MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia

Abstract

Heterozygous mutations in MECOM (MDS1 and EVI1 complex locus) have been reported to be causative of a rare association of congenital amegakaryocytic thrombocytopenia and radioulnar synostosis. Here we report on 12 patients with congenital hypomegakaryocytic thrombocytopenia caused by MECOM mutations (including 10 novel mutations). The mutations affected different functional domains of the EVI1 protein. The spectrum of phenotypes was much broader than initially reported for the first 3 patients; we found familial as well as sporadic cases, and the clinical spectrum ranged from isolated radioulnar synostosis with no or mild hematological involvement to severe bone marrow failure without obvious skeletal abnormality. The clinical picture included radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal malformations, B-cell deficiency, and presenile hearing loss. No single clinical manifestation was detected in all patients affected by MECOM mutations. Radioulnar synostosis and B-cell deficiency were observed only in patients with mutations affecting a short region in the C-terminal zinc finger domain of EVI1. We propose the term MECOM-associated syndrome for this heterogeneous hereditary disease and inclusion of MECOM sequencing in the diagnostic workup of congenital bone marrow failure.

Graphical abstract

Figure 1.

MECOM mutations in patients with congenital BMF and consequences for protein isoforms of MECOM. Exon structure of the MECOM locus together with the main transcript variants are shown together with constitutive mutations in MECOM found in this study. The transcript variants use different start codons and alternatively spliced amino termini. Truncating mutations are labeled in red, missense mutations in blue, and 5′ untranslated region mutations in black. Patient identifiers for those affected by RUSAT are labeled in green. Pathogenic mutations (P1-P12) are labeled in full color; mutations of uncertain significance of pathogenicity or benign variations (P13-P20) are labeled in pale colors. Diamonds indicate nonsense mutations; triangles indicate frameshift mutations. AD, acidic domain; NLS, nuclear localization sequence; RD, repression domain; S, splice site mutation; ZF, zinc finger motif.

Figure 2.

Pedigrees and radiographs of upper limbs of patients P1, P2, and P5. Pedigrees of the familial cases P1 (A) and P2 (B) showing the occurrence of RUS (left area black) and CAMT/congenital aplastic anemia (right area black); radiographs of the upper limbs demonstrating proximal RUS in family members (small symbols indicate stillborn fetuses). (C) Pedigree and radiograph of sporadic case P5; radiograph of the forearm of P5 in pronated state, ruling out RUS. Genotype is included for the analyzed individuals of the pedigrees. M, wild-type allele; m, mutated allele.

Figure 3.

Analysis of hematopoietic progenitors from P1. Flow cytometric analysis of BM cells of patient P1 at age 2.3 months. Cells were stained with CD38-FITC, CD34-APC, CD110-PE (or PE-labeled isotype control), and 4',6-diamidino-2-phenylindole as a viability marker. Gated on viable nucleated cells (A) and on CD34⁺CD38^lo cells (B). Red indicates isotype control; blue indicates CD110 (MPL).