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PL is a chronic debilitating disease caused by increased accumulation of interstitial fluid, predisposing to inflammation, infections and fibrosis. There is no cure, only symptomatic treatment is available. Thirty-two genes or loci have been linked to PL, and another 22 are suggested, including Hepatocyte Growth Factor (HGF). We searched for HGF variants in 770 index patients from the Brussels PL cohort. We identified ten variants predicted to cause HGF loss-of-function (six nonsense, two frameshifts, and two splice-site changes; 1.3% of our cohort), and 14 missense variants predicted to be pathogenic in 17 families (2.21%). We studied co-segregation within families, mRNA stability for non-sense variants, and in vitro functional effects of the missense variants. Analyses of the mRNA of patient cells revealed degradation of the nonsense mutant allele. Reduced protein secretion was detected for nine of the 14 missense variants expressed in COS-7 cells. Stimulation of lymphatic endothelial cells with these 14 HGF variant proteins resulted in decreased activation of the downstream targets AKT and ERK1\/2 for three of them. Clinically, HGF-associated PL was diverse, but predominantly bilateral in the lower limbs with onset varying from early childhood to adulthood. Finally, aggregation study in a second independent cohort underscored that rare likely pathogenic variants in HGF explain about 2% of PL. Therefore, HGF signalling seems crucial for lymphatic development and\/or maintenance in human beings and HGF should be included in diagnostic genetic screens for PL.<\/jats:p>","DOI":"10.1093\/hmg\/ddae060","type":"journal-article","created":{"date-parts":[[2024,4,27]],"date-time":"2024-04-27T08:01:42Z","timestamp":1714204902000},"page":"1250-1261","source":"Crossref","is-referenced-by-count":2,"title":["Pathogenic variants in <i>HGF<\/i> give rise to childhood-to-late onset primary lymphoedema by loss of function"],"prefix":"10.1093","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6684-341X","authenticated-orcid":false,"given":"Murat","family":"Alpaslan","sequence":"first","affiliation":[{"name":"Human Molecular Genetics , de Duve Institute, , Avenue Hippocrate 74, Brussels 1200 , Belgium"},{"name":"University of Louvain , de Duve Institute, , Avenue Hippocrate 74, Brussels 1200 , Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6583-4933","authenticated-orcid":false,"given":"Elodie","family":"Fastr\u00e9","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics , de Duve Institute, , Avenue Hippocrate 74, Brussels 1200 , Belgium"},{"name":"University of Louvain , de Duve Institute, , Avenue Hippocrate 74, Brussels 1200 , Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0500-6199","authenticated-orcid":false,"given":"Sandrine","family":"Mestre","sequence":"additional","affiliation":[{"name":"Department of vascular medicine , Hospital Saint-Eloi, , Avenue Augustin Fliche 80, Montpellier 34090 , France"},{"name":"University Hospital of Montpellier , Hospital Saint-Eloi, , Avenue Augustin Fliche 80, Montpellier 34090 , France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3786-6716","authenticated-orcid":false,"given":"Arie","family":"van Haeringen","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center, Albinusdreef 2 , Leiden 2333 , the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0120-5684","authenticated-orcid":false,"given":"Gabriela M","family":"Repetto","sequence":"additional","affiliation":[{"name":"Clinica Alemana Universidad del Desarrollo , Av Plaza 680, Las Condes, Lo Barnechea, Regi\u00f3n Metropolitana 7710167 , Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7349-641X","authenticated-orcid":false,"given":"Kathelijn","family":"Keymolen","sequence":"additional","affiliation":[{"name":"Clinical Sciences , Research Group Reproduction and Genetics, Centre for Medical Genetics, , Laarbeeklaan 101, Brussels 1090 , Belgium"},{"name":"Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel) , Research Group Reproduction and Genetics, Centre for Medical Genetics, , Laarbeeklaan 101, Brussels 1090 , Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8273-3328","authenticated-orcid":false,"given":"Laurence M","family":"Boon","sequence":"additional","affiliation":[{"name":"Center for Vascular Anomalies , Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, , Avenue Hippocrate 10, Brussels 1200 , Belgium"},{"name":"University of Louvain , Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, , Avenue Hippocrate 10, Brussels 1200 , Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2358-8014","authenticated-orcid":false,"given":"Florence","family":"Belva","sequence":"additional","affiliation":[{"name":"Department of Lymphatic Surgery, AZ 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Derby DE22 3NE , United Kingdom"},{"name":"University of Nottingham Medical School , Nottingham, East Block, Lenton, Nottingham NG7 2UH , United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6629-4118","authenticated-orcid":false,"given":"Sahar","family":"Mansour","sequence":"additional","affiliation":[{"name":"Cardiovascular and Genomics Research Institute, St. George's University of London , Blackshaw Rd, London SW17 0QT , United Kingdom"},{"name":"South West Thames Regional Centre for Genomics, St. George's Universities Hospitals NHS Foundation Trust , Blackshaw Rd, London SW17 0QT , United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7840-5644","authenticated-orcid":false,"given":"Kristiana","family":"Gordon","sequence":"additional","affiliation":[{"name":"Cardiovascular and Genomics Research Institute, St. George's University of London , Blackshaw Rd, London SW17 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