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Your search keyword '"Kulterer L"' showing total 2 results
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2 results on '"Kulterer L"'

1. Integration of proteomics with genomics and transcriptomics increases the diagnostic rate of Mendelian disorders

Author

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

Subjects
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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2. Expanding the clinical and genetic spectrum of FDXR deficiency by functional validation of variants of uncertain significance.

Author

Stenton SL, Piekutowska-Abramczuk D, Kulterer L, Kopajtich R, Claeys KG, Ciara E, Eisen J, Płoski R, Pronicka E, Malczyk K, Wagner M, Wortmann SB, and Prokisch H

Subjects
Humans, Phenotype, Exome Sequencing, Leigh Disease genetics, Mitochondrial Diseases genetics, Optic Atrophy genetics
Abstract

Ferrodoxin reductase (FDXR) deficiency is a mitochondrial disease described in recent years primarily in association with optic atrophy, acoustic neuropathy, and developmental delays. Here, we identified seven unpublished patients with FDXR deficiency belonging to six independent families. These patients show a broad clinical spectrum ranging from Leigh syndrome with early demise and severe infantile-onset encephalopathy, to milder movement disorders. In total nine individual pathogenic variants, of which seven were novel, were identified in FDXR using whole exome sequencing in suspected mitochondrial disease patients. Over 80% of these variants are missense, a challenging variant class in which to determine pathogenic consequence, especially in the setting of nonspecific phenotypes and in the absence of a reliable biomarker, necessitating functional validation. Here we implement an Arh1-null yeast model to confirm the pathogenicity of variants of uncertain significance in FDXR, bypassing the requirement for patient-derived material., (© 2020 The Authors. Human Mutation Published by Wiley Periodicals LLC.)

Published
2021
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