{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:57:56Z","timestamp":1791475076986,"version":"4.3.4"},"reference-count":102,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T00:00:00Z","timestamp":1765238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: The RET (Rearranged during Transfection) gene encodes a receptor tyrosine kinase. RET plays a critical role in embryonic development and postnatal physiology. This review provides a comprehensive overview of RET-associated disorders, focusing on the molecular mechanisms of RET activation, associated clinical phenotypes and therapeutic implications. In addition, we present an updated RET mutation database. Methods:\u00a0RET mutation database is built through the integration and curation of data from two major RET mutation repositories: the Leiden Open Variation Database (LOVD) and the Cancer Knowledge Base (CKB) as well as information derived from the ClinVar database. Results: To date, 78 pathogenic RET mutations have been identified, among these, 71 (91.0%) are single nucleotide substitutions (missense variants), 2 (2.6%) are deletions, 1 (1.3%) are indels, 2 (2.6%) are nonsense mutations and 1 (1.3%) mutation affecting the introns. A pronounced clustering was observed in exons 10\u201311, accounting for ~60% of cases, suggesting a potential mutational hotspot with structural or functional relevance. Conclusions: Aberrant RET activation, resulting from activating missense variants, gene fusions, or overexpression, underlies a wide spectrum of human diseases. These include multiple endocrine neoplasia type 2A (MEN2A), medullary thyroid carcinoma (MTC), Hirschsprung disease, and pheochromocytoma. The existence and use of a database classifying variants in the RET gene plays a fundamental role in molecular diagnostics and personalized medicine.<\/jats:p>","DOI":"10.3390\/genes16121472","type":"journal-article","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T12:42:43Z","timestamp":1765284163000},"page":"1472","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["RET Gene Alterations in Clinical Practice: A Comprehensive Review and Database Update"],"prefix":"10.3390","volume":"16","author":[{"given":"Claudio","family":"Ricciardi Tenore","sequence":"first","affiliation":[{"name":"Departmental Unit of Molecular and Genomic Diagnostics, Fondazione Policlinico Gemelli IRCCS, 00168 Rome, Italy"},{"name":"Genomics Core Facility, Gemelli Science and Technology Park (G-STeP), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenia","family":"Tulli","sequence":"additional","affiliation":[{"name":"Departmental Unit of Molecular and Genomic Diagnostics, Fondazione Policlinico Gemelli IRCCS, 00168 Rome, Italy"},{"name":"Genomics Core Facility, Gemelli Science and Technology Park (G-STeP), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Perrucci","sequence":"additional","affiliation":[{"name":"Departmental Unit of Molecular and Genomic Diagnostics, Fondazione Policlinico Gemelli IRCCS, 00168 Rome, Italy"},{"name":"Genomics Core Facility, Gemelli Science and Technology Park (G-STeP), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Bertozzi","sequence":"additional","affiliation":[{"name":"Departmental Unit of Molecular and Genomic Diagnostics, Fondazione Policlinico Gemelli IRCCS, 00168 Rome, Italy"},{"name":"Genomics Core Facility, Gemelli Science and Technology Park (G-STeP), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludovica","family":"Fortuna","sequence":"additional","affiliation":[{"name":"Departmental Unit of Molecular and Genomic Diagnostics, Fondazione Policlinico Gemelli IRCCS, 00168 Rome, Italy"},{"name":"Genomics Core Facility, Gemelli Science and Technology Park (G-STeP), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6455-8973","authenticated-orcid":false,"given":"Giulia","family":"Maneri","sequence":"additional","affiliation":[{"name":"Departmental Unit of Molecular and Genomic Diagnostics, Fondazione Policlinico Gemelli IRCCS, 00168 Rome, Italy"},{"name":"Genomics Core Facility, Gemelli Science and Technology Park (G-STeP), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Concetta","family":"Santonocito","sequence":"additional","affiliation":[{"name":"Departmental Unit of Molecular and Genomic Diagnostics, Fondazione Policlinico Gemelli IRCCS, 00168 Rome, Italy"},{"name":"Genomics Core Facility, Gemelli Science and Technology Park (G-STeP), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Urbani","sequence":"additional","affiliation":[{"name":"Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Departmental Unit of Chemistry, Biochemistry and Clinical Molecular Biology, Department of Diagnostic and Laboratory Medicine, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"De Bonis","sequence":"additional","affiliation":[{"name":"Departmental Unit of Molecular and Genomic Diagnostics, Fondazione Policlinico Gemelli IRCCS, 00168 Rome, Italy"},{"name":"Genomics Core Facility, Gemelli Science and Technology Park (G-STeP), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0833-4334","authenticated-orcid":false,"given":"Angelo","family":"Minucci","sequence":"additional","affiliation":[{"name":"Departmental Unit of Molecular and Genomic Diagnostics, Fondazione Policlinico Gemelli IRCCS, 00168 Rome, Italy"},{"name":"Genomics Core Facility, Gemelli Science and Technology Park (G-STeP), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/0092-8674(85)90115-1","article-title":"Activation of a Novel Human Transforming Gene, Ret, by DNA Rearrangement","volume":"42","author":"Takahashi","year":"1985","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Zhao, L., Wang, N., Zhang, D., Jia, Y., and Kong, F. 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