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Published on: November 3, 2018
Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM-associated syndromes
Michell M Lozano Chinga1,2, Alison A Bertuch3, Zeinab Afify1
1Primary Children's Hospital, University of Utah, Salt Lake City, Utah, 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.
Insights
The MECOM gene is crucial for blood stem cell maintenance. New variants expand understanding of MECOM-associated syndromes, highlighting the need for better variant databases and genetic counseling.
Area of Science:
- Genetics and Molecular Biology
- Hematology
- Developmental Biology
Background:
- The MECOM gene encodes critical protein isoforms for hematopoietic stem cell (HSC) self-renewal and maintenance.
- Germline MECOM variants are linked to congenital thrombocytopenia, radioulnar synostosis, and bone marrow failure.
- The phenotypic spectrum of MECOM-associated syndromes is expanding with the identification of novel pathogenic variants.
Purpose of the Study:
- To describe eight unrelated patients with novel MECOM variants, expanding the known phenotypes and genetic defects of MECOM-associated syndromes.
- To investigate potential genotype-to-phenotype correlations and the role of genetic modifiers in MECOM-associated disorders.
- To emphasize the importance of recognizing expanded clinical features for timely diagnosis and improved patient management.
Main Methods:
- Clinical characterization of eight unrelated patients presenting with diverse hematologic and non-hematologic features.
- Identification and analysis of unique MECOM variants in each patient.
- Review of existing literature on MECOM-associated syndromes and variants.
Main Results:
- Eight new cases contribute to the expanding spectrum of MECOM-associated syndromes, presenting unique MECOM variants.
- The series did not reveal a clear genotype-to-phenotype correlation, suggesting the influence of additional genetic modifiers.
- The study identified both previously known and novel hematologic and non-hematologic clinical manifestations associated with MECOM variants.
Conclusions:
- Recognition of the broadened clinical features of MECOM-associated syndromes is vital for rapid molecular diagnosis and early intervention.
- The lack of clear genotype-phenotype correlation suggests a complex interplay of genetic factors influencing disease presentation.
- Establishing a centralized, publicly accessible database for annotated MECOM variants is crucial for advancing clinical interpretation and functional studies.
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