Abstract
Imprinting defects in 15q11-q13 are a rare but significant cause of Prader–Willi syndrome (PWS) and Angelman syndrome (AS). Patients with an imprinting defect have apparently normal chromosomes 15 of biparental origin, but are recognised by @parental DNA methylation at D15S63 (PW71) or SNURF-SNRPN exon 1. We have investigated the methylation status of five additional loci in 12 such patients with or without a deletion in the imprinting centre. In each patient, the imprinting defect affected all loci tested. During routine diagnostic testing we identified four patients who had a normal methylation pattern at SNURF-SNRPN exon 1, but an abnormal pattern at D15S63. In two of these patients, who were suspected of having PWS, this change was restricted to D15S63. In two patients suspected of having AS, several but not all loci were affected. Using a newly developed methylation-specific PCR test for D15S63 we found that these methylation changes are rare in patients suspected of having AS. Although we can not prove that the methylation changes in the four patients are causally related to their disease, our findings demonstrate that spatially restricted changes in methylation can occur. In some cases, these changes may reflect incomplete imprint spreading.
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Acknowledgements
We thank Dr Eamonn Maher for providing us a DNA sample of a Beckwith–Wiedemann patient with an aberrant methylation pattern at K V DMR1 (11p15), Dr Dirk Prawitt for oligonucleotides for amplifying the probe DMRP, Dr Robert D Nicholls for NDN-primer sequences, and Dr Amy Lossie for hybridisation conditions for the NDN-locus. We also thank Dr Paul Jenkins, Paediatrician, Canberra, Australia and Dr Penny Johnson, Developmental Paediatrician, Canberra, Australia. They have both been very helpful with arranging appointments and follow up with the family MK, and providing a lot of background information. We also thank Dr Andreas Weinhäusel for sharing with us his experience with the D15S63 MSP test. Part of this work was supported by the Deutsche Forschungsgemeinschaft.
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Runte, M., Färber, C., Lich, C. et al. Comprehensive methylation analysis in typical and atypical PWS and AS patients with normal biparental chromosomes 15. Eur J Hum Genet 9, 519–526 (2001). https://doi.org/10.1038/sj.ejhg.5200661
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DOI: https://doi.org/10.1038/sj.ejhg.5200661
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