Evaluating Copy Number Variants with VSClinical's New ACMG Guideline Workflow
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The document describes funding that supported research conducted by Golden Helix. It lists several National Institute of General Medical Sciences grant numbers that supported the work. The principal investigator for the grants is named as Dr. Andreas Scherer, CEO of Golden Helix. It is noted that the content of any research supported by this funding is solely the responsibility of the authors and does not necessarily represent the views of the National Institutes of Health.
Evaluating Copy Number Variants with VSClinical's New ACMG Guideline Workflow
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- 2. NIH Grant Funding Acknowledgments 2 • Research reported in this publication was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under: o Award Number R43GM128485-01 o Award Number R43GM128485-02 o Award Number 2R44 GM125432-01 o Award Number 2R44 GM125432-02 o Montana SMIR/STTR Matching Funds Program Grant Agreement Number 19-51-RCSBIR-005 • PI is Dr. Andreas Scherer, CEO of Golden Helix. • The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
- 3. Who Are We? 3 Golden Helix is a global bioinformatics company founded in 1998
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- 7. VS-CNV: Power of NGS CNV Detection • One single testing paradigm • True simplification of clinical workflow • Saves time and money – all on site Small: 150bp+ Medium: 1 – 10Kb Large: 10Kb+ Gene Panel Whole Exome Whole Genome MLPA ✓ ✓ CMA ✓ ✓ VS-CNV ✓ ✓ ✓ ✓ ✓ ✓ 7 Detectable Events Supported Data Types 7
- 8. VS-CNV: 225+ Users and 15+ Publications 8 • Journals o Atherosclerosis o Journal of Clinical Lipidology o American Journal of Medical Genetics o BMC Medical Genomics o Medicine • Analysis Topics o Hypercholesterolemia o Retinal dystrophy o Pituitary hormone deficiency o Rare Mendelian disorders • Lacocca et al. o Whole exome CNV detection comparison o 100% concordance between MLPA and VSCNV o Improves resources, cost, analysis time
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- 10. New ACMG and ClinGen Guidelines 10 For the Interpretation of Copy Number Variants • Provides much needed framework for evaluation of small CNVs detected in gene panels • High level overview of CNV scoring system o Complex, 5 pages table with ~80 distinct criteria codes o Scoring system with criteria broken down into 5 sections • We designed a comprehensive workflow to score, classify, interpret and report CNVs following these guidelines Riggs ER, Andersen EF, Cherry AM, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020;22(2):245-257. doi:10.1038/s41436-019-0686-8 https://clinicalgenome.org/
- 11. CNV Guidelines Components 11 1 Genomic content of the gene: overlap protein coding genes 2 Overlaps known haploinsufficient genes or triplosensitive regions: ClinGen 3 Assigns points to CNVs overlapping a large number of genes Five Sections of the scoring system 4 5 Patient disorder and inheritance alignment to what is known for the gene Peer-reviewed publications and/or internal data; Phenotype and Inheritance
- 12. 12 Have you ever had to interpret a gene with limited evidence of pathogenicity: a gene without dosage sensitivity information or uncertain significance? Audience Poll
- 13. CNV Guidelines Components 13 Phenotype Specificity • Specificity of the patient’s phenotype and association with gene of interest • Generic phenotypes do not offer strong evidence • Important for novel genes
- 14. Section 4: Literature Consideration 14 • Individual/family evidence or case-control data • CNV deletion~LOF variants • Is the Phenotype consistent with what is expected for the gene? • Is the inheritance status known? o De novo or inherited (confirmed or assumed) • Confirmed Parental Relationships? • Segregation (Section 4F-H) o Proband is only affected individual or variant segregates; OR o Variant is absent in another affected individual and does not segregate • Phenotype specificity (highly specific or not)
- 15. Example: 12:27715514-29628122x1 15 • Shortening of the digits, mainly in the metacarpals (III-V) and metatarsals • Brachydactyly Type E yields 4 results (rare) • Given the limited heterogeneity, this is classified as “a highly specific, but not necessarily unique “phenotype • Overlaps 10 genes, PTHLH shows low evidence for dosage sensitivity PTHLH and Autosomal Dominant Brachydactyly Type E (BDE) David et al. (2015). Diagnostic and Interventional Imaging 96(5):443-448
- 16. Example: De Novo Variant 16 • PMID: 26640227 • c.101+3delAAGT • Influences donor splice site predicted to lead to premature stop codon • Female proband with no reported family history • Parental relationships were not confirmed • Highly specific but not necessarily unique phenotype represents moderate level of evidence (4B)
- 17. Example: Variants of Unknown Inheritance 17 • PMID: 20170896 • One individual with heterozygous nonsense variant (p.K120X) • Located more than 50bp away from the 3’ boundary of the second-to-last exon, expected to undergo NMD • Individual presented with Barchydactyly type • Affected sister and nephew,, unclear if tested • Parental testing was not performed
- 18. Example: Segregation Among Family Members 18 • PMID: 26763883 • p.N87Tfs*18 • Female proband with BDE • Sister and father were also reported to be affected • Tested positive for same mutation • Mother and paternal aunt unaffected • Segregations counted= 2
- 19. Example: Project Demonstration 19 • Start with Clinical Notes to identify phenotypes and disorders • Create a list of genes relevant for testing • Determine evidence for Section 2 and 3 • Move into Section 4 to incorporate literature publications • De novo variant • Variant of unknown inheritance • Segregation • Use this information to determine final classification • Render ACMG CNV clinical report
- 21. 21 Inc 5000 Recognition Golden Helix was named to the 2020 Inc 5000 List of Fastest-Growing Private Companies • Second year in a row receiving this award • Thank you to our customers and partners for our sustained success
- 22. COVID-19 Publications & Articles 22 Investigating the Global Spread of SARS-CoV-2 Leveraging Next-Gen Sequencing and Principal Component Analysis European Journal of Clinical and Biomedical Sciences Christiane Scherer, James Grover, Darby Kammeraad, Gabe Rudy, Andreas Scherer Diagnosing and Tracking COVID-19 Infections Leveraging Next-Gen Sequencing The Journal of Precision Medicine Feature | July 8, 2020 Golden Helix: Enabling Precision Medicine with Cutting- Edge NGS Technologies Clinical OMICs Feature | July 15, 2020 Leveraging Next-Generation Sequencing Technology in the Fight Against COVID-19 Clinical Lab Manager Feature | May 4, 2020 SARS-CoV-2 Global Spreading Investigation using Principal Component Analysis of Sequence Variants Journal of Genetics and Genome Research Christiane Scherer, James Grover, Darby Kammeraad, Gabe Rudy, Andreas Scherer
- 23. 23 ClinGen Requirements Genomic Analysis Software Platforms
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