Reverse Phenotyping Core

National Human Genome Research Institute

Investigators

Linked publications, trials & patents

Abstract

RPC was formally established in 2021 with the goal of providing an NHGRI core resource for facilitating genomic ascertainment-based clinical research. RPCs progress during the last year can be divided into three domains: 1) infrastructure of RPC operations, 2) aggregation and management of genomic data, 3) scientific pursuits. Infrastructure of RPC operations: RPC was established as an expansion of The Genomic Ascertainment Cohort (TGAC) clinical protocol (18-HG-0129). RPC has five full-time staff: a director (Clesson Turner), genetic counselor (Caralynn Wilczewski), research nurse specialist (Felicia Akinwande), post-bac IRTA (transitioned from Vera Zanker to Yeabsira Tufa), and a research coordinator (Ashley Glasper). Also, there are two part-time staff: a post-bac IRTA shared with the Cohort Analytics Core (Cassia Williams-Rogers), and a Bioinformatics Scientist (Justin Paschall). Travel reimbursement, covered through NHGRIs Office of the Clinical Director, and monetary compensation for participation were added to the RPC protocol to reduce financial barriers to participation in reverse phenotyping projects. The full-time team has been able to refine the workflow for reverse phenotyping research projects, which can be summarized as: evaluation of reverse phenotyping proposal from investigator, review of specific variants of interest identified by proposing investigator, plan for collection of linked electronic health record data from potential participants, re-contact of potential participants, enrollment onto TGAC/RPC clinical protocol, referral to requesting investigators protocol, targeted clinical evaluation, CLIA-confirmation of clinically meaningful genetic variants (performed by the Biesecker lab), genetic counseling, and deep phenotyping at the NIH Clinical Center of eligible participants.A website (https://dir.nhgri.nih.gov/nhgri_cores/RPC/), highlighting the RPC capabilities, was developed in the last year. The RPC team published a paper in the American Journal of Human Genetics highlighting the reverse phenotyping methodology. The nature of RPC is to enable research projects in which the proposed phenotyping is tailored specifically to the variants of interest identified, and the RPC team is tasked with ensuring the operation of various phenotyping needs for different proposals. Aggregation and management of genomic data: Since its establishment, RPC has been maintaining a genomic database that includes sequence data for individuals eligible for re-contact for research studies. These individuals currently come from four primary cohorts: NHGRIs ClinSeq cohort (n=1,500), National Institute of Allergy and Infectious Disease (NIAID)s CenSeq cohort (n=2,900), the Inova Healthcare Systems longitudinal sequencing cohort (n=6,000), and the National Institute of Environmental Health Sciences (NIEHS)s Personalized Environment and Genes study (n=4,800). On behalf of the RPC, the NHGRI bioinformatics core realigns and recalls genome and exome data to ensure data harmonization from the raw sequence data obtained from the different cohorts. Deidentified, unlinked genomic data has been made available to the NIH community on a genome browser (https://tgac.nhgri.nih.gov/). An update to the browser is in progress to ensure that the browser optimizes an investigators ability to identify variants of interest and subsequently propose reverse phenotyping projects. In addition, RPC has been working to bring in more sequence data from eligible participants to the shared genomic cohort. RPC is negotiating the addition of further cohorts from the National Cancer Institute (NCI). A Dell EMC ME484 Storage Expansion Enclosure was purchased to support long-term data storage needs for the RPC. Scientific Pursuits: RPC is actively recruiting, enrolling, and evaluating participants for reverse phenotyping projects. RPC has received several inquiries and has begun research activity for 11 new proposals in the past year. Among the new projects, four are evaluating a novel gene-disease association, and seven aim to measure the clinical yield of variants of interest in known disease associated genes. Three projects were closed out in the past year either because there was not compelling data upon review of available clinical data or participants declined to participate for further phenotyping. With the addition of the new projects, there are 26 projects for which active work has continued through the last year. Seven are evaluating a novel gene-disease association, 17 measure the clinical yield of variants of interest in known disease associated genes, and two aim to measure an ex vivo phenotype that may be associated with a common variant using blood samples from participants. One project was completed and the resulting manuscript is in revision at Biochimica et Biophysica Acta. The RPC presented one poster at the American Society of Human Genetics conference in Los Angeles, CA and one poster at the National Society of Genetic Counselors conference in Nashville, TN. . Additional work is underway to expand our variant analysis pipeline beyond single nucleotide variants and small insertions/deletions to include larger copy number changes and other structural variants. The RPC is scheduled to present a reverse phenotyping methodology seminar as part of the 2023 NIH Research Festival. Researchers interested in doing a reverse phenotyping project using RPC data can apply at https://tgac.nhgri.nih.gov/application.