Centralized Sequencing Program

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Summary of ongoing projects organized by topic: I. CLINICAL DIAGNOSTICS AND CONSULTATION A. CLIA reports in CRIS. A central deliverable for our initiative is the clinical analysis and CLIA reporting into the CC medical record. This has been completed for approximately 4500 patients since January 2019 and is a major accomplishment. During this same time period our turn around time has decreased to 7 months. B. Operational development and refinement. Given the scale of our initiative, we dedicate significant attention to optimizing the efficiency of our workflow and anticipating potential disruptions related to policy adjustment or special circumstances. Specifically, this year we have increased automation of data entry into reporting and tracking processes, developed a new rapid turnaround time workflow for rare cases with high clinical urgency, and streamlined the reporting process. C. Integration of medical geneticist in suite of consultation offerings. Recognizing room for improvement in our clinical consultation service for complex cases, we've started collaborating with a NIAID-NIAMS medical geneticist and are working concurrently with the NHGRI genetics consult service so we can continue to provide educational opportunities to genetics fellows. This has proven to be a clinically valuable service in multiple cases with complex clinical presentations or clinically significant molecular diagnoses outside the immune system. D. Reanalysis. Clinical reanalysis of exome data is known to be an important source of new diagnoses over time. We are implementing a limited re-analysis workflow to be alerted to recent publications on variants in our database, which in rare cases provides sufficient evidence to merit a new molecular diagnosis. E. Childrens collaboration. The CSI works with Gigi Notarangelo to recruit young patients from Children National Health System (site-PI: Mike Keller). The CSI protocol is the first protocol to be formally submitted under the new reliance agreement, paving the way for future studies and opening up a referral source of very young research participants who cannot typically be seen at the CC. F. Transition from exome to genome. The transition in the fall of 2020 from exome to genome sequencing has provided our program with challenging opportunities to make use of the expanded data set. G. RNA-seq pilot, to aid in the interpretation of splicing and intronic variants from genome sequencing. H. Validation projects on variant calling. The technologies for calling additional variant types from genome data are improving. We are pursuing validation projects in the following areas: copy number variation, pharmacogenomics, triplet repeat expansions, sex chromosome anueploidy. II. DISCOVERY A. New gene disease discovery. The CSI is contributing to at least three ongoing projects with DIR investigators characterizing new gene-disease relationships. There is a significant opportunity to further exploit this data for discovery. B. Collaboration with NHGRI on secondary findings evaluations. We have an ongoing collaboration with NHGRI to evaluate secondary findings for IRP participants. C. Collaboration with multiple groups on computable phenotypic data. The CSI has built a highly valuable dataset of genomic data associated with detailed clinical records, manually coded with relevant phenotypic terms. The integration of computable phenotypic and laboratory data into genomics is an area of great interest across the field. We are working with NLM for more efficient text mining approaches, the NIAID epidemiological unit on phenotypic modeling for machine learning in large datasets from other health centers, and other extramural collaborators on tailoring phenotypic data analysis approaches for Mendelian disorders of the immune system. D. Collaboration with The Genotype Ascertainment Cohort (TGAC), hosted by NHGRI. The CSI 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 CSI, 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. E. Collaboration with Megan Cooper on somatic contributions to disease based on ultra deep sequencing. F. Collaboration with William 'Doug' Figg from NCI and Les Biesecker and Teri Manolio from NHGRI on pharmacogenomics. The project compares PGx variant calls from the CLIA array run by NCI and the variant calls from genome data. III. SOCIAL AND BEHAVIORAL RESEARCH, POLICY A. Negative results comprehension. The CSI is studying patient perceptions and understanding of the inconclusive negative exome results released in the medical record without specific counseling. The objective of this substudy is to use survey and interview data to better understand how well patients understand their negative exome sequencing results and to identify patient characteristics associated with poor understanding. Modification of our policy or specific educational interventions may follow if needed. B. Secondary findings follow up collaboration. The CSI 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 CSI 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. C. Secondary findings in minors collaboration with Skye Miner from Bioethics.This interview study was recently accepted for publication. D. 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 will also be collecting 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. E. Impact of genetic counseling for participant with treatment resistant depression. F. Policy development on return of results from genetic clinical research for the intramural research program, at the request of IRB, project lead: Ben Berkman.