Understanding Genetic Classes of Angelman Syndrome

Dr. Charles Williams,

Professor of Pediatrics and Genetics, Division of  Genetics and Metabolism, Department of  Pediatrics, University of Florida

Conducting blood testing to diagnose Angelman syndrome (AS) can be a complicated matter.

Here I summarize the different genetic causes of AS and provide general guidelines about how to use genetic tests to confirm the diagnosis of AS.  First, let us look at the genetic mechanisms that cause AS:

A chromosome 15 pair is illustrated for each class depicted but the other chromosomes are not shown.  The P indicates the maternally-derived chromosome and the M indicates the maternally-derived one.  The shaded chromosomes have a paternal pattern of gene functioning while the unshaded chromosomes have a maternal pattern.  AS can be caused by either a large chromosome deletion (70% of the time); a disruptive mutations in the  UBE3A gene inherited from the mother (indicated by the X); inheritance from the father of 2 normal number 15 chromosomes (e.g., paternal uniparental disomy [UPD]); or an imprinting defect (ID), occurring when the chromosome 15 inherited from the mother has the paternal pattern of gene functioning because of a problem in the imprinting center (denoted by the small open circle).

In addition to these mechanisms, a clinical diagnosis of AS may be given even though the genetic testing is normal. The percentages indicate how common each mechanism occurs. How do we use genetic testing and what is the sequence of testing?  There are many pathways to diagnosis for families undergoing testing for AS but the most common testing pathway is summarized here: