{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:27:20Z","timestamp":1787016440001,"version":"build-2736575974"},"reference-count":51,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"634","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2022,3,2]]},"abstract":"<jats:p>\n                    Central conducting lymphatic anomaly (CCLA), characterized by the dysfunction of core collecting lymphatic vessels including the thoracic duct and cisterna chyli, and presenting as chylothorax, pleural effusions, chylous ascites, and lymphedema, is a severe disorder often resulting in fetal or perinatal demise. Although pathogenic variants in RAS\/mitogen activated protein kinase (MAPK) signaling pathway components have been documented in some patients with CCLA, the genetic etiology of the disorder remains uncharacterized in most cases. Here, we identified biallelic pathogenic variants in\n                    <jats:italic>MDFIC<\/jats:italic>\n                    , encoding the MyoD family inhibitor domain containing protein, in seven individuals with CCLA from six independent families. Clinical manifestations of affected fetuses and children included nonimmune hydrops fetalis (NIHF), pleural and pericardial effusions, and lymphedema. Generation of a mouse model of human\n                    <jats:italic>MDFIC<\/jats:italic>\n                    truncation variants revealed that homozygous mutant mice died perinatally exhibiting chylothorax. The lymphatic vasculature of homozygous\n                    <jats:italic>Mdfic<\/jats:italic>\n                    mutant mice was profoundly mispatterned and exhibited major defects in lymphatic vessel valve development. Mechanistically, we determined that MDFIC controls collective cell migration, an important early event during the formation of lymphatic vessel valves, by regulating integrin \u03b2\n                    <jats:sub>1<\/jats:sub>\n                    activation and the interaction between lymphatic endothelial cells and their surrounding extracellular matrix. Our work identifies\n                    <jats:italic>MDFIC<\/jats:italic>\n                    variants underlying human lymphatic disease and reveals a crucial, previously unrecognized role for MDFIC in the lymphatic vasculature. Ultimately, understanding the genetic and mechanistic basis of CCLA will facilitate the development and implementation of new therapeutic approaches to effectively treat this complex disease.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.abm4869","type":"journal-article","created":{"date-parts":[[2022,3,2]],"date-time":"2022-03-02T13:57:27Z","timestamp":1646229447000},"source":"Crossref","is-referenced-by-count":44,"title":["Pathogenic variants in\n                    <i>MDFIC<\/i>\n                    cause recessive central conducting lymphatic anomaly with lymphedema"],"prefix":"10.1126","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8141-1818","authenticated-orcid":true,"given":"Alicia B.","family":"Byrne","sequence":"first","affiliation":[{"name":"Centre for Cancer Biology, University of South Australia and SA Pathology, 5001 Adelaide, Australia."},{"name":"Clinical and Health Sciences, University of South Australia, 5001 Adelaide, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9548-8229","authenticated-orcid":true,"given":"Pascal","family":"Brouillard","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics, de Duve Institute, University of Louvain, 1200 Brussels, Belgium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1905-6023","authenticated-orcid":true,"given":"Drew L.","family":"Sutton","sequence":"additional","affiliation":[{"name":"Centre for Cancer Biology, University of South Australia and SA Pathology, 5001 Adelaide, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6216-3444","authenticated-orcid":true,"given":"Jan","family":"Kazenwadel","sequence":"additional","affiliation":[{"name":"Centre for Cancer Biology, University of South Australia and SA Pathology, 5001 Adelaide, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2478-0502","authenticated-orcid":true,"given":"Saba","family":"Montazaribarforoushi","sequence":"additional","affiliation":[{"name":"Adelaide Medical School, University of Adelaide, 5005 Adelaide, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5109-3222","authenticated-orcid":true,"given":"Genevieve A.","family":"Secker","sequence":"additional","affiliation":[{"name":"Centre for Cancer Biology, University of South Australia and SA Pathology, 5001 Adelaide, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1501-4184","authenticated-orcid":true,"given":"Anna","family":"Oszmiana","sequence":"additional","affiliation":[{"name":"Centre for Cancer Biology, University of South Australia and SA Pathology, 5001 Adelaide, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6526-1020","authenticated-orcid":true,"given":"Milena","family":"Babic","sequence":"additional","affiliation":[{"name":"Centre for Cancer Biology, University of South Australia and SA Pathology, 5001 Adelaide, Australia."},{"name":"Department of Genetics and Molecular Pathology, SA Pathology, 5000 Adelaide, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2509-6056","authenticated-orcid":true,"given":"Kelly L.","family":"Betterman","sequence":"additional","affiliation":[{"name":"Centre for Cancer Biology, University of South Australia and SA Pathology, 5001 Adelaide, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9570-5879","authenticated-orcid":true,"given":"Peter J.","family":"Brautigan","sequence":"additional","affiliation":[{"name":"Centre for Cancer Biology, University of South Australia and SA Pathology, 5001 Adelaide, Australia."},{"name":"Department of Genetics and Molecular Pathology, SA Pathology, 5000 Adelaide, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8748-9210","authenticated-orcid":true,"given":"Melissa","family":"White","sequence":"additional","affiliation":[{"name":"Adelaide Medical School, University of Adelaide, 5005 Adelaide, Australia."},{"name":"Genome Editing Program, South Australian Health and Medical Research Institute, 5000 Adelaide, Australia."},{"name":"South Australian Genome Editing Facility, University of Adelaide, 5005 Adelaide, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3386-8140","authenticated-orcid":true,"given":"Sandra G.","family":"Piltz","sequence":"additional","affiliation":[{"name":"Adelaide Medical School, University of Adelaide, 5005 Adelaide, Australia."},{"name":"Genome Editing Program, South Australian Health and Medical Research Institute, 5000 Adelaide, Australia."},{"name":"South Australian Genome Editing Facility, University of Adelaide, 5005 Adelaide, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul Q.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Adelaide Medical School, University of Adelaide, 5005 Adelaide, Australia."},{"name":"Genome Editing Program, South Australian Health and Medical Research Institute, 5000 Adelaide, Australia."},{"name":"South Australian Genome Editing Facility, University of Adelaide, 5005 Adelaide, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5105-2554","authenticated-orcid":true,"given":"Christopher N.","family":"Hahn","sequence":"additional","affiliation":[{"name":"Centre for Cancer Biology, University of South Australia and SA Pathology, 5001 Adelaide, Australia."},{"name":"Adelaide Medical School, University of Adelaide, 5005 Adelaide, Australia."},{"name":"Department of Genetics and Molecular Pathology, SA Pathology, 5000 Adelaide, Australia."},{"name":"ACRF Cancer Genomics Facility, Centre for Cancer Biology, University of South Australia and SA Pathology, 5001 Adelaide, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Rath","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, 17489 Greifswald, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ute","family":"Felbor","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, 17489 Greifswald, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4331-2453","authenticated-orcid":true,"given":"G. Christoph","family":"Korenke","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics, University Children\u2019s Hospital, Klinikum Oldenburg, 26133 Oldenburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3837-8338","authenticated-orcid":true,"given":"Christopher L.","family":"Smith","sequence":"additional","affiliation":[{"name":"Jill and Mark Fishman Center for Lymphatic Disorders, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."},{"name":"Division of Cardiology, Children\u2019s Hospital of Philadelphia and Department of Pediatrics Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6566-4885","authenticated-orcid":true,"given":"Kathleen H.","family":"Wood","sequence":"additional","affiliation":[{"name":"Division of Genomic Diagnostics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3480-8123","authenticated-orcid":true,"given":"Sarah E.","family":"Sheppard","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7450-4258","authenticated-orcid":true,"given":"Denise M.","family":"Adams","sequence":"additional","affiliation":[{"name":"Vascular Anomalies Centre, Division of Haematology\/Oncology, Cancer and Blood Disorders Centre, Boston Children\u2019s Hospital, Boston, PA 02115, 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VASCA European Reference Centre, Cliniques Universitaires Saint-Luc and University of Louvain, 1200 Brussels, Belgium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7120-4903","authenticated-orcid":true,"given":"Nicole","family":"Revencu","sequence":"additional","affiliation":[{"name":"Center for Vascular Anomalies, Division of Plastic Surgery, VASCERN VASCA European Reference Centre, Cliniques Universitaires Saint-Luc and University of Louvain, 1200 Brussels, Belgium."},{"name":"Centre for Human Genetics, Cliniques Universitaires Saint-Luc and University of Louvain, 1200 Brussels, Belgium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0487-3197","authenticated-orcid":true,"given":"Lynette","family":"Moore","sequence":"additional","affiliation":[{"name":"Adelaide Medical School, University of Adelaide, 5005 Adelaide, Australia."},{"name":"Anatomical Pathology, SA Pathology, 5000 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Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aax4063"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.06.039"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.sempedsurg.2014.07.006"},{"key":"e_1_3_3_5_2","first-page":"15","article-title":"Abnormal pulmonary lymphatic flow in patients with paediatric pulmonary lymphatic disorders: Diagnosis and treatment","volume":"36","author":"Itkin M.","year":"2020","unstructured":"M. Itkin, A. Chidekel, K. A. Ryan, D. Rabinowitz, Abnormal pulmonary lymphatic flow in patients with paediatric pulmonary lymphatic disorders: Diagnosis and treatment. Paediatr. Respir. Rev. 36, 15\u201324 (2020).","journal-title":"Paediatr. Respir. 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McCarter, R. Helaers, C. Galant, L. M. Boon, P. Brouillard, M. Vikkula, M. T. Dellinger, KRAS-driven model of Gorham-Stout disease effectively treated with trametinib. JCI Insight 6, e149831 (2021).","journal-title":"JCI Insight"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.318142"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00006.2020"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81511-1"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-05-428607"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/21.7.1505"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1013"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.167098"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-012-1110-6"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1094"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200901104"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2011.12.020"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI78888"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2015.10.022"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI80454"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1055\/a-1191-8380"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20160875"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.7.4848"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.758888"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1633"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.21.5.1866-1873.2001"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.12.5061-5072.2005"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0006152"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.16974811"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI63034"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.318145"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40257-020-00528-w"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.322904"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-8712-2_2"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI79386"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"e_1_3_3_47_2","first-page":"166","article-title":"TMbase - A database of membrane spanning proteins segments","volume":"374","author":"Hofmann K.","year":"1993","unstructured":"K. Hofmann, W. Stoffel, TMbase - A database of membrane spanning proteins segments. Biol. Chem. Hoppe Seyler 374, 166 (1993).","journal-title":"Biol. Chem. Hoppe Seyler"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/10.6.673"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btn221"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1021\/ci010263s"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.2000.4042"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1006\/excr.1998.4244"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.abm4869","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T12:46:49Z","timestamp":1705409209000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.abm4869"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,2]]},"references-count":51,"journal-issue":{"issue":"634","published-print":{"date-parts":[[2022,3,2]]}},"alternative-id":["10.1126\/scitranslmed.abm4869"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.abm4869","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,2]]},"article-number":"eabm4869"}}