Diagnosis of Rare Diseases: How Genome Sequencing and Blood Protein Analysis Work Together

Millions of people worldwide are affected by rare diseases. However, identifying the genetic cause of a disease in individual patients can sometimes pose an enormous challenge. Although genome sequencing has revolutionized the diagnosis of rare diseases, many patients still do not get a definitive diagnosis.

Researchers at the Berlin Institute of Health at Charité (BIH), Queen Mary University of London, and Genomics England have now shown that measuring proteins in the blood can provide important clues about the effects of genetic variants. Data on these blood proteins can aid in diagnosis and potentially identify new disease-causing genes that could not be detected by genome sequencing alone.

The team led by Claudia Langenberg, head of the BIH Computational Medicine research group and director of PHURI at Queen Mary University of London, analyzed blood samples from people with rare diseases for whom no genetic diagnosis could be made following testing as part of Genomics England’s 100,000 Genomes Project. Using information on nearly 1,500 proteins in the blood, combined with genomic data, the researchers were able to clarify previously unclear genetic findings. For some patients, they were able to confirm diagnoses that had already been made. For other patients, new genetic variants were identified that serve as possible explanations for their conditions. The researchers conclude that large-scale blood proteomics approaches could complement the genome sequencing methods traditionally used in the diagnosis of rare diseases.

Not Always Clear: The Effects of Genetic Variants

Genome sequencing can identify a wide range of genetic variants. However, it is not always clear what effects these variants have on humans or whether they could be responsible for a disease. Proteins in the blood can provide additional information on this matter. For example, an unusually high level of a specific protein in a patient’s blood may indicate that a genetic change also has a biological effect.

The research team also investigated whether, conversely, unusual protein concentrations might point to genes that had not yet been clearly identified as the cause of a specific rare disease. They found an example of this in the TIE1 protein, which is involved in blood vessel function. They identified a rare genetic variant in TIE1 in a patient with a previously unexplained hereditary heart condition who also had exceptionally low levels of the TIE1 protein in his blood. They found the same genetic variant in the patient’s father, who suffered from the same condition.

Further Research in Proteomics Is Needed

The researchers emphasize that further studies are needed to confirm their findings and interpretation. However, it is becoming clear that combining protein and genomic information could help researchers develop new approaches to diagnosing rare diseases.

Claudia Langenberg says: „The real opportunity is in bringing different layers of biological information together. The genome gives us the blueprint, but proteins can tell us something about how that blueprint is being translated into biology in an individual patient. This study demonstrates the potential of combining these technologies to extract more information from genomic data and, ultimately, to improve our ability to find answers for people affected by rare diseases.”