Kathy Stirrups, Samples Team Lead at NIHR BioResource for Translational Research, discussed the process of whole genome sequencing (WGS) and the two key research stages within this process: initial interactions with the participants and the interactions with researchers.
The first stage involves biobanking patient samples, obtaining consent, and collecting data. Meanwhile, the second stage requires engaging with the researchers, listening to their ideas, and arranging a feasibility assessment to check whether NIHR has relevant samples and the necessary data to support the research in question.
The NIHR focuses on a range of diseases such as inflammatory bowel disease, COVID-19, non-alcoholic fatty liver disease, and rare diseases. Stirrups focused on rare diseases; one in 17 people in the UK living with a rare disease and the average diagnosis time for rare diseases is five years. Thus, many patients face frustrating waiting times and their condition often worsens.
To overcome this, NIHR began collaborating with Genomics England on their rare disease pilot and conducted whole-genome sequencing of 8,000 individuals with rare diseases. Stirrups stated that the primary goal was to reduce diagnostic time, increase diagnostic yield, and ultimately transform healthcare for rare disease patients.
The WGS efforts yielded a 20% diagnostic rate for 8,000 rare disease patients, meaning there was room for improvement. Stirrups introduced NIHR’s RNA phenotyping project to improve the diagnostic rate by analysing RNA and protein profiles from blood samples. The project isolates specific cell types such as platelets, neutrophils, CD4 T cells, and monocytes. These cells were selected because they cover roughly 17,000 genes and expression of around 85% of genes.
The monocytes proved to be very useful because not only did they increase the number of genes, but they also gave further information on the state of the patient and potential causes of rare disease. NIHR partnered with Sanquin, a Dutch blood transfusion service to use mass spectrometry to analyse protein expression. Early findings show promising disease-specific protein expression patterns. For example, they found that F11 and PROZ were identified in unexplained rare thrombosis. Furthermore, MINPP1 was expressed in neurodegenerative conditions.
NIHR is also engaged in a long-read sequencing project with Oxford Nanopore Technologies which seeks to sequence 22,000 genomes using long-read technology. Stirrups commented that her team is particularly interested in structural variants that can be prevalent in rare diseases. These variants are not picked up with short-read sequencing. Additionally, long-read sequencing better detect methylation.  This project is in its early phase. The targets include 4,000 rare disease cases and 4,000 eating disorder cases.
In closing, this initiative is constructing a multi-layered omics dataset that integrates genomics, transcriptomics, proteomics, and epigenomics. It will hopefully improve diagnostic capabilities and create a valuable research resource for scientists interested in rare diseases.
