Genetic Imprinting in the Prader–Willi and Angelman Syndromes


Imprinted genes are expressed from only one of the two parental alleles: they are located in a few, specific chromosomal regions. The parental‐specific expression is obtained through epigenetic modifications (DNA methylation, histone tail modifications) which alter the conformation of chromatin fibre and therefore regulate the expression of the underlying genes. Deletions, duplications, mutations or imprinting defects of the only active allele, as well as uniparental disomy or loss of imprinting of the inactive allele lead to an unbalance (loss of function or gain of function) in the dosage of the gene product and do have phenotypic consequences. Two such examples in human pathology are represented by the Prader–Willi and Angelman syndromes, two phenotypically different conditions, whose phenotypes result from loss of paternal or maternal contribution of the 15q11–q13 genomic region, respectively.

Key Concepts:

  • Prader–Willi and Angelman syndromes are caused by loss of function of different genes located in a genomic region under the control of a single, bipartite imprinting centre.

  • These two condition represent the prototype of genomic imprinting disorders in humans.

  • Genomic imprinting regulates allelic expression according to the parental origin.

  • Imprinted genes are commonly expressed in half dosage.

  • Imprinted genes can be inactivated by different mechanisms: uniparental disomy, microdeletion, gene mutation, primary or secondary epigenetic mutation of the imprinting centre.

Keywords: imprinting; epimutation; Prader–Willi syndrome; Angelman syndrome

Figure 1.

Genomic imprinting: resetting, establishment and maintenance and possible imprinting defects. Erasure of imprinting occurs in primordial germ cells (actively on the maternal chromosome [pink] or by default on the paternal one [blue]); imprinting is reestablished in germ cells according to the male or female gonadic environment; the blue arrows indicate the specific stage and parental chromosome at which the error occurs. The phenotypic consequences (PWS or AS) of these errors are indicated. Adapted from Horsthemke .

Figure 2.

The PWSAS imprinting domain. The imprinting centre (IC) has bipartite structure: PWSIC (empty circle) and ASIC (black circle). The majority of the genes in the cluster is reported. Those paternally expressed are in blue, whereas those maternally expressed are in pink. In black boxes the nonimprinted genes are shown. Adapted from Buiting .



Angelman H (1965) Puppet children a report on three cases. Developmental Medicine and Child Neurology 7: 681–688.

Boyd SG, Harden A and Patton MA (1988) The EEG in early diagnosis of the Angelman (happy puppet) syndrome. European Journal of Pediatrics 147: 508–513.

Buiting K (2010) Prader–Willi syndrome and Angelman syndrome. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics 154C: 365–376.

Butler MG (1990) Prader–Willi syndrome: current understanding of cause and diagnosis. American Journal of Medical Genetics 35: 319–332.

Cassidy SB (1984) Prader–Willi syndrome. Current Problems in Pediatrics 14: 1–55.

Cassidy SB (1997) Prader–Willi syndrome. Journal of Medical Genetics 34: 917–923.

Cassidy SB, Dykens E and Williams CA (2000) Prader–Willi and Angelman syndromes: sister imprinted disorders. American Journal of Medical Genetics 97: 136–146.

Cassidy SB, Forsythe M, Heeger S et al. (1997) Comparison of phenotype between patients with Prader–Willi syndrome due to deletion 15q and uniparental disomy 15. American Journal of Medical Genetics 68: 433–440.

Cattanach BM and Kirk M (1985) Differential activity of maternally and paternally derived chromosome regions in mice. Nature 315: 496–498.

Clayton‐Smith J (1993) Clinical research on Angelman syndrome in the United Kingdom: observations on 82 affected individuals. American Journal of Medical Genetics 46: 12–15.

Clayton‐Smith J and Laan L (2003) Angelman syndrome: a review of the clinical and genetic aspects. Journal of Medical Genetics 40: 87–95.

Duker AL, Ballif BC, Bawle EV et al. (2010) Paternally inherited microdeletion at 15q11.2 confirms a significant role for the SNORD116 C/D box snoRNA cluster in Prader–Willi syndrome. European Journal of Human Genetics 18: 1196–1201.

Dykens EM, Hodapp RM, Walsh K and Nash LJ (1992) Profiles, correlates, and trajectories of intelligence in Prader–Willi syndrome. Journal of the American Academy of Child and Adolescent Psychiatry 31: 1125–1130.

Dykens EM, Leckman JF and Cassidy SB (1996) Obsessions and compulsions in Prader–Willi syndrome. Journal of Child Psychology and Psychiatry, and Allied Disciplines 37: 995–1002.

Eiholzer U (2005) Deaths in children with Prader–Willi syndrome. A contribution to the debate about the safety of growth hormone treatment in children with PWS. Hormone Research 63: 33–39.

Gilfillan GD, Selmer KK, Roxrud I et al. (2008) SLC9A6 mutations cause X‐linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome. American Journal of Human Genetics 82: 1003–1010.

Gunay‐Aygun M, Cassidy SB and Nicholls RD (1997) Prader–Willi and other syndromes associated with obesity and mental retardation. Behavior Genetics 27: 307–324.

Hall JG (1990) Genomic imprinting: review and relevance to human diseases. American Journal of Human Genetics 46: 857–873.

Holm VA and Laurnen EL (1981) Prader–Willi syndrome and scoliosis. Developmental Medicine and Child Neurology 23: 192–201.

Hore TA, Rapkins RW and Graves JA (2007) Construction and evolution of imprinted loci in mammals. Trends in Genetics 23: 440–448.

Horsthemke B (2006) Epimutations in human disease. Current Topics in Microbiology and Immunology 310: 45–59.

Horsthemke B (2010) Mechanisms of imprint dysregulation. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics 154C: 321–328.

