Genetic Testing When Angelman Syndrome is Not Suspected

Genetic testing is often performed when a health care provider notices delays in development or after a seizure occurs.  In many cases, the provider will order a broad genetic test that looks for many disorders at once. 

Some examples of testing that might be done are chromosomal microarray, whole exome sequencing, or a panel of genes that are associated with delays or epilepsy.    

CMA Genetic Testing

Many individuals living with AS have a chromosomal microarray (CMA) as the first genetic test.  The CMA is commonly recommended if a health care provider does not suspect a specific diagnosis and wants to screen for many conditions at once.  CMA is a method of checking the chromosomes for small missing or extra pieces of chromosomes.  Most CMA performed in the USA can identify the exact size of a deletion on chromosome 15, but the test cannot tell if the deletion is on the maternal 15 or the paternal 15.  

Because the same deletion can cause both AS and Prader-Willi syndrome (PWS), additional testing may be needed to determine the diagnosis.  In some instances, an individual may already have a clinical diagnosis of AS, so the identification of a deletion confirms the AS diagnosis.  In other instances, DNA methylation testing needs to be performed to see if the deletion is on the maternal chromosome 15 (AS) or the paternal chromosome 15 (PWS). 

If the deletion is on the maternal chromosome, this is typically called Deletion AS.

Whole exome sequencing, whole genome sequencing, or panel genetic testing

Some individuals living with AS are diagnosed after genetic testing of multiple genes identifies a variant in the UBE3A gene.  Some individuals only have sequencing for the UBE3A gene, while other individuals will have sequencing for a panel of genes that includes UBE3A and other genes that may cause similar characteristics. Some individuals have sequencing of almost all their genes through whole genome sequencing (WGS) or whole exome sequencing (WES).   

The UBE3A gene, like all genes, is made up of nucleotides (the DNA chemicals) that provide the instruction for the UBE3A protein.  The chemicals need to be arranged in a particular order for the protein to be made correctly. Genetic sequencing looks at all the nucleotides in a gene, looking for any differences from the typical functioning gene sequence.  

Sequencing results will report genetic variants that are pathogenic or likely pathogenic, meaning that the variant in the gene is either known to cause the condition or very likely to cause the condition. A pathogenic or likely pathogenic variant in UBE3A confirms the diagnosis of AS.

This is often referred to as Mutation AS.   

Sequencing reports will also include any variants of uncertain significance, sometimes called VUS or VOUS.  VUS are differences from the typical gene sequence, but it is not clear whether the difference affects the function of the protein.  VUS results can be tricky–in some cases a variant is called a VUS but it harms the UBE3A protein enough to cause AS; in other cases the VUS is just a random, harmless genetic difference.  Family testing is often offered to try to better understand the VUS.  If an individual has genetic testing for multiple genes, like in a panel or whole exome or genome sequencing, it is very common for the laboratory to find one or more VUSs in one of the genes that was tested.  

CMA and whole exome or genome sequencing are good tests that screen for many different genetic disorders at once. However, they can NOT rule out Angelman syndrome.  Individuals who had UPD-heterodisomy and ICD-Methylation or ICD-Deletion will typically have normal CMA and whole exome/genome sequencing.  DNA methylation testing is needed to diagnose those genotypes. 

Once the diagnosis of AS is confirmed, genetic testing for parents is often suggested.  If you want to learn more about parental testing for AS, click here.