The researchers emphasized, however, that only rare cases of Angelman are caused by imprinting defects, and that the risk associated with the common variation is too weak to call for prenatal diagnosis.
The study, “Common genetic variation in the Angelman syndrome imprinting centre affects the imprinting of chromosome 15,” was published in the European Journal of Human Genetics.
Each person inherits two copies of every gene — one from each parent. While most cells in the body use both the paternal and the maternal gene copies to produce proteins, some cells depend only on one of the copies, due to a mechanism called genomic imprinting.
Genomic imprinting is the process by which one copy of a gene — either the maternal or the paternal copy — is silenced, or “turned off,” by a chemical DNA modification called methylation. This does not affect the genetic code.
Angelman syndrome is caused by a deficiency in the maternal copy of the ubiquitin protein ligase E3A (UBE3A) gene, which provides instructions for making an enzyme that targets other proteins to be broken down within cells. That copy of UBE3A, located on chromosome 15, is the only active copy in specific regions of the brain.
The deficiency found in Angelman results in a complete lack or malfunction of the UBE3A protein, also known as E6AP, which is thought to play a key role in the normal development and function of the nervous system.
Thus, mutations in the maternal UBE3A gene copy lead to the neurodevelopmental symptoms seen in patients with Angelman syndrome.
While the most common cause of Angelman syndrome is a deletion of the maternal copy of the UBE3A gene, about 3–5% of cases are caused by errors in genomic imprinting.
The underlying mechanisms of these defects in people with Angelman are still poorly understood. Only rare cases are caused by a genetic deletion in the imprinting center, a region that regulates imprinting of UBE3A and other genes in chromosome 15.
Now, researchers in Germany have shed some light on other genetic changes in the region associated with Angelman’s imprinting defects.
The team searched for genetic changes in the imprinting center region associated with UBE3A in a total of 168 Angelman patients. In all of them, the disease was associated with imprinting defects, and there was no genetic deletion in the imprinting center region.
The data showed that there were no additional genetic alterations in the imprinting center region besides the known common genetic variations reported for that region. Common variations are genetic changes that are often found in the population and are not directly associated with the development of a disease.
Using the transmission disequilibrium test, the researchers then evaluated whether any of these common variants were associated with an increased risk of imprinting defects and the development of Angelman syndrome. That family-based test looks for the presence of a genetic link between a genetic marker and a trait.
Data from 119 patients and their respective parents were used for the test. Only one common variation, called H-AS3, was significantly associated with an increased risk of maternally inherited imprinting defects, the results showed.
The researchers noted that H-AS3 was the only variation that contained a genetic deletion within the center. This deletion affected the binding site of SOX2, a protein that regulates the activity of other genes, the findings showed.
Thus, the team hypothesized that this common variant may affect the ability of SOX2 to bind to this region and impair the activity of the imprinting center, potentially increasing the risk for a maternal imprinting defect and Angelman syndrome.
However, Angelman syndrome caused by such defects is “extremely rare,” and the risk associated with H-AS3 was too weak to warrant prenatal diagnosis, the researchers said.
“Our data strengthen the notion that the [imprinting center] is important for establishing and/or maintaining DNA methylation … and show that common genetic variation can affect genomic imprinting,” the researchers wrote.
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