{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:48:53Z","timestamp":1787028533020,"version":"build-2736575974"},"reference-count":54,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T00:00:00Z","timestamp":1707350400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Koeln Fortune Program\/Faculty of Medicine, University of Cologne","award":["131\/2023"],"award-info":[{"award-number":["131\/2023"]}]},{"name":"Koeln Fortune Program\/Faculty of Medicine, University of Cologne","award":["371\/2021"],"award-info":[{"award-number":["371\/2021"]}]},{"name":"Koeln Fortune Program\/Faculty of Medicine, University of Cologne","award":["243\/2022"],"award-info":[{"award-number":["243\/2022"]}]},{"name":"Koeln Fortune Program\/Faculty of Medicine, University of Cologne","award":["413543196"],"award-info":[{"award-number":["413543196"]}]},{"DOI":"10.13039\/501100001659","name":"Cologne Clinician Scientist Program\/Medical Faculty\/University of Cologne and German Research Foundation","doi-asserted-by":"publisher","award":["131\/2023"],"award-info":[{"award-number":["131\/2023"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Cologne Clinician Scientist Program\/Medical Faculty\/University of Cologne and German Research Foundation","doi-asserted-by":"publisher","award":["371\/2021"],"award-info":[{"award-number":["371\/2021"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Cologne Clinician Scientist Program\/Medical Faculty\/University of Cologne and German Research Foundation","doi-asserted-by":"publisher","award":["243\/2022"],"award-info":[{"award-number":["243\/2022"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Cologne Clinician Scientist Program\/Medical Faculty\/University of Cologne and German Research Foundation","doi-asserted-by":"publisher","award":["413543196"],"award-info":[{"award-number":["413543196"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Max Planck Gesellschaft","award":["131\/2023"],"award-info":[{"award-number":["131\/2023"]}]},{"name":"Max Planck Gesellschaft","award":["371\/2021"],"award-info":[{"award-number":["371\/2021"]}]},{"name":"Max Planck Gesellschaft","award":["243\/2022"],"award-info":[{"award-number":["243\/2022"]}]},{"name":"Max Planck Gesellschaft","award":["413543196"],"award-info":[{"award-number":["413543196"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Heterozygous variants in the Poly(U) Binding Splicing Factor 60kDa gene (PUF60) have been associated with Verheij syndrome, which has the key features of coloboma, short stature, skeletal abnormalities, developmental delay, palatal abnormalities, and congenital heart and kidney defects. Here, we report five novel patients from unrelated families with PUF60-related disorders exhibiting novel genetic and clinical findings with three truncating variants, one splice-site variant with likely reduced protein expression, and one missense variant. Protein modeling of the patient\u2019s missense variant in the PUF60 AlphaFold structure revealed a loss of polar bonds to the surrounding residues. Neurodevelopmental disorders were present in all patients, with variability in speech, motor, cognitive, social-emotional and behavioral features. Novel phenotypic expansions included movement disorders as well as immunological findings with recurrent respiratory, urinary and ear infections, atopic diseases, and skin abnormalities. We discuss the role of PUF60 in immunity with and without infection based on recent organismic and cellular studies. As our five patients showed less-severe phenotypes than classical Verheij syndrome, particularly with the absence of key features such as coloboma or palatal abnormalities, we propose a reclassification as PUF60-related neurodevelopmental disorders with multi-system involvement. These findings will aid in the genetic counseling of patients and families.<\/jats:p>","DOI":"10.3390\/ijms25042053","type":"journal-article","created":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T03:36:17Z","timestamp":1707363377000},"page":"2053","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Novel Genetic and Phenotypic Expansion in Ameliorated PUF60-Related Disorders"],"prefix":"10.3390","volume":"25","author":[{"given":"Emily","family":"Baum","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany"},{"name":"Max-Planck-Institute for Biology of Ageing, 50931 Cologne, Germany"},{"name":"Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenming","family":"Huang","sequence":"additional","affiliation":[{"name":"Max-Planck-Institute for Biology of Ageing, 50931 Cologne, Germany"},{"name":"Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2194-5176","authenticated-orcid":false,"given":"Catherine","family":"Vincent-Delorme","sequence":"additional","affiliation":[{"name":"Clinical Genetics Unit Guy Fontaine, University Hospital of Lille, F-59037 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3589-6885","authenticated-orcid":false,"given":"Perrine","family":"Brunelle","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique M\u00e9dicale, University of Lille, ULR7364 RADEME, CHU Lille, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Antebi","sequence":"additional","affiliation":[{"name":"Max-Planck-Institute for Biology of Ageing, 50931 Cologne, Germany"},{"name":"Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3483-5009","authenticated-orcid":false,"given":"Hormos Salimi","family":"Dafsari","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany"},{"name":"Max-Planck-Institute for Biology of Ageing, 50931 Cologne, Germany"},{"name":"Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), 50931 Cologne, Germany"},{"name":"Department of Pediatric Neurology, Evelina\u2019s Children Hospital, Guy\u2019s & St. Thomas\u2019 Hospital NHS Foundation Trust, London SE1 7EH, UK"},{"name":"Randall Division of Cell and Molecular Biophysics, Muscle Signaling Section, King\u2019s College London, London WC2R 2LS, UK"},{"name":"Center for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1016\/j.tig.2023.04.008","article-title":"Pre-MRNA Splicing and Its Cotranscriptional Connections","volume":"39","author":"Shenasa","year":"2023","journal-title":"Trends Genet."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Cilloni, D., Itri, F., Bonuomo, V., and Petiti, J. 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