Current product limitations¶
The Rare Disease DSS is an evolving product, undergoing continuous development and improvement (as per best practice) based on user feedback and emerging service requirements. Initial focus was placed on supporting the end-to-end interpretation of small variants. The remaining functionality, required for end-to-end interpretation of all GMS cases, is therefore not yet available, but is earmarked for future releases (you can check our roadmap and tell us what is important to you).
Existing limitations of the Rare Disease DSS are listed below:
| Limitation | Impact | Workaround |
|---|---|---|
| The Rare Disease DSS only displays non-PASS STRs that are green in the applied panels. Other non-PASS STRs are not displayed, neither are STR loci that are not part of the GMS. | This is an improvement upon the Interpretation Portal, which doesn't display non-PASS STRs that are green in the applied panels. | No real workaround required as there is no routine requirement to look at the other non-PASS STRs, or loci that are not part of the GMS. If required, the VCF can be downloaded from the Interpretation Portal in order to look at the other non-PASS STRs. |
| Cases with Tiered STRs that became available for review in the IP before v4.3.0 of the Rare Disease DSS are not available in the Rare Disease DSS.. This is because earlier versions of the product did not support cases with Tiered STRs (~23% of GMS cases), therefore those cases were not dispatched to the Rare Disease DSS at the time. | These cases will not have an active (blue) Rare Disease DSS button in the Interpretation Portal, to indicate that you can’t open them in the Rare Disease DSS for analysis. | Continue to analyse these unsupported cases via existing products, including for reporting of any Tier Null STRs. These continue to require analysis via the Interpretation Portal. |
| Cases with Tiered CNVs that became available for review in the IP before v4.2.0 of the Rare Disease DSS are not available in the Rare Disease DSS.. This is because earlier versions of the product did not support cases with Tiered CNVs (~59% of GMS cases), therefore those cases were not dispatched to the Rare Disease DSS. | These cases will not have an active (blue) Rare Disease DSS button in the Interpretation Portal, to indicate that you can’t open them in the Rare Disease DSS for analysis. | Continue to analyse these unsupported cases via existing products. |
| Cases processed by the pipeline prior to the 4.3 Rare Disease DSS release will continue to display CNVs as Tier A / Tier B instead of Tier 1 / Tier 2 | This has no material impact, as Tier A CNVs are equivalent to Tier 1, and Tier B equivalent to Tier 2 | Analyse cases bearing in mind that in older cases CNVs will appear as Tier A/B instead of 1/2 |
| CVA only supports SNVs, but both SNVs, CNVs and STRs go to the summary of findings | Variant interpretations for CNVs and STRs will not be sent to CVA, so it is not possible to see how a variant has been classified previously in the GMS. | No workaround. |
| Case-level information (e.g. panel coverage, BAF plots, Summary of Findings) and raw sequencing files (VCFs) for the case are not yet supported in the Rare Disease DSS. | You won't be able to see the gene panel coverage data, BAF plots and download VCFs for the case in the Rare Disease DSS | Continue to use the Interpretation Portal to review coverage and BAF data, or download raw sequencing files. |
| Filters are now supported for SNVs and CNVs, but there is no ability to save preset filters. | Lack of preset filters means more time required to manually select filters at the start of case analysis, if the GEL default filters are not sufficient. | There is currently no work-around for this, beyond manual selection of filters when analysing each case. |
| Basic support for Compound Heterozygous (CompHets) variants. | There is minimal visual indication for compound heterozygous variants within the product - only SNVs are indicated. | Use the Segregation, inheritance and penetrance column, or the Tier overlay, to identify compound heterozygous SNVs, which show CompHet (N.B. segregation/inheritance/penetrance groupings in this column come from the Tiering events for the variant - groupings from Exomiser are not displayed here, and untiered variants will not have any data present in this column). Currently, no indication is provided in the product for compound heterozygous CNVs, and for STRs this can only be seen in the Tier overlay. It is recommended to use the Interpretation Browser to identify compound heterozygous groups. Improvements to CompHets are in our roadmap. |
| Variant segregation and inheritance annotations are only available for variants considered by Tiering and Exomiser. | The Segregation, inheritance and penetrance column will be empty for variants that were not part of the Interpreted Genome. | Use the zygosity columns and IGV to infer inheritance, if you are reviewing a variant outside the core set of variants mandated for review. |
| Explanation for non-PASS variant status is not provided. | You will be able to see that a variant is non-PASS, with the Dragen QC filter shown, but you won’t know why it failed QC. | Consult the Dragen user guide to understand what the QC status refers to, if you’re reviewing any non-PASS SNV. This is not yet in our roadmap, but tell us if it is important to you. |
| Case list and email notification for ready cases in the Rare Disease DSS are not yet available. | You won’t see a list of cases in the Rare Disease DSS, and can only open up specific cases, via the Interpretation Portal. | Start your interpretation journey by selecting cases to analyse via the Interpretation Portal. The case list will be ported over from IP into the Rare Disease DSS at a future stage (undefined currently). We will engage with you to understand you needs when the time comes. |
| There is currently no direct link-out to previous versions of the case after a case has been reprocessed for re-analysis. | If you do not make a direct note of the URL for the case, then there will be no way for you to access the previous version of the case. | Make a note of the URL for the case that you have analysed, as it will be accessible directly via the URL in the browser. Alternatively, please open a Service Desk ticket if you need to locate a case and you do not have a note of the URL. Link-outs to previous versions of the case will be provided as a new feature in version 5.1 of the product. |
The above limitations are included in the Clinical Safety Case Report for the Rare Disease DSS, Hazard Log (DCB 0129) and our internal Risk Registry. All documents are available upon request.
The Rare Disease DSS is currently available alongside the existing RD Interpretation products and workflows; these remain unchanged for the time being. Existing systems can therefore still be used as pathway for analysis or used as failsafe.
Abbreviations
| Abbreviation | Definition |
|---|---|
| ACGS | Association for Clinical Genomic Science |
| ACMG | American College of Medical Genetics and Genomics |
| CDS | Coding DNA Sequence |
| CIP-API | Genomics England Clinical Interpretation API |
| CNV | Copy Number Variant |
| CVA | Clinical Variant Ark |
| EQ | Exit Questionnaire |
| RDDSS | Rare Disease Decision Support System |
| GEL | Genomics England |
| GMS | Genomic Medicine Service |
| GLH | Genomic Laboratory Hub |
| HGVS | Human Genome Variation Society |
| HTML | Hyper Text Markup Language |
| HSCN | Health and Social Care Network (N3) |
| IGV | Integrative Genomics Viewer |
| IB | Interpretation Browser |
| IP | Interpretation Portal |
| NGIS | National Genomics Informatics System |
| PID | Patient Identifiable Data |
| QC | Quality Control |
| SoF | Summary of Findings |
| SO | Sequence Ontology |
| SNV | Single Nucleotide Variant |
| SV | Structural Variant |
| TOMS | Test Order Management System |
| UAT | User Acceptance Testing |
| VCF | Variant Call Format File |
| VILs | Variant Interpretation Logs |
| WGS | Whole Genome Sequencing |