Next-generation sequencing has transformed clinical diagnostics for rare and single-gene Mendelian disorders. Still, issues of variant annotation, data interpretation, and incidental findings present challenges. Cambridge Healthtech Institute's Inaugural Inherited Disease Diagnostics will tackle the pros and cons of single-gene tests versus whole genome and whole exome sequencing and examine techniques for establishing whether a variant is pathological or non-pathological. In addition to strategies for interpreting clinical data and creating a genomic profile, ethical considerations around incidental findings and prenatal screening will be debated. Finally, experts will weigh in on implementing genetic screening into routine clinical practice.
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NGS Data Analysis – Determining Clinical Utility of Genome Variants
NGS as a Diagnostics Platform
*Separate registration required
TUESDAY, AUGUST 19
7:30 am Main Conference Registration & Morning Coffee
8:30 Chairperson’s Opening Remarks
8:40 KEYNOTE PRESENTATION: We Have the Technology, Now What Happens? Policy, Ethics, And Law Meet Clinical Sequencing
Robert Cook-Deegan, M.D., Research Professor, Institute for Genome Sciences & Policy, Sanford School of Public Policy, Duke University
Sequencing technologies have found their first clinical footholds in oncology, Mendelian disorder diagnostics, and prenatal screening using cell-free fetal DNA. In each area, the technology is a powerful new tool demonstrating clinical impact. In each domain, however, serious policy concerns have emerged. Controversies have flared up through patent litigation; problems in constructing pipelines for interpreting the clinical significance of sequence variants; complications in developing databases constructed for clinical rather than scientific use; privacy, confidentiality, and informed consent; inconsistent policies about who controls and has access to raw data; weak norms over data access and research transparency; and strong disagreement over what and when to convey clinical interpretations of the data to patients and families. Policy needs to catch up. Can we glimpse the road ahead through the fog?
9:10 Use of Exome Sequencing for Genetic Diagnosis: Clinical Experience and Case Examples
Wayne W. Grody, M.D., Ph.D., Professor, Medical Genetics and Molecular Pathology, Pathology & Lab Medicine, Pediatrics, and Human Genetics; Director, Molecular Diagnostic Laboratories and Clinical Genomics Center, UCLA School of Medicine
The advent of massively parallel or next-generation DNA sequencing has finally brought into reach the long-anticipated “Thousand Dollar Genome”, or the ability to sequence an individual’s entire genome at reasonable cost. This presentation will review such aspects as clinical utility, challenges in test interpretation and genetic counseling, return of incidental findings and reimbursement, all within the context of our own experience performing clinical whole-exome sequencing at an academic medical center.
9:40 Disease Causing Potential of Variants in Untranslated Regions
Peter Nagy, Ph.D., Director, Clinical Next-Generation Sequencing Lab; Assistant Professor, Pathology and Cell Biology, Columbia University
Our laboratory offers whole exome sequencing for clinical diagnosis of inherited disorders since the beginning of 2013. Using the Agilent SureSelect v.5 +UTRs kit allows us to capture the UTRs in addition to the coding regions. We currently do not report variants of unknown significance in the UTRs, but we are developing tools to predict the structural and functional consequences of the variants to assess their pathogenic role.
10:10 Coffee Break in the Exhibit Hall with Poster Viewing
10:55 Chairperson’s Remarks
Peter Nagy, Ph.D., Columbia University
11:00 An Integrated Approach to Genome-Wide Variant Analysis in the Pediatric Population
Laura Conlin, Ph.D., FACMG, Scientific Director, Division of Genomic Diagnostics, Children’s Hospital of Philadelphia; Assistant Professor, Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania
With advances in technology, both copy number and point mutations can be detected from genome-wide testing. Taken together, a more comprehensive genetic diagnosis is provided for the patient. This talk will focus on the benefits and challenges related to integrative variant interpretation in the pediatric population.
11:30 Beyond Sanger Confirmation of Genomic Results: The Role of Expert Interpretation, Clinical Correlation, and Collaboration
Carol Saunders, Ph.D., FACMG, Director, Molecular Genetics Laboratory, Department of Pathology & Laboratory Medicine; Associate Professor, Department of Pathology, UMKC School of Medicine, Children’s Mercy Hospital
I will discuss the strategies and assumptions used for interpreting genomic variants in pediatric patients, and how to determine what is diagnostic. Illustrative cases will be presented, including those where such assumptions would backfire.
