Clinical genomics, read and reviewed for you

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.