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Description:
Germline variants underlie a host of hematologic disorders: inherited neutropenias, anemias, thrombocytopenias, erythrocytosis, thrombophilia, and predisposition to hematopoietic malignancies (HMs). Academic and commercial laboratories offer clinical testing for many of these conditions, but health care providers need to be careful about the precise test(s) being ordered; the capabilities of the test(s); and inherent limitations. Standard molecular profiling of HMs using next-generation sequencing (NGS)-based panel testing of malignant cells performed for diagnostic and prognostic purposes often cannot distinguish somatic from germline alleles. This case-based session will cover genomic sequencing methodologies in clinical use, especially focused on those designed for detection of inherited bone marrow failure and HMs, and the nuances of this testing relevant to the practicing provider. Topics will include: consistent variant interpretation; detection of potential germline alleles from NGS assays performed on malignant cells; and the ethical challenges for clinicians and patients in testing for germline predisposition.
Dr. David Wu will present a case-based discussion of the clinical interpretation of variants identified in testing for hematologic disorders and the current international efforts to provide uniform variant interpretation based on standardized curation rules. Curation of gene variants is the systematic evidenced-based process leading to a designation of clinical significance based on a five-tier system. Unfortunately, increasing numbers of genes variants are classified with uncertain or conflicting classifications. Dr. Wu will explain common NGS testing platforms, their assumptions and capabilities, and how to use current curation guidelines in daily practice to allow for optimal clinical care.
Dr. Lucy A. Godley will explain the complexities of data interpretation when NGS panels are used on blood and bone marrow samples, especially regarding the identification of somatic variants/clonal hematopoiesis versus germline variants and the limitations of most NGS assays from ‘tumor-only’ sequencing. She will discuss the frequency of detecting incidental germline findings from ‘tumor-only’ sequencing and the impact of identifying such variants. Dr. Godley will also emphasize the usefulness in comparing NGS data across time as a means of identifying individuals likely to have an inherited predisposition variant.
Dr. Jonathan Marron will discuss the numerous ethical challenges inherent in germline testing for HMs. He will focus on how informed consent for NGS testing performed for diagnostic and prognostic purposes differs from consent for other tests and procedures, given that it can allow for discovery of additional incidental germline alleles and other complex phenomena. Dr. Marron will also explain approaches to minimize anxiety for patients and families, particularly in light of the significant uncertainty related to NGS-based assays. Finally, he will examine several ethically challenging but common cases involving germline testing for HMs.
Dr. David Wu will present a case-based discussion of the clinical interpretation of variants identified in testing for hematologic disorders and the current international efforts to provide uniform variant interpretation based on standardized curation rules. Curation of gene variants is the systematic evidenced-based process leading to a designation of clinical significance based on a five-tier system. Unfortunately, increasing numbers of genes variants are classified with uncertain or conflicting classifications. Dr. Wu will explain common NGS testing platforms, their assumptions and capabilities, and how to use current curation guidelines in daily practice to allow for optimal clinical care.
Dr. Lucy A. Godley will explain the complexities of data interpretation when NGS panels are used on blood and bone marrow samples, especially regarding the identification of somatic variants/clonal hematopoiesis versus germline variants and the limitations of most NGS assays from ‘tumor-only’ sequencing. She will discuss the frequency of detecting incidental germline findings from ‘tumor-only’ sequencing and the impact of identifying such variants. Dr. Godley will also emphasize the usefulness in comparing NGS data across time as a means of identifying individuals likely to have an inherited predisposition variant.
Dr. Jonathan Marron will discuss the numerous ethical challenges inherent in germline testing for HMs. He will focus on how informed consent for NGS testing performed for diagnostic and prognostic purposes differs from consent for other tests and procedures, given that it can allow for discovery of additional incidental germline alleles and other complex phenomena. Dr. Marron will also explain approaches to minimize anxiety for patients and families, particularly in light of the significant uncertainty related to NGS-based assays. Finally, he will examine several ethically challenging but common cases involving germline testing for HMs.