Genotype-Phenotype Correlations in Angelman Syndrome

Genes (Basel). 2021 Jun 28;12(7):987. doi: 10.3390/genes12070987.


Angelman syndrome (AS) is a rare neurodevelopmental disease that is caused by the loss of function of the maternal copy of ubiquitin-protein ligase E3A (UBE3A) on the chromosome 15q11-13 region. AS is characterized by global developmental delay, severe intellectual disability, lack of speech, happy disposition, ataxia, epilepsy, and distinct behavioral profile. There are four molecular mechanisms of etiology: maternal deletion of chromosome 15q11-q13, paternal uniparental disomy of chromosome 15q11-q13, imprinting defects, and maternally inherited UBE3A mutations. Different genetic types may show different phenotypes in performance, seizure, behavior, sleep, and other aspects. AS caused by maternal deletion of 15q11-13 appears to have worse development, cognitive skills, albinism, ataxia, and more autistic features than those of other genotypes. Children with a UBE3A mutation have less severe phenotypes and a nearly normal development quotient. In this review, we proposed to review genotype-phenotype correlations based on different genotypes. Understanding the pathophysiology of the different genotypes and the genotype-phenotype correlations will offer an opportunity for individualized treatment and genetic counseling. Genotype-phenotype correlations based on larger data should be carried out for identifying new treatment modalities.

Keywords: Angelman syndrome; genotype; imprinting; intellectual disability; neurodevelopment; phenotype.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Angelman Syndrome / diagnosis
  • Angelman Syndrome / genetics*
  • Angelman Syndrome / physiopathology
  • Chromosomes, Human, Pair 15 / genetics
  • Genetic Association Studies*
  • Genetic Counseling
  • Genotype
  • Humans
  • Mutation / genetics
  • Phenotype
  • Seizures / diagnosis
  • Seizures / genetics*
  • Seizures / physiopathology
  • Ubiquitin-Protein Ligases / genetics*


  • UBE3A protein, human
  • Ubiquitin-Protein Ligases