Document Type : Original Paper


1 1 Social Welfare Organization of South Khorasan Province, Birjand, Islamic Republic of Iran

2 2 Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Islamic Republic of Iran

3 2 Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Islamic Republic of Iran 3 Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Islamic Republic of Iran


Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe developmental delay or intellectual disability caused by either disruption of the maternal UBE3A gene or deletion in the maternal 15q11-q13. Diagnosis of AS in two siblings with normal four-generation history was confirmed through a staged genetic evaluation, G-banding karyotype, Fluorescence in situ Hybridization analysis, and methylation pattern in 15q11-q13. Despite detecting impaired methylation patterns in the region of interest, distinguishing the imprinting defects from uniparental disomy (UPD) was not feasible since we did not have access to the parents' sample. However, regarding the low risk of AS recurrence within families with UPD in the literature and the healthy family history, mosaicism of cryptic imprinting center deletion in the mother's germline should be the most probable cause of AS recurrence in our cases.


Main Subjects

  1. Williams CA, Driscoll DJ, Dagli AI. Clinical and genetic aspects of Angelman syndrome. Genet Med. 2010;12(7):385.
  2. Buiting K, Williams C, Horsthemke B. Angelman syndrome—insights into a rare neurogenetic disorder. Nat Rev Neurol. 2016;12(10):584.
  3. Keute M, Miller MT, Krishnan ML, Sadhwani A, Chamberlain S, Thibert RL, et al. Angelman syndrome genotypes manifest varying degrees of clinical severity and developmental impairment. Mol Psychiatry. 2021;26(7):3625-33.
  4. Yesodharan D, Thampi M, Koshy T, Nampoothiri S. Recurrence of Angelman syndrome in siblings: challenges in genetic counseling. Indian J Pediatr. 2014;81(3):292-5.
  5. Frohlich J, Miller MT, Bird LM, Garces P, Purtell H, Hoener MC, et al. Electrophysiological phenotype in Angelman syndrome differs between genotypes. Biol Psychiatry. 2019;85(9):752-9.
  6. Dagli AI, Mathews J, Williams CA. Angelman Syndrome. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews(®). Seattle (WA): University of Washington, Seattle. Copyright © 1993-2022, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 1993.
  7. Beygo J, Buiting K, Ramsden SC, Ellis R, Clayton-Smith J, Kanber D. Update of the EMQN/ACGS best practice guidelines for molecular analysis of Prader-Willi and Angelman syndromes. Eur J Hum Genet 2019;27(9):1326-40.
  8. McGowan-Jordan J, Simons A, Schmid M. An international system for human cytogenomic nomenclature (2016). Cytogenetic and Genome Research Basel, Switzerland. 2016;149.
  9. Wang Q, Wu W, Xu Z, Luo F, Zhou Q, Li P, et al. Copy number changes and methylation patterns in an isodicentric and a ring chromosome of 15q11-q13: report of two cases and review of literature. Mol Cytogenet. 2015;8:97-.


  1. Le Fevre A, Beygo J, Silveira C, Kamien B, Clayton‐Smith J, Colley A, et al. Atypical Angelman syndrome due to a mosaic imprinting defect: case reports and review of the literature. Am J Med Genet A. 2017;173(3):753-7.
  2. Bürger J, Buiting K, Dittrich B, Groß S, Lich C, Sperling K, et al. Different Mechanisms and Recurrence Risks of Imprinting Defects in Angelman Syndrome. Am J Hum Genet. 1997;61(1):88-93.
  3. Kurtovic-Kozaric A, Mehinovic L, Stomornjak-Vukadin M, Kurtovic-Basic I, Catibusic F, Kozaric M, et al. Diagnostics of common microdeletion syndromes using fluorescence in situ hybridization: single center experience in a developing country. Bosn J Basic Med Sci. 2016;16(2):121.
  4. Yang L, Shu X, Mao S, Wang Y, Du X, Zou C. Genotype–phenotype correlations in Angelman syndrome. Genes. 2021;12(7):987.
  5. Buiting K, Groß S, Lich C, Gillessen-Kaesbach G, El-Maarri O, Horsthemke B. Epimutations in Prader-Willi and Angelman Syndromes: A Molecular Study of 136 Patients with an Imprinting Defect. Am J Hum Genet. 2003;72(3):571-7.
  6. Reis A, Dittrich B, Greger V, Buiting K, Lalande M, Gillessen-Kaesbach G, et al. Imprinting mutations suggested by abnormal DNA methylation patterns in familial Angelman and Prader-Willi syndromes. Am J Hum Genet 1994;54(5):741.
  7. Baker EK, Merton CF, Tan W-H, Dudding-Byth T, Godler DE, Sadhwani A. Methylation analysis and developmental profile of two individuals with Angelman syndrome due to mosaic imprinting defects. Eur J Med Genet. 2022;65(4):104456.
  8. Buiting K, Barnicoat A, Lich C, Pembrey M, Malcolm S, Horsthemke B. Disruption of the Bipartite Imprinting Center in a Family with Angelman Syndrome. Am J Hum Genet 2001;68(5):1290-4.