Horsthemke B and Buiting K (2008) Genomic imprinting and imprinting defects in humans. Advances in Genetics 61: 225–246.

Jiang YH, Bressler J and Beaudet AL (2004) Epigenetics and human disease. Annual Review of Genomics and Human Genetics 5: 479–510.

Kajii T and Ohama K (1977) Androgenetic origin of hydatidiform mole. Nature 268: 633–634.

Kanber D, Giltay J, Wieczorek D et al. (2009) A paternal deletion of MKRN3, MAGEL2 and NDN does not result in Prader–Willi syndrome. European Journal of Human Genetics 17: 582–590.

Killian JK, Byrd JC, Jirtle JV et al. (2000) M6P/IGF2R imprinting evolution in mammals. Molecular Cell 5: 707–716.

Kishino T, Lalande M and Wagstaff J (1997) UBE3A/E6‐AP mutations cause Angelman syndrome. Nature Genetics 15: 70–73.

Laan LA, den Boer AT, Hennekam RC, Renier WO and Brouwer OF (1996) Angelman syndrome in adulthood. American Journal of Medical Genetics 66: 356–360.

LaSalle JM (2007) The odyssey of MeCP2 and parental imprinting. Epigenetics 2: 5–10.

Li E (2002) Chromatin modification and epigenetic reprogramming in mammalian development. Nature Reviews 3: 662–673.

Linder D, McCaw BK and Hecht F (1975) Parthenogenic origin of benign ovarian teratomas. The New England Journal of Medicine 292: 63–66.

Lindgren AC, Hagenas L, Muller J et al. (1998) Growth hormone treatment of children with Prader–Willi syndrome affects linear growth and body composition favourably. Acta Paediatrica 87: 28–31.

Lossie AC, Whitney MM, Amidon D et al. (2001) Distinct phenotypes distinguish the molecular classes of Angelman syndrome. Journal of Medical Genetics 38: 834–845.

Matsuura T, Sutcliffe JS, Fang P et al. (1997) De novo truncating mutations in E6‐AP ubiquitin‐protein ligase gene (UBE3A) in Angelman syndrome. Nature Genetics 15: 74–77.

McGrath J and Solter D (1984) Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell 37: 179–183.

Nicholls RD, Knoll JH, Butler MG, Karam S and Lalande M (1989) Genetic imprinting suggested by maternal heterodisomy in nondeletion Prader–Willi syndrome. Nature 342: 281–285.

Owen CM and Segars JH Jr (2009) Imprinting disorders and assisted reproductive technology. Seminars in Reproductive Medicine 27: 417–428.

Reik W, Dean W and Walter J (2001) Epigenetic reprogramming in mammalian development. Science (New York, NY) 293: 1089–1093.

Sahoo T, del Gaudio D, German JR et al. (2008) Prader–Willi phenotype caused by paternal deficiency for the HBII‐85 C/D box small nucleolar RNA cluster. Nature Genetics 40: 719–721.

Shemer R, Hershko AY, Perk J et al. (2000) The imprinting box of the Prader–Willi/Angelman syndrome domain. Nature Genetics 26: 440–443.

de Smith AJ, Purmann C, Walters RG et al. (2009) A deletion of the HBII‐85 class of small nucleolar RNAs (snoRNAs) is associated with hyperphagia, obesity and hypogonadism. Human Molecular Genetics 18: 3257–3265.

Summers JA, Allison DB, Lynch PS and Sandler L (1995) Behaviour problems in Angelman syndrome. Journal of Intellectual Disability Research 39(part 2): 97–106.

Surani MA, Barton SC and Norris ML (1984) Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature 308: 548–550.

Tan WH, Bacino CA, Skinner SA et al. (2011) Angelman syndrome: mutations influence features in early childhood. American Journal of Medical Genetics Part A 155A: 81–90.

Tauber M, Diene G, Molinas C and Hebert M (2008) , Review of 64 cases of death in children with Prader–Willi syndrome (PWS). American Journal of Medical Genetics Part A 146: 881–887.

Varela MC, Kok F, Otto PA and Koiffmann CP (2004) Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects. European Journal of Human Genetics 12: 987–992.

Williams CA, Beaudet AL, Clayton‐Smith J et al. (2006) Angelman syndrome 2005: updated consensus for diagnostic criteria. American Journal of Medical Genetics Part A 140: 413–418.

Zogel C, Bohringer S, Gross S et al. (2006) Identification of cis‐ and trans‐acting factors possibly modifying the risk of epimutations on chromosome 15. European Journal of Human Genetics 14: 752–758.

Zweier C, Peippo MM, Hoyer J et al. (2007) Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt–Hopkins syndrome). American Journal of Human Genetics 80: 994–1001.

Further Reading

Katari S, Turan N, Bibikova M et al. (2009) DNA methylation and gene expression differences in children conceived in vitro or in vivo. Human Molecular Genetics 18: 3769–3778.

Ronan A, Buiting K and Dudding T (2008) Atypical Angelman syndrome with macrocephaly due to a familial imprinting center deletion. American Journal of Medical Genetics Part A 146A: 78–82.

Sahoo T, Bacino CA, German JR et al. (2007) Identification of novel deletions of 15q11q13 in Angelman syndrome by array‐CGH: molecular characterization and genotype‐phenotype correlations. European Journal of Human Genetics 15: 943–949.

Wawrzik M, Unmehopa UA, Swaab DF et al. (2010) The C15orf2 gene in the Prader–Willi syndrome region is subject to genomic imprinting and positive selection. Neurogenetics 11: 153–161.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Gurrieri, Fiorella, and Sangiorgi, Eugenio(Nov 2011) Genetic Imprinting in the Prader–Willi and Angelman Syndromes. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005532.pub2]