{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T05:02:48Z","timestamp":1784264568672,"version":"3.55.0"},"reference-count":51,"publisher":"BMJ","issue":"4","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2026,1,22]]},"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      <jats:italic>MECOM<\/jats:italic>\n                      encodes a developmental and haematopoietic transcription factor associated with a rare early-onset syndrome including bone marrow failure, skeletal and other congenital anomalies. Heterozygous de novo variants are the primary cause. We previously identified\n                      <jats:italic>MECOM<\/jats:italic>\n                      as a candidate gene for paediatric pulmonary arterial hypertension (PAH) using trio exome sequencing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To test the role of\n                      <jats:italic>MECOM<\/jats:italic>\n                      in paediatric PAH and further define the clinical phenotype of\n                      <jats:italic>MECOM<\/jats:italic>\n                      -associated syndrome, we queried GeneMatcher and screened rare disease databases for individuals with predicted deleterious\n                      <jats:italic>MECOM<\/jats:italic>\n                      variants. We analysed the clinical spectrum of patients, performed protein modelling of genetic variants and assessed cardiopulmonary expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified 15 individuals with\n                      <jats:italic>MECOM<\/jats:italic>\n                      variants, including 11 unrelated probands and 8 de novo variants. 11 individuals had severe or mild thrombocytopenia, 9 had skeletal issues, 8 had cardiac anomalies, 6 had PAH and 10 had additional conditions. Three were diagnosed in utero and died in the neonatal period. All missense variants map to the zinc finger 6 or zinc finger 8\/9 region, a known hotspot for\n                      <jats:italic>MECOM<\/jats:italic>\n                      -associated syndrome. Protein modelling predicted that both regions are DNA-binding, and that the variants may interfere with binding to a\n                      <jats:italic>VEGFR2<\/jats:italic>\n                      \/\n                      <jats:italic>KDR<\/jats:italic>\n                      enhancer. Data from LungMAP showed that\n                      <jats:italic>MECOM<\/jats:italic>\n                      is primarily expressed in pulmonary arterial endothelial cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Rare\n                      <jats:italic>MECOM<\/jats:italic>\n                      variants are associated with early-onset syndromic PAH. PAH monitoring should be considered for all individuals with rare\n                      <jats:italic>MECOM<\/jats:italic>\n                      variants. We speculate that the pathogenetic mechanism for PAH and cardiac defects may be impaired\n                      <jats:italic>VEGFR2<\/jats:italic>\n                      \/\n                      <jats:italic>KDR<\/jats:italic>\n                      signalling.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmg-2025-111027","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T18:20:34Z","timestamp":1769797234000},"page":"225-234","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Expanding the phenotypic spectrum of\n                    <i>MECOM<\/i>\n                    -associated syndrome: rare variants are associated with syndromic pulmonary arterial hypertension"],"prefix":"10.1136","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3521-4458","authenticated-orcid":false,"given":"Carrie L","family":"Welch","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Boston, Massachusetts, USA"},{"name":"Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3496-3337","authenticated-orcid":false,"given":"Meriel","family":"McEntagart","sequence":"additional","affiliation":[{"name":"St George\u2019s University Hospitals NHS Foundation Trust, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahin","family":"Moledina","sequence":"additional","affiliation":[{"name":"Great Ormond Street Hospital, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7038-6286","authenticated-orcid":false,"given":"Cara","family":"Morgan","sequence":"additional","affiliation":[{"name":"Great Ormond Street Hospital, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia","family":"Swietlik","sequence":"additional","affiliation":[{"name":"Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK"},{"name":"University of Warmia and Mazury, Olsztyn, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4806-7637","authenticated-orcid":false,"given":"Chao","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Columbia University Irving Medical Center, New York, United States, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Qiao","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Columbia University Irving Medical Center, New York, United States, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Callejo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Savanna","family":"Craib","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Columbia University Irving Medical Center, New York, United States, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damian","family":"Smedley","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Queen Mary University of London, London, England, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2443-3906","authenticated-orcid":false,"given":"Emilia K","family":"Bijlsma","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrice","family":"Bouvagnet","sequence":"additional","affiliation":[{"name":"Laboratoire g\u00e9n\u00e9tique mol\u00e9culaire, Eurofins Biomnis, Lyon, France"},{"name":"H\u00f4pital MFME, CHU Martinique, Fort de France, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahir","family":"Cortes-Santiago","sequence":"additional","affiliation":[{"name":"Department of Pathology, Texas Children\u2019s Hospital, Houston, Texas, USA"},{"name":"Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamir","family":"Dagan","sequence":"additional","affiliation":[{"name":"Schneider Children\u2019s Medical Center, Petah Tikva, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Eason","sequence":"additional","affiliation":[{"name":"Nottingham University Hospitals NHS Trust, Nottingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances","family":"Flinter","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Guy's and St Thomas\u2019 NHS Foundation Trust, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aakash","family":"Joshi","sequence":"additional","affiliation":[{"name":"Oxford University Hospital NHS Foundation Trust, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2914-1961","authenticated-orcid":false,"given":"Jeremie","family":"Mortreux","sequence":"additional","affiliation":[{"name":"Laboratoire g\u00e9n\u00e9tique mol\u00e9culaire, Eurofins Biomnis, Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadel E","family":"Ruiz","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pulmonology, Baylor College of Medicine, Houston, Texas, USA"},{"name":"Pulmonary Medicine and Pulmonary Hypertension Center, Texas Children\u2019s Hospital, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Shears","sequence":"additional","affiliation":[{"name":"Oxford University Hospital NHS Foundation Trust, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2907-0091","authenticated-orcid":false,"given":"Celia","family":"Azevedo Soares","sequence":"additional","affiliation":[{"name":"Medical Genetics Department, Centro de Gen\u00e9tica M\u00e9dica Dr. Jacinto Magalh\u00e3es, Unidade Local de Sa\u00fade Santo Ant\u00f3nio, Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nidhy P","family":"Varghese","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pulmonology, Baylor College of Medicine, Houston, Texas, USA"},{"name":"Pulmonary Medicine and Pulmonary Hypertension Center, Texas Children\u2019s Hospital, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy K","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Boston, Massachusetts, USA"},{"name":"Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,1,30]]},"reference":[{"key":"2026032009001272000_63.4.225.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcmd.2014.01.002"},{"key":"2026032009001272000_63.4.225.2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2018016501"},{"key":"2026032009001272000_63.4.225.3","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1007\/s10875-023-01545-0","article-title":"MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development","volume":"43","author":"Voit","year":"2023","journal-title":"J Clin Immunol"},{"key":"2026032009001272000_63.4.225.4","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01345-2024"},{"key":"2026032009001272000_63.4.225.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2023.100925"},{"key":"2026032009001272000_63.4.225.6","doi-asserted-by":"crossref","first-page":"2003337","DOI":"10.1183\/13993003.03337-2020","article-title":"Characterisation of paediatric pulmonary hypertensive vascular disease from the PPHNet Registry","volume":"59","author":"Abman","year":"2022","journal-title":"Eur Respir J"},{"key":"2026032009001272000_63.4.225.7","doi-asserted-by":"crossref","DOI":"10.1186\/s13073-018-0566-x","article-title":"Rare variants in SOX17 are associated with pulmonary arterial hypertension with congenital heart disease","volume":"10","author":"Zhu","year":"2018","journal-title":"Genome Med"},{"key":"2026032009001272000_63.4.225.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2021.104211"},{"key":"2026032009001272000_63.4.225.9","doi-asserted-by":"crossref","first-page":"114422","DOI":"10.1016\/j.jpeds.2024.114422","article-title":"SOX17-Associated Pulmonary Hypertension in Children: A Distinct Developmental and Clinical Syndrome","volume":"278","author":"Mullen","year":"2025","journal-title":"J Pediatr"},{"key":"2026032009001272000_63.4.225.10","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202206-1039TR"},{"key":"2026032009001272000_63.4.225.11","doi-asserted-by":"crossref","DOI":"10.1186\/s13073-021-00891-1","article-title":"Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH","volume":"13","author":"Zhu","year":"2021","journal-title":"Genome Med"},{"key":"2026032009001272000_63.4.225.12","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22844"},{"key":"2026032009001272000_63.4.225.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.03.010"},{"key":"2026032009001272000_63.4.225.14","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.k1687","article-title":"The 100\u2009000 Genomes Project: bringing whole genome sequencing to the NHS","volume":"361","author":"Turnbull","year":"2018","journal-title":"BMJ"},{"key":"2026032009001272000_63.4.225.15","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-018-03672-4","article-title":"Identification of rare sequence variation underlying heritable pulmonary arterial hypertension","volume":"9","author":"Gr\u00e4f","year":"2018","journal-title":"Nat Commun"},{"key":"2026032009001272000_63.4.225.16","doi-asserted-by":"publisher","DOI":"10.1038\/S41588-022-01148-2"},{"key":"2026032009001272000_63.4.225.17","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3970"},{"key":"2026032009001272000_63.4.225.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2024.08.024"},{"key":"2026032009001272000_63.4.225.19","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1002\/ajmg.a.63208","article-title":"Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM-associated syndromes","volume":"191","author":"Lozano Chinga","year":"2023","journal-title":"Am J Med Genet A"},{"key":"2026032009001272000_63.4.225.20","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"2026032009001272000_63.4.225.21","doi-asserted-by":"crossref","DOI":"10.1126\/science.adg7492","article-title":"Accurate proteome-wide missense variant effect prediction with AlphaMissense","volume":"381","author":"Cheng","year":"2023","journal-title":"Science"},{"key":"2026032009001272000_63.4.225.22","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24088"},{"key":"2026032009001272000_63.4.225.23","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0430-y"},{"key":"2026032009001272000_63.4.225.24","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae1010"},{"key":"2026032009001272000_63.4.225.25","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07487-w"},{"key":"2026032009001272000_63.4.225.26","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3235"},{"key":"2026032009001272000_63.4.225.27","doi-asserted-by":"publisher","DOI":"10.1002\/PRO.3943"},{"key":"2026032009001272000_63.4.225.28","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw454"},{"key":"2026032009001272000_63.4.225.29","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-023-38002-w","article-title":"Epigenetic landscape reveals MECOM as an endothelial lineage regulator","volume":"14","author":"Lv","year":"2023","journal-title":"Nat Commun"},{"key":"2026032009001272000_63.4.225.30","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.3c01153"},{"key":"2026032009001272000_63.4.225.31","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1021\/acs.jpcb.3c06662","article-title":"OpenMM 8: Molecular Dynamics Simulation with Machine Learning Potentials","volume":"128","author":"Eastman","year":"2024","journal-title":"J Phys Chem B"},{"key":"2026032009001272000_63.4.225.32","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-40173-5"},{"key":"2026032009001272000_63.4.225.33","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0590-4"},{"key":"2026032009001272000_63.4.225.34","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-09-806489"},{"key":"2026032009001272000_63.4.225.35","doi-asserted-by":"publisher","DOI":"10.1097\/MCD.0000000000000200"},{"key":"2026032009001272000_63.4.225.36","doi-asserted-by":"crossref","DOI":"10.1002\/pbc.26959","article-title":"Somatic MECOM mosaicism in a patient with congenital bone marrow failure without a radial abnormality","volume":"65","author":"Osumi","year":"2018","journal-title":"Pediatr Blood Cancer"},{"key":"2026032009001272000_63.4.225.37","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2017.178723"},{"key":"2026032009001272000_63.4.225.38","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2017.183855"},{"key":"2026032009001272000_63.4.225.39","doi-asserted-by":"crossref","DOI":"10.1002\/pbc.27574","article-title":"A novel mutation in the MECOM gene causing radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT-2) in an infant","volume":"66","author":"Loganathan","year":"2019","journal-title":"Pediatr Blood Cancer"},{"key":"2026032009001272000_63.4.225.40","doi-asserted-by":"crossref","DOI":"10.1002\/pbc.29761","article-title":"A novel MECOM variant associated with congenital amegakaryocytic thrombocytopenia and radioulnar synostosis","volume":"69","author":"Al-Abboh","year":"2022","journal-title":"Pediatr Blood Cancer"},{"key":"2026032009001272000_63.4.225.41","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020003812"},{"key":"2026032009001272000_63.4.225.42","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1016\/j.gim.2022.01.021","article-title":"MECOM-related disorder: Radioulnar synostosis without hematological aberration due to unique variants","volume":"24","author":"Shen","year":"2022","journal-title":"Genet Med"},{"key":"2026032009001272000_63.4.225.43","doi-asserted-by":"crossref","DOI":"10.1161\/CIRCGEN.120.003155","article-title":"Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension","volume":"14","author":"Swietlik","year":"2020","journal-title":"Circ Genom Precis Med"},{"key":"2026032009001272000_63.4.225.44","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0089397","article-title":"Mice carrying a hypomorphic Evi1 allele are embryonic viable but exhibit severe congenital heart defects","volume":"9","author":"Bard-Chapeau","year":"2014","journal-title":"PLoS ONE"},{"key":"2026032009001272000_63.4.225.45","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4773(97)00057-9"},{"key":"2026032009001272000_63.4.225.46","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1002\/pd.6113","article-title":"COL4A1\/COL4A2 and inherited platelet disorder gene variants in fetuses showing intracranial hemorrhage","volume":"42","author":"Coste","year":"2022","journal-title":"Prenat Diagn"},{"key":"2026032009001272000_63.4.225.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.12.008"},{"key":"2026032009001272000_63.4.225.48","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7691"},{"key":"2026032009001272000_63.4.225.49","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00337-2023"},{"key":"2026032009001272000_63.4.225.50","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/s41398-024-03094-5","article-title":"Evaluating the association between placenta DNA methylation and cognitive functions in the offspring","volume":"14","author":"Diez-Ahijado","year":"2024","journal-title":"Transl Psychiatry"},{"key":"2026032009001272000_63.4.225.51","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3050"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg-2025-111027","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T16:00:39Z","timestamp":1774022439000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg-2025-111027"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,30]]},"references-count":51,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,3,20]]},"published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1136\/jmg-2025-111027"],"URL":"https:\/\/doi.org\/10.1136\/jmg-2025-111027","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,30]]}}}