{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T10:57:48Z","timestamp":1779101868867,"version":"3.51.4"},"reference-count":40,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2018,8,1]],"date-time":"2018-08-01T00:00:00Z","timestamp":1533081600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["SP\/13\/5\/30288"],"award-info":[{"award-number":["SP\/13\/5\/30288"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["FS\/11\/40\/28739"],"award-info":[{"award-number":["FS\/11\/40\/28739"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["FS\/15\/39\/31526"],"award-info":[{"award-number":["FS\/15\/39\/31526"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lymphedema is characterized by chronic swelling of any body part caused by malfunctioning or obstruction in the lymphatic system. Primary lymphedema is often considered genetic in origin. VEGFC, which is a gene encoding the ligand for the vascular endothelial growth factor receptor 3 (VEGFR3\/FLT4) and important for lymph vessel development during lymphangiogenesis, has been associated with a specific subtype of primary lymphedema. Through Sanger sequencing of a proband with bilateral congenital pedal edema resembling Milroy disease, we identified a novel mutation (NM_005429.2; c.361+5G&gt;A) in VEGFC. The mutation induced skipping of exon 2 of VEGFC resulting in a frameshift and the introduction of a premature stop codon (p.Ala50ValfsTer18). The mutation leads to a loss of the entire VEGF-homology domain and the C-terminus. Expression of this Vegfc variant in the zebrafish floorplate showed that the splice-site variant significantly reduces the biological activity of the protein. Our findings confirm that the splice-site variant, c.361+5G&gt;A, causes the primary lymphedema phenotype in the proband. We examine the mutations and clinical phenotypes of the previously reported cases to review the current knowledge in this area.<\/jats:p>","DOI":"10.3390\/ijms19082259","type":"journal-article","created":{"date-parts":[[2018,8,1]],"date-time":"2018-08-01T11:22:34Z","timestamp":1533122554000},"page":"2259","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon"],"prefix":"10.3390","volume":"19","author":[{"given":"Noeline","family":"Nadarajah","sequence":"first","affiliation":[{"name":"Molecular and Clinical Sciences Institute, St George\u2019s University of London, London SW17 0RE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D\u00f6rte","family":"Schulte","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU M\u00fcnster, 48149 M\u00fcnster, Germany"},{"name":"CiM Cluster of Excellence (EXC1003 CiM), University of M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivienne","family":"McConnell","sequence":"additional","affiliation":[{"name":"Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast Health and Social Care Trust, Belfast BT9 7AB, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5282-6662","authenticated-orcid":false,"given":"Silvia","family":"Martin-Almedina","sequence":"additional","affiliation":[{"name":"Molecular and Clinical Sciences Institute, St George\u2019s University of London, London SW17 0RE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Karapouliou","sequence":"additional","affiliation":[{"name":"Molecular and Clinical Sciences Institute, St George\u2019s University of London, London SW17 0RE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter S.","family":"Mortimer","sequence":"additional","affiliation":[{"name":"Molecular and Clinical Sciences Institute, St George\u2019s University of London, London SW17 0RE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steve","family":"Jeffery","sequence":"additional","affiliation":[{"name":"Molecular and Clinical Sciences Institute, St George\u2019s University of London, London SW17 0RE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3617-8807","authenticated-orcid":false,"given":"Stefan","family":"Schulte-Merker","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU M\u00fcnster, 48149 M\u00fcnster, Germany"},{"name":"CiM Cluster of Excellence (EXC1003 CiM), University of M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristiana","family":"Gordon","sequence":"additional","affiliation":[{"name":"Molecular and Clinical Sciences Institute, St George\u2019s University of London, London SW17 0RE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sahar","family":"Mansour","sequence":"additional","affiliation":[{"name":"Molecular and Clinical Sciences Institute, St George\u2019s University of London, London SW17 0RE, UK"},{"name":"South West Thames Regional Genetics Unit, St George\u2019s University Hospitals, London SW17 0RE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2190-1356","authenticated-orcid":false,"given":"Pia","family":"Ostergaard","sequence":"additional","affiliation":[{"name":"Molecular and Clinical Sciences Institute, St George\u2019s University of London, London SW17 0RE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,8,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1111\/cge.12173","article-title":"The classification and diagnostic algorithm for primary lymphatic dysplasia: An update from 2010 to include molecular findings","volume":"84","author":"Connell","year":"2013","journal-title":"Clin. 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