EpiSign

Episignatures

Pathogenic variants in different genes (usually genes involved in the regulation of epigenetic processes and chromatin structure) can give a very specific abnormal genome-wide methylation profile. The specific profile is called an “episignature”. Such an episignature has now been established for more than 60 disorders.

Imprinting disorders

the methylation status of the differentially methylated regions in/around the imprinted genes will be evaluated. If abnormal methylation is detected, follow-up testing may be necessary to determine the underlying cause, such as UPD or deletion. There are currently 8 imprinting disorders detectable with EpiSign.

Methylation of the promoter region of the FMR1 gene (Fragile X syndrome, FX)

In males with FX, the FMR1 gene is inactivated by extension of a CGG repeat in the gene’s promoter region. With EpiSign, the consequence of CGG repeat elongation, inactivation of the FMR1 gene due to hypermethylation of the FMR1 promoter, can be detected (EpiSign is therefore not a test for determining the repeat length). In case of a positive result, an additional repeat analysis will have to be done to confirm the diagnosis of FX. EpiSign is only suitable for diagnosing FX in males.

Indications for requesting EpiSign test:

• When the patient has a variant of unknown clinical relevance (VUS) in one of the genes for which an Episignature is available. A methylation profile similar to that of the associated syndrome supports pathogenicity of the variant.
• When previous research has not resulted in a diagnosis. A positive episignature could provide a direction for further research, or targeted (re)analysis of existing data. EpiSign can also detect imprinting disorders and FX, which cannot be detected with WES.

Please note: if Silver Russell Syndrome (SRS) or Beckwith-Wiedemann Syndrome (BWS) is suspected, we advise to request (first) a targeted MLPA analysis for these syndromes. The methylation aberrations on chromosome 11 are often mosaic and can be very subtle. The sensitivity of the MLPA is greater than EpiSign. The methylation aberrations on chromosome 11 are often mosaic and can be very subtle. The sensitivity of the MLPA is greater than EpiSign.

Abnormalities detected using this initial screen may require additional targeted testing to confirm and further characterize the underlying genomic abnormality.

EpiSign compleet

With EpiSign complete, all disorders included in the EpiSign panel are examined.

EpiSign compleet – Early onset

The late onset condition is excluded in this test (Autosomal Dominant Cerebellar ataxia, Deafness and Narcolepsy; DNMT1 gene).

EpiSign targeted

It is possible to request a specific analysis if you only want to have one disorder/variant investigated.

Note: You can also request a complete analysis for patients with a VUS in a certain gene. In addition to the specific condition, all other conditions will also be tested. If the patient has a methylation profile that matches another condition, this will also be reported.

Pheripheral blood collected in an EDTA (lavender top) tube is the required specimen type. See Conditions application Genome Diagnostics .

EpiSign can only be performed on DNA isolated from peripheral blood.

The test CANNOT be performed on DNA isolated from umbilical cord blood, blood from premature babies or other tissues.

Extracted DNA is also accepted for this test; given the original specimen was whole blood collected in an EDTA tube. The minimum required amount is 5 ug.

Profile matches to a specific syndrome

• Variant present: This result supports the diagnosis and pathogenicity of the variant has become more likely.
• No variant present: This result supports the diagnosis and further investigation of the linked gene(s) is recommended. However, it cannot be completely ruled out that a mutation is located in another (yet to be discovered) gene that results in the same or largely overlapping episignature.

Profile does not match a specific syndrome or any of the syndromes in the EpiSign panel

• Variant present: pathogenicity of the variant is not completely ruled out. It is possible that a new variant results in a (yet unidentified) different methylation profile.

A number of profiles have been designated as less sensitive because they have either a less strong profile, or are based on a small number of patients or limited mutation type. For these syndromes (see list of disorders) the chance of an uncertain result or a false negative test is slightly higher. EpiSign is also less sensitive in patients with a mosaic variant, or in women with an X-linked disorder.