{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T23:31:36Z","timestamp":1788823896881,"version":"build-2803163510"},"reference-count":180,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,7,3]],"date-time":"2022-07-03T00:00:00Z","timestamp":1656806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Provincia Autonoma di Bolzano in the framework of LP 15\/2020","award":["dgp 3174\/2021"],"award-info":[{"award-number":["dgp 3174\/2021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lymphedema is a chronic inflammatory disorder caused by ineffective fluid uptake by the lymphatic system, with effects mainly on the lower limbs. Lymphedema is either primary, when caused by genetic mutations, or secondary, when it follows injury, infection, or surgery. In this study, we aim to assess to what extent the current genetic tests detect genetic variants of lymphedema, and to identify the major molecular pathways that underlie this rather unknown disease. We recruited 147 individuals with a clinical diagnosis of primary lymphedema and used established genetic tests on their blood or saliva specimens. Only 11 of these were positive, while other probands were either negative (63) or inconclusive (73). The low efficacy of such tests calls for greater insight into the underlying mechanisms to increase accuracy. For this purpose, we built a molecular pathways diagram based on a literature analysis (OMIM, Kegg, PubMed, Scopus) of candidate and diagnostic genes. The PI3K\/AKT and the RAS\/MAPK pathways emerged as primary candidates responsible for lymphedema diagnosis, while the Rho\/ROCK pathway appeared less critical. The results of this study suggest the most important pathways involved in the pathogenesis of lymphedema, and outline the most promising diagnostic and candidate genes to diagnose this disease.<\/jats:p>","DOI":"10.3390\/ijms23137414","type":"journal-article","created":{"date-parts":[[2022,7,3]],"date-time":"2022-07-03T22:50:46Z","timestamp":1656888646000},"page":"7414","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Low Efficacy of Genetic Tests for the Diagnosis of Primary Lymphedema Prompts Novel Insights into the Underlying Molecular Pathways"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0666-9616","authenticated-orcid":false,"given":"Gabriele","family":"Bonetti","sequence":"first","affiliation":[{"name":"MAGI\u2019s LAB, 38068 Rovereto, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5551-7520","authenticated-orcid":false,"given":"Stefano","family":"Paolacci","sequence":"additional","affiliation":[{"name":"MAGI\u2019s LAB, 38068 Rovereto, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0705-340X","authenticated-orcid":false,"given":"Michele","family":"Samaja","sequence":"additional","affiliation":[{"name":"MAGI Group, 25010 San Felice del Benaco, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1974-4937","authenticated-orcid":false,"given":"Paolo Enrico","family":"Maltese","sequence":"additional","affiliation":[{"name":"MAGI\u2019s LAB, 38068 Rovereto, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandro","family":"Michelini","sequence":"additional","affiliation":[{"name":"Vascular Diagnostics and Rehabilitation Service, Marino Hospital, ASL Roma 6, 00047 Marino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Michelini","sequence":"additional","affiliation":[{"name":"Unit of Physical Medicine, \u201cSapienza\u201d University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Michelini","sequence":"additional","affiliation":[{"name":"Neurosurgery, University of Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Ricci","sequence":"additional","affiliation":[{"name":"Division of Rehabilitation Medicine, Azienda Ospedaliero-Universitaria, Ospedali Riuniti di Ancona, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Cestari","sequence":"additional","affiliation":[{"name":"Study Centre Pianeta Linfedema, 05100 Terni, Italy"},{"name":"Lymphology Sector of the Rehabilitation Service, USLUmbria2, 05100 Terni, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6385-3444","authenticated-orcid":false,"given":"Astrit","family":"Dautaj","sequence":"additional","affiliation":[{"name":"MAGI\u2019s LAB, 38068 Rovereto, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Chiara","family":"Medori","sequence":"additional","affiliation":[{"name":"MAGI\u2019s LAB, 38068 Rovereto, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9552-221X","authenticated-orcid":false,"given":"Matteo","family":"Bertelli","sequence":"additional","affiliation":[{"name":"MAGI\u2019s LAB, 38068 Rovereto, Italy"},{"name":"MAGI Group, 25010 San Felice del Benaco, Italy"},{"name":"MAGI Euregio, 39100 Bolzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1111\/j.1939-1676.1992.tb00353.x","article-title":"Lymphedema: Etiopathogenesis","volume":"6","author":"Fossum","year":"1992","journal-title":"J. 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