New Blood Test May Help Diagnose Prader-Willi Syndrome, Other Complex Disorders

A new blood test called EpiSign may help identify complex and hard-to-diagnose genomic imprinting disorders such as Prader-Willi syndrome (PWS).

EpiSign, available in two versions, can diagnose 19 complex disorders. This newly available diagnostic tool, which identifies common DNA modifications, may also help researchers understand the clinical significance of genetic variations linked to human disorders.

EpiSign was developed by Greenwood Diagnostic Laboratories at the Greenwood Genetic Center, in South Carolina, in collaboration with London Health Sciences Centre (LHSC), in Canada.

Instead of detecting changes in the sequence of DNA — which stores information for the production of all human proteins — EpiSign identifies a common DNA modification that regulates the sequence readout, called DNA methylation.

This alteration refers to the addition of methyl chemical groups to the DNA molecule without changing its sequence. Varying levels of methylation can change a gene’s activity, turning it more active or silent, and thus can change the ability of that gene to work as it should.

Some DNA methylation patterns, also known as epigenetic signatures, are unique to specific disorders. EpiSign explores this fact, detecting specific epigenetic signatures to better diagnose 19 such disorders.

“Current diagnostic technologies such as microarray and whole exome sequencing are not able to assess non-coding and more complex variants, and cannot provide information on epigenetic changes,” Bekim Sadikovic, PhD, head of the Molecular Genetics department at LHSC and associate professor at Western University, said in a press release.

“This technology provides a new level of analysis beyond the genome,” said Sadikovic, who is also the lead of the epigenetic signature research.

The EpiSign device uses an Illumina proprietary bead chip array to analyze DNA methylation at hundreds of thousands of regions across all DNA content (genome). It comes with computer software that analyzes the data and identifies the disorders based on the detected DNA methylation pattern.

The most important factor of this new technology is its ability to identify more complex genetic variants, whose function or impact for health is unknown, and provide a layer of information beyond the DNA sequence itself.

“The power of this technology lies in the ability to resolve diagnoses for patients with clinical uncertainty, some of whom have unclear phenotypic features [clinical manifestations], and others who may have a VUS [variant of uncertain significance] in an associated gene,” Mike Friez, PhD, director of Greenwood Diagnostic Laboratories, said in the press release.

Variants of uncertain significance are particularly abundant in patients with unexplained intellectual disabilities or congenital disabilities.

“Even with advanced sequencing and powerful array technology, the current diagnostic yield for these patients is between 42-62%, leaving many without a clear diagnosis,” Friez said. He said EpiSign is a new tool for clinicians “to help end the diagnostic odyssey for many families.”

Another important advantage of EpiSign is that it can detect multiple methylation defects that are linked to inherited genomic silencing or DNA repeat expansions, according to the Greenwood Genetic Center. This makes it useful as a complementary diagnostic tool for individuals suspected of having disorders such as Prader-Willi syndrome, Fragile X syndrome, Angelman syndrome, and Beckwith-Wiedemann syndrome.

EpiSign can also be used to diagnose other complex genetic disorders, including CHARGE syndrome, Cornelia de Lange syndrome, Kabuki syndrome, Sotos syndrome, and Williams syndrome.

The test is offered in two versions: EpiSign Complete, which identifies 19 disorders, including PWS; and EpiSign Variant, which helps researchers understand variations of uncertain clinical significance.

For more information, visit the EpiSign website.