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

Author:

Hock Daniella H.ORCID,Caruana Nikeisha J.,Semcesen Liana N.,Lake Nicole J.ORCID,Formosa Luke E.,Amarasekera Sumudu S. C.,Stait Tegan,Tregoning Simone,Frajman Leah E.,Robinson David R. L.,Ball Megan,Reljic Boris,Ryder Bryony,Wallis Mathew J.,Vasudevan Anand,Beck Cara,Peters Heidi,Lee Joy,Tan Natalie B.,Freckmann Mary-Louise, ,Karlaftis Vasiliki,Attard Chantal,Monagle Paul,Samarasinghe Amanda,Brown Rosie,Bi Weimin,Lek Monkol,McFarland RobertORCID,Taylor Robert W.,Ryan Michael T.ORCID,Stark Zornitza,Christodoulou JohnORCID,Compton Alison G.,Thorburn David R.ORCID,Stroud David A.ORCID

Abstract

AbstractOnly half of individuals with suspected rare diseases receive a definitive genetic diagnosis following genomic testing. A genetic diagnosis allows access to appropriate patient care and reduces the number of potentially unnecessary interventions and related healthcare costs. Here, we demonstrate that an untargeted quantitative mass-spectrometry approach quantifying >6,000 proteins in primary fibroblasts representing >80% of known mitochondrial disease genes can provide functional evidence for 83% of individuals in a cohort of known primary mitochondrial diseases. We profiled >90 individuals, including 28 with confirmed disease and diagnosed 6 individuals with variants in both nuclear and mitochondrial genes. Lastly, we developed an ultra-rapid proteomics pipeline using minimally invasive peripheral blood mononuclear cells to support upgrade of variant pathogenicity in as little as 54 hours in critically ill infants with suspected mitochondrial disorders. This study supports the integration of a single untargeted proteomics test into routine diagnostic practice for the diagnosis of rare genetic disorders in clinically actionable timelines, offering a paradigm shift for the functional validation of genetic variants.

Publisher

Cold Spring Harbor Laboratory

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