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. RPC’s 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 Elliott Wack to Prince Appiah), and a research coordinator (Anna Sharp, departed March 2025 and not replaced ). Also, there are two part-time staff: a post-bac IRTA shared with Dr. Teri Manolio (Shehreen Siddiqui), and a Bioinformatics Scientist (Justin Paschall). Travel reimbursement, covered through NHGRI’s Office of the Clinical Director, and monetary compensation for participation are included in 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 investigator’s 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 has been developed. 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). Bioinformatics support 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 have been made available to the NIH community on a genome browser (https://rpc.nhgri.nih.gov/). The browser was updated to ensure that the browser optimizes an investigator’s ability to identify variants of interest and subsequently propose reverse phenotyping projects. A new bioinformatics pipeline was developed to assess HLA genotypes. The RPC performed paired RNA sequencing and genome sequencing in 167 samples that previously only had exome data. Several of these samples will additionaly undergo long-read sequencing to identify structural genomic variants. 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 is available 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 eight new proposals in the past year. Among the new projects, all eight 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 were 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 28 projects for which active work has continued through the last year. Four are evaluating a novel gene-disease association, 22 that are measuring the clinical yield of variants of interest in known disease associated genes, and two are aiming to measure an ex vivo phenotype that may be associated with a common variant using blood samples from participants. The RPC presented one poster at the American Society of Human Genetics conference in Denver, CO. The RPC had one abstract accepted for a poster presentation at the American College of Medical Genetics and Genomics Annual Meeting in Los Angeles, CA. Our variant analysis pipeline has been expanded beyond single nucleotide variants and small insertions/deletions to include larger copy number changes and other structural variants. A new bioinformatics pipeline was developed to assess HLA genotypes. The RPC is scheduled to present a reverse phenotyping methodology seminar as part of the 2025 NIH Research Festival. Researchers interested in doing a reverse phenotyping project using RPC data can apply at https://rpc.nhgri.nih.gov/research-application. The RPC, in collaboration with the Biesecker and Denny laboratories has submitted a proposal to access All of Us data as a source for participants for genotype first studies to travel to the NIH Clinical Center. While deidentified data from All of Us are widely and readily available to intramural investigators, this proposal would in addition lead to individual All of Us participants to become identified, in person participants in NIH CC deep phenotyping studies. This proposal received an enthusiastic evaluation from the quadrennial review of the BSC at the Center for Precision Health Research (CPHR) site visit in October of 2023. It was presented as a joint aim of the Biesecker and Denny laboratories, in collaboration with the RPC. The review processes in All of Us are extensive, laborious, and slow. The approval of this program with All of Us would scale our access to individuals with variants by one to two orders of magnitude, which would magnify our successes by a large margin. We are highly optimistic and excited about this development. The issue of core oversight is worth addressing in this report as well. As the core is still in the development phase, it is overseen by CPHR, rather than the Deputy SD, as is the case for most other cores. As well, CPHR leadership, with input from the SD, will soon be exploring the scaling of the core beyond our institute. With this consideration, and the above AoU development still in process, we request that this CPHR oversight of the core be maintained for continuity of support.