Mutations in RNA Methyltransferase Gene Confer High Risk of Outflow Tract Malformation.

, encoding a cytosine-5 RNA methyltransferase and located in the 7q11.23 locus, is a candidate gene for tetralogy of Fallot (TOF). Deletion of the 7q11.23 locus in humans is linked to cardiac outflow tract (OFT) disorders including TOF. We identified four potential pathogenic mutations in the coding region of and which were enriched in TOF patients by an association study of 132 TOF patients and 2,000 in-house controls ( = 1.44 × 10). We then generated a null ( ) mouse model to validate the human findings by defining the functions of in OFT morphogenesis. The OFT did not develop properly in the deletion embryonic heart. We found a misalignment of the aorta and septum defects caused by the delayed fusion of the membraneous ventricular spetum as an OFT development delay. This caused OFT development delay in 27 of 64 (42.2%) mice. Moreover, we also found OFT development delay in 8 of 51 (15.7%) mice. Further functional experiments showed that the loss of function impaired the 5-methylcytosine (mC) modification and translation efficiency of essential cardiac genes. is required for normal OFT morphogenesis and it regulates the mC modification of essential cardiac genes. Our findings suggest the involvement of in the pathogenesis of TOF.