What question did this study set out to answer?

The aim is to evaluate the impact of clinical proteomics on variant classification for rare diseases.

February 22, 2026Pathology0 citations

Clinical proteomics in variant classification: are we there yet?

DHDaniella H. Hock LSLiana N. Semcesen NCNikeisha J. Caruana

Key Points

The aim is to evaluate the impact of clinical proteomics on variant classification for rare diseases.
Developed an untargeted mass spectrometry-based proteomics pipeline
Quantified proteins encoded by over 50% of mendelian disease genes
Utilized clinically relevant specimens including fibroblasts and skeletal muscle
Functional tests currently lack scalability and standardization
The new pipeline improves identification of variants of uncertain significance
Potential to enhance diagnostic capabilities in rare diseases

Abstract

Variants of uncertain significance (VUS) represent a major barrier to diagnosis in rare diseases. Functional evidence is critical for variant classification under ACMG/AMP guidelines, yet most functional tests lack scalability and standardisation, making them unsuitable for implementation in diagnostic labs. We developed an untargeted mass spectrometry-based proteomics pipeline that quantifies proteins encoded by >50% of mendelian disease genes in clinically relevant specimens, including fibroblasts, skeletal muscle, and peripheral blood mononuclear cells. 1

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