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NHGRI GREGoR Consortium: Genomics Research to Elucidate the Genetics of Rare Disease

The NHGRI GREGoR (Genomics Research to Elucidate the Genetics of Rare Disease) Consortium was established in June 2021 with the goal of developing novel tools and approaches to advance the discovery of the genetic basis of rare conditions. Numerous types of molecular data are generated in GREGoR and available on the AnVIL cloud platform via dbGaP application, including short- and long-read genome and exome sequencing, transcriptomics, metabolomics, methylomics, and proteomics. De-identified clinical and demographic data is obtained, with a focus on standardized ontologies.

The Consortium comprises five Research Centers (RCs - see below), a Data Coordinating Center (DCC), and various partner members and external collaborators.

Baylor College of Medicine Research Center (BCM-GREGoR)

The Baylor College of Medicine GREGoR program, which is part of the GREGoR consortium, enrolls individuals, families, and cohorts with suspected rare disease across a range of syndromic and non-syndromic phenotypes. Subjects are enrolled from national and international collaborating physician referrals. Subjects provide written informed consent for future re-contact. Data generated and shared include family structure, detailed phenotypes, exome or short-read genome data, and in some cases long-read genome or RNA-sequencing, and these are shared upon completion of standard quality control checks and annotation.

Broad Institute (Broad)

The Broad Center for Mendelian Genomics, part of the GREGoR consortium uses next-generation sequencing (exome, genome, transcriptome, and long read sequencing), computational approaches, and functional studies to discover the variants and genes that underlie Mendelian conditions with a particularly focus on neuromuscular, neurodevelopmental, and syndromic phenotypes. Samples come from collaborators and direct enrollment through the Rare Genomes Project and we are committed to rapid data sharing without an embargo period.

Children's National Hospital / Invitae - Pediatric Mendelian Genomics (CNH/Invitae)

The Pediatric Mendelian Genomics Research Center, a joint collaboration between Children's National Hospital Research Institute and Invitae, is part of the GREGoR consortium to discover disease-causing variants. Our center uses a combination of short-read and long-read next-generation sequencing technologies (genomes and transcriptomes), computational approaches, and protein-level functional modeling to discover novel gene-variant associations for Mendelian disease. Research participants, and often family members, were consented and enrolled directly into our research study. Most of our participants are single families with a wide range of likely genetic phenotypes including congenital malformations, neurodevelopmental features, or connective tissue differences who have had negative standard of care genetic testing such as panels or exomes. Several specific phenotype cohorts of interest include holoprosencephaly, leukodystrophies, cardiomyopathies, differences of sexual development, congenital renal disease, and epilepsy. De-identified clinical phenotype and sequence data are linked to all samples.

GREGoR Stanford Site (GSS)

The goal of the GREGoR Stanford Site (GSS) is to provide a platform for functional genomics research and validation to improve diagnosis in Mendelian disease. Participants included individuals with undiagnosed suspected Mendelian disease who had non-diagnostic exome sequencing and their immediate family members. Participants and their family members provided written, informed consent and biological samples from which DNA, RNA, plasma, fibroblasts, PBMCs and other cell types were generated and stored. Samples from research participants and their immediate family members may have undergone short and long-read genome sequencing, transcriptome sequencing, metabolomics and/or lipidomics profiling, methyl-capture-sequencing and ATAC-sequencing. De-identified clinical data extracted from participant medical records are linked to the samples.

University of Washington Center for Rare Disease Research (UW-CRDR)

The goals of the University of Washington Center for Rare Disease Research are to: (1) maximize novel gene discovery for Mendelian conditions by recruitment, short- and long-read whole genome sequencing, transcriptome sequencing and analysis of families with rare conditions for which the gene is either unknown or the gene is known but no pathogenic variant can be identified via clinical testing; (2) develop new strategies for gene discovery for Mendelian conditions caused by variants that are difficult to detect using conventional testing strategies, variants of unknown function effect (e.g., regulatory, structural variants) or have unusual modes of inheritance; and (3) implement high-throughput screening and targeted follow-up functional studies to prioritize and validate candidate non-coding variants. De-identified data and phenotypic information are shared via MyGene2, ClinVar, and AnViL.