Updates (February 12th, 2024)

Hotfix released for the following issues:

• Pipeline | Fixed a bug that rarely caused discordant AI Shortlist results between a first and second analysis due to model selection.

• Pipeline | Fixed an issue causing some reanalysis cases to fail due to insufficient backward compatibility with previous zygosity values. This fix will improve pipeline robustness.

Updates (October 26th, 2023)

Hotfix released for the following issues:

• Pipeline | Improved error logging for DRAGEN for easier troubleshooting.

• Pipeline | SMN Caller | Fixed multiple issues causing case failures from FASTQ & BAM.

• Pipeline | SMN Caller | Fixed issue for GRCh37 & SMN caller where relatedness isn’t calculated due to Peddy failure.

New Features

• Improvements to pipeline speed (in hours):

• Support for non-GC corrected PONs in the CNV analysis pipeline for panels, in alignment with DRAGEN recommendations.

• Updated case status when sample pipeline fails, for quicker troubleshooting and resolution.

• Emedgene supports case ingestion from VCF for customer variant callers, as defined in customer’s implementation plans. Several new customer callers were added in this version, and updates made to existing callers. Full documentation is available in the Help Center.

Fixed Issues

• Emedgene DRAGEN Pipeline | Save DRAGEN logs for easy troubleshooting of pipeline failures.

• Compound Het | Optimized performance to eliminate timeouts during case annotation.

Known Issues

• ClinVar sanity check fails case if there are no known variants in ChrY. Workaround: Manual delivery. Fix planned in 33.0.

• Visualization is not supported for users storing VCF and CRAM on ICA V1 and BSSH. Only VCF and BAM are supported.

V33.3 hotfix released for the following issues:

• Analysis Tools | Preset filters | Fixed an issue introduced with v33.2 that caused some LOF preset filters to not return variants. Customers impacted by this issue were notified individually and resolution offered for potentially affected cases.

• Propagation of fixes included in . See release notes for detail.

V33.2 hotfix released for the following issues:

• Add New Case | NovaseqX added to selectable sequencers.

• Add New Case | Fixed a batch uploader issue where sex column was used correctly but also imported in additional data

• Pipeline | Fixed an issue where cases running with DRAGEN 4.2 on HG19 fail the pipeline

V33.1 hotfix released for the following issues:

• Add New Case | Fixed issue where new ethnicities added in v32 were not supported for reanalysis in subsequent versions.

• Batch Upload | Fixed issue for singleton cases uploaded with batch uploader that resulted in inability to edit cases after creation.

• Batch Upload | Fixed issue causing Not Authenticated error for customers with more than 100 BSSH projects.

1. New Variant Types Supported

   1. STR

   2. SV Deletion and Duplications

New Variant Types Supported

STR

You can now interpret STRs on Emedgene, including proprietary annotation and visualization.

STRs are available for customers starting from FASTQ. Calling is performed using ExpansionHunter, for which recent specificity/sensitivity data can be found in this publication. Annotation sources include gnomAD and a unique 1K genomes dataset.

This release also includes an easy way to visualize population data as well as the pathogenicity associated with the number of repeats for the variant you are viewing.

SV Deletion and Duplications

Support for SV deletions and duplications for customers starting from FASTQ is now available in all regions. Calling will be performed with the DRAGEN SV caller, and all the interpretation features available for CNVs are applied to SVs, including our time-saving automated ACMG-ClinGen classification.

Gene Curations

Emedgene Curate now supports genes, enabling you to save and view gene interpretations and preferred transcripts.

Private Networking

You can now create private networks and share curated data between organizations in Emedgene Curate. This is in addition to the private networking feature available in emedgene Analyze and enables sharing and transfer of curated data between trusted organizations.

Additional new features

• Increased automated ACMG classification accuracy

• In the analysis tools table, you can hover on disease to see all related diseases

• View allele frequency full decimal number

1. New AI Models

   1. Shortlist CNVs and Compound Heterozygous SNV-CNV Variants

   2. Improved Phenotypic Match Model

New AI Models

This version was primarily focused on introducing new AI innovation, with the goal of streamlining workflows and further reducing time-per-case.

Shortlist CNVs and Compound Heterozygous SNV-CNV Variants

Our AI Shortlist now compiles CNVs with evidence, along with compound heterozygous SNV-CNV variants. We expect this exciting new capability to drive significant time savings.

The model expands our core AI Shortlist model to CNV variants, and similarly considers dozens of features used by geneticists to interpret a case. The model was validated in a cohort of 51 singletons previously solved by a CNV variant. In 92% of cases (n=47 / 51) the solving variant was identified in a short list of 10 variants. In 6% (n=3), the solving variant was present in the candidate list. Only 2% (n=1), or a single case, was missed by the new AI Shortlist.

Due to the challenging quality nature of CNV variants, the conventional successful AI Shortlist model for SNV is not affected by newly added CNV results. CNV and compound heterozygous variants shortlisted variants are cumulative to SNV/indels, and the default short list for your organization will be extended by 5 variants on average.

The model supports deletions and duplications called both by the DRAGEN CNV read-depth caller and DRAGEN SV caller.

