Blood-based RNA-Seq of 5412 individuals with rare disease identifies new candidate diagnoses in the National Genomic Research Library
Year: 2026
Type: preprint
Abstract: RNA sequencing (RNA-Seq) is increasingly used alongside exome and genome sequencing to identify causal variants underlying rare Mendelian disorders. We present short-read RNA-Seq data from 5,412 individuals with a diverse range of rare disorders recruited to Genomics England's 100,000 Genomes Project. We show that the proportion of genes from gene panels applied to different disorders which are well captured (transcripts per million (TPM) ≥ 5) from blood RNA varies widely, highlighting differences in applicability across disorder types. Using OUTRIDER and FRASER2 to identify gene expression and splicing outliers respectively, we identify at least one outlier event in a disorder relevant gene in 20% of the cohort. To prioritise likely diagnostic candidates, we apply multiple strategies including focussing on outlier events in known haploinsufficient genes (n=78), integrating outliers with structural variant calls (n=19), and using strategies integrating phenotypic presentation (Exomiser, n=39). We present a series of candidate diagnoses involving diverse variant types and disease mechanisms, demonstrating the broad utility of RNA-Seq in identifying and prioritising diagnostic candidates in individuals with a variety of different rare conditions and no known genetic diagnosis. Our findings demonstrate that blood-based RNA-Seq can deliver clinically relevant findings across a broad range of rare disorders.
Source: medRxiv
Authors: Jenny Lord, Alistair T Pagnamenta, Letizia Vestito, Susan Walker, Carolina Jaramillo Oquendo, Anthony EF McGuigan, Alexander Ho, Christopher Odhams, Julius OB Jacobsen, Sarju Mehta, Evan Reid, Mary O’Driscoll, Christopher M Watson, Laura A Crinnion, Rachel L Robinson, Hannah Musgrave, Richard J Martin, Terena P James, Mark T Ross, Marianna Kyritsi, Leonardo Carnielli, Nicholas Walker, Dunja Vucenovic, Uma Maheswari, Francisco E Baralle, Jenny C Taylor, Jamie M Ellingford, Dalia Kasperaviciute, Lily Hoa, Greg Elgar, Matthew A Brown, Damian Smedley, Diana Baralle
Institutions: University of Southampton, University of Sheffield, University of Exeter, Queen Mary University of London, William Harvey Research Institute, Genomics England, Centre for Human Genetics, University of Oxford, University of Cambridge, Addenbrooke's Hospital, Birmingham Women’s and Children’s NHS Foundation Trust, University of Birmingham, University of Leeds, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Newcastle upon Tyne Hospitals NHS Foundation Trust, Illumina (United Kingdom), NIHR Oxford Biomedical Research Centre, University of Manchester
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7140088818