A new approach combining information about proteins in the blood with genomic data could help diagnose some people with rare conditions who remained undiagnosed after genome sequencing, according to new research.
Researchers from Queen Mary University of London, the Berlin Institute of Health at Charité (BIH) and Genomics England have shown that measuring proteins in the blood can provide important additional clues about the effects of genetic variants, helping to identify diagnoses and potential new condition-causing genes that genome sequencing alone has been unable to resolve.
The study, recently published in Science Translational Medicine, analysed blood samples from people with rare conditions who remained without a genetic diagnosis following analysis through Genomics England's 100,000 Genomes Project. Researchers were able to combine these proteomic measurements with genomic and clinical data held within Genomics England's National Genomic Research Library, a secure research resource that enables approved researchers to study genomic data alongside health information to advance understanding of rare conditions.
By measuring nearly 1,500 proteins in blood and combining this information with genomic data, the researchers were able to resolve previously uncertain genetic findings and provide evidence supporting diagnoses for some patients. The approach also helped identify candidate genetic variants and genes that could potentially explain the conditions of other patients and warrant further investigation.
The findings provide proof-of-principle that large-scale blood proteomics, the measurement of many proteins simultaneously, could complement genome sequencing in the diagnosis of rare conditions.
Rare conditions collectively affect millions of people worldwide, but finding the genetic cause of an individual patient's condition can be extremely challenging. Although genome and exome sequencing have transformed rare conditions diagnosis, a large proportion of patients still receive no definitive answer.
One particular challenge is interpreting genetic changes known as ‘variants of uncertain significance’ (VUS). These are variants identified through sequencing where there is not enough evidence to determine whether they are responsible for a patient's condition.
Proteins offer an additional source of information because they can provide a functional readout of what is happening as a result of a genetic variant. An unusually high or low level of a particular protein in a patient's blood can therefore provide evidence that a genetic change is having a biological effect.
The researchers found the approach was particularly useful in patients with hereditary haemorrhagic telangiectasia (HHT), a rare inherited disorder affecting blood vessels. Combining protein and genomic information helped resolve cases that had remained undiagnosed following genomic analysis.
Protein measurements also helped researchers identify genetic changes that had been missed by standard approaches to analysing genome sequencing data. The team additionally investigated whether unusual protein levels could point towards genes not previously firmly established as causing a particular rare condition.
One example involved TIE1, a protein involved in blood vessel function. Researchers identified a rare genetic variant in TIE1 in a patient with a previously unexplained inherited cardiac disorder who also had exceptionally low levels of the TIE1 protein in their blood.
The same genetic variant was present in the patient's father, who had the same condition, and was not found in other participants in the 100,000 Genomes Project. Further laboratory experiments using cells derived from the patient supported the finding by showing markedly reduced levels and signalling of the TIE1 protein.
The researchers stress that findings such as this represent candidate gene-condition links requiring further evidence rather than confirmed new causes of rare conditions. However, they demonstrate how combining protein and genomic information could help researchers prioritise promising leads that would otherwise be difficult to identify.
Dr Julia Carrasco-Zanini, of Queen Mary University's Precision Healthcare University Research Institute and first author of the study, commented: “Genome sequencing has transformed our ability to diagnose rare conditions, but for many patients it still doesn't provide an answer. Our study shows how looking at proteins alongside the genome can give us another layer of evidence. If a genetic variant is accompanied by an unusually low level of the corresponding protein, for example, that can help us understand whether that variant is actually disrupting the way the gene functions. This could help us make more sense of genetic information we already have, rather than simply looking for more and more variants.”
- Carrasco-Zanini J, Andrade J, Pietzner M, et al. Proteomics identify disease-associated variants in patients with rare diseases undiagnosed after genome sequencing. Sci Transl Med. 2026;18(866):eaeb1331. doi:10.1126/scitranslmed.aeb1331