{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T01:46:55Z","timestamp":1791424015682,"version":"4.3.3"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Wolfram syndrome is a rare genetic disorder characterized by antibody\u2010negative early\u2010onset atypical diabetes mellitus, optic nerve atrophy, sensorineural hearing loss, central diabetes insipidus (arginine vasopressin deficiency), and progressive neurodegeneration, with significant variability in disease severity. We assessed the accuracy of a genotype\u2010based severity scoring system for predicting the onset of cardinal symptoms in Wolfram syndrome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The scoring system is based on the type of WFS1 variants (in\u2010frame or out\u2010of\u2010frame) and their location relative to transmembrane domains, defining six severity classes. Severity scores were assigned to 324 patients with documented onset ages for diabetes mellitus, optic atrophy, hearing loss, and central diabetes insipidus. A computational rule-based framework and genotype\u2010only gradient\u2010boosting machine\u2010learning models were developed to independently evaluate the scoring system and to estimate age of onset.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The severity score showed a clear association with earlier onset of diabetes mellitus and, less consistently, optic atrophy, but no correlation with hearing loss or central diabetes insipidus. Patients with in\u2010frame variants outside transmembrane domains showed milder disease, especially the WFS1 c.1672C&amp;gt;T (p.Arg558Cys) variant, which is associated with a mild form of Wolfram syndrome prevalent in the Ashkenazi Jewish population, whereas out\u2010of\u2010frame variants showed the earliest onset. Severity scores 3 and 4 deviated from the expected progression, suggesting that transmembrane\u2010domain involvement in both alleles increases severity. Consolidation into three tiers (Mild, Moderate, Severe) yielded median diabetes mellitus onset ages of 9.0, 6.5, and 4.6 years. The computational framework reproduced the six\u2010class annotation with 94.4% accuracy, and the engineered genotype model outperformed the original registry score (diabetes mellitus exact\u2010sextile accuracy 29.4% vs. 19.3%).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The genotype\u2010based severity score is most informative for diabetes mellitus, modestly informative for optic atrophy, and not currently useful for hearing loss or central diabetes insipidus. Because the analysis relies on observed events without time\u2010to\u2010event censoring and the three\u2010tier consolidation is a post hoc summary of the same dataset, results should be regarded as exploratory and hypothesis\u2010generating rather than as a validated clinical prediction tool, while still offering useful insight into genotype\u2010related progression of Wolfram syndrome.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1839135","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T22:10:30Z","timestamp":1784067030000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Genotype-based severity scoring system in Wolfram Syndrome: correlation with onset of cardinal symptoms and WFS1 gene variant types"],"prefix":"10.3389","volume":"17","author":[{"given":"Liam","family":"Oiknine","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine","place":["St. Louis, MO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abby F.","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine","place":["St. Louis, MO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan M.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine","place":["St. Louis, MO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nila","family":"Palaniappan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine","place":["St. Louis, MO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megha","family":"Verma","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine","place":["St. Louis, MO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasra","family":"Vand","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering and Informatics, Luddy School of Informatics, Computing and Engineering, Indiana University Indianapolis (IUI)","place":["Indianapolis, IN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahiti","family":"Somalraju","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering and Informatics, Luddy School of Informatics, Computing and Engineering, Indiana University Indianapolis (IUI)","place":["Indianapolis, IN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarath","family":"Chandra Janga","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering and Informatics, Luddy School of Informatics, Computing and Engineering, Indiana University Indianapolis (IUI)","place":["Indianapolis, IN, United States"]},{"name":"Department of Medical and Molecular Genetics, Indiana University School of Medicine","place":["Indianapolis, IN, United States"]},{"name":"Center for Computational Biology and Bioinformatics, Indiana University School of Medicine","place":["Indianapolis, IN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumihiko","family":"Urano","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine","place":["St. Louis, MO, United States"]},{"name":"Department of Pathology and Immunology, Washington University School of Medicine","place":["St. Louis, MO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e145188","DOI":"10.1172\/jci.insight.145188","article-title":"A phase Ib\/IIa clinical trial of dantrolene sodium in patients with Wolfram syndrome","volume":"6","author":"Abreu","year":"2021","journal-title":"JCI Insight"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2501","DOI":"10.1093\/hmg\/10.22.2501","article-title":"Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss","volume":"10","author":"Bespalova","year":"2001","journal-title":"Hum. 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