A novel Mecom gene mutation associated with amegakaryocytic thrombocytopenia in a premature infant

Abstract

Background. Hereditary bone marrow failure syndromes are a category of biologically different syndromes that can cause cytopenia in at least one hematopoietic cell lineage. Case. We present a 29-week-old male infant who had a low Apgar Score, advanced delivery room resuscitation, widespread petechial rash, and ecchymoses at birth, without any dysmorphic features. Initial laboratory tests revealed bicytopenia (platelet count 7x10 3 /uL, hemoglobin of 3.9 g/dL, neutrophil 2.0x103 /uL) with findings of disseminated intravasculer coagulation (DIC). Imaging studies demonstrated accompanying left-sided congenital pulmonary airway malformation. On the second postnatal week pancytopenia occurred and the bone marrow findings were consistent with congenital amegakaryocytic thrombocytopenia. Further evaluations for differential diagnosis of pancitopenia were performed and the results of congenital viral infections, metabolic and immunologic tests were negative. While supportive treatments were in progress, haploidentical bone marrow transplantation (BMT) was performed from the father at 84th day due to unavailability of HLA-matched relative or nonrelative donor. Whole exome sequencing revealed a novel heterozygous frameshift variation (c.1242dupT [p. Thr538fs]) in exon 8 of the MECOM gene and validated by Sanger sequencing. No variation was detected in the parents genetic analysis. Conclusions. In this report, we present a patient with congenital bone marrow failure successfully treated with haploidentic BMT and describe a novel, de novo pathogenic variant in MECOM gene.

Mecom mutation related to radioulnar synostosis with amegakaryocytic thrombocytopenia reduces HSPCs in mice

“…Recent studies have identified MECOM variants in individuals with congenital bone marrow failure with or without RUS ( supplemental Figure 1 ). 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 19 , 20 , 21 , 22 In addition, other skeletal anomalies of the forearms and hands, congenital heart diseases, and renal anomalies were also involved with variable penetrance. 1 , 2 , 4 , 5 , 6 , 7 , 9 , 20 , 22 The term “MECOM-associated syndrome” is proposed to represent this heterogeneous disease.…”

“… 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 19 , 20 , 21 , 22 In addition, other skeletal anomalies of the forearms and hands, congenital heart diseases, and renal anomalies were also involved with variable penetrance. 1 , 2 , 4 , 5 , 6 , 7 , 9 , 20 , 22 The term “MECOM-associated syndrome” is proposed to represent this heterogeneous disease. 2 Individuals with congenital bone marrow failure without RUS exhibit nonsense, insertion/deletion, or splicing variants that result in a premature termination codon in MECOM ( supplemental Figure 1 ).…”

“… 2 Individuals with congenital bone marrow failure without RUS exhibit nonsense, insertion/deletion, or splicing variants that result in a premature termination codon in MECOM ( supplemental Figure 1 ). 1 , 2 , 19 , 20 , 22 , 23 , 24 , 25 , 26 RUSAT-associated mutations are located in the eighth and ninth zinc finger motifs, suggesting that RUSAT-associated mutations may have particular intravital effects ( supplemental Figure 1 ). 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 Thus far, no RUSAT animal models have been developed.…”