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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
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
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Submitted on : Tuesday, September 8, 2015 - 1:09:32 PM
Last modification on : Thursday, May 27, 2021 - 5:08:03 PM

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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, Wiley, 2015, 36 (9), pp.894--902. ⟨10.1002/humu.22824⟩. ⟨hal-01195734⟩



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