Expanding the phenotypic spectrum of <i>MECOM</i>-associated syndrome: rare variants are associated with syndromic pulmonary arterial hypertension.

Abstract

<i>MECOM</i> 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 <i>MECOM</i> as a candidate gene for paediatric pulmonary arterial hypertension (PAH) using trio exome sequencing. To test the role of <i>MECOM</i> in paediatric PAH and further define the clinical phenotype of <i>MECOM</i>-associated syndrome, we queried GeneMatcher and screened rare disease databases for individuals with predicted deleterious <i>MECOM</i> variants. We analysed the clinical spectrum of patients, performed protein modelling of genetic variants and assessed cardiopulmonary expression. We identified 15 individuals with <i>MECOM</i> 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 <i>MECOM</i>-associated syndrome. Protein modelling predicted that both regions are DNA-binding, and that the variants may interfere with binding to a <i>VEGFR2</i>/<i>KDR</i> enhancer. Data from LungMAP showed that <i>MECOM</i> is primarily expressed in pulmonary arterial endothelial cells. Rare <i>MECOM</i> variants are associated with early-onset syndromic PAH. PAH monitoring should be considered for all individuals with rare <i>MECOM</i> variants. We speculate that the pathogenetic mechanism for PAH and cardiac defects may be impaired <i>VEGFR2</i>/<i>KDR</i> signalling.