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Genotype

The Angelman syndrome (AS) is caused by different genetic mechanisms affecting the 15q11-q13 region which is regulated by imprinting. Thus, only one of the two copies of the genes in this region will be expressed depending on its parental origin. One of the genes in this region is the UBE3A gene that is only expressed from the maternal allele in the brain. Genetic abnormalities on the maternal copy of this gene cause the AS. It is important to confirm the clinical diagnosis and establish the genetic mechanism in order to offer a genetic counselling.
The genetic causes are:

1. Deletions of 15q11-q13: ~70% of individuals with AS have a deletion of 15q11-q13 on the maternal chromosome.
2. Paternal uniparental disomy of chromosome 15: ~2-5% of individuals with AS have paternal uniparental disomy for chromosome 15.
3. Imprinting defect: ~1-5% of individuals with AS are caused by an imprinting defect causing the lack of expression of maternal UBE3A gene copy. The 85% of the imprinting defects are considered a de novo event caused by epigenetic abnormalities. The 15% of the imprinting defects are caused by deletions in the imprinting control region that could be de novo or familial.
4. UBE3A mutations: ~10% of individuals with AS have mutations of the UBE3A gene.
5. Chromosome abnormalities: in few cases the genetic cause of AS could be a chromosome reorganization affecting the critical region of the syndrome.