Broad Institute Mendelian Genomic Research Center

This administrative supplement request seeks additional support for analysis and data sharing within the GREGoR consortium under parent grant U01HG011755, “Broad Institute Mendelian Genomic Research Center.” Although GREGoR sites have generated extensive long-read (lrGS) and short-read genome sequencing (srGS) data, heterogeneous methodologies—including different technologies, chemistries, read depths, and analysis pipelines—have resulted in fragmented datasets, limiting cross-cohort discovery and standardized evaluation of the diagnostic yield generated in rare disease studies. This proposal leverages cloud-based, standardized pipelines (as employed by the All of Us Research Program and HGSVC) to harmonize lrGS data across >1,500 individuals, generates a uniform long-read callset, and integrates these findings with a joint structural variant (SV) callset from srGS data and complementary multiomics analyses (including DNA methylation data). We will also develop the seqr platform to expand controlled-access sharing of the GREGoR dataset. Finally, we will complete analysis of the samples that have been sequenced to date in GREGoR by applying a variant prioritization algorithm and generating a structural variant callset from the short read genome data. We will also deploy novel methods in transcriptomic analysis, noncoding variant prioritization, and tandem repeat expansion discovery. Results will continue to be returned to participants, and individual gene-disease relationships and variant classifications will be shared through GenCC and ClinVar, respectively. Our approaches will work towards achieving the GREGoR consortium’s goals of enabling robust joint analyses across GREGoR sites, providing a rigorously annotated, controlled-access resource designed to maximize diagnostic yield, benchmarking novel variant discoveries, and facilitating widespread innovation in the application of short-read and long-read sequencing technologies for rare disease research. Project Number: 3U01HG011755-05S1 | Fiscal Year: 2026 | NIH Institute/Center: National Human Genome Research Institute (NHGRI) | Principal Investigator: Anne O'Donnell-Luria (+1 co-PI) | Institution: BROAD INSTITUTE, INC., CAMBRIDGE, MA | Award Amount: $2,348,207 | Activity Code: U01 View on NIH RePORTER: https://reporter.nih.gov/project-details/11498018