Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM‐associated syndromes

Abstract

AbstractThe MECOM gene encodes multiple protein isoforms that are essential for hematopoietic stem cell self‐renewal and maintenance. Germline MECOM variants have been associated with congenital thrombocytopenia, radioulnar synostosis and bone marrow failure; however, the phenotypic spectrum of MECOM‐associated syndromes continues to expand and novel pathogenic variants continue to be identified. We describe eight unrelated patients who add to the previously known phenotypes and genetic defects of MECOM‐associated syndromes. As each subject presented with unique MECOM variants, the series failed to demonstrate clear genotype‐to‐phenotype correlation but may suggest a role for additional modifiers that affect gene expression and subsequent phenotype. Recognition of the expanded hematologic and non‐hematologic clinical features allows for rapid molecular diagnosis, early identification of life‐threatening complications, and improved genetic counseling for families. A centralized international publicly accessible database to share annotated MECOM variants would advance their clinical interpretation and provide a foundation to perform functional MECOM studies.