent
authors.affiliation: CHU de Nantes, Service de Génétique, Nantes, France.|INSERM, UMR-S 957, Nantes, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Isidor
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, INSERM UMR-1163, Paris, France.|Département de Génétique,  Hôpital Universitaire Necker-Enfants Malades, AP-HP, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.affiliation: CHU de Marseille, Hôpital Timone Enfant, Service de Génétique Médicale, Marseille, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Sigaudy
authors.affiliation: CHU de Nancy, Pôle Enfants, Service de Médecine Infantile et Génétique Clinique, Centre de référence Syndrome Malformatif et Anomalies du Développement, Vandoeuvre, France.|Université de Lorraine Faculté de Médecine, Unité INSERM U954, Vandoeuvre, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Leheup
authors.affiliation: CHU Morvan, Service de Génétique médicale, Brest, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Audebert-Bellanger
authors.affiliation: AP-HP, Hôpital Armand Trousseau, Centre de référence des malformations et maladies congénitales du cervelet, service de génétique, F-75012, Paris, France.|INSERM U1141, F-75019, Paris, France.
authors.forename: Lydie
authors.initials: L
authors.lastname: Burglen
authors.affiliation: CHU de Nice, Hôpital Archet2, Service de Génétique Médicale, Nice, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Giuliano
authors.affiliation: CHU de La Réunion, CH Felix Guyon, Pole Femme Mere Enfant Saint-Denis, La Réunion, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Alessandri
authors.affiliation: IMAGINE Institute, Hôpital Necker Enfants Malade, Paris, France.|Université Paris Descartes, INSERM UMR1163, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
authors.affiliation: CHU Estaing, Service de Génétique Médicale, Clermont-Ferrand, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Laffargue
authors.affiliation: CHU de Tours, Service de Génétique, Tours, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Blesson
authors.affiliation: CHU Arnaud de Villeneuve, Service de Génétique Médicale, Unité d'oncogénétique, Montpellier, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coupier
authors.affiliation: Centre Hospitalier de Chambéry-Hôtel-Dieu, UF de Génétique Chromosomique, Chambéry, France.
authors.forename: James
authors.initials: J
authors.lastname: Lespinasse
authors.affiliation: CHU Arnaud de Villeneuve, Service de Génétique Médicale, Unité de Génétique Clinique, Montpellier, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Blanchet
authors.affiliation: CHRU de Lille, Service de Génétique, Lille, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Boute
authors.affiliation: AP-HP, Hôpital Robert Debré, Department of Medical Genetics and INSERM UMR 1141, Paris, France.
authors.forename: Clarisse
authors.initials: C
authors.lastname: Baumann
authors.affiliation: AP-HP, Hôpital Universitaire Necker Enfants Malades, Endocrinologie gynécologie diabétologie pédiatriques, Paris, France.|Université Paris Descartes, INSERM U1016, IMAGINE Institute, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Polak
authors.affiliation: Service de Génétique Médicale, Centre de Référence pour les Anomalies du Développement (FECLAD), Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Berenice
authors.initials: B
authors.lastname: Doray
authors.affiliation: AP-HP, Hôpital Robert Debré, Department of Medical Genetics and INSERM UMR 1141, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
authors.affiliation: AP-HP, Hôpital Port-Royal, Service de Génétique, Paris, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Viot
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, F-75005, Paris, France.|AP-HP, Hôpital Armand Trousseau, Explorations Fonctionnelles Endocriniennes, F-75012, Paris, France.|INSERM, UMR_S 938, Centre de recherche Saint-Antoine, F-75012, Paris, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Le Bouc
authors.affiliation: INSERM, UMR_S 938, Centre de recherche Saint-Antoine, F-75012, Paris, France.|Service de Génétique Médicale, Centre de Référence pour les Anomalies du Développement (FECLAD), Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rossignol
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001506:Beckwith-Wiedemann Syndrome / Q000175:diagnosis* / Q000235:genetics*; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D018392:Genomic Imprinting; D005838:Genotype; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016415:Sequence Alignment
chemical_list: C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57
keywords: Beckwith-Wiedemann; CDKN1C; cell cycle; imprinting; overgrowth syndrome