Improved Phenotypic Match Model

We have a new and improved phenotypic match model, Phenomeld. Phenotypic match algorithms estimate the concordance between patient phenotypes and an associated disease, and are a critical component in the AI Shortlist model.

Phenomeld, which achieves an AUC of 0.94, is used both as part of the AI Shortlist model, and as an independent filter in the analysis tools. The improvement was achieved with ensemble machine learning, which utilizes several phenotypic match models to improve model performance.

The Phenomeld model was validated against two data sets.

Utilizing an internal dataset of 314 well characterized cases, Phenomeld was compared to the open source model, as well as to the previous Emedgene Phenomatch model, outperforming both.

Internal Validation Set

A second validation used a set of 4648 ClinVar cases, and compared Phenomeld with phen2gene, where Phenomeld demonstrated improved results.

ClinVar Validation Set

For exploration of phenotypic match results outside of the AI Shortlist models, you can use the Phenomeld filter in the analysis tools.

Support for DRAGEN 4.0

This version supports DRAGEN 4.0 with ML and graph mapper, both for customers using the Emedgene DRAGEN pipeline and customers bringing their own DRAGEN.

DRAGEN 4.0 improves accuracy and reduces analysis time by ~26%.

Learn more about the .

Workflow Improvements

Related Cases Enrichment

The component in the variant page has been enriched with interpretation and classification data, in order to streamline use of lab curated data.

The table now includes: solved/unsolved status, zygosity and affected and overlap % (for CNVs only).

When a case is selected, additional data is displayed: interpretation, phenotypes, proband ID, demographics, ACMG tags and case type.

Bulk Translation of Reports

Our reporting system now enables customers to upload custom data sets to reports. This enables customizable and flexible bulk translation and augmentation of reports with proprietary data.

Emedgene Curate Improvements

• Private Networks now support CNV variants, with selectable % overlap.

• Store gene interpretations and auto-populate to reports

• New gene metrics card for easier gene curation

Enhancements

• Lab Page | Gene Coverage - Region coverage statistics will now be calculated based on the case’s kit associated BED file. If none is defined, a default clinical exome BED will be used.

• Variant Page | ACMG - You can now write and store notes on ACMG tags for SNV variants (previously available only for CNV variants).

• Analysis Tools | Presets - New search bar in gene lists, for faster addition of gene lists to preset filters.

• In organization settings, you can now view and manage Enrichment Kits.

  • Standard users can view the BED file used for any kit

  • Users with permissions can upload new BED files for any reference, both for existing and new kits. Please follow the for BED files (link accessible only to Emedgene platform users).

• PolyPhen2 is back! Illumina has acquired a license to include this data in tertiary analysis platforms.

• Gene Lists | When creating a gene list, the platform will save the NCBI ID for any gene in order to maintain compatibility with future gene symbol updates without the need for a lab gene list audit.

• Expanded ethnicity list to support an increasingly global and diverse customer base.

New Features (June 8th, 2023)

New AI Shortlist Features and Enhancements

On this version we continued focusing on new AI innovation, with the goal of streamlining workflows and further reducing time-per-case.

AI Shortlist now shortlists mtDNA variants

For users analyzing mtDNA variants in Emedgene, the AI Shortlist will now shortlist SNV/CNV mtDNA variants (homoplasmy or heteroplasmy) that are likely to solve the case.

AI Shortlist now shortlists STR variants

For users analyzing STR variants in Emedgene, the AI Shortlist will now shortlist STR variants with expansion size within the pathogenic range according to gnomAD STR and that are likely to solve the case, with evidence.

AI Shortlist now shortlists SV insertions

For users analyzing SV insertions in Emedgene, the AI Shortlist will now shortlist SV insertions that are likely to solve the case, with evidence. Due to variant calling accuracy limitations, insertions, as well as other CNVs, are considered by the AI Shortlist in addition to the regular SNVs.

Shortlisting with evidence for Carrier Screening

Support for sequential (single parent) carrier status.

This new setting will prioritize variants for carrier status, rather than affected, in order to reduce time per case for expanded carrier screening applications.

• AI Shortlist can be configured on the organization level to consider only known P/LP variants or both known and high severity variants.

• Analysis type ‘carrier’ should be selected during case accessioning.

• Output of the AI Shortlistwill be variants tagged as ‘carrier’ rather than the typical ‘most likely’ and ‘candidates’.

Improved recall for AI Shortlist Focused Mode to 96%

Our AI Shortlist model can be run in two modes, including genes of unknown significance (GUS), labeled Discovery Modeor excluding GUS, labeled Focused Mode. In this version, we improved the recall for the Focused Modeto 96%, nearing the results of our Discovery Mode at 97%. The Focused Mode will display up to 7 SNVs, indels, mtDNA and STR variants, and up to an additional 3 CNV variants.

This new Focused Mode was validated on 3 datasets totaling 330 cases solved by SNV, indel, and CNV variants, and demonstrated 96% recall.

Performance Enhancement

AI Shortlist code was refactored to improve performance, scalability, and clean up errors. A bit-exact validation was performed on 3 datasets totaling 330 cases solved by SNV, indel, and CNV variants. A comparison of the precise ranking of most-likely and candidate variants was performed to ensure recall was not affected for cases solved by SNV, indels or CNV variants.

