Genotypes

Deletions are the most common cause of AS (~65-75%).  Most individuals living with Deletion AS are missing the maternal UBE3A gene as well as an additional  ~10 additional genes that surround the UBE3A gene. To understand more about deletions click here.

Mutation is when there is a difference or variant within the DNA nucleotides of the maternal UBE3A gene (10-15%). This variant could insert a stop into the gene or change the code of the gene, such that that UBE3A protein that is made is less functional or nonfunctional. To understand more about mutations click here.  

Uniparental disomy (UPD; ~3-5%) is when both copies of a chromosome pair came from one parent, instead of the usual one chromosome from the egg, one chromosome from the sperm.   UPD AS happens when both copies of chromosome 15 came from the father.  Because the paternal UBE3A gene is always turned off in neurons, when both copies of chromosome 15 come from the father, both UBE3A genes are turned off, and no UBE3A protein is made in the brain. To understand more about UPD click here.

An imprinting center defect (ICD, ~3-4%) is when the maternal imprinting center does not work correctly.  When we make eggs or sperm, we need to reset the chromosome 15's so that they have the correct imprinting-- we need all chromosome 15s coming from an egg to have the "maternal" imprinting and all 15's coming from the sperm to have the  "paternal" imprinting.  The imprinting center is responsible for the resetting of the imprinting.   When there is an ICD, the imprinting center doesn't work. Consequently, a chromosome 15 that the mother received from her father will still have "paternal" imprinting.  As a result, the UBE3A gene is turned off on the maternal chromosome 15.  Because the paternal UBE3A gene is always turned off in neurons, an ICD on the maternal chromosome 15 results in no UBE3A protein being made.  ICDs can be caused by a deletion of the imprinting center or by methylation of the imprinting center. To understand more about ICD click here.

Mosiacism (~1%) happens when the genetic difference that causes AS occurs after fertilization, during the development of an embryo. ICD is a common cause of mosaicism, but it can also occur with other genotypes.  A person with mosaicism has a mixture of cells that make UBE3A and cells that do not make UBE3A in the body. Most reported cases have an estimated 5-20% of cells that have maternal expression, though between 1-40% are reported. To understand more about mosaicism click here.