Neurodevelopmental outcome in Angelman syndrome: Genotype-phenotype correlations

Angelman syndrome (AS) is a neurogenetic disorder that is characterised by intellectual disability, developmental delay, lack of speech and epileptic seizures. Angelman syndrome is caused by missing or altered genetic information on the maternal copy of chromosome 15. The genetic alterations of chromosome 15 that results in Angelman Syndrome can occur in four different ways, and these are described as the genetic subtypes of Angelman syndrome.

  • Deletion – information is missing from the maternal copy of chromosome 15
  • Paternal uniparental disomy (pUPD) – both copies of chromosome 15 have been inherited from the father
  • Imprinting Defect – maternal copy of chromosome 15 is not expressed properly
  • UBE3A Mutation – there is a mutation in the UBEA3A gene that lies within the critical region


Previous studies have indicated that children with Angelman syndrome due to a 15q11.2-q13 deletion have more severe developmental delays and present with more autistic features than children who have Angelman syndrome caused by other genetic subtypes.


In a recent study, researchers in Denmark studied the neurodevelopmental profiles of the different genetic subtypes of Angelman syndrome, including children with both Class I and Class II deletions- where Class 1 deletions being just slightly larger than Class 2 deletions, as well as examining the evolution of cognitive development and autistic features in children with a deletion over a 12-year period.


The researchers used the Mullen Scale of Early Learning to assess cognitive and motor functioning of the children who took part in the study. Children with a deletion (Class I and Class II) displayed significantly reduced developmental age in visual perception, receptive language and expressive language and fine motor development when compared to children with a UBE3A mutation or paternal uniparental disomy (pUPD). In all evaluations, children with Class I deletions showed the lowest scores.


Behaviour associated with autism and autism spectrum disorder was assessed using Autism Diagnostic Observation Schedule (ADOS) which assesses communication, social interaction, play and imagination skills. Compared to children with an UBE3A mutation or pUPD, children with deletions (Class I and Class II) had significantly higher ADOS scores indicating that they display more autism related behaviours. Children with Class I deletions were the group who were more likely to reach the cut-off level for an autism diagnosis.


Seven children took part in the twelve year follow-up, two children had Class I deletions and five children had Class II deletions.  

This follow up study showed that both receptive and expressive language skills increased significantly during the follow-up period, whereas there were no differences observed regarding their ADOS scores.


The study found that children with 15q11.2-q13 deletions were significantly less advanced than children with Angelman syndrome caused by other genetic subtypes, in all aspects of development. The authors report that cognitive development of children with a deletion does not appear to develop beyond 12-14 months and language development generally stays between 4 and 8 months of age. However, the study showed that all children with Angelman syndrome show stronger skills in receptive language compared to expressive language.

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