Scaling Strategies to Assess Pathogenicity of Variants of Uncertain Significance
About This Grant
PROJECT SUMMARY/ABSTRACT Sequencing human genomes, especially those from individuals with Mendelian disorders, has yielded discovery of thousands of new disease genes and has led to personalized treatments, improving the lives of patients and their families. Unfortunately, less than half of this population is able to reap these benefits because, despite continued advances in sequencing technology and data analysis, many patients remain without a molecular diagnosis. A major barrier to increasing the diagnostic yield is the abundance of variants of uncertain significance (VUS), and in particular missense VUS, which are found in more than half of all patients. As more individuals are sequenced, the number and proportion of patients with missense VUS continues to grow, much faster than the field is currently able to interpret the functional significance of these variants. Therefore, it is critical to both scale up existing methods and develop new approaches to determine the pathogenicity of these VUS in as many genes as possible to help patients and families in need. One such method that offers hope for solving this VUS problem is Deep Mutational Scanning (DMS), which uses cell-based assays to simultaneously test thousands of missense variants by changing each residue in a protein of interest to all 19 other possible amino acids. However, it is currently very challenging to generate a cell-based assay that reliably reports the activity of a given gene of interest. Fortunately, combining DMS with a multiplexed fluorescence-based approach, SortSeq, gives an accurate assessment of deleteriousness and pathogenicity for variants in the GLI2 gene, which operates in the Sonic Hedgehog (SHH) signaling pathway. This proposed work will use this same well-validated assay to interrogate multiple genes involved in SHH signaling in order to determine the feasibility of a pathway-based approach for efficiently conducting DMS in many genes with the same molecular read-out. The scope of work is expanded to include a second pathway, the retinal development pathway, including DMS of CRX and OTX2, and leverages identical assays for paralogous families of transcription factors to further scale up the approach. This proposal also tests and validates an innovative computational pipeline that includes de novo biophysical predictions to understand the effects of variants in intrinsically disordered regions (IDRs), which is particularly synergistic with the focus on transcription factors, which typically contain large stretches of IDRs. Successful completion of these aims will establish multiple strategies for pathway-based and paralog-based scaling that can be quickly and easily adapted across many disease-causing genes, resulting in improved genome-based diagnostics and future therapeutics.
Grant Summary
Scaling Strategies to Assess Pathogenicity of Variants of Uncertain Significance is a NHGRI - National Human Genome Research Institute grant providing up to $428K for university, nonprofit, healthcare org. Applications are due 2027-09-29 (open). Check eligibility and apply with FindGrants.
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How to Apply
Up to $428K
2027-09-29
- 1Confirm your organization is eligible for Scaling Strategies to Assess Pathogenicity of Variants of Uncertain Significance from NHGRI - National Human Genome Research Institute, checking organization type, location, and any population or project requirements.
- 2Gather the required documents and information, including your organization details, project plan, and budget figures.
- 3Draft your application narrative and budget addressing the funder's priorities and review criteria. FindGrants can draft each section for you to review and edit.
- 4Review every section against the requirements checklist, then export a submission-ready application pack and submit it to NHGRI - National Human Genome Research Institute before the deadline.
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Scaling Strategies to Assess Pathogenicity of Variants of Uncertain Significance: Frequently Asked Questions
Who is eligible for the Scaling Strategies to Assess Pathogenicity of Variants of Uncertain Significance?
Scaling Strategies to Assess Pathogenicity of Variants of Uncertain Significance is offered by NHGRI - National Human Genome Research Institute and is generally open to university, nonprofit, healthcare org. It is open to organizations nationwide unless the funder specifies otherwise. Review the specific eligibility terms before applying, since funders set their own requirements around organization type, location, and the population or project being served.
How much funding does the Scaling Strategies to Assess Pathogenicity of Variants of Uncertain Significance provide?
Scaling Strategies to Assess Pathogenicity of Variants of Uncertain Significance provides up to $428K per award from NHGRI - National Human Genome Research Institute. Actual award sizes depend on the scope of your project, available program funds, and the number of applicants, so build a budget that reflects realistic, allowable costs rather than the maximum figure.
When is the Scaling Strategies to Assess Pathogenicity of Variants of Uncertain Significance deadline?
Applications for Scaling Strategies to Assess Pathogenicity of Variants of Uncertain Significance are due 2027-09-29 (open). Because deadlines can change, verify the date with the funder, NHGRI - National Human Genome Research Institute, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the Scaling Strategies to Assess Pathogenicity of Variants of Uncertain Significance?
To apply for Scaling Strategies to Assess Pathogenicity of Variants of Uncertain Significance, confirm your eligibility, gather the required documents, and prepare a narrative and budget that address the funder's priorities. FindGrants guides you step by step and can draft each section, then exports a submission-ready application pack for this grant from NHGRI - National Human Genome Research Institute.