Serum proteomics led to genetic diagnoses in 13 rare disease patients after genome sequencing came up empty
Researchers analyzed serum samples from 424 patients in the 100,000 Genomes Project who had no genetic diagnosis despite whole genome sequencing. They measured 1,463 proteins using the Olink Explore 1536 assay and looked for abnormally low protein levels, defined as a z-score below -2. Those outliers helped confirm genetic causes in 13 patients by resolving variants of uncertain significance or flagging genes for targeted reanalysis. Another 23 patients gained candidate variants through convergent evidence from low protein outliers and the Exomiser variant prioritization tool. Missense variants made up 52.5 percent of the prioritized variants, splice region changes 27.5 percent. The work appeared in Science Translational Medicine on 29 January 2025.
Patients who remain undiagnosed after genome sequencing may benefit from serum protein profiling to resolve ambiguous variants or flag candidate genes, though success depends on tissue-specific expression, blood detectability, platform coverage, and assay sensitivity.
Written by the Genomes desk from the primary source cited and linked above and checked against it. Research use only; not medical advice. Corrections: [email protected].