| Affiliation: | 1. Primary Children's Hospital, University of Utah, Salt Lake City, Utah, USA University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA;2. Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA;3. Primary Children's Hospital, University of Utah, Salt Lake City, Utah, USA;4. Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado, USA;5. Johns Hopkins Hospital, Baltimore, Maryland, USA;6. Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston Children's Hospital, Boston, Massachusetts, USA |
| Abstract: | The 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. |
