EpiSign is a newly developed blood test that helps diagnose several diseases, including Angelman syndrome, based on specific genetic changes in cells.
Diseases can develop in several different ways. One of the most common is by acquiring a mutation in a gene that ultimately leads to lower levels of a protein or a faulty one. Another is through an epigenetic change in the gene.
Epigenetics refers to any change in gene expression — the process by which information in a gene is synthesized to create a protein — that does not occur as a result of a mutation. One of the most well-known is change in the methylation pattern of DNA.
DNA methylation is a chemical process where a compound known as a methyl group is added to the DNA molecule. Methylation can change the activity of a gene without changing its sequence.
EpiSign was designed to analyze the epigenetic patterns of DNA using samples from patients’ blood. EpiSign uses technology from the Illumina Infinium Methylation EPIC bead chip array, which can analyze DNA methylation patterns at hundreds of thousands of sites across an individual’s genome.
The methylation data obtained from EpiSign is then used as input for a computational algorithm developed to recognize and identify methylation signatures that are unique to each syndrome.
Currently, EpiSign can diagnose 19 diseases, for which methylation patterns have been established over the years by several groups of researchers.
“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, division head of molecular diagnostics at LHSC and associate professor at Ontario’s Western University, said in a press release. “This technology provides a new level of analysis beyond the genome.”
EpiSign can also detect imprinting defects in addition to modified methylation patterns. Genomic imprinting refers to an epigenetic phenomenon in which either the maternal or the paternal gene is specifically “turned on” (usually both copies of each gene are active). Inappropriate imprinting of certain genes leads to diseases such as Angelman syndrome and Prader-Willi syndrome.
Therefore, this test is particularly useful to confirm a suspected diagnosis of fragile X syndrome, Prader-Willi syndrome, Beckwith-Wiedemann syndrome or Angelman syndrome, particularly because several clinical characteristics of these diseases overlap and can lead to misdiagnosis.
“The power of this technology lies in the ability to resolve diagnoses for patients with clinical uncertainty, some of whom have unclear phenotypic features, and others who may have a VUS (variant of uncertain significance) in an associated gene,” said Mike Friez, PhD, director of Greenwood Diagnostic Laboratories at the Greenwood Genetic Center.
VUS refers to the variant form of a gene that is identified through genetic testing but whose significance to the function or health of an organism is not known. EpiSign can help determine whether the VUS actually causes an epigenetic modification.
EpiSign can also help achieve an accurate diagnosis for conditions involving intellectual disability (ID) or congenital anomalies (CA), which can otherwise be challenging to diagnose.
“[ID and CA] are often associated with variable, complex, and overlapping features. 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. EpiSign is another tool now at the clinician’s disposal to help end the diagnostic odyssey for many families,” Friez said.