Centralized Sequencing Program

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Summary of ongoing projects organized by topic: I. CLINICAL DIAGNOSTICS AND CONSULTATION A. Clinical Pipeline. This FY we enrolled most participants from more IC's than ever before, while simultaneously maintaining a turn around time from enrollment to CLIA CRIS report of 6 months for most cases. This deliverable is a central component to our mission, as well as the clinical pipeline that catalyzes collaborative research across the clinical center. B. Integration of Structural Variant Calls. We have continued to incorporate technological developments into our services. This year we integrated structural variant calling into our standard pipeline and have seen approximately an additional 1% molecular diagnostic yield increase with this development. Such structural variation has been historically underascertained and we look forward to the continued development of that knowledge base. C. Pharmacogenomics. We have successfully validated our genome data as a source of pharmacogenomic data and piloted in a subset of NIAID participants. In the coming months we look forward to incorporating into our clinical reporting pipeline as we have evidence that many of our participants stand to benefit from optimization of their medications based on genomics. II. DISCOVERY A. New gene disease discovery. The CSP contributed infrastructure, data, and molecular expertise to at least two new gene-disease discoverie this FY, including human immune disorders associated with defects in CLEC7A and TCF3. Multiple other discovery projects are ongoing. B. Statistical genomics. Methods for modeling complex genetic contributions to disease have rapidly expanded and improved in recent years. Our program has developed a rich database of genotypes and phenotypes and we have had early success in using polygenic risk scores for atopic dermatitis to predict phenotypic variation in Job's syndrome. C. Secondary findings. We have an ongoing collaboration with NHGRI to evaluate secondary findings for IRP participants, with particular attention to the growing list of ACMG secondary findings and evolving variant classification guidelines. Manuscript in preparation. D. Somatic variants. Our somatic variant research effort include multiple projects. We have explored new algorithmic methods for calling somatic variants from exome and genome data, particularly in the context of myelodysplastic evolution for patients with GATA2 deficiency. In paralle, we have collaborated with Megan Cooper on somatic contributions to disease across >100 NIAID probands, based on ultra deep sequencing. Manuscripts in preparation. E. Pharmacogenomics. Collaboration with NCI and NHGRI on pharmacogenomics. The project compares PGx variant calls from the CLIA array run by NCI and the variant calls from genome data using the algorithm Aldy. We used internal genome data to estimate the clinical utility of clinical implementation of high value PGx targets on CSP participants. Manuscript in preparation. F. Genotype First Ascertainment. Collaboration with The Genotype Ascertainment Cohort (TGAC), hosted by NHGRI. The CSP seeks to model genomic data sharing approaches that optimize both patient confidentiality and research productivity. In addition to the required deposition into dbGAP, CSI contributes data to TGAC. Exome and genome data from patients in contributing cohorts, including CSP, are available to view in aggregate by DIR researchers. This project is designed to enable further study of individuals via genomic ascertainment without prior knowledge of phenotype. CSI staff has also participated in the review board for patient access requests. This year multiple CSP participants were offered follow up through this collaboration. III. SOCIAL AND BEHAVIORAL RESEARCH, POLICY A. Reproductive decision making for patients with IEI. CSP participants were invited to participate in an in-depth interview project on the highly personalized and complex considerations involved in reproductive decision making. Pariticpants described factors related to their values, access to care, quality of care, and genetic uncertainty that shaped their decisions and care needed. Manuscript in preparation. B. Psychological outcomes in PID patients: A survey and interview project. The survey is a mix of open-ended requests for feedback and structured, validated measures of if/how genetic testing and counseling has allowed them to better understand their disease, identify relatives as risk, identify and feel in control of relevant decisions for managing their disease, and come to terms with their illness. As part of this we also collected data on possible positive psychological adaptation to illness, as well as the potential, well-documented negative psychological effects of illness (depression, anxiety, isolation, etc.), to try to better understand those correlates in this population. We also conducted in-depth follow up interviews to understand adaptation over time and mental health concerns. One manuscript is accepted pending minor revisions; the other is in preparation. C. Impact of genetic counseling for participant with treatment resistant depression & interest in polygenic risk scores: a survey and interview study. Participants with treatment resistant depression received genetic counseling and testing and completed surveys at two time points (baseline and two weeks). Participants also described interest in and concerns regarding polygenic risk scores for depression. In-depth interviews asked participants to share about experiences with pharmacogenomics and the potential meaning one may make out of that type of information. Initial results will be presented at 2023 conferences. D. Inconclusive negative report comprehension: a survey and interview study. This project assessed participant receipt of negative reports along with their understanding of the report's message. Importantly, few participants accessed the patient portal or were aware that they had a negative report. When reviewing the negative report they generally understood the limitations, with some exceptions. Manuscript accepted for publication. E. Secondary findings follow up collaboration. The CSP is collaboratively studying the clinical follow up of secondary findings with researchers at NHGRI. There is some evidence that a minority of participants do not seek recommended follow up care for the potentially life threatening disorders which are returned on CSP as secondary findings. The objective of this substudy is to better understand patient cognitive, emotional, and behavioral reactions to receiving a secondary finding, over time, including the motivators and barriers to clinical follow up.