Submission Details

MECOM was first reported in relation to Autosomal dominant MECOM-associated syndrome in 2015 (Niihori et al., PMID:26581901). This is a syndromic disease with a variable phenotypic pattern, ranging from isolated radioulnar synostosis with no or mild hematological involvement to severe bone marrow failure without obvious skeletal abnormalities. The clinical picture can also include clinodactyly, cardiac and renal malformations, B-cell deficiency, amegakaryocytic thrombocytopenia, and presenile hearing loss. MECOM codes for a zinc finger transcription factor with important roles in normal development and oncogenesis. The MECOM locus encodes a number of differentially spliced transcripts yielding the MDS1, MDS1-EVI1, and EVI1 protein isoforms. At least 10 missense variants and 5 predicted null variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 16 probands in 4 publications (PMID: 26581901, 29519864, 29540340, 29097497). The mechanism for disease may be haploinsufficiency. This gene-disease association is supported by expression studies consistent with roles in bone marrow (PMID: 22084405) and limb development (PMID: 1893871) and mouse models with partial recapitulation of phenotypes (PMIDs: 24586749, 17029558). In summary, MECOM is definitively associated with Autosomal Dominant MECOM-associated syndrome. This has been repeatedly demonstrated in research and has been upheld over time.