Mutations of the Imprinted CDKN1C Gene as a Cause of the Overgrowth Beckwith–Wiedemann Syndrome: Clinical Spectrum and Functional Characterization

Frederic Brioude (1) , Irène Netchine (1) , Françoise Praz (1) , Marilyne Le Jule (2) , Claire Calmel (1) , Didier Lacombe (3) , Patrick Edery (4) , Martin Catala (5) , Sylvie Odent (6) , Bertrand Isidor (7) , Stanislas Lyonnet (8) , Sabine Sigaudy (9) , Bruno Leheup (10, 11) , Séverine Audebert-Bellanger (12) , Lydie Burglen (2, 2) , Fabienne Giuliano (13) , Jean-Luc Alessandri , Valérie Cormier-Daire (14) , Fanny Laffargue (15) , Sophie Blesson , Isabelle Coupier (16, 17) , James Lespinasse (18) , Patricia Blanchet (19) , Odile Boute (20) , Clarisse Baumann (21) , Michel Polak (22, 23) , Bérénice Doray (24) , Alain Verloes (25, 26) , Géraldine Viot (27) , Yves Le Bouc , Sylvie Rossignol (28, 1)

1 UMRS893 - Centre de Recherche Saint-Antoine
2 CHU Trousseau [APHP]
3 Service de génétique médicale
4 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
5 LBD - Laboratoire de Biologie du Développement
6 IGDR - Institut de Génétique et Développement de Rennes
7 Service de génétique médicale - Unité de génétique clinique [Nantes]
8 INSERM - Institut National de la Santé et de la Recherche Médicale
9 GMGF - Génétique Médicale et Génomique Fonctionnelle
10 Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy]
11 NGERE - Nutrition-Génétique et Exposition aux Risques Environnementaux
12 Service de Pédiatrie et de Génétique Médicale
13 Service de génétique médicale
14 Service de génétique médicale
15 Service de Génétique Médicale [CHU Clermont-Ferrand]
16 Service de génétique médicale [Montpellier]
17 Unité d'Oncogénétique
18 Département de Génétique Chromosomique
19 Hôpital Arnaud de Villeneuve [CHRU Montpellier]
20 Service de Génétique clinique
21 Département de Génétique Médicale
22 IC UM3 (UMR 8104 / U1016) - Institut Cochin
23 CHU Necker - Enfants Malades [AP-HP]
24 Service de Génétique
25 Physiopathologie et neuroprotection des atteintes du cerveau en développement
26 Département de génétique
27 Service de Génétique [Cochin]
28 Les Hôpitaux Universitaires de Strasbourg (HUS)

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

Keywords: CDKN1C; Beckwith–Wiedemann; Cell Cycle; overgrowth syndrome; imprinting

Domains: Life Sciences [q-bio]

Frederic Brioude, Irène Netchine, Françoise Praz, Marilyne Le Jule, Claire Calmel, et al.. Mutations of the Imprinted CDKN1C Gene as a Cause of the Overgrowth Beckwith–Wiedemann Syndrome: Clinical Spectrum and Functional Characterization. Human Mutation, 2015, 36 (9), pp.894--902. ⟨10.1002/humu.22824⟩. ⟨hal-01195734⟩