MECOM – Radioulnar Synostosis-Amegakaryocytic Thrombocytopenia Syndrome

Multiple unrelated individuals with radioulnar synostosis and amegakaryocytic thrombocytopenia (RUSAT) harbor heterozygous MECOM variants, supporting an autosomal dominant mechanism for this syndrome. Three de novo missense mutations in MECOM were identified by whole‐exome sequencing in three unrelated probands presenting with congenital fusion of the radius and ulna and severe thrombocytopenia ([PMID:26581901]). Functional studies demonstrate that these variants cluster within the eighth zinc finger motif of EVI1 and impair DNA binding at ETS‐like motifs, reducing chromatin immunoprecipitation signal and altering AP-1 and TGF-β transcriptional responses in reporter assays ([PMID:26581901]).

Clinical Validity and Genetic Evidence

The association between MECOM and RUSAT is classified as Moderate by ClinGen criteria based on identification of three unrelated probands with de novo missense variants, absence of alternative genetic causes, and concordant functional data ([PMID:26581901]). Inheritance is autosomal dominant with no reported segregation beyond de novo occurrences. Genetic evidence is moderate: three de novo missense variants clustered in a critical functional domain support pathogenicity.

Functional Evidence

Mechanistically, mutant EVI1 exhibits reduced binding to known ETS‐like DNA motifs in chromatin immunoprecipitation and qPCR assays, and reporter assays reveal dysregulation of AP-1 and TGF-β signaling pathways. These assays provide moderate experimental support for transcriptional dysregulation as the basis of RUSAT pathogenesis ([PMID:26581901]).

Integration and Conclusion

Collectively, the genetic and experimental data establish MECOM variants as causative for RUSAT, linking impaired zinc‐finger–mediated transcriptional regulation of hematopoiesis and forelimb development to the clinical phenotype. No conflicting evidence has been reported to date. Further studies may elucidate additional genotype–phenotype correlations and potential therapeutic targets.

Key Take-home: Heterozygous missense mutations in MECOM disrupt EVI1 zinc‐finger function and cause autosomal dominant RUSAT, guiding molecular diagnosis and genetic counseling.

References

• American journal of human genetics • 2015 • Mutations in MECOM, Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia. PMID:26581901

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