Full Featured Genome: New! Support for SMN, ROH, Ploidy & BAF visualization

Support for the DRAGEN SMN caller

DRAGEN SMN calls SMN1 and SMN2 copy numbers, enabling the analysis of 95% of SMA cases by determining the absence of the functional SMN1 allele in any copy of SMN. This targeted caller overcomes the challenge in producing complete variant caller results with standard WGS due to a high-similarity duplication of SMN1 and the paralog SMN2. Learn more about the .

• SMN1 copy number variants can be shortlisted by the AI Shortlist and interpreted just like other CNVs.

• SMN2 copy number can also be reviewed and interpreted as a prognostic biomarker of SMA clinical severity.

• Carrier status can be assessed by interpreting SMN1 copy number.

Support for the DRAGEN ROH (Regions of Homozygosity) caller

DRAGEN ROH detects and outputs the runs of homozygosity from whole genome calls on autosomal human chromosomes. Sex chromosomes are ignored. ROH output enables screening and prediction of consanguinity between the parents of the proband subject (see DRAGEN™ Bio-IT Platform documentation for more details about the algorithm).

In Emedgene, the ROH BED will be displayed in the IGV viewer. On hover, ROH score, # of Hom SNPs and # of Het SNPs in the region as well as Location (start to end positions) will be displayed.

Support for the DRAGEN Ploidy estimator

DRAGEN Ploidy estimator is used to assess if there are any copy number variants of complete chromosomes (Trisomy, Monosomy etc). ​ The results of the Ploidy estimator will be displayed on the lab tab. If ploidy estimation is marked as fail, the lab tab will have a warning in the page header. Results will be available to download from the sample quality section. (see DRAGEN™ Bio-IT Platform documentation for more details about the algorithm).

Support for B Allele Frequency visualization

The BAF bigwig file is available to view in the additional tracks, both in simple and advanced modes. It will be available for WES and WGS samples called with the Emedgene DRAGEN pipeline.

To avoid confusion, the TNF track, previously labeled as BigWig, is renamed TNF.

Research genome test type

A new Research Genome test type enables full analysis of a genome with no BED intersect. Most of the newly available variants will receive limited or no annotations. The Research Genome significantly increases time per case and performance and is only recommended for research labs with a need to interpret non-coding variants. The Emedgene Whole Genome test type covers 5Kbp upstream/downstream gene and known variants from the non-coding regions, all of which will be annotated.

Support for Illumina Complete Long Reads Interpretation

Support for the recommended Illumina Complete Long Reads interpretation flow.

• Ingests the combined long-read/short-read callers for both SVs and SNVs, along with the long read BAM.

• Short read callers supported by Emedgene from VCF can be added as well (CNV read-depth, STR (starting from DRAGEN 4.2)).

• Once ingested, ICLR variants will be shortlisted by the AI Shortlist and automated ACMG classification will be applied where relevant.

Limitations

• Emedgene does not yet support the interpretation of complex SV variants such as inversions and translocations.

• ICLR cases must start from VCF, Emedgene doesn’t support case accessioning from both VCF and FASTQ.

Enhanced private sharing of curated data

Set sharing levels, opt-in/opt-out, improved interpretation workflow

• Private sharing of curated data between collaborating organizations in Analyze now include granular sharing permissions per network and opt-in/opt-out per case.

• Networks are managed from [Settings | Network]. Here the dedicated network manager can:

  • Create networks; Labs can belong to multiple networks.

Currently, to invite other organizations to their network(s), the network manager must reach out to tech support. (Network invitation flow will be enabled in a future version).

• Level of sharing of a particular case with a particular network of collaborators is defined by:

Sharing mode set for each data field for a particular network. There are 4 levels of sharing that can be applied to each data field: Mandatory – always shared by default; Not shared – never shared; Restricted – shared in cases with or without patient’s consent to Extended sharing; Extended – shared only in cases with patient’s consent to Extended sharing.

Sharing patterns are defined by the network manager in [Settings | Network]. Data fields that could be shared via Analyze Network include:

• Case subject consent for Extended data sharing.

• Review details of variants tagged by collaborators within organization network(s) in the [Variant page | Related cases tab].

• View modes for [Variant page | Related cases tab]: Simple (check/uncheck Network data from all collaborators) and Advanced (select collaborators).

• For each variant, extended sharing details are available at a click, as is the ability to contact a collaborator.

Analysis tools improvements: Exclude variants based on pathogenicity, view Presets & sort columns

Exclude variants based on pathogenicity

Exclude variants from your Preset filters based on their pathogenicity in ClinVar or Curate

Save time by excluding benign variants from your Preset filters. Benign variants can be identified from multiple sources (ClinVar, Curate) and can be excluded, as defined by the user. For ClinVar, the classification can also be matched with a star review classification for more granularity in what you exclude. This filter may be applied to any individual preset bin. Contact to request an update to your Preset filters.

View Presets

Added the ability to view the filters underlying each Preset. For variant analysts working on a preset filter, this will enable a quick refresher on the Preset composition, within the analysis flow.

Actions:

• Click on the name of the Preset to review the Preset variants.

• Click on the dropdown arrow to expand the Preset definition.

• Click on the checkbox to indicate that you have completed your review of this Preset.

