The mutation genotype affects between 5-11% of cases of Angelman Syndrome. There are different types of mutations in the UBE3A gene, or variants, as described below.

Important Notice:

• If you have questions about Angelman Syndrome or types of mutations, consult a geneticist or a neuropediatrician experienced in rare diseases. The text on this website does not replace professional medical advice.

• Genetic counseling can be useful to assess the risk of recurrence in families with a history of the syndrome.

• Prenatal genetic testing may be considered in specific cases.

Additional Information:

• National Institute Genome Research Institute  https://www.genome.gov/genetics-glossary

• Angelman Syndrome Foundation: https://www.angelman.org

• FAST  https://www.cureangelman.org

• NIH National Library of Medicine - Angelman Syndrome: https://www.ncbi.nlm.nih.gov/books/NBK560870

• GeneReviews - Angelman Syndrome: https://www.ncbi.nlm.nih.gov/books/NBK1144

Missense Mutation:

A missense mutation occurs when a single base pair change leads to the substitution of one amino acid for another in the resulting protein. This type of mutation can have varied effects on the protein's function, from no significant change to complete loss of function, depending on the importance of the altered amino acid to the protein's structure and function.

In simple terms: in a missense variant, there is a change in the nucleotides that results in the replacement of one piece of the protein, called an amino acid, with a different amino acid. In some cases, a missense variant still allows for some UBE3A protein production, although depending on the location of the variant, the protein may not be functional. If the UBE3A protein still has some function, the individual may have fewer or less severe symptoms. (FAST, 2024)

Nonsense Mutation:

A nonsense mutation is also a change of a single base pair but results in a premature stop codon. This interrupts the protein translation, generally leading to a truncated protein that is often non-functional.

In simple terms: in a nonsense variant, a STOP signal is inserted into the gene. As a result, when cells are reading the gene, they stop at that location in the gene, and the rest of the gene after the stop signal cannot be read. The UBE3A protein produced is typically small, non-functional, and rapidly broken down by the body.  (FAST, 2024)

Frame Shift Mutation:

A frameshift mutation is caused by the insertion or deletion of a number of bases that is not a multiple of three. This alters the reading frame of the messenger RNA during translation, potentially changing the entire amino acid sequence from the point of the mutation, often resulting in a dysfunctional or non-functional protein.

In-Frame Deletion or Insertion:

An in-frame deletion or insertion is the loss or addition of a number of bases that is a multiple of three, which does not alter the reading frame (frame) of the gene. Although the reading frame is preserved, the loss or addition of amino acids may affect the protein's function.

Splice Site Mutation:

Splice site mutations affect the regions of DNA that guide the cutting and splicing of pre-messenger RNA. These mutations can lead to the loss of an exon, inclusion of an intron, or the creation of a new splice site that alters the messenger RNA and, consequently, the protein.

Others:

The types of mutations listed do not exclude other possibilities. Scientific research continues to explore how different mutations and variants affect the function of the UBE3A gene and contribute to the spectrum of phenotypes observed in neurodevelopmental disorders.