Carrie L. Welch , Meriel McEntagart, Shahin Moledina, Cara Morgan, Emilia Swietlik, Chao Hou, Lu Qiao, Emily Callejo, Savanna Craib, Damian Smedley, Emilia K. Bijlsma, Patrice Bouvagnet, Nahir Cortes-Santiago, Tamir Dagan, Jacqueline Eason, Frances Flinter, Aakash Joshi, Jeremie Mortreux, Fadel E. Ruiz, Deborah Shears, Celia Azevedo Soares, Nidhy P. Varghese, Wendy K Chung
Boston Children’s Hospital, Boston and Harvard Medical School. St George’s University Hospitals NHS Foundation Trust. Great Ormond Street Hospital. Cambridge University Hospitals NHS Foundation Trust. University of Warmia and Mazury. Columbia University Irving Medical Center. Queen Mary University of London. Leiden University Medical Center. Hôpital MFME. Texas Children’s Hospital and Baylor College of Medicine. Schneider Children’s Medical Center. Nottingham University Hospitals NHS Trust. Guy’s and St Thomas’ NHS Foundation Trust. Oxford University Hospital NHS Foundation Trust. Centro de Genética Médica Dr. Jacinto Magalhães and Unidade Local de Saúde Santo António.
United States, United Kingdom, Poland, Netherlands, France, Israel and Portugal
Journal of Medical Genetics
J Med Genet 2026;
DOI: 10.1136/jmg-2025-111027
Abstract
Background: MECOM 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 MECOM as a candidate gene for paediatric pulmonary arterial hypertension (PAH) using trio exome sequencing.
Methods: To test the role of MECOM in paediatric PAH and further define the clinical phenotype of MECOM-associated syndrome, we queried GeneMatcher and screened rare disease databases for individuals with predicted deleterious MECOM variants. We analysed the clinical spectrum of patients, performed protein modelling of genetic variants and assessed cardiopulmonary expression.
Results: We identified 15 individuals with MECOM 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 MECOM-associated syndrome. Protein modelling predicted that both regions are DNA-binding, and that the variants may interfere with binding to a VEGFR2/KDR enhancer. Data from LungMAP showed that MECOM is primarily expressed in pulmonary arterial endothelial cells.
Conclusion: Rare MECOM variants are associated with early-onset syndromic PAH. PAH monitoring should be considered for all individuals with rare MECOM variants. We speculate that the pathogenetic mechanism for PAH and cardiac defects may be impaired VEGFR2/KDR signalling.
Category
Class I. Heritable Pulmonary Hypertension
Genetic Factors Associated with Pulmonary Vascular Disease
Symptoms and Findings Associated with Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
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