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These conditions are generally milder than autosomal recessive Wolfram syndrome, except for Hattersley-Urano syndrome. Despite growing recognition of these disorders, data on clinical progression and long-term outcomes remain limited. This study aims to expand knowledge on disease severity and progression in autosomal dominant\n                      <jats:italic>WFS1<\/jats:italic>\n                      -related disorders.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach<\/jats:title>\n                    <jats:p>Clinical data were obtained from the Washington University International Registry and Clinical Study for Wolfram Syndrome and related disorders and the Endoplasmic Reticulum Disease Patient Registry and Biorepository. Fifteen participants with autosomal dominant WFS1 pathogenic variants presenting with both optic nerve atrophy and sensorineural hearing loss were included.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The 15 cases included seven distinct autosomal dominant\n                      <jats:italic>WFS1<\/jats:italic>\n                      variants: c.923C&gt;G (p.Ser308Cys), c.2051C&gt;T (p.Ala684Val), c.2389G&gt;T (p.Asp797Tyr), c.2402A&gt;G (p.Asp801Gly), c.2456A&gt;C (p.Gln819Pro), c.2492G&gt;C (p.Gly831Ala), and c.2590G&gt;A (p.Glu864Lys). Among these, the c.2402A&gt;G, c.2456A&gt;C, and c.2492G&gt;C variants have not been previously published. Median age at optic atrophy diagnosis was 10 years. Visual acuity and RNFL thickness did not change significantly with age. Of eight patients with Optical coherence tomography (OCT) scans, six showed outer plexiform layer (OPL) lamination, a characteristic feature of this disorder. Hearing loss was diagnosed at a median age of 2.0 years; all 15 participants use hearing aids, and eight have bilateral cochlear implants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Patients with autosomal dominant\n                      <jats:italic>WFS1<\/jats:italic>\n                      -related disorders experience early-onset hearing loss and late-childhood optic atrophy, with stable visual acuity and RNFL thickness over time. OPL lamination is a highly characteristic finding, and three novel variants with four clinical presentations are described.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-026-04348-9","type":"journal-article","created":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T11:52:06Z","timestamp":1776513126000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Natural history of 15 patients with autosomal dominant WFS1 pathogenic variants associated with sensorineural hearing loss and optic atrophy"],"prefix":"10.1186","volume":"21","author":[{"given":"Jessica P.","family":"Roberts","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abby F.","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Hernandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brianna","family":"Carman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liam","family":"Oiknine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cris","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacy","family":"Hurst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunshuo","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9944-6293","authenticated-orcid":false,"given":"Fumihiko","family":"Urano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,18]]},"reference":[{"issue":"1","key":"4348_CR1","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1007\/s11892-015-0702-6","volume":"16","author":"F Urano","year":"2016","unstructured":"Urano F. 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He is the current principal investigator of the Phase 2 clinical trial of AMX0035 in patients with Wolfram syndrome, sponsored by Amylyx Pharmaceuticals. He has received grants from the National Institutes of Health (NIH) and royalties from Novus Biologicals and Sana Biotechnology. He has also received licensing and\/or consulting fees from Opris Biotechnologies and Emerald Biotherapeutics, and travel support from Wolfram France, Wolfram UK, and the Snow Foundation. He serves in unpaid advisory roles for the Snow Foundation and the Be A Tiger Foundation. He holds U.S. patents (9,891,231; 10,441,574; 10,695,324) and was previously President and a shareholder of the now-dissolved CURE4WOLFRAM.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"210"}}