What methods and technologies is GREGoR leveraging for rare disease research?

Much of rare disease research is focused on understanding the cause for a rare or undiagnosed disease. This may include analysis of biological samples (blood and other body tissues) using existing, established technologies or technologies that are newly applied to study rare diseases. The results and progress from rare disease research can help clinicians make more accurate diagnoses, help inform targeted therapies to ease disease burdens, and identify ways to improve the lives of people and families living with rare disease.

Rare and undiagnosed disease research can be challenging for many reasons. Historically, rare disease research has relied on the collection of individual cases who have similar features or symptoms, often one or a very few at a time. This can make it difficult to build a better understanding of the condition because of the limited amount of data available. Individuals with rare disease are dispersed across the globe, and may be difficult for individual researchers to reach. In a similar way, it can be difficult or impractical for individual researchers to gather data from enough individuals with rare disease to be able to do deep analysis of these data (sometimes called “deep phenotyping”) that goes beyond typical clinical care.

Additionally, individuals with the same rare or genetic condition can have symptoms that can be quite different or variable compared to others with the same genetic condition. When determining if a newly discovered gene could be the cause of a condition, it can be hard to show that it is causative.

GREGoR is actively applying emerging genomic technology for rare disease research, with the goal of overcoming the current limitations in standard genetic testing. For instance, GREGoR researchers and collaborators are applying RNA-sequencing to look for changes in RNA (e.g. splicing and gene expression changes) with impacts on protein structure and function. This information can provide insights that help prioritize and interpret DNA variants, particularly variants in non-coding regions of the genome.

Genome sequencing is a genetic test that sequences a person’s genome, including the protein-coding and non-protein-coding regions of the genome. Genome sequencing can identify genetic changes that were not detected in exome sequencing but still impact health. The role of the non-protein-coding regions of the genome and how changes in those regions impact health can be hard to interpret and is an active area of scientific research.

Exome sequencingis a genetic test that focuses on the protein-coding region (the exome) of a person’s genome (entire genetic makeup). In humans, the exome is about 1.5% of the genome. Exome sequencing is technology that evaluates genetic changes that could impact protein function and lead to genetic conditions.

GREGoR researchers and collaborators are applying long-read sequencing to unsolved cases of rare disease. This is a new technology that can identify complex genetic changes and provide biological insights previously obscured in standard genome sequencing. This is accomplished by sequencing much longer DNA fragments compared to standard genome sequencing, and by providing additional chemical signals that reflect changes that impact how genes are regulated (methylation).

An important component of GREGoR is the re-analysis of genomic data. The field of genomics is rapidly evolving and the application of new/improved analysis methods can yield causal variants that were not previously identified. Re-analysis can leverage updates to the human genome reference or novel computational methods for variant detection. It can also involve the joint analysis of rare disease data, particularly as more and more genetic data becomes available.

In addition, GREGoR researchers and collaborators are aiming to improve our understanding of rare disease through the use of novel assays and genetic modeling systems. In rare disease, an assay is a laboratory experiment to look more closely at the function of a gene or biological process. Rare disease can also be studied by recreating or modeling the condition in cells and animals (in vitro and in vivo). Functional assays and modeling systems are being used to determine and provide additional evidence about how variants and genes contribute to rare disease.

In rare and undiagnosed disease, it is important to be able to connect with and collaborate with researchers with similar expertise and interests. By combining resources, including sharing research and genomic data, researchers can more quickly make scientific discoveries and those studies can have a broader impact.

As of 2023, the National Institutes of Health (NIH) has a policy that requires open data sharing. The NIH sees this policy as a way to “accelerate biomedical research discovery, in part, by enabling validation of research results, providing accessibility to high-value datasets, and promoting data reuse for future research studies.

When health and genomic data is used in research, it is important to have policies in place for how data is shared and when it can be used. See How does research participation work? for more information on how patient data is used and protected during a research study, and what “consent” means when considering participation in a research study.

Collaboration is critical to GREGoR’s progress toward our scientific goals and ways of working. This includes the Consortium’s commitment to data sharing, and working together both among the Consortium’s Research Centers and members and also with external scientific collaborators to develop and share knowledge and progress on new methods and tools. See information about each Research Center’s areas of focus and research, and information for interested external scientific collaborators.