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

Frederic Brioude; Irène Netchine; Françoise Praz; Marilyne Le Jule; Claire Calmel; Didier Lacombe; Patrick Edery; Martin Catala; Sylvie Odent; Bertrand Isidor; Stanislas Lyonnet; Sabine Sigaudy; Bruno Leheup; Séverine Audebert-Bellanger; Lydie Burglen; Fabienne Giuliano; Jean-Luc Alessandri; Valérie Cormier-Daire; Fanny Laffargue; Sophie Blesson; Isabelle Coupier; James Lespinasse; Patricia Blanchet; Odile Boute; Clarisse Baumann; Michel Polak; Bérénice Doray; Alain Verloes; Géraldine Viot; Yves Le Bouc; Sylvie Rossignol

doi:10.1002/humu.22824

Journal articles

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 ^{13, 14} Fabienne Giuliano ¹⁵ Jean-Luc Alessandri Valérie Cormier-Daire ¹⁶ Fanny Laffargue ¹⁷ Sophie Blesson Isabelle Coupier ^{18, 19} James Lespinasse ²⁰ Patricia Blanchet ²¹ Odile Boute ²² Clarisse Baumann ²³ Michel Polak ^{24, 25} Bérénice Doray ²⁶ Alain Verloes ^{27, 28} Géraldine Viot ²⁹ Yves Le Bouc Sylvie Rossignol ^{30, 1}

1 CR Saint-Antoine - Centre de Recherche Saint-Antoine

2 CHU Trousseau [APHP]

3 Service de génétique médicale

4 CRNL - Centre de recherche en neurosciences de Lyon

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 et d'Embryologie Médicale

14 Service de neuropédiatrie et pathologie du développement

15 Service de génétique médicale

16 Service de génétique médicale

17 Service de Génétique Médical

18 Service de génétique médicale [Montpellier]

19 Unité d'Oncogénétique

20 Département de Génétique Chromosomique

21 Hôpital Arnaud de Villeneuve [CHRU Montpellier]

22 Service de Génétique clinique

23 Département de Génétique Médicale

24 IC UM3 (UMR 8104 / U1016) - Institut Cochin

25 CHU Necker - Enfants Malades [AP-HP]

26 Service de Génétique

27 Physiopathologie et neuroprotection des atteintes du cerveau en développement

28 Département de génétique

29 Service de Génétique [Cochin]

30 Les Hôpitaux Universitaires de Strasbourg (HUS)

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

Keywords : Cell Cycle imprinting overgrowth syndrome CDKN1C Beckwith–Wiedemann

Document type :

Journal articles

Domain :

Life Sciences [q-bio]

Complete list of metadatas

https://hal-univ-rennes1.archives-ouvertes.fr/hal-01195734
Contributor : Laurent Jonchère <>
Submitted on : Tuesday, September 8, 2015 - 1:09:32 PM
Last modification on : Wednesday, October 14, 2020 - 3:09:05 AM

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

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

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