Human Molecular Genetics Advance Access originally published online on December 11, 2006
Human Molecular Genetics 2007 16(3):254-264; doi:10.1093/hmg/ddl448
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Mechanisms causing imprinting defects in familial Beckwith–Wiedemann syndrome with Wilms' tumour
1 Dipartimento di Scienze Ambientali, Seconda Università di Napoli, via Vivaldi 43, 81100 Caserta, Italy, 2 Laboratorio di Citogenetica e Genetica Molecolare, Istituto Auxologico Italiano, Milano, Italy, 3 Servizio diGenetica Medica, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy, 4 Clinica Pediatrica, Universita'degli Studi di Milano, Fondazione Policlinico, Milano, Italy, 5 Department of Experimental and Diagnostic Medicine and Interdepartmental Center for Cancer Research, University of Ferrara, Ferrara, Italy, 6 Dipartimento di Scienze Pediatriche e dell'Adolescenza, Università di Torino, Torino, Italy, 7 Department of Paediatrics, Obstetrics and Reproductive Medicine, University of Siena, Italy and 8 Division of Medical Genetics, San Paolo School of Medicine, University of Milan, Milano, Italy
* To whom correspondence should be addressed. Fax: +39 0823274605; Email: andrea.riccio{at}unina2.it
Received October 10, 2006; Accepted November 23, 2006
The imprinted expression of the IGF2 and H19 genes is controlled by the Imprinting Centre 1 (IC1) at chromosome 11p15.5. This is a methylation-sensitive chromatin insulator that works by binding the zinc-finger protein CTCF in a parent-specific manner. Microdeletions abolishing some of the CTCF target sites (CTSs) of IC1 have been associated with the Beckwith–Wiedemann syndrome (BWS). However, the link between these mutations and the molecular and clinical phenotypes was debated. We have identified two novel families with IC1 deletions, in which individuals with the clinical features of the BWS are present in multiple generations. By analysing the methylation pattern at the IGF2-H19 locus together with the clinical phenotypes in the individuals with maternal and those with paternal transmission of five different deletions, we demonstrate that maternal transmission of 1.4–1.8 kb deletions in the IC1 region co-segregates with the hypermethylation of the residual CTSs and BWS phenotype with complete penetrance, whereas normal phenotype is observed upon paternal transmission. Although gene expression could not be assayed in all cases, the methylation detected at the IGF2 DMR2 and H19 promoter suggests that IC1 hypermethylation is consistently associated with biallelic activation of IGF2 and biallelic silencing of H19. Comparison of these deletions with a 2.2 kb one previously reported by another group indicates that the spacing of the CTSs on the deleted allele is critical for the gain of the abnormal methylation and penetrance of the clinical phenotype. Furthermore, we observe that the hypermethylation resulting from the deletions is always mosaic, suggesting that the epigenetic defect at the IGF2-H19 locus is established post-zygotically and may cause body asymmetry and heterogeneity of the clinical phenotype. Finally, the IC1 microdeletions are associated with a high incidence of Wilms' tumour, making their molecular diagnosis particularly important for genetic counselling and tumour surveillance at follow-up.
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