Comprehensive methylation analysis in typical and atypical PWS and AS patients with normal biparental chromosomes 15

Maren Runte; Claudia Färber; Christina Lich; Michael Zeschnigk; Tina Buchholz; Arabella Smith; Lionel Van Maldergem; Joachim Bürger; Françoise Muscatelli; Gabriele Gillessen-Kaesbach; Bernhard Horsthemke; Karin Buiting

doi:10.1038/sj.ejhg.5200661

Comprehensive methylation analysis in typical and atypical PWS and AS patients with normal biparental chromosomes 15

Maren Runte, Claudia Färber, Christina Lich, Michael Zeschnigk, Tina Buchholz, Arabella Smith, Lionel Van Maldergem, Joachim Bürger, Françoise Muscatelli, Gabriele Gillessen-Kaesbach, Bernhard Horsthemke^*, Karin Buiting

^*Corresponding author for this work

Institute of Human Genetics

15 Citations (Scopus)

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 uniparental 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.

Original language	English
Journal	European Journal of Human Genetics
Volume	9
Issue number	7
Pages (from-to)	519-526
Number of pages	8
ISSN	1018-4813
DOIs	https://doi.org/10.1038/sj.ejhg.5200661
Publication status	Published - 2001

Funding

We thank Dr Eamonn Maher for providing us a DNA sample of a Beckwith – Wiedemann patient with an aberrant methylation pattern at KVDMR1 (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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Research Area: Medical Genetics

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10.1038/sj.ejhg.5200661

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Runte, M., Färber, C., Lich, C., Zeschnigk, M., Buchholz, T., Smith, A., Van Maldergem, L., Bürger, J., Muscatelli, F., Gillessen-Kaesbach, G., Horsthemke, B., & Buiting, K. (2001). Comprehensive methylation analysis in typical and atypical PWS and AS patients with normal biparental chromosomes 15. European Journal of Human Genetics, 9(7), 519-526. https://doi.org/10.1038/sj.ejhg.5200661

@article{97dd2118600b457fb53c96e90af32c6d,

title = "Comprehensive methylation analysis in typical and atypical PWS and AS patients with normal biparental chromosomes 15",

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 uniparental 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.",

author = "Maren Runte and Claudia F{\"a}rber and Christina Lich and Michael Zeschnigk and Tina Buchholz and Arabella Smith and \{Van Maldergem\}, Lionel and Joachim B{\"u}rger and Fran{\c c}oise Muscatelli and Gabriele Gillessen-Kaesbach and Bernhard Horsthemke and Karin Buiting",

note = "Funding Information: We thank Dr Eamonn Maher for providing us a DNA sample of a Beckwith – Wiedemann patient with an aberrant methylation pattern at KVDMR1 (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 Weinh{\"a}usel for sharing with us his experience with the D15S63 MSP test. Part of this work was supported by the Deutsche Forschungsgemeinschaft.",

year = "2001",

doi = "10.1038/sj.ejhg.5200661",

language = "English",

volume = "9",

pages = "519--526",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

publisher = "Springer Nature",

number = "7",

}

Runte, M, Färber, C, Lich, C, Zeschnigk, M, Buchholz, T, Smith, A, Van Maldergem, L, Bürger, J, Muscatelli, F, Gillessen-Kaesbach, G, Horsthemke, B & Buiting, K 2001, 'Comprehensive methylation analysis in typical and atypical PWS and AS patients with normal biparental chromosomes 15', European Journal of Human Genetics, vol. 9, no. 7, pp. 519-526. https://doi.org/10.1038/sj.ejhg.5200661

TY - JOUR

T1 - Comprehensive methylation analysis in typical and atypical PWS and AS patients with normal biparental chromosomes 15

AU - Runte, Maren

AU - Färber, Claudia

AU - Lich, Christina

AU - Zeschnigk, Michael

AU - Buchholz, Tina

AU - Smith, Arabella

AU - Van Maldergem, Lionel

AU - Bürger, Joachim

AU - Muscatelli, Françoise

AU - Gillessen-Kaesbach, Gabriele

AU - Horsthemke, Bernhard

AU - Buiting, Karin

N1 - Funding Information: We thank Dr Eamonn Maher for providing us a DNA sample of a Beckwith – Wiedemann patient with an aberrant methylation pattern at KVDMR1 (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.

PY - 2001

Y1 - 2001

N2 - 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 uniparental 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.

AB - 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 uniparental 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.

UR - https://www.scopus.com/pages/publications/17844405567

U2 - 10.1038/sj.ejhg.5200661

DO - 10.1038/sj.ejhg.5200661

M3 - Journal articles

C2 - 11464243

AN - SCOPUS:17844405567

SN - 1018-4813

VL - 9

SP - 519

EP - 526

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 7

ER -

Comprehensive methylation analysis in typical and atypical PWS and AS patients with normal biparental chromosomes 15

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