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Hum Mutat. 2015 Sep;36(9):894-902. doi: 10.1002/humu.22824. Epub 2015 Aug 6.

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

Author information

1
Sorbonne Universités, UPMC Univ Paris 06, F-75005, Paris, France.
2
AP-HP, Hôpital Armand Trousseau, Explorations Fonctionnelles Endocriniennes, F-75012, Paris, France.
3
INSERM, UMR_S 938, Centre de recherche Saint-Antoine, F-75012, Paris, France.
4
CHU Bordeaux, Service de Génétique Médicale, Bordeaux, France.
5
Laboratoire Maladies Rares: Génétique et Métabolisme (MRGM), Université de Bordeaux, EA4576, Bordeaux, France.
6
Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Service de Génétique, Bron, France.
7
Centre de Recherche en Neurosciences de Lyon, Inserm 1028, CNRS 5292 UMR UCBL, Lyon, France.
8
Fédération de Neurologie Groupe Hospitalier Pitié-Salpêtrière, F-75651, Paris, France.
9
Laboratoire de Biologie du Développement UMR 7622, CNRS and Université Pierre et Marie Curie, F-75252, Paris, France.
10
CHU de Rennes, Hôpital Sud, Service de Génétique clinique, F-35203, Rennes, France.
11
Université de Rennes 1, Rennes, France.
12
CHU de Nantes, Service de Génétique, Nantes, France.
13
INSERM, UMR-S 957, Nantes, France.
14
Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, INSERM UMR-1163, Paris, France.
15
Département de Génétique,  Hôpital Universitaire Necker-Enfants Malades, AP-HP, Paris, France.
16
CHU de Marseille, Hôpital Timone Enfant, Service de Génétique Médicale, Marseille, France.
17
CHU de Nancy, Pôle Enfants, Service de Médecine Infantile et Génétique Clinique, Centre de référence Syndrome Malformatif et Anomalies du Développement, Vandoeuvre, France.
18
Université de Lorraine Faculté de Médecine, Unité INSERM U954, Vandoeuvre, France.
19
CHU Morvan, Service de Génétique médicale, Brest, France.
20
AP-HP, Hôpital Armand Trousseau, Centre de référence des malformations et maladies congénitales du cervelet, service de génétique, F-75012, Paris, France.
21
INSERM U1141, F-75019, Paris, France.
22
CHU de Nice, Hôpital Archet2, Service de Génétique Médicale, Nice, France.
23
CHU de La Réunion, CH Felix Guyon, Pole Femme Mere Enfant Saint-Denis, La Réunion, France.
24
IMAGINE Institute, Hôpital Necker Enfants Malade, Paris, France.
25
Université Paris Descartes, INSERM UMR1163, Paris, France.
26
CHU Estaing, Service de Génétique Médicale, Clermont-Ferrand, France.
27
CHU de Tours, Service de Génétique, Tours, France.
28
CHU Arnaud de Villeneuve, Service de Génétique Médicale, Unité d'oncogénétique, Montpellier, France.
29
Centre Hospitalier de Chambéry-Hôtel-Dieu, UF de Génétique Chromosomique, Chambéry, France.
30
CHU Arnaud de Villeneuve, Service de Génétique Médicale, Unité de Génétique Clinique, Montpellier, France.
31
CHRU de Lille, Service de Génétique, Lille, France.
32
AP-HP, Hôpital Robert Debré, Department of Medical Genetics and INSERM UMR 1141, Paris, France.
33
AP-HP, Hôpital Universitaire Necker Enfants Malades, Endocrinologie gynécologie diabétologie pédiatriques, Paris, France.
34
Université Paris Descartes, INSERM U1016, IMAGINE Institute, Paris, France.
35
Service de Génétique Médicale, Centre de Référence pour les Anomalies du Développement (FECLAD), Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
36
AP-HP, Hôpital Port-Royal, Service de Génétique, Paris, France.

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:

Beckwith-Wiedemann; CDKN1C; cell cycle; imprinting; overgrowth syndrome

Comment in

PMID:
26077438
DOI:
10.1002/humu.22824
[Indexed for MEDLINE]

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