Skip to main content
NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1998 Jul;63(1):170–180. doi: 10.1086/301935

Sporadic imprinting defects in Prader-Willi syndrome and Angelman syndrome: implications for imprint-switch models, genetic counseling, and prenatal diagnosis.

K Buiting 1, B Dittrich 1, S Gross 1, C Lich 1, C Färber 1, T Buchholz 1, E Smith 1, A Reis 1, J Bürger 1, M M Nöthen 1, U Barth-Witte 1, B Janssen 1, D Abeliovich 1, I Lerer 1, A M van den Ouweland 1, D J Halley 1, C Schrander-Stumpel 1, H Smeets 1, P Meinecke 1, S Malcolm 1, A Gardner 1, M Lalande 1, R D Nicholls 1, K Friend 1, A Schulze 1, G Matthijs 1, H Kokkonen 1, P Hilbert 1, L Van Maldergem 1, G Glover 1, P Carbonell 1, P Willems 1, G Gillessen-Kaesbach 1, B Horsthemke 1
PMCID: PMC1377255  PMID: 9634532

Abstract

The Prader-Willi syndrome (PWS) and the Angelman syndrome (AS) are caused by the loss of function of imprinted genes in proximal 15q. In approximately 2%-4% of patients, this loss of function is due to an imprinting defect. In some cases, the imprinting defect is the result of a parental imprint-switch failure caused by a microdeletion of the imprinting center (IC). Here we describe the molecular analysis of 13 PWS patients and 17 AS patients who have an imprinting defect but no IC deletion. Heteroduplex and partial sequence analysis did not reveal any point mutations of the known IC elements, either. Interestingly, all of these patients represent sporadic cases, and some share the paternal (PWS) or the maternal (AS) 15q11-q13 haplotype with an unaffected sib. In each of five PWS patients informative for the grandparental origin of the incorrectly imprinted chromosome region and four cases described elsewhere, the maternally imprinted paternal chromosome region was inherited from the paternal grandmother. This suggests that the grandmaternal imprint was not erased in the father's germ line. In seven informative AS patients reported here and in three previously reported patients, the paternally imprinted maternal chromosome region was inherited from either the maternal grandfather or the maternal grandmother. The latter finding is not compatible with an imprint-switch failure, but it suggests that a paternal imprint developed either in the maternal germ line or postzygotically. We conclude (1) that the incorrect imprint in non-IC-deletion cases is the result of a spontaneous prezygotic or postzygotic error, (2) that these cases have a low recurrence risk, and (3) that the paternal imprint may be the default imprint.

Full Text

The Full Text of this article is available as a PDF (1.2 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Albrecht U., Sutcliffe J. S., Cattanach B. M., Beechey C. V., Armstrong D., Eichele G., Beaudet A. L. Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. Nat Genet. 1997 Sep;17(1):75–78. doi: 10.1038/ng0997-75. [DOI] [PubMed] [Google Scholar]
  2. Beckmann J. S., Tomfohrde J., Barnes R. I., Williams M., Broux O., Richard I., Weissenbach J., Bowcock A. M. A linkage map of human chromosome 15 with an average resolution of 2 cM and containing 55 polymorphic microsatellites. Hum Mol Genet. 1993 Dec;2(12):2019–2030. doi: 10.1093/hmg/2.12.2019. [DOI] [PubMed] [Google Scholar]
  3. Beuten J., Hennekam R. C., Van Roy B., Mangelschots K., Sutcliffe J. S., Halley D. J., Hennekam F. A., Beaudet A. L., Willems P. J. Angelman syndrome in an inbred family. Hum Genet. 1996 Mar;97(3):294–298. doi: 10.1007/BF02185757. [DOI] [PubMed] [Google Scholar]
  4. Buiting K., Dittrich B., Robinson W. P., Guitart M., Abeliovich D., Lerer I., Horsthemke B. Detection of aberrant DNA methylation in unique Prader-Willi syndrome patients and its diagnostic implications. Hum Mol Genet. 1994 Jun;3(6):893–895. doi: 10.1093/hmg/3.6.893. [DOI] [PubMed] [Google Scholar]
