{"doi":"10.3390/genes16101207","title":"ROGDI-Related Disorder Resulting from Disruption of Complex Interactive Neuro-Dental Developmental Networks: A Review and Description of the First Missense Variant","abstract":"<jats:p>ROGDI-related neurodevelopmental and dental disorder (ROGDI-RD), also known as Kohlschütter–Tönz 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–environment 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—a dental anomaly not previously associated with the syndrome—alongside 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>","journal":"Genes","year":2025,"id":665025,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":325735,"name":"Trine Bjørg Hammer","orcid":"0000-0001-8935-5761","position":1,"is_corresponding":false},{"id":1736548,"name":"Xenia Hermann","orcid":null,"position":2,"is_corresponding":false},{"id":1736549,"name":"Noemi Becser Andersen","orcid":null,"position":3,"is_corresponding":false},{"id":1022491,"name":"David Ros‐Pardo","orcid":"0000-0002-8934-8585","position":4,"is_corresponding":false},{"id":745165,"name":"Íñigo Marcos‐Alcalde","orcid":"0000-0002-0674-6423","position":5,"is_corresponding":false},{"id":745162,"name":"Paulino Gómez‐Puertas","orcid":"0000-0003-3131-729X","position":6,"is_corresponding":false},{"id":1736550,"name":"Alan Henry Brook","orcid":"0000-0002-3484-3888","position":7,"is_corresponding":false},{"id":1736551,"name":"Asli Silahtaroglu","orcid":"0000-0001-6181-2705","position":8,"is_corresponding":false},{"id":338862,"name":"Zeynep Tümer","orcid":"0000-0002-4777-5802","position":9,"is_corresponding":false},{"id":1736547,"name":"Sopio Gverdtsiteli","orcid":"0000-0002-7404-3631","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"ROGDI-Related Disorder Resulting from Disruption of Complex Interactive Neuro-Dental Developmental Networks: A Review and Description of the First Missense Variant","abstract":"<jats:p>ROGDI-related neurodevelopmental and dental disorder (ROGDI-RD), also known as Kohlschütter–Tönz 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–environment 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—a dental anomaly not previously associated with the syndrome—alongside 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>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41153423","pmcid":"PMC12563357","openalex_id":"https://openalex.org/W4415145712","authors":[],"funders":[{"funder_name":"Spanish government","grant_id":"PID2021-126625OB-I00","title":null},{"funder_name":"European Union","grant_id":"N°101156387","title":null},{"funder_name":"Spanish government grant","grant_id":"MCIN/AEI/10.13039/501100011033/FEDER,EU.2022","title":null}],"total_grants":3,"fwci":0.0,"citation_percentile":0.17177119,"influential_citations":0,"citation_trend":[],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.mdpi.com/2073-4425/16/10/1207/pdf?version=1760437097","host_type":"journal"},{"url":"https://www.mdpi.com/2073-4425/16/10/1207/pdf?version=1760437097","host_type":"publisher"},{"url":"https://www.mdpi.com/2073-4425/16/10/1207/pdf","host_type":"publisher"},{"url":"https://doi.org/10.3390/genes16101207","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41153423","host_type":"repository"},{"url":"http://hdl.handle.net/10261/404697","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/12563357","host_type":"repository"},{"url":"https://researchprofiles.ku.dk/da/publications/ac41ccfe-e723-424f-b8d7-670af70ee82e","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12563357","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12563357?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["dental development and anomalies","Congenital heart defects research","RNA modifications and cancer","Humans","Mutation, Missense","Neurodevelopmental Disorders","Phenotype","Tooth Abnormalities"],"mesh_terms":["Female","Humans","Male","Phenotype","Tooth Abnormalities","Mutation, Missense","Neurodevelopmental Disorders"],"keywords":["Amelogenesis imperfecta","Phenotype","Missense mutation","Frameshift mutation","Osteogenesis imperfecta","Dentinogenesis imperfecta","Clinical phenotype","Autism spectrum disorder","Rogdi","Kohlschütter–tönz Syndrome","Rogdi-related Neurodevelopmental And Dental Disorder","Amelocerebrohypohidrotic Syndrome","Complex Interactive Developmental Networks"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"omim"},{"name":"uniprot"},{"name":"pdb"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-13T05:10:14.190489Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}