12:00 pm ClinVar: An Archive of Clinically Relevant Variant-Phenotype Relationships
Melissa J. Landrum, Ph.D., Staff Scientist, NIH/NLM/NCBI
ClinVar is a freely available archive of reports of the relationship between clinically relevant variants and phenotypes, along with supporting evidence. ClinVar aggregates submissions genetic testing labs, research labs, LSDBs, and expert curation groups such that agreement or disagreement in clinical assertions is evident. The data is available on the web for interactive users and as downloadable files that can be incorporated into users’ daily workflows.
12:30 Sponsored Presentation (Opportunity Available)
1:00 Luncheon Presentation: (Sponsorship Opportunity Available)
Speaker to be Announced
1:30 Luncheon Presentation: (Sponsorship Opportunity Available)
2:00 Session Break
2:15 Chairperson’s Remarks
Wayne W. Grody, M.D., Ph.D., UCLA School of Medicine
2:20 Incidental Findings in Genomic Testing
Lora J.H. Bean, Ph.D., F.A.C.M.G., Assistant Professor, Senior Director, Molecular Diagnostic Laboratory, Emory Genetics Laboratory, Human Genetics, Emory University
Clinical sequencing of single genes, gene panels, whole exomes or genomes, and gene-targeted and whole genome array CGH have become important tools in diagnosing genetic conditions in children. The huge amount of data generated by these tests may include unexpected or unwanted clinically relevant findings such as carrier status or diagnostic findings unrelated to the current clinical presentation. Incidental findings from testing performed at Emory Genetics Laboratory will be discussed.
2:50 Incidental Findings, Unwanted Information, and the “Safety” of Genomic Testing
Thomas May, Ph.D., Associate Professor, Bioethics and Medical Humanities; Director, Graduate Program in Bioethics, Center for Bioethics and Medical Humanities, Medical College of Wisconsin
This presentation will examine the different frameworks potentially relevant to assessing the desirability of genomic information, and whether these differences justify recognition of a “right” to genetic ignorance. It will then apply these frameworks to recent ACMG recommendations concerning return of incidental findings to assess the “safety” of genomic testing in contemporary society.
3:20 Sponsored Presentation (Opportunity Available)
3:50 Refreshment Break in the Exhibit Hall with Poster Viewing
4:30 Generating a Comprehensive Genomic Profile Using the High-Performance Integrated Virtual Environment (HIVE)
Raja Mazumder, Ph.D., Associate Professor, Biochemistry and Molecular Biology, George Washington University
The High-performance Integrated Virtual Environment (HIVE) platform provides a means to store, analyze, and compute on the extra-large NGS data. However, generation of mutation profiles is only part of the story and must be followed by functional analysis of the variations if we are to derive biological and clinical meaning from the data. HIVE contains computational tools allowing for exactly this type of variation analysis and therefore serves as a vital tool in attempts to bridge whole genome analysis to disease diagnostics. Comparative analysis of mutation profiles allows better classification, and further comparison across different groups and strata can be used to create phylogenetic trees of the data set samples.
5:00 Interpretation of Clinical Genetic Data in the NGS Era
Sami S. Amr, Ph.D., Instructor, Pathology, Harvard Medical School; Director, PCPGM Research Core; Assistant Director, Lab for Molecular Medicine, Partners Center for Personalized Genetic Medicine
The rapid transition of genetic testing from Sanger sequencing to NGS technologies has paved the way for expanded gene panels as well as exome/genome sequencing. While the influx of genetic data led to increased detection rates for inherited diseases, it has also become a double-edged sword due to interpretative challenges. Standardized variant and gene assessment approaches, coupled with data sharing across diagnostic laboratories, will alleviate the interpretation bottleneck and provide more meaningful genetic results to patients.
5:30 Wine and Cheese Pairing Welcome Reception in the Exhibit Hall with Poster Viewing
6:30 Close of Day
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