This track is part of the Episignatures collection.
It shows the genes and genomic regions behind the disorders that the EpiSign clinical test can detect, as of EpiSign version 6.1.0. EpiSign is a diagnostic DNA methylation test run by the EpiSign Clinical Testing Network, a group of clinical laboratories in Canada, the United States and Europe. A blood sample is measured on a methylation array and compared to the episignatures in the EpiSign Knowledge Database. Unlike the other tracks in this collection, this track does not show the CpG sites of a signature. Instead, each feature marks the locus whose alteration causes the methylation pattern: the causative gene for single-gene disorders, or the deleted or duplicated region for copy-number syndromes such as Wolf-Hirschhorn or Potocki-Lupski syndrome.
EpiSign also tests a set of imprinted regions and the FMR1 promoter directly, by looking at methylation at that region itself rather than across the genome. These differentially methylated regions (DMRs) are included as a second type of feature.
The track contains 231 features for more than 170 disorder codes and more than 240 episignatures. A disorder that can be caused by several genes, for example the BAFopathies or Fanconi anemia, has one feature per gene.
Each feature is labeled with the EpiSign disorder code followed by the gene or region in parentheses. The colors are the ones chosen by the data provider:
| Dark blue — episignature: gene or region whose alteration causes a genome-wide DNA methylation episignature | |
| Gray — imprinting or promoter DMR tested directly (imprinting disorders, fragile X syndrome, BCLAF3 5' UTR) |
The mouse-over and the details page list the disorders, the gene, and the EpiSign IDs of the episignatures for that locus. A disorder often has several episignature IDs. Suffixes such as _SEN and _SPC, _PLA and _PLB, or _SEC denote alternative versions of the signature for the same disorder. For a DMR, the label shows the codes of the disorders tested at that region, separated by commas, and the details page gives the region and EpiSign's name for it.
The features can be filtered by type on the track configuration page. Disorder codes can be typed into the position box, e.g. BAFopathy or CHARGE.
EpiSign analysis is performed on genomic DNA from peripheral blood, measured with Illumina Infinium methylation arrays (MethylationEPIC). Each sample is normalized and compared to the EpiSign Knowledge Database, which holds thousands of methylation profiles of patients with confirmed genetic diagnoses and of controls, using unsupervised clustering and a support vector machine classifier that assigns a methylation variant pathogenicity (MVP) score for every episignature. In parallel, methylation at imprinted regions and at the FMR1 promoter is assessed. Kerkhof et al. 2024 describe the results of 2399 clinical cases tested through the EpiSign Clinical Testing Network and give recommendations for reporting.
The data was provided by the EpiSign group as a BED file, UCSC_EpiSign6.1.0_hg38.bed, with one row per disorder and locus and with the coordinates already on the hg38 assembly. We split its free-text description into the disorders and the gene, removed the explanatory paragraph that was repeated on every row, and converted the file to bigBed format. All 231 rows of the file are shown in the track, none were removed. The steps are documented in the makeDoc file and the scripts are in our source repository.
The data can be explored interactively in table format with the Table Browser or the Data Integrator and exported from there to spreadsheet or tab-separated tables. From scripts, the data can be accessed through our API, track=episign.
For automated download and analysis, the annotation is stored in a bigBed file that can be downloaded from our download server. The file for this track is called episign.bb. Individual regions or the whole annotation can be obtained using our tool bigBedToBed, which can be compiled from the source code or downloaded as a precompiled binary for your system. Instructions for downloading source code and binaries can be found here. The tool can also be used to obtain features within a given range, e.g. bigBedToBed https://hgdownload.soe.ucsc.edu/gbdb/hg38/episignatures/episign.bb -chrom=chr21 -start=0 -end=100000000 stdout
More information about EpiSign testing is available at episign.com.
Thanks to Bekim Sadikovic and the EpiSign group at the Verspeeten Clinical Genome Centre, London Health Sciences Centre, for providing the data.
Kerkhof J, Rastin C, Levy MA, Relator R, McConkey H, Demain L, Dominguez-Garrido E, Kaat LD, Houge SD, DuPont BR et al. Diagnostic utility and reporting recommendations for clinical DNA methylation episignature testing in genetically undiagnosed rare diseases. Genet Med. 2024 May;26(5):101075. PMID: 38251460