MECOM – Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia 2

MECOM encodes the transcription factor EVI1, essential for hematopoietic stem‐cell maintenance and limb development. Heterozygous variants in MECOM underlie Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia 2 (RUSAT-2), an autosomal dominant bone marrow failure syndrome characterized by congenital thrombocytopenia, proximal radioulnar fusion, variable skeletal anomalies, and in severe cases, fetal hydrops and demise.

Clinical Validity

The gene–disease association is classified as Strong. Over 20 unrelated probands have been reported across multiple cohorts, including de novo loss-of-function and missense variants in the C-terminal zinc-finger domain, with concordant clinical phenotypes and supporting functional studies. Experimental assays and an animal model recapitulate key features of RUSAT-2, bolstering causality.

Genetic Evidence

RUSAT-2 is inherited in an autosomal dominant manner, often arising de novo. Probands include a hydropic fetus with a pathogenic MECOM truncating variant ([PMID:37160698]), a Chinese boy with a novel missense allele ([PMID:38245683]), two infants with de novo variants including c.2812C>T (p.Arg938Trp) ([PMID:37230770]), and a cohort of 12 patients harboring diverse missense and loss-of-function alleles clustered in zinc-finger motifs ([PMID:29540340]). Variant spectrum comprises missense (e.g., c.2816A>G (p.His939Arg)), splice (c.2772-4A>G), frameshift, and in‐frame indels. Familial segregation is limited but consistent with dominant transmission.

Functional / Experimental Evidence

Missense mutations in the eighth and ninth zinc-finger motifs disrupt DNA binding and transcriptional regulation, as shown by reduced chromatin immunoprecipitation and altered AP-1/TGF-β reporter responses in vitro ([PMID:26581901]). A knockin mouse model of a human RUSAT-associated missense variant demonstrates embryonic lethality in homozygotes and hematopoietic stem/progenitor cell depletion with delayed postnatal recovery after myelosuppression in heterozygotes ([PMID:37099686]). These data support a mechanism of dominant‐negative or haploinsufficient transcriptional dysregulation.

Conflicting Evidence

No studies have disputed the association or assigned alternative phenotypes to MECOM variants in RUSAT-2.

Conclusion

Integrating genetic and functional data establishes MECOM as a Strong gene for RUSAT-2. Diagnostic sequencing of MECOM should be considered in fetuses or infants presenting with unexplained hydrops, thrombocytopenia, or radioulnar synostosis to enable early management, genetic counseling, and treatment planning.

References

• Prenatal diagnosis • 2023 • Fetal hydrops caused by a novel pathogenic MECOM variant. PMID:37160698
• BMC Pediatrics • 2024 • A novel missense mutation in the MECOM gene in a Chinese boy with radioulnar synostosis with amegakaryocytic thrombocytopenia. PMID:38245683
• American Journal of Human Genetics • 2015 • Mutations in MECOM, Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia. PMID:26581901
• Blood Advances • 2018 • MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia. PMID:29540340
• Blood Advances • 2023 • Mecom mutation related to radioulnar synostosis with amegakaryocytic thrombocytopenia reduces HSPCs in mice. PMID:37099686
• Journal of Medical Genetics • 2023 • Spectrum of MECOM pathogenic variants in infants with bone marrow failure and fetal hydrops. PMID:37230770

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