  5. Buiting K., Saitoh S., Gross S., Dittrich B., Schwartz S., Nicholls R. D., Horsthemke B. Inherited microdeletions in the Angelman and Prader-Willi syndromes define an imprinting centre on human chromosome 15. Nat Genet. 1995 Apr;9(4):395–400. doi: 10.1038/ng0495-395. [DOI] [PubMed] [Google Scholar]
  6. Bürger J., Buiting K., Dittrich B., Gross S., Lich C., Sperling K., Horsthemke B., Reis A. Different mechanisms and recurrence risks of imprinting defects in Angelman syndrome. Am J Hum Genet. 1997 Jul;61(1):88–93. doi: 10.1086/513900. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dittrich B., Buiting K., Gross S., Horsthemke B. Characterization of a methylation imprint in the Prader-Willi syndrome chromosome region. Hum Mol Genet. 1993 Dec;2(12):1995–1999. doi: 10.1093/hmg/2.12.1995. [DOI] [PubMed] [Google Scholar]
  8. Dittrich B., Buiting K., Korn B., Rickard S., Buxton J., Saitoh S., Nicholls R. D., Poustka A., Winterpacht A., Zabel B. Imprint switching on human chromosome 15 may involve alternative transcripts of the SNRPN gene. Nat Genet. 1996 Oct;14(2):163–170. doi: 10.1038/ng1096-163. [DOI] [PubMed] [Google Scholar]
  9. Dittrich B., Robinson W. P., Knoblauch H., Buiting K., Schmidt K., Gillessen-Kaesbach G., Horsthemke B. Molecular diagnosis of the Prader-Willi and Angelman syndromes by detection of parent-of-origin specific DNA methylation in 15q11-13. Hum Genet. 1992 Nov;90(3):313–315. doi: 10.1007/BF00220089. [DOI] [PubMed] [Google Scholar]
  10. Ferguson-Smith A. C. Imprinting moves to the centre. Nat Genet. 1996 Oct;14(2):119–121. doi: 10.1038/ng1096-119. [DOI] [PubMed] [Google Scholar]
  11. Glatt K. A., Sinnett D., Lalande M. Dinucleotide repeat polymorphism at the GABAA receptor alpha 5 (GABRA5) locus at chromosome 15q11-q13. Hum Mol Genet. 1992 Aug;1(5):348–348. doi: 10.1093/hmg/1.5.348. [DOI] [PubMed] [Google Scholar]
  12. Glenn C. C., Porter K. A., Jong M. T., Nicholls R. D., Driscoll D. J. Functional imprinting and epigenetic modification of the human SNRPN gene. Hum Mol Genet. 1993 Dec;2(12):2001–2005. doi: 10.1093/hmg/2.12.2001. [DOI] [PubMed] [Google Scholar]
  13. Glenn C. C., Saitoh S., Jong M. T., Filbrandt M. M., Surti U., Driscoll D. J., Nicholls R. D. Gene structure, DNA methylation, and imprinted expression of the human SNRPN gene. Am J Hum Genet. 1996 Feb;58(2):335–346. [PMC free article] [PubMed] [Google Scholar]
  14. Gyapay G., Morissette J., Vignal A., Dib C., Fizames C., Millasseau P., Marc S., Bernardi G., Lathrop M., Weissenbach J. The 1993-94 Généthon human genetic linkage map. Nat Genet. 1994 Jun;7(2 Spec No):246–339. doi: 10.1038/ng0694supp-246. [DOI] [PubMed] [Google Scholar]
  15. Hudson T. J., Engelstein M., Lee M. K., Ho E. C., Rubenfield M. J., Adams C. P., Housman D. E., Dracopoli N. C. Isolation and chromosomal assignment of 100 highly informative human simple sequence repeat polymorphisms. Genomics. 1992 Jul;13(3):622–629. doi: 10.1016/0888-7543(92)90133-d. [DOI] [PubMed] [Google Scholar]
  16. Jay P., Rougeulle C., Massacrier A., Moncla A., Mattei M. G., Malzac P., Roëckel N., Taviaux S., Lefranc J. L., Cau P. The human necdin gene, NDN, is maternally imprinted and located in the Prader-Willi syndrome chromosomal region. Nat Genet. 1997 Nov;17(3):357–361. doi: 10.1038/ng1197-357. [DOI] [PubMed] [Google Scholar]
  17. Kishino T., Lalande M., Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet. 1997 Jan;15(1):70–73. doi: 10.1038/ng0197-70. [DOI] [PubMed] [Google Scholar]
  18. Kosaki K., McGinniss M. J., Veraksa A. N., McGinnis W. J., Jones K. L. Prader-Willi and Angelman syndromes: diagnosis with a bisulfite-treated methylation-specific PCR method. Am J Med Genet. 1997 Dec 19;73(3):308–313. [PubMed] [Google Scholar]
  19. Kubota T., Aradhya S., Macha M., Smith A. C., Surh L. C., Satish J., Verp M. S., Nee H. L., Johnson A., Christan S. L. Analysis of parent of origin specific DNA methylation at SNRPN and PW71 in tissues: implication for prenatal diagnosis. J Med Genet. 1996 Dec;33(12):1011–1014. doi: 10.1136/jmg.33.12.1011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kubota T., Das S., Christian S. L., Baylin S. B., Herman J. G., Ledbetter D. H. Methylation-specific PCR simplifies imprinting analysis. Nat Genet. 1997 May;16(1):16–17. doi: 10.1038/ng0597-15. [DOI] [PubMed] [Google Scholar]
