GREGoR Consortium Breaks Ground in Rare Disease Diagnostics

The National Institutes of Health (NIH) has made significant strides in the field of rare disease diagnostics through the establishment of the Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium in 2021. The consortium aims to uncover molecular diagnoses for individuals with rare diseases who remain undiagnosed following clinical testing. Among its notable participants is Baylor College of Medicine, one of five clinical sites involved in this groundbreaking initiative.

A recent publication in the journal Nature reviews the accomplishments of GREGoR during its first five years and outlines the future challenges in genomic medicine that researchers will address. Rare diseases, which collectively affect approximately one in 20 people globally, remain a pressing concern. Advances in genomic sequencing, particularly the widespread application of exome sequencing and computational analysis, have markedly enhanced the diagnostics of these conditions.

More than 5,000 protein-coding genes are currently linked to various diseases. According to Dr. Richard Gibbs, director of the Human Genome Sequencing Center and professor of molecular and human genetics at Baylor, identifying the genes associated with rare diseases is essential. He stated, “Identifying the genes underlying rare disease remains the most powerful gateway to the understanding of basic molecular processes in humans. The GREGoR program has advanced this cause enormously.”

Over its operational period, GREGoR has investigated thousands of complex rare disease cases, gathering genomic data from approximately 7,500 patients and their families. Despite notable progress, researchers acknowledge that significant gaps remain. Current estimates suggest that over 10,000 relationships between diseases and protein-coding genes are yet to be discovered. Co-corresponding author Moez Dawood, a graduate student in the Medical Scientist Training Program at Baylor, emphasized, “As a field, we are working toward finishing the job of discovering all the novel disease genes. New technologies and diagnostic approaches are going to drive clinical discovery.”

Unlocking the Noncoding Genome

An essential aspect of this ongoing effort involves exploring the noncoding genome, which plays a critical role in regulating gene expression. The GREGoR Consortium has pioneered a framework that incorporates both short-read and long-read genome sequencing, utilizing many of the latest innovations in next-generation sequencing technologies. The consortium has published multiple papers assessing the effectiveness of these methods in enhancing diagnostic yields.

Data sharing is another crucial element in advancing research within this field. All data generated by the consortium is made publicly available to researchers. Dawood remarked, “We’re hoping people use this data as positive controls to test new tools for rare disease analysis. There’s also a wealth of data from patients with unsolved cases. We hope people will bring their new tools and ideas to try to solve these cases as well.”

The GREGoR Consortium represents a collaborative effort to address the challenges posed by rare diseases. As researchers continue to push the boundaries of genomic medicine, the insights gained from this initiative may pave the way for novel diagnostic tools and treatments, ultimately benefiting countless individuals worldwide.

For further reading, refer to the study by Moez Dawood et al, titled “GREGoR: accelerating genomics for rare diseases,” published in Nature in 2025. The DOI for the paper is 10.1038/s41586-025-09613-8.