Combining blood protein profiling with genome sequencing can identify rare disease diagnoses that DNA analysis misses alone, according to a study published by researchers from Queen Mary University of London, the Berlin Institute of Health at Charité, and Genomics England. The approach measures nearly 1,500 proteins simultaneously to provide functional readouts of genetic variants, offering clinicians a new layer of evidence when standard genomic testing yields uncertain results.
Rare diseases affect millions of people worldwide, but finding a definitive genetic cause remains difficult. Genome and exome sequencing have transformed diagnostics, yet a large proportion of patients still receive no answers. According to the research team, a primary hurdle involves interpreting variants of uncertain significance, which are genetic changes identified through sequencing that lack sufficient evidence to determine whether they are responsible for a patient’s disease.
How Blood Proteomics Complements Genome Sequencing
Proteins act as functional readouts of what happens inside the body as a result of a genetic variant, according to the study. An unusually high or low level of a specific protein in a patient’s blood indicates that a genetic change has a biological effect. Dr. Julia Carrasco-Zanini of the Precision Healthcare University Research Institute at Queen Mary University of London and first author of the study noted that looking at proteins alongside the genome gives researchers another layer of evidence to understand whether a variant disrupts gene function.
By analyzing blood samples from patients who remained undiagnosed following the 100,000 Genomes Project, the research team resolved previously uncertain genetic findings. The method proved especially useful for patients with hereditary haemorrhagic telangiectasia, a rare inherited disorder that affects blood vessels.
Identifying Novel Disease-Causing Genes
Beyond resolving existing genetic uncertainties, the combination of proteomic and genomic data helped researchers uncover genetic changes missed by standard sequencing analysis. According to the findings, the approach assists in identifying candidate genes that might cause rare conditions.
In one case investigated by the team, a patient with an unexplained inherited cardiac disorder had exceptionally low levels of TIE1, a protein involved in blood vessel function. Researchers identified a rare genetic variant in TIE1 of that patient. The same variant appeared in the patient’s father, who shared the condition, but was absent in other participants of the 100,000 Genomes Project. Subsequent laboratory experiments using patient-derived cells confirmed markedly reduced levels and signaling of the TIE1 protein.
Frequently Asked Questions
- What is blood protein profiling in rare disease diagnosis? It is the simultaneous measurement of nearly 1,500 proteins in a patient’s blood to see how genetic variants affect protein levels and biological functions.
- Why do some rare disease patients not get answers from DNA sequencing? DNA sequencing often uncovers variants of uncertain significance, where insufficient evidence exists to prove the variant causes disease.
- Which institutions conducted this research? The study was conducted by researchers from Queen Mary University of London, the Berlin Institute of Health at Charité, and Genomics England, utilizing data from the 100,000 Genomes Project.
The findings provide proof-of-principle that large-scale blood proteomics can complement genome sequencing for rare diseases. The research team emphasizes that discoveries involving genes like TIE1 serve as candidate findings that require further investigation to confirm their role in pathology.
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