Sort columns

Sort any column in the analysis table, with the exception of Phenomatch score (which will be available in v33) and Tags.

Primary and secondary sorting are enabled.

Search alternative allele

In the search bar, we now enable searching by a specific SNV/indel variant following the : >  format.

• Spaces are supported.

• This search will return an exact match.

Add New Case: Single click batch upload of cases

Case accessioning now enables batch upload of cases from the UI! This single click upload of a case manifest file, allows users without API integrations to easily upload batches of 50 cases at once.

• Download the Batch Upload csv template, which is compatible with Sample Sheet v2, adding fields needed for tertiary analysis.

• Every field available in manual case creation and API, is included in the template: including Family Id, Case Type, Files Names, Visualization Files, Execute Now, BioSample Name, Relation, Gender, Phenotypes, Phenotypes Id, Boost Genes, Gene List Id, Kit Id, Selected Preset, Due Date, Label Id, Clinical Notes, Opt In, Storage Provider Id, Date Of Birth, Default Project including Additional Fields.

• Cases can be created with or without samples, just like in UI and API.

• Once the full batch has been uploaded and no issues are identified, the cases will be created and analysis will begin.

• Up to 50 cases can be created at once.

Workbench | Workflow Improvements: IGV desktop integration, finalize case & more

Improved IGV desktop integration

The Emedgene variant page contains an IGV web viewer, which has limited functionality compared to IGV desktop. Some users prefer to work in a dual screen set up, with IGV desktop open on a second screen.

Emedgene has an existing IGV desktop API integration for users who start from VCF. In this version, the integration was expanded to users who start from FASTQ or store files in an AWS S3 storage bucket.

By clicking the Load to IGV button, all available BAM/CRAM files will be loaded to the desktop IGV (only if the application is already running), and users can further enhance and customize their viewer.

Case interpretation flow update

Users must select a case interpretation status (confidently solved, likely solved, uncertain, negative) before moving the case status to ‘Finalized’.

Interpretation notes, Gene interpretation and Recommendations are saved even if interpretation status is not selected.

Importantly, finalize case via API remains possible.

Add new case | Create existing gene lists

Increase flexibility to support user workflows by enabling the creation of new gene lists that are identical to existing gene lists from API and UI. This will enable users with a complex and large panel test menu to more accurately manage case creation.

Support for gene lists with up to 10,000 genes

Increase flexibility to support user workflows by enabling the creation of large gene lists. Previous limitation was 900 genes.

Gene lists can be created via API and UI; Very large gene lists (>6700 genes) may return a false error message during creation, despite being successfully created.

New ACMG SNV Scoring!

In order to ease the burden of interpreting Variant of Unknown Significance, we have added a score according to the guidelines in Tavtigian et al., fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines. Hum Mutat. 2020 Oct;41(10):1734-1737 PMCID: .

* The score appears next to the pathogenicity, along with the ruler familiar to users from CNV ACMG calculations.

• Each tag can be edited, and editing will modify the score.

Additional:

• API | New query returns a list of genes and NCBI IDs associated to the case phenotypes using the Phenomeld algorithm. This query will help laboratories meet compliance requirements.

• Variant Interpretation Paragraph - Now supports Catalan, Spanish, Portuguese, and Hebrew symbols.

New Settings

Manage your own S3 credentials

Users (with the Manager and Manage S3 Credentials) can now manage access to Emedgene AWS S3 buckets for Upload & Outputs, under Settings -> Management.

• Users can create up to two access keys.

• When creating a new key, there is only one opportunity to save/copy the access key and settings (warning appears).

• Users can deactivate keys.

Gene Lists | View NCBI ID associated with a gene symbol; Download gene lists with NCBI IDs

The Emedgene pipeline and platform associates NCBI IDs to gene symbols, and preferentially utilizes NCBI IDs throughout the software to alleviate gene list changes due to gene symbol changes or user errors.

In the Management Page, users can view the NCBI IDs associated to the gene symbols within a list and download gene lists with NCBI IDs for review.

Limitations

• The accuracy of the AI Shortlist for the new variants (INS, mtDNA, STR, CNV/SV) depends on the variant calling accuracy. The user should be careful when interpreting these challenging-to-call variants.

• The new callers and visualizations – SMN, ROH, Ploidy, BAF - are only available for users running WGS from FASTQ on Emedgene, with the exception of BAF, which is also available for users running WES from FASTQ on Emedgene.

• To enable the SMN caller on your account please contact Support.

Fixed Issues

• The AI Shortlist typically ignores commonly occurring variants. There is an exception list of common variants known to cause disease. This list was expanded, and now includes:

• SV calling from WES | Updated DRAGEN SV command line for exomes, per DRAGEN recommendations.

• Disabled STR calling from WES | The DRAGEN ExpansionHunter method is only available for WGS.

• Update of the Emedgene UI to use the most updated version of the API, in alignment with the batch uploader and new Add New Case features.

Known Issues

• CNV variants larger than 20 Mbp are not annotated with genes name and effect, these variants are shortlisted by default by the AI Shortlist, but ACMG automation is not applied to them. (Fix planned for v33).

