Diagnosing,discarding, or de-VUSsing: A practical guide to (un)targeted metabolomics as variant-transcending functional tests |
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| Affiliation: | 1. Department of Pediatrics, Emma Children’s Hospital, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands;2. United for Metabolic Diseases, Amsterdam, The Netherlands;3. Department of Pediatrics, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, The Netherlands;4. Department of Laboratory Medicine, Translational Metabolic Laboratory (TML), Radboud University Medical Center, Nijmegen, The Netherlands;5. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands;6. Department of Pediatric Nephrology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, The Netherlands;7. Department of Pediatric Neurology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, The Netherlands;8. Department of Pediatrics, Maastricht University Medical Centre, Maastricht University, Maastricht, The Netherlands;9. Department of Clinical Genetics, Maastricht University Medical Center, Maastricht University, Maastricht, The Netherlands;10. GROW-School for Oncology and Developmental Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands;11. Division of Pediatric Neurology, Department of Pediatrics and Adolescent Medicine, University Medical Centre Göttingen, University of Göttingen, Göttingen, Germany;12. Department of Pediatrics, Deventer Ziekenhuis, Deventer, The Netherlands;13. Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands;14. Department of Human Genetics, Amsterdam Reproduction and Development, Amsterdam University Medical Centers, Amsterdam, The Netherlands;15. Department of Clinical Chemistry and Hematology, Elisabeth-TweeSteden Hospital, Tilburg, The Netherlands |
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| Abstract: | PurposeFor patients with inherited metabolic disorders (IMDs), any diagnostic delay should be avoided because early initiation of personalized treatment could prevent irreversible health damage. To improve diagnostic interpretation of genetic data, gene function tests can be valuable assets. For IMDs, variant-transcending functional tests are readily available through (un)targeted metabolomics assays. To support the application of metabolomics for this purpose, we developed a gene-based guide to select functional tests to either confirm or exclude an IMD diagnosis.MethodsUsing information from a diagnostic IMD exome panel, Kyoto Encyclopedia of Genes and Genomes, and Inborn Errors of Metabolism Knowledgebase, we compiled a guide for metabolomics-based gene function tests. From our practical experience with this guide, we retrospectively selected illustrative cases for whom combined metabolomic/genomic testing improved diagnostic success and evaluated the effect hereof on clinical management.ResultsThe guide contains 2047 metabolism-associated genes for which a validated or putative variant-transcending gene function test is available. We present 16 patients for whom metabolomic testing either confirmed or ruled out the presence of a second pathogenic variant, validated or ruled out pathogenicity of variants of uncertain significance, or identified a diagnosis initially missed by genetic analysis.ConclusionMetabolomics-based gene function tests provide additional value in the diagnostic trajectory of patients with suspected IMD by enhancing and accelerating diagnostic success. |
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| Keywords: | Exome sequencing Functional test Genome sequencing Inborn errors of metabolism Metabolomics |
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