New Geneyx Analysis Features:  

ACMG Guidelines for CNV/SVs: The CNV/SV tab now supports the technical standards for reporting of constitutional copy number variants according to the joint consensus recommendations of ACMG and ClinGen, reference article here https://pubmed.ncbi.nlm.nih.gov/31690835. ACMG guidelines will be calculated automatically for all deletion and duplication events and there is an interface to modify criteria using internal evidence. The interface reflects a similar approach as the ClinGen CNV calculator with full transparency of activated or inactivated criteria, as well as audit trails for all actions implemented. This will drastically improve CNV interpretation times and aid in workflow automation.

Somatic Databases: Clinical trials from clinicaltrials.gov are now accessible on the gene level as a hyperlink. This will enable users to perform quick searches for FDA trials that correlate to the gene.  

DRAGEN version selection: Users now have the option to select what version of DRAGEN is being utilized for the secondary pipeline. The baseline DRAGEN version will remain v4.0.5. This option will allow users to conform to their existing workflows whilst enabling the exploration of updated DRAGEN features. The optional DRAGEN version (4.2.4) enables several additional features, discussed below, including advanced callers and low pass whole genome options. For upgrading to the newest Dragen caller, please reach out to our support (support@geneyx.com). *Please be aware that over time DRAGEN v4.0.5 will be deprecated.

DRAGEN v4.2.4: The comprehensive updates included in DRAGEN v4.2.4 can be found here. At a high level, this update includes improvements to small variant calling at high depths for WGS (>100X), High sensitivity mode results in increased sensitivity for reads with low MAPQ and low allele frequency (mosaic variants), Joint CNV/SV signal improves CNV detection for events ranging from 1-10kbp.

Advanced DRAGEN Callers: When running whole genome workflows from the secondary pipeline, there are new sequence-graph realignment settings that run on the backend to improve calling for genes that have high identity paralogs. This includes genes such as: GBA, SMN1, HBA, LPA, RH, CYP2D6, CYP21A2, CYP2B6. For analyses that have whole genome workflows with at least 30X coverage, output metrics for these genes will be present in the Advanced Analysis link in the “Info” section of the analysis. All outputs are taken from Illumina and each output will reference the associated hyperlink.  

DRAGEN Low pass whole genome sequencing: Low-pass whole genome sequencing (low-pass WGS) is a genomic sequencing approach where the entire genome is sequenced at a relatively low depth, typically less than 5x coverage. Low pass whole genome sequencing is now supported in the secondary pipeline of Geneyx. To implement, the sequencing target will need to be set to Whole Genome Low Pass.

BIRD/OCEAN Pipeline: Results from DNA and RNA analyses are critical for advancing our understanding of genetics and molecular biology, leading to improved diagnostics, therapeutics, and insights into the fundamental biology of organisms. Geneyx has partnered with OCEAN Genomics to advance the DNA and RNA joint pipeline. This feature will be available upon request. For more details contact support@geneyx.com.  

Microarray to VCF Converter: For customers that have microarray data, such as those from Affymetrix, Geneyx now provides a script to convert the file into a compatible VCF format. The script is available here, https://github.com/geneyx/geneyx.analysis.api/tree/main/apps/microarray. The converted files can then be loaded into the CNV/SV genetic model of Geneyx. Users can also select this as a sequencing target during data upload.  

Let’s Help You Transition from Agilent Alissa to Geneyx

Geneyx Analysis Updates:  

GnomAD v4.0: The v4 data set includes data from 807,162 individuals, including 730,947 exomes and 76,215 genomes, all mapped to the GRCh38 reference sequence. This release is nearly 5x larger than the combined v2/v3 releases and adds additional global diversity including nearly 138,000 individuals of non-European genetic ancestry. This annotation is only available for GRCh38-based analyses.  

SnpEff v5.2c: SnpEff is the genetic variant annotation, and functional effect prediction toolbox that is used to annotate and predict the effects of genetic variants on genes and proteins (such as amino acid changes). This has been updated to the latest version (5.2c) and will improve HGVS nomenclature and adhere to CAP Guidelines for variant naming conventions.  

ACMG Criteria: PS4-This criterion is now activated when the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. This logic will be activated when the variant is rare in allele frequency databases and has been classified as Likely Pathogenic or Pathogenic by 10 reviewers. PP5- This criterion is now activated when ClinVar classification is conflicting if there is greater than 8 submissions of LP/P in ClinVar.  

Copy Analysis Feature Improvement: When a user creates a copy of analysis, there is now an option to include the annotations and audits performed on the previous case This will prevent the need to reanalyze the sample from scratch and maintain previous records of the case.  

Local Variant Popup for CNV/SV: The local variant dialog for CNV/SVs will now display the sequencing target for the matching event. This will improve transparency for case comparisons.

Google Search Function: Geneyx now supports the ability to easily search for the variant in google with a useful hyperlink output. This can then be used for other downstream purposes and aims to enhance searching functionalities.  

ClinVar Review Status Filter: One of the key features of ClinVar is its review status for each variant, which indicates the level of evidence and consensus supporting the clinical significance of the variant. The review status of ClinVar submissions is now a separate column that can also be filtered on.  

ClinGen Variant Curated Expert Panels: ClinGen (Clinical Genome Resource) defines the clinical relevance of genes and variants and the ClinGen Variant Curation Expert Panels (VCEPs) play a crucial role in this process by providing expert evaluation of genetic variants to determine their clinical significance. This information is now available on the Gene dialogue.

Digenic Inheritance: Digenic inheritance refers to a mode of genetic inheritance in which two genes contribute jointly to the phenotype, meaning that variations in both genes are necessary to produce a specific trait or disease. Unlike classical Mendelian inheritance, where a single gene mutation is typically responsible for a disorder, digenic inheritance involves the interaction between mutations in two different genes. If a gene is associated with a phenotype with digenic inheritance, the second gene will be displayed in the Genes tab of the application with associated phenotype.  

VUS Monitor: The VUS Monitor will now be updated with all annotated variants classified as VUS from the previous version. Additionally, current variants in the VUS Monitor dialog will be refreshed with the latest version of annotation sources. 

We are excited to announce the release of Geneyx 6.0, a significant update that brings advanced features and enhancements to our comprehensive genomic analysis platform. This version introduces improved algorithms for variant detection and annotation, offering increased accuracy and speed. Enhanced integration with external databases provides seamless access to the latest genetic information. The user interface has been refined for a more intuitive experience, and new visualization tools have been added to simplify data interpretation. Additionally, Geneyx 6.0 includes expanded support for multi-omic data, enabling more holistic insights into genetic research and clinical diagnostics. These updates underscore our commitment to providing cutting-edge tools for geneticists and clinicians, empowering them to make more informed decisions and drive advancements in precision medicine. 

All the best,

Eli Sward, PhD. and Suzie Drury, PhD. (FAS at Geneyx)

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