  21. Lalande M. Parental imprinting and human disease. Annu Rev Genet. 1996;30:173–195. doi: 10.1146/annurev.genet.30.1.173. [DOI] [PubMed] [Google Scholar]
  22. Lindeman R., Kouts S., Woodage T., Smith A., Trent R. J. Dinucleotide repeat polymorphism of D15S10 in the Prader-Willi chromosome region (PWCR). Nucleic Acids Res. 1991 Oct 11;19(19):5449–5449. doi: 10.1093/nar/19.19.5449-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lohmann D. R., Brandt B., Höpping W., Passarge E., Horsthemke B. The spectrum of RB1 germ-line mutations in hereditary retinoblastoma. Am J Hum Genet. 1996 May;58(5):940–949. [PMC free article] [PubMed] [Google Scholar]
  24. Lyko F., Buiting K., Horsthemke B., Paro R. Identification of a silencing element in the human 15q11-q13 imprinting center by using transgenic Drosophila. Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1698–1702. doi: 10.1073/pnas.95.4.1698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. MacDonald H. R., Wevrick R. The necdin gene is deleted in Prader-Willi syndrome and is imprinted in human and mouse. Hum Mol Genet. 1997 Oct;6(11):1873–1878. doi: 10.1093/hmg/6.11.1873. [DOI] [PubMed] [Google Scholar]
  26. Matsuura T., Sutcliffe J. S., Fang P., Galjaard R. J., Jiang Y. H., Benton C. S., Rommens J. M., Beaudet A. L. De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat Genet. 1997 Jan;15(1):74–77. doi: 10.1038/ng0197-74. [DOI] [PubMed] [Google Scholar]
  27. Mutirangura A., Greenberg F., Butler M. G., Malcolm S., Nicholls R. D., Chakravarti A., Ledbetter D. H. Multiplex PCR of three dinucleotide repeats in the Prader-Willi/Angelman critical region (15q11-q13): molecular diagnosis and mechanism of uniparental disomy. Hum Mol Genet. 1993 Feb;2(2):143–151. doi: 10.1093/hmg/2.2.143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Mutirangura A., Kuwano A., Ledbetter S. A., Chinault A. C., Ledbetter D. H. Dinucleotide repeat polymorphism at the D15S11 locus in the Angelman/Prader-Willi region (AS/PWS) of chromosome 15. Hum Mol Genet. 1992 May;1(2):139–139. doi: 10.1093/hmg/1.2.139-a. [DOI] [PubMed] [Google Scholar]
  29. Mutirangura A., Ledbetter S. A., Kuwano A., Chinault A. C., Ledbetter D. H. Dinucleotide repeat polymorphism at the GABAA receptor beta 3 (GABRB3) locus in the Angelman/Prader-Willi region (AS/PWS) of chromosome 15. Hum Mol Genet. 1992 Apr;1(1):67–67. doi: 10.1093/hmg/1.1.67. [DOI] [PubMed] [Google Scholar]
  30. Nakao M., Sutcliffe J. S., Durtschi B., Mutirangura A., Ledbetter D. H., Beaudet A. L. Imprinting analysis of three genes in the Prader-Willi/Angelman region: SNRPN, E6-associated protein, and PAR-2 (D15S225E). Hum Mol Genet. 1994 Feb;3(2):309–315. doi: 10.1093/hmg/3.2.309. [DOI] [PubMed] [Google Scholar]
  31. Ozçelik T., Leff S., Robinson W., Donlon T., Lalande M., Sanjines E., Schinzel A., Francke U. Small nuclear ribonucleoprotein polypeptide N (SNRPN), an expressed gene in the Prader-Willi syndrome critical region. Nat Genet. 1992 Dec;2(4):265–269. doi: 10.1038/ng1292-265. [DOI] [PubMed] [Google Scholar]
  32. Polymeropoulos M. H., Rath D. S., Xiao H., Merril C. R. Tetranucleotide repeat polymorphism at the human c-fes/fps proto-oncogene (FES). Nucleic Acids Res. 1991 Jul 25;19(14):4018–4018. [PMC free article] [PubMed] [Google Scholar]
  33. Polymeropoulos M. H., Xiao H., Rath D. S., Merril C. R. Tetranucleotide repeat polymorphism at the human aromatase cytochrome P-450 gene (CYP19). Nucleic Acids Res. 1991 Jan 11;19(1):195–195. doi: 10.1093/nar/19.1.195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Reed M. L., Leff S. E. Maternal imprinting of human SNRPN, a gene deleted in Prader-Willi syndrome. Nat Genet. 1994 Feb;6(2):163–167. doi: 10.1038/ng0294-163. [DOI] [PubMed] [Google Scholar]
