{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T04:43:17Z","timestamp":1760589797848,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:00:00Z","timestamp":1760400000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish government","award":["PID2021-126625OB-I00"],"award-info":[{"award-number":["PID2021-126625OB-I00"]}]},{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","award":["N\u00b0101156387"],"award-info":[{"award-number":["N\u00b0101156387"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>ROGDI-related neurodevelopmental and dental disorder (ROGDI-RD), also known as Kohlsch\u00fctter\u2013T\u00f6nz syndrome (KTZS, MIM #226750), is a rare condition characterized by developmental abnormalities affecting both the central nervous system (CNS) and the dentition. These phenotypes highlight the role of complex gene\u2013environment interactions and developmental networks shared by the nervous and stomatognathic systems, both of which originate mostly from neural crest-derived cells. In this review, we analyze clinical and genetic data from 54 previously reported ROGDI-RD patients to better define the phenotypic spectrum of the disorder. Most of the reported cases harbor protein-truncating variants. Here, we also present the first description of a patient carrying a missense variant in ROGDI atypical leucine zipper gene, ROGDI in trans to a frameshift variant. This individual presented with tooth agenesis\u2014a dental anomaly not previously associated with the syndrome\u2014alongside classic neurological and dental enamel features, suggesting that the phenotypic spectrum of ROGDI-RD may be broader than currently recognized. Using a complexity and network science framework, we discuss how dysregulation in multilevel, interacting developmental systems may explain the pleiotropic features of ROGDI-RD. Our findings underscore the importance of early, interdisciplinary clinical evaluation in patients with neurodevelopmental symptoms and enamel defects. As enamel phenotypes such as amelogenesis imperfecta are heterogeneous, comprehensive genomic analyses and collaborative clinical approaches are essential for accurate diagnosis and improved care.<\/jats:p>","DOI":"10.3390\/genes16101207","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T10:37:14Z","timestamp":1760438234000},"page":"1207","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ROGDI-Related Disorder Resulting from Disruption of Complex Interactive Neuro-Dental Developmental Networks: A Review and Description of the First Missense Variant"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7404-3631","authenticated-orcid":false,"given":"Sopio","family":"Gverdtsiteli","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Trine Bj\u00f8rg","family":"Hammer","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xenia","family":"Hermann","sequence":"additional","affiliation":[{"name":"Resource Center for Rare Oral Diseases, Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noemi Becser","family":"Andersen","sequence":"additional","affiliation":[{"name":"The Epilepsy Clinic, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8934-8585","authenticated-orcid":false,"given":"David","family":"Ros-Pardo","sequence":"additional","affiliation":[{"name":"Molecular Modeling Group, Centro de Biologia Molecular Severo Ochoa (CBM, CSIC-UAM), E-28049 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0674-6423","authenticated-orcid":false,"given":"I\u00f1igo","family":"Marcos-Alcalde","sequence":"additional","affiliation":[{"name":"Molecular Modeling Group, Centro de Biologia Molecular Severo Ochoa (CBM, CSIC-UAM), E-28049 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3131-729X","authenticated-orcid":false,"given":"Paulino","family":"G\u00f3mez-Puertas","sequence":"additional","affiliation":[{"name":"Molecular Modeling Group, Centro de Biologia Molecular Severo Ochoa (CBM, CSIC-UAM), E-28049 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3484-3888","authenticated-orcid":false,"given":"Alan Henry","family":"Brook","sequence":"additional","affiliation":[{"name":"Adelaide Dental School, The University of Adelaide, Adelaide, SA 5000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6181-2705","authenticated-orcid":false,"given":"Asli","family":"Silahtaroglu","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4777-5802","authenticated-orcid":false,"given":"Zeynep","family":"T\u00fcmer","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/adj.12158","article-title":"General and Craniofacial Development Are Complex Adaptive Processes Influenced by Diversity","volume":"59","author":"Brook","year":"2014","journal-title":"Aust. 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