• GRCh37<-->GRCh38 Liftover not available for older components of Network infrastructure, as a result, [Variant Page | Clinical Significance | Networks Classified] may remain erroneously empty while [Variant page | Related cases tab] shows relevant information. Same gap for manually classified variants.

• Zygosity, even when set in extended sharing, may remain blank for older cases. Once you click on a case missing zygosity it will be saved for all future views.

Version 2.19 features improved CNV interpretation capabilities, most notably the ability to add a curated CNV database of chromosomal microarray results. We’ve also enhanced variant visualization, expanded Preset filter capabilities, and added the ability to reflex Case Type up to a broader testing option.

• Add your curated CNV database

You can now upload your own curated CNV database, even using historical microarray data. The data can be accessed through a corresponding filter under the Analysis tools > Variant filters in Advanced mode and in the Clinical Significance tab.

• Filter by CNV length

We’ve added a CNV Length filter under the to help you filter out small CNVs that are typically noise.

• Improved visualization

We’ve added gene names to tracks. You can also conveniently expand/collapse transcripts through a new control panel on the right. Stay tuned for more visualization tracks coming soon.

• Reflex case type

You can if the results of more targeted testing are inconclusive. You may reflex from Custom Panel to Exome or Genome, or from Exome to Genome.

To do this, you should change the Case type in flow, thereby rerunning the broader analysis.

• Preset filters by test type

Everyone’s favorite feature, Preset filters, is getting an upgrade. You can now create different Preset filters for each of your test types. We hope this will streamline analysis and save you lots of time.

• Enhanced reporting

Are you using our slick new customizable reporting module? We now support all test types AND all variant types. Let us know if you’d like a demo.

• Support Help Center

Our live support knowledge base is finally here! If you’re looking for clarifications we’ve loaded answers to our most frequently asked questions, and we will continue to add articles on a weekly basis. You can also conveniently chat with the support team or send us a message.

Support and the new Help Center are accessible at all times via the question mark icon on the platform top bar.

Updates (August 25th 2022)

• Support for DRAGEN 3.10 (support for Graph coming in 5.30)

• Automated ACMG/ClinGen CNV classification

The ACMG CNV classification wizard automatically scores sections 1, 2, 3, and partially - sections 4 and 5 of the guidelines, including the full PVS1 calculation needed for intragenic variants. It also summarizes all of the pertinent CNV data in an accessible table.

To view the automated classification, simply tag a variant.

According to a small study we ran (ASHG 2020 abstract), the tool is highly accurate and saves 75-90% of manual review time. Check out a detailed demo on our webinar.

• Enhancements to Case Interpretation & Reporting

When on Emedgene, you’ve always been able to specify whether the case was confidently solved or not and select the solving variant.

Now we’ve added three additional fields for case finalization notes - Interpretation Notes, Gene Interpretation and Recommendations. This data is saved per case. If you’re using our brand new customizable and editable reporting solution, the fields will automatically populate in the report.

For finalized cases, you can view the Case Result, Interpretation Notes and Finalized Variants in a new Finalize tab in the righthand panel of the webpage. Alternatively, to see the variants that were selected while signing off the case, select Finalized in the dropdown onthe .

• View lab coverage data by gene list

You’ve always been able to by gene. This version also allows you to search by any of your gene lists - streamlining quality review for gene lists applied on the fly.

Simply click the Add Gene List button and select any of your pre-loaded gene lists.

• Okta Identity Management

The Emedgene platform now utilizes the solution to control user access. This improves user management, enhances access and authentication security, and allows organizations to implement single sign-on for their users. Transitioning to Okta is a prerequisite for getting access to version 2.16.

1. Unified workflow for GRCh38 & GRCh37

2. Cases tab: new design and functionality

Unified workflow for GRCh38 & GRCh37

With gnomAD no longer releasing GRCh37 versions, we expect increased lab transitions to GRCh38. We have incorporated the two most requested GRCh38 features in this release, thus offering you complete support for GRCh38:

• A totally unified workflow for tests running on different in the same organization.

• A solution for historical data. Curated and historical data are automatically lifted over on the fly and made available as you perform your analysis (in either reference).

Cases tab: new design and functionality

The has a brand new design, but more importantly - a new feature set:

• cases by Case Status,

• refined case ,

• effortless ,

Release Highlights

2. - New self-serve features available to customers

Emedgene users can select their preferred version out of any of the past 5 releases. Customers on v29.0 should select an upgrade path at this time.

The software release includes the following components, which can be selected independently:

• Platform 33

• Pipeline 33

Pipeline: Support for DRAGEN 4.2 Release

All supported DRAGEN callers can now be run with DRAGEN 4.2, for customers starting from FASTQ or VCF.

DRAGEN 4.2 includes enhanced multigenome (graph) reference and Machine Learning (ML) models that improve small variant calling accuracy. Emedgene supports the new graph and ML while maintaining backward compatibility for customers on previous DRAGEN versions.

Improved CNV calling accuracy achieved through joint CNV/SV detection is available for customers starting from VCF (FASTQ support coming in 34.0). In order to minimize duplication, SV variants that are not merged with CNVs are removed from the CNV_SV VCF, and are ingested separately via the SV VCF.

