{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:00:38Z","timestamp":1790593238555,"version":"4.1.0"},"reference-count":19,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100016062","name":"Stichting Metakids","doi-asserted-by":"publisher","award":["UMD\u2010ZOE\u20102022\u2010012"],"award-info":[{"award-number":["UMD\u2010ZOE\u20102022\u2010012"]}],"id":[{"id":"10.13039\/100016062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Inherited metabolic disorders (IMDs) arise from defects in metabolic pathways essential for normal biochemical function. Although the pathogenic genetic variants are present at birth, clinical manifestations may not emerge until adolescence or adulthood. Symptoms may be more subtle compared to those of childhood onset IMDs and may have overlap with signs and symptoms of acquired disorders. This makes diagnosing IMDs in adulthood challenging. To identify how routine diagnostic care for adults suspected of having an IMD could be improved, we conducted a reanalysis study in a cohort of 31 adult participants. The participants, who remained undiagnosed after standard diagnostic care, were seen by a clinical geneticist, adult metabolic specialist and neurologist for deep phenotyping and data collection. Subsequently, exome sequencing data were reanalyzed and possible disease\u2010causing variants were prioritized for further evaluation by a multidisciplinary team including both clinicians and geneticists (biochemical and molecular). This approach led to a (partial) diagnosis for nine participants from six families, giving a 25% diagnostic yield. We could distinguish four possible reasons why the identified disease\u2010associated variants were not detected during routine diagnostic care. Beyond the expected impact of technical advancements and emerging knowledge of disease genes, we found that the most impactful factor was of organizational nature. Our findings underscore the value of reviewing all strong genetic variants within a multidisciplinary team setting, facilitating a bidirectional exchange of expertise. This approach enhances diagnostic accuracy, particularly when the underlying cause of the disease is not immediately apparent.<\/jats:p>","DOI":"10.1002\/jimd.70238","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T05:16:35Z","timestamp":1787289395000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An Optimized Diagnostic Approach for Adults With Suspected Inherited Metabolic Disorders"],"prefix":"10.1002","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4864-9346","authenticated-orcid":false,"given":"Machteld M.","family":"Oud","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour Radboud University Medical Center  Nijmegen the Netherlands"},{"name":"United for Metabolic Diseases  the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9397-942X","authenticated-orcid":false,"given":"Elise A.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"United for Metabolic Diseases  the Netherlands"},{"name":"Department of Paediatrics, Emma Children's Hospital Amsterdam University Medical Center  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara D. M.","family":"van Karnebeek","sequence":"additional","affiliation":[{"name":"United for Metabolic Diseases  the Netherlands"},{"name":"Department of Paediatrics, Emma Children's Hospital Amsterdam University Medical Center  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Wijngaard","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour Radboud University Medical Center  Nijmegen the Netherlands"},{"name":"United for Metabolic Diseases  the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1721-0728","authenticated-orcid":false,"given":"Nicole I.","family":"Wolf","sequence":"additional","affiliation":[{"name":"Amsterdam Leukodystrophy Center, Department of Child Neurology, Emma Children's Hospital and Amsterdam Neuroscience Amsterdam University Medical Center, Vrije Universiteit Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Engelen","sequence":"additional","affiliation":[{"name":"Department of Neurology and Pediatric Neurology, Emma Children's Hospital, Amsterdam Leukodystrophy Center Amsterdam University Medical Center  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mareen","family":"Datema","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Amsterdam UMC University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7738-5709","authenticated-orcid":false,"given":"Sacha","family":"Ferdinandusse","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Laboratory Genetic Metabolic Diseases Amsterdam UMC Location University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7989-4910","authenticated-orcid":false,"given":"Andr\u00e9 B. P.","family":"van Kuilenburg","sequence":"additional","affiliation":[{"name":"Department of Genetic Metabolic Diseases, Amsterdam UMC Vrije Universiteit Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7076-8662","authenticated-orcid":false,"given":"Laura","family":"Steinbusch","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics and Genome Services Maastricht Maastricht University Medical Centre+  Maastricht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8619-1511","authenticated-orcid":false,"given":"Saskia N.","family":"van der Crabben","sequence":"additional","affiliation":[{"name":"United for Metabolic Diseases  the Netherlands"},{"name":"Department of Human Genetics, Amsterdam University Medical Center University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9934-6831","authenticated-orcid":false,"given":"Mirjam","family":"Langeveld","sequence":"additional","affiliation":[{"name":"United for Metabolic Diseases  the Netherlands"},{"name":"Department of Endocrinology and Metabolism, Amsterdam UMC University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the ZOEMBA Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.70005"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.70057"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-019-1232-0"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2023.1206106"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-018-0022-8"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes16030289"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fradi.2026.1782924"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-020-0933-z"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv057"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1056843"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2018-00338"},{"key":"e_1_2_13_13_1","article-title":"Scalable Automated Reanalysis of Genomic Data in Research and Clinical Rare Disease Cohorts","author":"Welland M. 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