{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T14:06:07Z","timestamp":1792073167754,"version":"4.4.0"},"reference-count":56,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T00:00:00Z","timestamp":1770595200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T00:00:00Z","timestamp":1770595200000},"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":["2023\u2010102"],"award-info":[{"award-number":["2023\u2010102"]}],"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":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Newborn screening (NBS) for X\u2010linked adrenoleukodystrophy (ALD) enables early identification of boys at risk for adrenal insufficiency (AI) and cerebral ALD (CALD). However, NBS frequently identifies\n                    <jats:italic>ABCD1<\/jats:italic>\n                    variants of uncertain significance (VUS), which are associated with only borderline\u2010elevated C26:0\u2010lysophosphatidylcholine (LPC(26:0)) levels. Traditional American College of Medical Genetics and Genomics (ACMG) pathogenicity classification does not account for age\u2010dependent penetrance or the broader phenotypic spectrum, complicating risk assessment and clinical management. Through the Grey Zone Project, we developed a risk\u2010stratification framework using a receiver operating characteristic (ROC)\u2010based approach prioritizing 95% sensitivity. This framework incorporates biochemical and longitudinal clinical data from 1627 control subjects and 196 confirmed ALD patients. Three pediatric risk categories were defined: \u201cno ALD\u201d (&lt;110\u2009nmol\/L LPC(26:0)), \u201clower\u2010risk AI\/CALD\u201d (110\u2013177\u2009nmol\/L), and \u201cat\u2010risk AI\/CALD\u201d (&gt;177\u2009nmol\/L). When applied to 108 samples carrying 51 unique\n                    <jats:italic>ABCD1<\/jats:italic>\n                    VUSs, 26 variants were reclassified as \u201cno ALD,\u201d 15 as \u201clower\u2010risk AI\/CALD,\u201d and 10 as \u201cat\u2010risk AI\/CALD.\u201d The framework reclassifies\n                    <jats:italic>ABCD1<\/jats:italic>\n                    variants based on biochemical risk profiles, reducing false\u2010positive referrals, avoiding unnecessary MRI surveillance, and alleviating parental anxiety by identifying children who are unlikely to develop childhood\u2010onset disease. Integrating biochemical thresholds with genetic and longitudinal clinical data improves the specificity of NBS without compromising its sensitivity. Providing systematic feedback on false\u2010positive cases to screening laboratories will further refine cut\u2010offs. This framework provides a scalable, evidence\u2010based model for interpreting variants and enabling personalized follow\u2010up in ALD and other disorders with a variable age of onset.\n                  <\/jats:p>","DOI":"10.1002\/jimd.70157","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T03:46:41Z","timestamp":1770695201000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Grey Zone Project: Risk\u2010Based Classification of\n                    <scp>\n                      <i>ABCD1<\/i>\n                    <\/scp>\n                    Variants in X\u2010Linked Adrenoleukodystrophy"],"prefix":"10.1002","volume":"49","author":[{"given":"Troy C.","family":"Lund","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Pediatric Blood and Marrow Transplantation and Cellular Therapy University of Minnesota Medical School  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Miettunen","sequence":"additional","affiliation":[{"name":"ALD Connect (https:\/\/aldconnect.org\/)  Middleton Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yorrick R. J.","family":"Jaspers","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC, Amsterdam Gastroenterology Endocrinology Metabolism University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Bergner","sequence":"additional","affiliation":[{"name":"Department of Neurology University Medical Center  Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua L.","family":"Bonkowsky","sequence":"additional","affiliation":[{"name":"Center for Personalized Medicine, Primary Children's Hospital, Division of Pediatric Neurology University of Utah School of Medicine  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4419-7381","authenticated-orcid":false,"given":"Fabio","family":"Bruschi","sequence":"additional","affiliation":[{"name":"Center for Diagnosis and Treatment of Leukodystrophies and Genetic Leukoencephalopathies (COALA) Vittore Buzzi Children's Hospital  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie S.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Moser Center for Leukodystrophies, Kennedy Krieger Institute, Department of Neurology The Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inge M. E.","family":"Dijkstra","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC, Amsterdam Gastroenterology Endocrinology Metabolism University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian S.","family":"Eichler","sequence":"additional","affiliation":[{"name":"Center for Rare Neurological Diseases, Department of Neurology Harvard Medical School, Massachusetts General Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric J.","family":"Mallack","sequence":"additional","affiliation":[{"name":"Moser Center for Leukodystrophies, Kennedy Krieger Institute, Department of Neurology The Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gajja S.","family":"Salomons","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC, Amsterdam Gastroenterology Endocrinology Metabolism University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Thompson","sequence":"additional","affiliation":[{"name":"Center for Rare Neurological Diseases, Department of Neurology Harvard Medical School, Massachusetts General Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Tonduti","sequence":"additional","affiliation":[{"name":"Center for Diagnosis and Treatment of Leukodystrophies and Genetic Leukoencephalopathies (COALA) Vittore Buzzi Children's Hospital  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith P.","family":"van Haren","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences Stanford University School of Medicine  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9382-613X","authenticated-orcid":false,"given":"Mirjam M. 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