Human Molecular Genetics Advance Access originally published online on February 1, 2008
Human Molecular Genetics 2008 17(10):1427-1435; doi:10.1093/hmg/ddn031
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Different mechanisms cause imprinting defects at the IGF2/H19 locus in Beckwith–Wiedemann syndrome and Wilms' tumour
1 Dipartimento di Scienze Ambientali, Seconda Università di Napoli, via Vivaldi 43, 81100 Caserta, Italy 2 Institute of Genetics and Biophysics ‘A. Buzzati Traverso’, CNR, Naples, Italy 3 Dipartimento di Biologia Strutturale e Funzionale 4 Dipartimento di Pediatria, Università di Napoli ‘Federico II’, Naples, Italy 5 U.O.C. Genetica Medica, A.O.R.N.A. Cardarelli, Naples, Italy 6 Institute of Medical Genetics, Università Cattolica del Sacro Cuore, Rome, Italy 7 Dipartimento Materno-Infantile, Azienda Ospedale-Università, Parma, Italy 8 Unit of Paediatric Hematology and Oncology, ‘G. Di Cristina’ Children Hospital, Palermo, Italy 9 Department of Anatomic Pathology 10 Department of Experimental Oncology and Laboratories, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy 11 Medical and Molecular Genetics Section, University of Birmingham, The Medical School, Birmingham, UK
* To whom correspondence should be addressed. Tel: +39 0823274599; Fax: +39 082274605; Email: andrea.riccio{at}unina2.it
Received November 19, 2007; Accepted January 29, 2008
The parent of origin-dependent expression of the IGF2 and H19 genes is controlled by the imprinting centre 1 (IC1) consisting in a methylation-sensitive chromatin insulator. Deletions removing part of IC1 have been found in patients affected by the overgrowth- and tumour-associated Beckwith–Wiedemann syndrome (BWS). These mutations result in the hypermethylation of the remaining IC1 region, loss of IGF2/H19 imprinting and fully penetrant BWS phenotype when maternally transmitted. We now report that 12 additional cases with IC1 hypermethylation have a similar clinical phenotype but showed neither a detectable deletion nor other mutation in the local vicinity. Likewise, no IC1 deletion was detected in 40 sporadic non-syndromic Wilms' tumours. A detailed analysis of the BWS patients showed that the hypermethylation variably affected the IC1 region and was generally mosaic. We observed that all these cases were sporadic and in at least two families affected and unaffected members shared the same maternal IC1 allele but not the abnormal maternal chromosome epigenotype. Furthermore, the chromosome with the imprinting defect derived from either the maternal grandfather or maternal grandmother. Overall, these results indicate that methylation-imprinting defects at the IGF2–H19 locus can result from inherited mutations of the IC and have high recurrence risk or arise independently from the sequence context and generally not transmitted to the progeny. Despite these differences, the epigenetic abnormalities are usually present in the patients in the mosaic form and probably acquired by post-zygotic de novo methylation. Distinguishing between these two groups of cases is important for genetic counselling.