Supported DRAGEN 4.2 outputs in 33.0:

Limitations

• Discrepancies between DRAGEN callers supported from VCF and FASTQ, where some are only supported from FASTQ and some from VCF, will be addressed in Emedgene 34.0 (Q4 23).

• Not all DRAGEN 4.2 callers are supported.

• High sensitivity caller will be supported in 34.0.

Platform: Organization Settings. New self-serve features available to customers

A new Organization Settings page will enable customers to progressively control their organization settings without requesting ILMN support. To access the page: Click on the user initials or profile picture > > Organization Settings.

In 33.0 we’ve added the following self-serve capabilities:

i. Select your own URLs from the available URLs in your domain

Customers on ILMN clouds can now select their preferred URLs. It takes 1-15 minutes for URL changes to go live.

ii. Select a platform version for your organization from officially released versions

This feature is available for both Emedgene and Illumina cloud users. It takes 1-15 minutes for changes to go live.

Note:

1. This is available only on 33.0 and up. If you select a previous version the feature will disappear from your organization settings, and you will need to contact support to change platform versions.

2. Note that this will not change your pipeline version, only the software platform. To change a pipeline version please contact .

iii. Set your own case identifier to display on the case and variant page

Emedgene by default displays the EMGXXXXXXXXX case identifier. Customers can now choose to display the proband ID instead. The proband ID has a visible 13-character limitation, and the remaining characters will be visible on hover.

Candidate page displaying a proband ID:

Variant page displaying a proband ID:

Each of these new features requires a unique . Contact your support team or to add these roles to your organization.

IV. Improved BED validation errors

When attaching a BED file to a kit in the Management tab, the system will generate clear and actionable error messages for any exceptions that may occur.

Limitations

• Proband ID field is limited to 13 characters.

• Changing a preferred URL or a platform version takes 1-15 minutes to go live.

Platform: Workflow enhancements

Support for ACMG Secondary Findings v3.2

The gene list has been updated in both the XAI and the filters.

For the XAI, when a user selects to receive secondary findings, we will apply the v3.2 gene list (requires pipeline 33).

The has also been updated to this new list of 81 genes.

Edit a case label after case creation from the UI

can now be edited after case creation through the UI in the , in addition to the existing capability via the API. This is -based, please contact your support team or to add these to your organization.

New export capabilities

• Added CNV annotations to the mini VCF – Emedgene produces a lightly annotated VCF that is available for customers to for every case. In this version the following CNV annotations were added to this file: decipher_sv, dgv_sv, GnomAD_SV, clinvar_benign_sv, clinvar_uncertain_sv, clinvar_pathogenic_sv, clingen_benign, clingen_uncertain, clingen_pathogenic and DDD (requires pipeline 33).

• Export/report on the gene list associated with the case HPO terms. This gene list is produced with the Phenomeld phenotypic match algorithm. The capability was added in 32.0 but now customers can include the gene list in their report.

Limitations

• Analysis Tools | Sort by phenomatch score and tags is not yet available

• Curate | Some HGVS p-values not accepted yet, discrepancy between Curate and Analyze

Fixed issues

• ClinVar sanity check fails case if there are no known variants in ChrY with wrong message. Cases will still fail but with the correct error message.

• Variant Page | Fixed an issue where a manually added transcript would display twice.

• Analysis Table | Filters | Polymorphism Filters | Fixed an issue where a filter was mislabeled Het or Het Count instead of Allele Count. No variants were missed due to this mislabeling, as the Allele Count filter is more inclusive.

Known issues

• Organization Settings | Set mandatory fields - does not work from the UI. Please contact support if you’d like to configure these fields for your account.

• Gene Lists | Very large gene lists (>6700 genes) may return a false error message during creation, despite being successfully created.

• Visualization is not supported for users storing VCF and CRAM on ICA V1 and BSSH. Only VCF and BAM are supported.

V32.4 hotfix released for the following issues:

• Add New Case | Storage | Fixed a timeout issue retrieving BSSH projects for customers with very large numbers of projects.

• Pipeline | Fixed an issue that caused variants with GT = “.” to be displayed as Hemizygotes on the user interface.

• AI | Fixed a limitation of the AI with processing variants with large ClinVar annotations.

V32.3 hotfix released for the following issues:

• Add New Case | NovaseqX added to selectable sequencers.

• Cases Page | A search on this page will only search for EMG ID, sample names, or any string in the test data. This fix will improve performance.

• Analysis Tools | Fixed variant count issue for compound heterozygous filters caused by using a single source for what is essentially a two-step process. Only count displayed was incorrect.

V32.2 hotfix released for the following issues:

• Performance: Additional updates to increase performance through infrastructure modifications.

V32.1 hotfix released for the following issues:

• Batch Upload | Fixed issue for singleton cases uploaded with batch uploader that resulted in inability to edit cases after creation.

• Batch Upload | Fixed issue causing Not Authenticated error for customers with more than 100 BSSH projects.

• Batch Upload | Improved backward compatibility for Gender changed to Sex field (in v33)

1. Smooth Accessioning

   1. File validations are here

   2. New API Schema Validation

Smooth Accessioning

File validations are here

Files get corrupted, lines deleted, missing columns, that’s a fact of the bioinformatics life. We’ve added automatic file validation, so if there is an error with your file you will get a clear and detailed message right away, no support needed! We want to get your files running as soon as possible.

