Screening and Functional Validation of Genomic Variants Associated with Human Congenital Anomalies (R01 Clinical Trial Not Allowed)

The NIH, in partnership with NICHD, NIDCR, and ORIP, is offering funding through the R01 mechanism for research focused on the screening, validation, and characterization of genomic variants linked to human congenital anomalies. This initiative aims to promote the functional analysis of genetic variants associated with structural congenital anomalies (SCAs), intellectual developmental disabilities (IDDs), and inborn errors of metabolism (IEMs), utilizing genetic and phenotypic databases to identify variants and appropriate models. This NOFO seeks to close the gap between identifying genetic variants and understanding their functional effects on development and health outcomes, enhancing molecular diagnosis, treatment, and prevention strategies for congenital anomalies. The FOA encourages applications proposing innovative approaches to validate and characterize genetic variants identified from public resources such as the Kids First Data Resource Portal, dbGaP, and others. Applicants may use computational tools, in vitro models, animal models, or a combination of these methods to assess how specific genetic variants impact developmental pathways and phenotypes. Research objectives may include investigating coding and non-coding region variants, single base pair substitutions, structural variations, and chromosomal rearrangements. Proposed studies should aim to deepen the mechanistic understanding of how variants contribute to congenital disorders and should be able to provide direct functional evidence, ideally across multiple systems (in silico, in vitro, and in vivo). Eligible entities include higher education institutions, nonprofits, small businesses, local and state governments, and foreign institutions, among others. The maximum project period is five years, and the budget cannot exceed $499,999 in direct costs per year. The award is not intended to support clinical trials. Applications are accepted on standard NIH due dates starting February 5, 2025, and continuing until October 5, 2027. Applicants are encouraged to submit a letter of intent 30 days before the application due date, although it is not required. Key considerations for selection include the scientific merit, innovative approach, and relevance to program priorities, with specific attention to projects that leverage model systems like Drosophila, zebrafish, or induced pluripotent stem cells. Applications should include a detailed research strategy, highlighting the congenital anomaly under investigation, variant selection, and the models or assays to be used. They should demonstrate the likely impact of their findings on the understanding of congenital anomalies and discuss how they might contribute to diagnostics or therapeutic approaches. Projects focusing exclusively on in vitro or cell-free assays without in vivo validation, or those that do not assess the function of human genomic variants specifically associated with congenital anomalies, will be deemed non-responsive. The review process will consider factors such as the significance and innovation of the research, rigor and feasibility of the methodology, and expertise of the investigative team. NIH reviewers will prioritize applications that provide robust, reproducible results and a feasible research timeline. Awards are expected to begin in December 2025 for applications submitted in early 2025, following peer and advisory council review. Applicants must ensure compliance with all NIH policies and guidance, including data management and sharing requirements. For more specific guidance or assistance, applicants are encouraged to contact program staff from NICHD, NIDCR, or ORIP, as listed in the FOA.