1. Integration of proteomics with genomics and transcriptomics increases the diagnostic rate of Mendelian disorders
- Author
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Christian Staufner, Slama A, Agnieszka Nadel, von Kleist-Retzow J, Mayr H, Thomas Meitinger, Ines F. Scheller, Loipfinger S, Peter Freisinger, Christina Ludwig, Kei Murayama, Smirnov D, Bucher M, Felix Distelmaier, Nasca A, Chen Meng, René Santer, Kulterer L, Sarah L. Stenton, Yepez, Jürgen Behr, Akira Ohtake, Maja Hempel, T. M. Strom, Metodi D. Metodiev, Saskia B. Wortmann, Christian Mertes, Mirjana Gusic, Holger Prokisch, Baski R, Dorota Piekutowska-Abramczuk, Verloo P, Riccardo Berutti, Rikke Katrine Jentoft Olsen, Robert Kopajtich, Daniele Ghezzi, Costanza Lamperti, Detlev Schindler, Julien Gagneur, Yasushi Okazaki, and Roetig A
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Transcriptome ,symbols.namesake ,Mendelian inheritance ,symbols ,Genomics ,Computational biology ,Biology ,Proteomics ,Omics ,Tandem mass tag ,Gene ,Genome - Abstract
By lack of functional evidence, genome-based diagnostic rates cap at approximately 50% across diverse Mendelian diseases. Here, we demonstrate the effectiveness of combining genomics, transcriptomics, and, for the first time, proteomics and phenotypic descriptors, in a systematic diagnostic approach to discover the genetic cause of mitochondrial diseases. On fibroblast cell lines from 145 individuals, tandem mass tag labelled proteomics detected approximately 8,000 proteins per sample and covered over 50% of all Mendelian disease-associated genes. Aberrant protein expression analysis allowed the validation of candidate protein-destabilising variants, in addition to providing independent complementary functional evidence to variants leading to aberrant RNA expression. Overall, our integrative computational workflow led to genetic resolution for 22% of 121 genetically unsolved whole exome or whole genome negative cases and to the discovery of two novel disease genes. With increasing democratization of high-throughput omics assays, our approach and code provide a blueprint for implementing multi-omics based Mendelian disease diagnostics in routine clinical practice.
- Published
- 2021
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