  35. Reis A., Dittrich B., Greger V., Buiting K., Lalande M., Gillessen-Kaesbach G., Anvret M., Horsthemke B. Imprinting mutations suggested by abnormal DNA methylation patterns in familial Angelman and Prader-Willi syndromes. Am J Hum Genet. 1994 May;54(5):741–747. [PMC free article] [PubMed] [Google Scholar]
  36. Rougeulle C., Glatt H., Lalande M. The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain. Nat Genet. 1997 Sep;17(1):14–15. doi: 10.1038/ng0997-14. [DOI] [PubMed] [Google Scholar]
  37. Saitoh S., Buiting K., Cassidy S. B., Conroy J. M., Driscoll D. J., Gabriel J. M., Gillessen-Kaesbach G., Glenn C. C., Greenswag L. R., Horsthemke B. Clinical spectrum and molecular diagnosis of Angelman and Prader-Willi syndrome patients with an imprinting mutation. Am J Med Genet. 1997 Jan 20;68(2):195–206. [PubMed] [Google Scholar]
  38. Saitoh S., Buiting K., Rogan P. K., Buxton J. L., Driscoll D. J., Arnemann J., König R., Malcolm S., Horsthemke B., Nicholls R. D. Minimal definition of the imprinting center and fixation of chromosome 15q11-q13 epigenotype by imprinting mutations. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7811–7815. doi: 10.1073/pnas.93.15.7811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Schuffenhauer S., Buchholz T., Stengel-Rutkowski S., Buiting K., Schmidt H., Meitinger T. A familial deletion in the Prader-Willi syndrome region including the imprinting control region. Hum Mutat. 1996;8(3):288–292. doi: 10.1002/(SICI)1098-1004(1996)8:3<288::AID-HUMU18>3.0.CO;2-Z. [DOI] [PubMed] [Google Scholar]
  40. Schulze A., Hansen C., Baekgaard P., Blichfeldt S., Petersen M. B., Tommerup N., Brøndum-Nielsen K. Clinical features and molecular genetic analysis of a boy with Prader-Willi syndrome caused by an imprinting defect. Acta Paediatr. 1997 Aug;86(8):906–910. doi: 10.1111/j.1651-2227.1997.tb08622.x. [DOI] [PubMed] [Google Scholar]
  41. Shemer R., Birger Y., Riggs A. D., Razin A. Structure of the imprinted mouse Snrpn gene and establishment of its parental-specific methylation pattern. Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10267–10272. doi: 10.1073/pnas.94.19.10267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Sutcliffe J. S., Nakao M., Christian S., Orstavik K. H., Tommerup N., Ledbetter D. H., Beaudet A. L. Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region. Nat Genet. 1994 Sep;8(1):52–58. doi: 10.1038/ng0994-52. [DOI] [PubMed] [Google Scholar]
  43. Tada T., Tada M., Hilton K., Barton S. C., Sado T., Takagi N., Surani M. A. Epigenotype switching of imprintable loci in embryonic germ cells. Dev Genes Evol. 1998 Feb;207(8):551–561. doi: 10.1007/s004270050146. [DOI] [PubMed] [Google Scholar]
  44. Teshima I., Chadwick D., Chitayat D., Kobayashi J., Ray P., Shuman C., Siegel-Bartelt J., Strasberg P., Weksberg R. FISH detection of chromosome 15 deletions in Prader-Willi and Angelman syndromes. Am J Med Genet. 1996 Mar 29;62(3):217–223. doi: 10.1002/(sici)1096-8628(19960329)62:3<216::aid-ajmg3>3.3.co;2-0. [DOI] [PubMed] [Google Scholar]
  45. Vu T. H., Hoffman A. R. Imprinting of the Angelman syndrome gene, UBE3A, is restricted to brain. Nat Genet. 1997 Sep;17(1):12–13. doi: 10.1038/ng0997-12. [DOI] [PubMed] [Google Scholar]
  46. Wagstaff J., Shugart Y. Y., Lalande M. Linkage analysis in familial Angelman syndrome. Am J Hum Genet. 1993 Jul;53(1):105–112. [PMC free article] [PubMed] [Google Scholar]
  47. Wevrick R., Kerns J. A., Francke U. Identification of a novel paternally expressed gene in the Prader-Willi syndrome region. Hum Mol Genet. 1994 Oct;3(10):1877–1882. doi: 10.1093/hmg/3.10.1877. [DOI] [PubMed] [Google Scholar]
  48. Zeschnigk M., Lich C., Buiting K., Doerfler W., Horsthemke B. A single-tube PCR test for the diagnosis of Angelman and Prader-Willi syndrome based on allelic methylation differences at the SNRPN locus. Eur J Hum Genet. 1997 Mar-Apr;5(2):94–98. [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES