Expanding the phenotypic spectrum of MECOM -associated syndrome: rare variants are associated with syndromic pulmonary arterial hypertension

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.