Program seeks Council approval for the reissue of this initiative titled “ClinGen Genomic Curation Expert Panels.”
This PAR will support continued stimulation of expert panels that manually curate, review, and define the clinical relevance of genes and variants as part of the NHGRI-funded Clinical Genome Resource (ClinGen). Despite advances in genomic sequencing technologies and increasing adoption in clinical practice, there are many genomic variants with unknown significance (VUS), and there is limited understanding of their function. This presents barriers to genomic and precision medicine. Using the standardized, FDA-approved ClinGen infrastructure and standards (including data standards, evidence frameworks, and biocuration tools), these Expert Panels will contribute to an authoritative, centralized, public resource of clinically relevant genes and variants by collaboratively aggregating, systematically evaluating, and sharing expert-curated data about genetic conditions, and the genetic variants that cause them.
Continued support of expert panels is needed given the large number of genes and variants that are yet to be curated and unclear evidence about how changes in DNA contribute to human health and disease. As routine genetic testing becomes more prevalent and is utilized by patients and providers in the determination of interventions, there are more identified variants and an even greater need to assess their impact on diseases. While many ICs support genomics research, few have provided focused support on gene and variant curation – by renewing this multi-institute PAR, NICHD will continue its leadership in this important domain, promoting curation efforts in genes and conditions relevant to our scientific mission, and accelerating patient care.
To address this need for better knowledge about the links between genes, variants, and disease, this PAR will facilitate the development of expert panels to select genes and genomic variants associated with diseases or conditions of high priority for participating NIH Institutes and Centers (ICs) and to systematically determine their clinical significance for diagnosis and treatment of these diseases or conditions.
This PAR aligns with branch priorities of IDDB, understanding the etiology of IDD conditions, and encourages applications related to priority areas for the following branches: MPIDB, PPB, PGNB, DBCAB, FIB, GHDB, OPPTB.
This proposed concept aligns with the NICHD Strategic goal 1 (“Understanding the molecular, cellular, and structural basis of development), and is crosscutting will all four other strategic goals: 2 (“Advancing gynecologic, andrologic, and reproductive health”), 3 (“Setting the foundation for healthy pregnancies and lifelong wellness”’), 4 (“Improving child and adolescent health and the transition to adulthood), as expert panels review genes and variants to determine clinical significance across these areas, to drive genomic medicine forward as in Strategic goal 5 (“Fostering safe and effective therapeutics and devices for pregnant women, lactating women, children, and people with disabilities).
NICHD has issued three Notices of Funding Opportunity (NOFOs): an RFA in 2016, and a reissued multi-IC PAR in 2020 and 2023. These NOFOs were designed to support the gene and variant curation activities of expert panels working in domains of high priority to NICHD and other participating ICs. Under the first iteration, RFA-HD-17-001, NICHD received nine applications and funded three U24 projects focused on pediatric mitochondrial diseases, monogenic diabetes, and brain malformations. The second iteration of this NOFO, PAR-20-101, had three application cycles for FY21-23.In the FY21 cycle, 17 applications were received and seven were awarded; three were funded in whole or in part by NICHD, focusing on primary mitochondrial diseases (with co-funding from NINDS), prenatal phenotypes (hydrops and stillbirth), and combined immunodeficiency and infections in children. The primary mitochondrial diseases panel was a continuation of the pediatric mitochondrial disorders panel from RFA-HD-17-001, using the reissued PAR as an opportunity to expand its curation scope to all primary mitochondrial disorders. In the FY22 cycle 11 applications were received and 6 were awarded; two of these were funded in whole or in part by NICHD, focusing on syndromic disorders (with co-funding from NINDS) and congenital heart disease. Finally, in the third application cycle, 4 applications were received and three were awarded; two of these were funded by NICHD, focusing on urea cycle disorders and monogenic diabetes.
Under the third (and current) iteration of this NOFO (PAR-23-199), there have been two application cycles, and awards will be made in FY24-26. During the first application cycle, which had a shortened length of time “on the streets” before applications were due, 6 applications were received and 3 were awarded; none of the applications were assigned to NICHD, and NICHD program staff provided co-funding support to one NINDS award focused on brain malformations. During the second application cycle, 18 applications were received, making this the most robust application cycle of the NOFO. Funding decisions will be made before the end of FY25.
Across all iterations of this NOFO, NICHD and our partner ICs have been able to fund gene and variant curation expert panels across 9 of the 16 CDWGs in ClinGen. NICHD specifically has provided funding support for panels in five CDWGs: cardiovascular, immunology, inborn errors of metabolism, neurodevelopmental disorders, and “other” (prenatal phenotypes, syndromic disorders).
The overall return on investment has been high. Expert panels that count support from these NOFOs have helped curate over 3800 variants and 800 genes. 71 publications cite NIH ClinGen expert panel funding.
Program Contact
Jiaqi O’Reilly
Intellectual and Developmental Disabilities Branch (IDDB)
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