These are the most common error categories we see:

• Extraction of data (reference, columns) has failed

• Gzip file is invalid

• Mismatch of data between samples or patient

New API Schema Validation

We view automation as a critical piece of the lab workflow and want to make it as easy as possible for our customers to automate accessioning via API.

That’s why our new and simplified API comes with Swagger. Swagger is a combination of live API documentation and testing sandbox that allows you to try out your API code before deploying, and identify errors and their origin immediately (and clearly!).

New Variant Types Supported

SV (Del/Dup)

We now support SV Del/Dups called with the DRAGEN Manta SV caller. All the interpretation features available for CNVs are applied to SVs, including our time-saving automated ACMG-ClinGen classification.

Compound Heterozygote with CNVs

We’ve updated our compound heterozygote algorithm and it now considers CNV deletions, CNV intra-genic duplications and SNVs. You can access the results through the filtering - whether ad hoc or presets.

We hope these features will help you solve more patient cases!

Workflow Automations

Emedgene Curate keeps getting better

You can now import an existing curated variant interpretation into your case workflow, and populate it to a report with a single click if you are using our reporting system.

Panel Workflow Improvement - Hide Gene List

We’ll be gradually improving the panel interpretation workflow. For this version, we added a ‘Hide Gene List’ capability from both the API and UI.

Most labs work with hundreds of pre-defined gene lists, most often created via the API. Then, when creating a gene list on the fly for a specific test, it can be hard to find and apply it from the UI.

Hide gene list allows you to hide your pre-defined panels, so that the UI can be utilized for applying gene lists on the fly. Users with the relevant will have control of whether a gene list is hidden or exposed.

Genome runtimes reduced to support rWGS

For those of you running from FASTQ, a genome trio now runs in under 7 hours. Don’t forget the output is a highly accurate AI Shortlist - with evidence! - that reduces time-to-preliminary-report to a few minutes in cases solvable with SNV/Indels.

1. New CNV Analysis Tools:

   1. New Gene Filters: LoF Genes, Established HI/TS Genes

   2. New Quality Filter: Bin Count

2. :

New CNV Analysis Tools

New Gene Filters: LoF Genes, Established HI/TS Genes

Two new CNV filters will help you focus on the genes that are most likely to be pathogenic:

• LoF Genes will present all genes with a gnomAD pLI≥0.9;

• Established HI/TS Genes filter will only return variants genes with an HI/TS score of 3.

Both are available under and can be added to your preset filters.

New Quality Filter: Bin Count

If you’d like to focus on high-quality CNVs, you can now set a minimum bin count of 1, 5, 10, 25, 50, 100 or 500 in CNV Bin Count filter. The filter appears under in Advanced mode.

Extended CNV Quality Metrics

for CNVs got updated! For each sample, you can now see copy number, CNV quality, size, and bin count.

UI & Workflow Improvements

Variant page redesign: brand new Summary tab and updated Quality tab

The now features a clear that spotlights essential variant information - saving you precious clicks! If after the first glance you feel like diving deeper into the variant details - proceed to other Variant page tabs below.

We redesigned : it has a slightly different style,

To change the sample in review for the particular variant, click on the corresponding icon in the family tree.

If you've read this far, here is a bonus insider tip! 🤫

Did you know that you can view the for any tagged variant? We redesigned the See evidence button on the to make it pop!

Variant type filter & column

Piping hot at your command! Ready to filter variants by type (SNV, Indel, DEL, DUP). Additionally, variant type is shown in the variant table.

Full control over your gene lists

Administrators of your account now have total control over and can create and edit them in .

Restricted access to Finalized Case status

The Finalized locks the case to prevent further changes to interpretation notes, ACMG tags, variant tags, pathogenicity and case-level interpretations.

Starting from this version, access to requires a dedicated , so the organization's manager can restrict access to a specific set of users.

1. mtDNA variants are here!

   1. mtDNA variant callers

   2. mtDNA variant filter

mtDNA variants are here! ✨

You can now on the Emedgene platform, using a streamlined workflow that makes it easy to focus your analysis on the clinically meaningful variants.

mtDNA variant callers

• Our secondary analysis pipeline uses and leverages improved quality metrics to help reduce the number of variants for review,

• We also support VCF files from , , and .

mtDNA variant filter

You can focus on mtDNA variants by using the updated mtDNA filter in the . The filter can be added to your custom presets.

mtDNA variant annotation

The and reflect basic mtDNA variant annotations including:

• genes,

• transcripts,

• population annotations (gnomAD and ),

mtDNA variant classification

The ACMG SNV Classification wizard is now . It utilizes only relevant ACMG criteria and automatically defines the resulting ACMG class based on the manually assigned criteria.

Related cases

is a new tab of the that highlights information on previous variant curation activity (i.e., assigning a and/or assigning Pathogenicity and/or adding Variant Interpretation notes).

Stay tuned for the curated data sharing between partner organizations!

Add virtual variants

You can now not present in the VCF or not called from FASTQ to your case. This is useful when:

• you need to complement NGS with data from other genetic tests (long-read sequencing, optical mapping, CGH, SNP array, karyotyping/FISH, repeat-primed PCR, MLPA, Southern blot, etc);

• you want to report a few adjacent variants as a single multi-nucleotide variant.

