{
  "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.",
  "authors": [
    {
      "affiliations": [
        "Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, USA",
        "Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA"
      ],
      "name": "Carrie L Welch"
    },
    {
      "affiliations": [
        "St George’s University Hospitals NHS Foundation Trust, London, UK"
      ],
      "name": "Meriel McEntagart"
    },
    {
      "affiliations": [
        "Great Ormond Street Hospital, London, UK"
      ],
      "name": "Shahin Moledina"
    },
    {
      "affiliations": [
        "Great Ormond Street Hospital, London, UK"
      ],
      "name": "Cara Morgan"
    },
    {
      "affiliations": [
        "Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK",
        "University of Warmia and Mazury, Olsztyn, Poland"
      ],
      "name": "Emilia Swietlik"
    },
    {
      "affiliations": [
        "Department of Systems Biology, Columbia University Irving Medical Center, New York, United States, USA"
      ],
      "name": "Chao Hou"
    },
    {
      "affiliations": [
        "Department of Systems Biology, Columbia University Irving Medical Center, New York, United States, USA"
      ],
      "name": "Lu Qiao"
    },
    {
      "affiliations": [
        "Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, USA"
      ],
      "name": "Emily Callejo"
    },
    {
      "affiliations": [
        "Department of Pediatrics, Columbia University Irving Medical Center, New York, United States, USA"
      ],
      "name": "Savanna Craib"
    },
    {
      "affiliations": [
        "William Harvey Research Institute, Queen Mary University of London, London, England, UK"
      ],
      "name": "Damian Smedley"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands"
      ],
      "name": "Emilia K Bijlsma"
    },
    {
      "affiliations": [
        "Laboratoire génétique moléculaire, Eurofins Biomnis, Lyon, France",
        "Hôpital MFME, CHU Martinique, Fort de France, France"
      ],
      "name": "Patrice Bouvagnet"
    },
    {
      "affiliations": [
        "Department of Pathology, Texas Children’s Hospital, Houston, Texas, USA",
        "Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA"
      ],
      "name": "Nahir Cortes-Santiago"
    },
    {
      "affiliations": [
        "Schneider Children’s Medical Center, Petah Tikva, Israel"
      ],
      "name": "Tamir Dagan"
    },
    {
      "affiliations": [
        "Nottingham University Hospitals NHS Trust, Nottingham, UK"
      ],
      "name": "Jacqueline Eason"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Guy's and St Thomas’ NHS Foundation Trust, London, UK"
      ],
      "name": "Frances Flinter"
    },
    {
      "affiliations": [
        "Oxford University Hospital NHS Foundation Trust, Oxford, UK"
      ],
      "name": "Aakash Joshi"
    },
    {
      "affiliations": [
        "Laboratoire génétique moléculaire, Eurofins Biomnis, Lyon, France"
      ],
      "name": "Jeremie Mortreux"
    },
    {
      "affiliations": [
        "Department of Pediatrics, Division of Pulmonology, Baylor College of Medicine, Houston, Texas, USA",
        "Pulmonary Medicine and Pulmonary Hypertension Center, Texas Children’s Hospital, Houston, Texas, USA"
      ],
      "name": "Fadel E Ruiz"
    },
    {
      "affiliations": [
        "Oxford University Hospital NHS Foundation Trust, Oxford, UK"
      ],
      "name": "Deborah Shears"
    },
    {
      "affiliations": [
        "Medical Genetics Department, Centro de Genética Médica Dr. Jacinto Magalhães, Unidade Local de Saúde Santo António, Porto, Portugal"
      ],
      "name": "Celia Azevedo Soares"
    },
    {
      "affiliations": [
        "Department of Pediatrics, Division of Pulmonology, Baylor College of Medicine, Houston, Texas, USA",
        "Pulmonary Medicine and Pulmonary Hypertension Center, Texas Children’s Hospital, Houston, Texas, USA"
      ],
      "name": "Nidhy P Varghese"
    },
    {
      "affiliations": [
        "Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, USA",
        "Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA"
      ],
      "name": "Wendy K Chung"
    }
  ],
  "title": "Expanding the phenotypic spectrum of MECOM-associated syndrome: rare variants are associated with syndromic pulmonary arterial hypertension",
  "uid": "0649c86c-2ea0-5170-a7f6-9bb2345232bc"
}