Diagnosing, discarding, or de-VUSsing: A practical guide to (un)targeted metabolomics as variant-transcending functional tests

Elise A Ferreira; Annemarijne R J Veenvliet; Udo F H Engelke; Leo A J Kluijtmans; Marleen C D G Huigen; Brechtje Hoegen; Lonneke de Boer; Maaike C de Vries; Bregje W van Bon; Erika Leenders; Elisabeth A M Cornelissen; Charlotte A Haaxma; Jolanda H Schieving; M Estela Rubio-Gozalbo; Irene M L W Körver-Keularts; Lara M Marten; Susann Diegmann; Jeroen Mourmans; Alexander J M Rennings; Clara D M van Karnebeek; Richard J Rodenburg; Karlien L M Coene

doi:10.1016/j.gim.2022.10.002

Diagnosing, discarding, or de-VUSsing: A practical guide to (un)targeted metabolomics as variant-transcending functional tests

Elise A Ferreira, Annemarijne R J Veenvliet, Udo F H Engelke, Leo A J Kluijtmans, Marleen C D G Huigen, Brechtje Hoegen, Lonneke de Boer, Maaike C de Vries, Bregje W van Bon, Erika Leenders, Elisabeth A M Cornelissen, Charlotte A Haaxma, Jolanda H Schieving, M Estela Rubio-Gozalbo, Irene M L W Körver-Keularts, Lara M Marten, Susann Diegmann, Jeroen Mourmans, Alexander J M Rennings, Clara D M van KarnebeekRichard J Rodenburg^*, Karlien L M Coene

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

PURPOSE: For 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.

METHODS: Using 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.

RESULTS: The 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.

CONCLUSION: Metabolomics-based gene function tests provide additional value in the diagnostic trajectory of patients with suspected IMD by enhancing and accelerating diagnostic success.

Original language	English
Pages (from-to)	125-134
Number of pages	10
Journal	Genetics in Medicine
Volume	25
Issue number	1
Early online date	8 Nov 2022
DOIs	https://doi.org/10.1016/j.gim.2022.10.002
Publication status	Published - Jan 2023

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Ferreira, E. A., Veenvliet, A. R. J., Engelke, U. F. H., Kluijtmans, L. A. J., Huigen, M. C. D. G., Hoegen, B., de Boer, L., de Vries, M. C., van Bon, B. W., Leenders, E., Cornelissen, E. A. M., Haaxma, C. A., Schieving, J. H., Rubio-Gozalbo, M. E., Körver-Keularts, I. M. L. W., Marten, L. M., Diegmann, S., Mourmans, J., Rennings, A. J. M., ... Coene, K. L. M. (2023). Diagnosing, discarding, or de-VUSsing: A practical guide to (un)targeted metabolomics as variant-transcending functional tests. Genetics in Medicine, 25(1), 125-134. https://doi.org/10.1016/j.gim.2022.10.002

@article{2c0e76f140924b5f81f9d6067798851e,

title = "Diagnosing, discarding, or de-VUSsing: A practical guide to (un)targeted metabolomics as variant-transcending functional tests",

abstract = "PURPOSE: For 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.METHODS: Using 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.RESULTS: The 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.CONCLUSION: Metabolomics-based gene function tests provide additional value in the diagnostic trajectory of patients with suspected IMD by enhancing and accelerating diagnostic success.",

author = "Ferreira, {Elise A} and Veenvliet, {Annemarijne R J} and Engelke, {Udo F H} and Kluijtmans, {Leo A J} and Huigen, {Marleen C D G} and Brechtje Hoegen and {de Boer}, Lonneke and {de Vries}, {Maaike C} and {van Bon}, {Bregje W} and Erika Leenders and Cornelissen, {Elisabeth A M} and Haaxma, {Charlotte A} and Schieving, {Jolanda H} and Rubio-Gozalbo, {M Estela} and K{\"o}rver-Keularts, {Irene M L W} and Marten, {Lara M} and Susann Diegmann and Jeroen Mourmans and Rennings, {Alexander J M} and {van Karnebeek}, {Clara D M} and Rodenburg, {Richard J} and Coene, {Karlien L M}",

year = "2023",

month = jan,

doi = "10.1016/j.gim.2022.10.002",

language = "English",

volume = "25",

pages = "125--134",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Nature Publishing Group",

number = "1",

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Ferreira, EA, Veenvliet, ARJ, Engelke, UFH, Kluijtmans, LAJ, Huigen, MCDG, Hoegen, B, de Boer, L, de Vries, MC, van Bon, BW, Leenders, E, Cornelissen, EAM, Haaxma, CA, Schieving, JH, Rubio-Gozalbo, ME, Körver-Keularts, IMLW, Marten, LM, Diegmann, S, Mourmans, J, Rennings, AJM, van Karnebeek, CDM, Rodenburg, RJ & Coene, KLM 2023, 'Diagnosing, discarding, or de-VUSsing: A practical guide to (un)targeted metabolomics as variant-transcending functional tests', Genetics in Medicine, vol. 25, no. 1, pp. 125-134. https://doi.org/10.1016/j.gim.2022.10.002

TY - JOUR

T1 - Diagnosing, discarding, or de-VUSsing

T2 - A practical guide to (un)targeted metabolomics as variant-transcending functional tests

AU - Ferreira, Elise A

AU - Veenvliet, Annemarijne R J

AU - Engelke, Udo F H

AU - Kluijtmans, Leo A J

AU - Huigen, Marleen C D G

AU - Hoegen, Brechtje

AU - de Boer, Lonneke

AU - de Vries, Maaike C

AU - van Bon, Bregje W

AU - Leenders, Erika

AU - Cornelissen, Elisabeth A M

AU - Haaxma, Charlotte A

AU - Schieving, Jolanda H

AU - Rubio-Gozalbo, M Estela

AU - Körver-Keularts, Irene M L W

AU - Marten, Lara M

AU - Diegmann, Susann

AU - Mourmans, Jeroen

AU - Rennings, Alexander J M

AU - van Karnebeek, Clara D M

AU - Rodenburg, Richard J

AU - Coene, Karlien L M

PY - 2023/1

Y1 - 2023/1

N2 - PURPOSE: For 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.METHODS: Using 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.RESULTS: The 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.CONCLUSION: Metabolomics-based gene function tests provide additional value in the diagnostic trajectory of patients with suspected IMD by enhancing and accelerating diagnostic success.

AB - PURPOSE: For 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.METHODS: Using 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.RESULTS: The 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.CONCLUSION: Metabolomics-based gene function tests provide additional value in the diagnostic trajectory of patients with suspected IMD by enhancing and accelerating diagnostic success.

U2 - 10.1016/j.gim.2022.10.002

DO - 10.1016/j.gim.2022.10.002

M3 - Article

C2 - 36350326

SN - 1098-3600

VL - 25

SP - 125

EP - 134

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 1

ER -