Proteomics identify disease-associated variants in patients with rare diseases undiagnosed after genome sequencing.

Serum proteomics (Olink Explore 1536): low-protein outliers used as indirect functional evidence, combined with Exomiser variant prioritization

Serum proteomic profiling with the Olink Explore 1536 assay (1,463 proteins) was performed in 424 rare disease patients from the 100,000 Genomes Project who remained without a genetic diagnosis after genome sequencing. In 13 patients, low serum protein outliers (z-score < -2) led to a confirmed genetic diagnosis by resolving a variant of uncertain significance or by prioritizing genes for targeted genome reanalysis. In 23 further patients (64% of findings), convergence between low protein outliers and Exomiser-ranked variants yielded candidate gene-disease links, including a heterozygous missense variant in TIE1 (gnomAD minor allele frequency 0.006%) found only in a patient with markedly low serum TIE1 (z-score = -5.12) and his father, both affected by the same monogenic cardiac disorder. Missense (52.5%) and splice region (27.5%) variants accounted for most prioritized variants.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Serum proteomics is used here exactly where it should be: settling a variant of uncertain significance through an indirect functional readout, without a new tissue biopsy. The yield stays modest — 13 confirmed diagnoses out of 424 patients — and depends entirely on three conditions the authors themselves list: the protein must be expressed in a tissue from which it reaches blood, be covered by the proteomic panel, and be measurable with sufficient sensitivity. A credible adjunct to genome reanalysis, not a first-line test.

Analysis by Dr Thibaut Benquey