Supported variant types are SNV, CNV, UPD, ROH, and STR. SV is coming soon!

CNV calling from exomes

We now support using DRAGEN. High precision and recall are achieved through a lab-optimized panel of normals (PON). Results vary per laboratory/sample preparation protocol, and validation is performed upon request.

Visualize variants from a VCF

The now includes a Test Subject VCF track presenting proband's variants stored in the VCF file.

1. New Variant Types Supported

   1. SV Insertions

   2. STR Improvements

New Variant Types Supported

SV Insertions

Emedgene now supports calling and interpretation of SV insertions called by the DRAGEN Manta SV caller.

Calling:

The DRAGEN Manta SV caller detects simple insertion/deletion events , and detects both fully-assembled and partially-assembled (inferred) insertions. Minimum size of SV insertion is 50bp. Indels smaller than 50bp are called by the regular SNV caller and annotated as SNV.

Known caller limitations:

• The maximum fully-assembled insertion size should correspond to approximately twice the read-pair fragment size, but note that power to fully assemble the insertion should fall off to impractical levels before this size.

• Note that Manta does detect and report very large insertions when the breakend signature of such an event is found, even though the inserted sequence cannot be fully assembled.

• In the case of partial assembled insertions, the size of the variant displayed does not reflect its true size.

Note that for customers bringing their own DRAGEN pipeline into Emedgene, specific VCF headers in the SV file need to be added before sample ingestion. Contact support for more information.

Annotation:

SV insertions are annotated with gnomAD SV and ClinVar SV data, for population frequencies and known pathogenicity. Insertion annotation is performed on the basis of the insertion start position; the sequencing content is not considered.

Interpretation:

Variant page and analysis tools have been adapted to support SV insertions.

• Variant type will be clearly marked in the header

• New filters added for filtering SV insertions, quality filtering for both length and bin count can be applied (see remark above regarding the INS size).

STR Improvements

• New pathogenicity filter

• Allele frequency is now viewable in the proprietary STR visualization

Summary Table of Variant Types Supported by Test Type and Version

New Visualization Tracks

Curated Data Tracks

You can now add ClinVar and ClinVar SV tracks to the in-platform visualization. Pathogenicity corresponds to the ClinVar color scheme, with black denoting a conflict.

BigWig Track for CNV Visualization

BigWig visualization is now available for WGS cases, specifically the tangent normalized signal points view. This visualization helps interpret CNVs by clearly showing the bins and breakpoints.

For customers bringing their own DRAGEN output, a VCF and BigWig data can be shared via the API and batch upload tool.

These new tracks are available in both simple and advanced modes, allowing you to configure the visualization tab as needed.

Additional

A known mtDNA visualization discrepancy on GRCh37 was fixed in this version.

As always, we support synchronization with IGV desktop, and all settings in the platform can be mirrored to the IGV desktop environment which continuously displays the current selected variant data.

Emedgene Curate + CNVs

CNVs are now supported in Emedgene Curate! Including streamlined annotation and analysis flow integration, all the way through to auto-populating report template fields.

• Add a CNV variant directly to Emedgene Curate, or import during your case analysis;

• Search for a CNV by range, type or gene;

• Variant header, info card and gene’s related disease components have been adapted for CNVs;

• In your Curate navigation, you will notice a new column denoting Variant Type. For labs with enabled private networks, the icon will denote pathogenicity by color, with a hover showing more details.

Additionally:

• Once you have curated a CNV variant, all future cases including in your private network if enabled, will be annotated with your data.

• Once a variant is reviewed, curated data can be imported and used to automatically populate a report template field.

Additional new features

Gene-related disease card update

The gene-related disease has always shown a numeric summary of phenotypic match, for patient phenotypes found in the disease out of all patient phenotypes.

This card now shows a numerical match between patient phenotypes and disease phenotypes. The full list of disease phenotypes is displayed, with the phenotypic match strength for each. A link to the full list of patient phenotypes will open the side car for an easy view and comparison.*

Edit interpretation summary

Edit the interpretation summary at the top of the page, in addition to the edit capability in the evidence tab.*

*Note that both of these new capabilities are only available for variants tagged by the AI Shortlist or users as most likely or candidates.

Variant page sidecar redesign

The variant page sidecar has been redesigned.

• Includes a default view:

  • Sample names of proband and family members.

  • Proband phenotypes, and family if available

Enhancement to Analysis Table

In the analysis tools, the known variant column colors had previously ignored VUS (variants of unknown significance) classifications if appearing in conjunction with P/LP or B/LB.

This has now been updated and if a variant has both P/LP and VUS classifications or B/LB and VUS classification, the appropriate mixed colors will appear.

If a variant has conflicting classifications it will appear in black.

Lab Page Enhancement

For labs using the Emedgene DRAGEN pipeline, QC metrics are now available for download.

ACMG 78

Updated filters to support full ACMG 78 gene list.

This update follows the latest recommendation from ACMG for reporting secondary findings: .

Expose input file errors

The majority of case pipeline failures are due to errors in customer input files. We now expose explicit and detailed input file errors on the cases page.