Mutations of the ImprintedCDKN1CGene 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.

p57Kip2knock-in mouse reveals CDK-independent contribution in the development of Beckwith-Wiedemann syndrome

“…Herein, we investigated whether the development of BWS, a disease whose aetiology has been attributed so far to the deregulation of CDK activity due to loss of p57 function, could be caused, at least in part, by the loss of CDK‐independent roles of p57, as suggested by the pattern of p57 point mutations observed in 8% of BWS patients and that occur mostly outside of the cyclin–CDK inhibitory region . Our studies provide clear genetic evidence for the importance of p57 CDK‐independent functions during embryonic development and in BWS pathogenesis.…”

Chromosomal rearrangements in the 11p15 imprinted region: 17 new 11p15.5 duplications with associated phenotypes and putative functional consequences

“…Loss of function mutations of maternally expressed CDKN1C leads to BWS,11 whereas a gain of function mutation of this gene has been described in a family with SRS 12. Loss of function mutations of the paternally expressed IGF2 gene and genes which are upstream regulators of IGF2 such as HMGA2 or PLAG1 have also been described 13–16.…”

Juvenile Granulosa Cell Ovarian Tumor in a Child With Beckwith–Wiedmann Syndrome

“…Brioude et al. recently reviewed the phenotype of 50 patients and seven fetuses with CDKN1C mutation and reported four tumors: neuroblastoma, ganglioneuroblastoma, melanoma, and acute lymphoid leukemia . To the best of our knowledge, this is a novel tumor (JGCT) in a patient with BWS.…”