Untargeted proteomics enables ultra-rapid variant prioritisation in mitochondrial and other rare diseases

Abstract

Background: Only half of individuals with suspected rare diseases receive a genetic diagnosis following genomic testing. A genetic diagnosis allows access to appropriate care, restores reproductive confidence and reduces the number of potentially unnecessary interventions. A major barrier is the lack of disease agnostic functional tests suitable for implementation in routine diagnostics that can provide evidence supporting pathogenicity of novel variants, especially those refractory to RNA sequencing. Methods: Focusing on mitochondrial disease, we describe an untargeted mass-spectrometry based proteomics pipeline that can quantify proteins encoded by > 50% of Mendelian disease genes and > 80..