Different Mechanisms Cause Imprinting defects at the IGF2/H19 locus in Beckwith-Wiedemann Syndrome and Wilms' Tumour Export

@article{citeulike:2349431, abstract = {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 Imprinting Centre 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 postzygotic de novo methylation. Distinguishing between these two groups of cases is important for genetic counselling. 10.1093/hmg/ddn031}, author = {Cerrato, Flavia and Sparago, Angela and Verde, Gaetano and De Crescenzo, Agostina and Citro, Valentina and Cubellis, Maria V. and Rinaldi, Maria M. and Boccuto, Luigi and Neri, Giovanni and Magnani, Cinzia and D'Angelo, Paolo and Collini, Paola and Perotti, Daniela and Sebastio, Gianfranco and Maher, Eamonn and Riccio, Andrea}, citeulike-article-id = {2349431}, citeulike-linkout-0 = {http://dx.doi.org/10.1093/hmg/ddn031}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/18245780}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=18245780}, day = {1}, doi = {10.1093/hmg/ddn031}, journal = {Hum. Mol. Genet.}, keywords = {cancer, disease, epiallele, epigenetics, imprinting, inheritance, methylation}, month = {February}, pages = {ddn031+}, posted-at = {2008-02-07 15:16:42}, priority = {5}, title = {Different Mechanisms Cause Imprinting defects at the IGF2/H19 locus in Beckwith-Wiedemann Syndrome and Wilms' Tumour}, url = {http://dx.doi.org/10.1093/hmg/ddn031}, year = {2008} }

TY - JOUR ID - citeulike:2349431 L3 - citeulike-article-id:2349431 N2 - 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 Imprinting Centre 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 postzygotic de novo methylation. Distinguishing between these two groups of cases is important for genetic counselling. 10.1093/hmg/ddn031 JF - Hum. Mol. Genet. TI - Different Mechanisms Cause Imprinting defects at the IGF2/H19 locus in Beckwith-Wiedemann Syndrome and Wilms' Tumour SP - ddn031 KW - cancer KW - disease KW - epiallele KW - epigenetics KW - imprinting KW - inheritance KW - methylation AU - Cerrato, Flavia AU - Sparago, Angela AU - Verde, Gaetano AU - De Crescenzo, Agostina AU - Citro, Valentina AU - Cubellis, Maria AU - Rinaldi, Maria AU - Boccuto, Luigi AU - Neri, Giovanni AU - Magnani, Cinzia AU - D'Angelo, Paolo AU - Collini, Paola AU - Perotti, Daniela AU - Sebastio, Gianfranco AU - Maher, Eamonn AU - Riccio, Andrea PY - 2008/02/01/ UR - http://dx.doi.org/10.1093/hmg/ddn031 ER -