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Coarctation of the aorta (CoA) and hypoplastic left heart syndrome (HLHS) have been reported in rare individuals with large terminal deletions of chromosome 15q26. However, no single gene important for left ventricular outflow tract (LVOT) development has been identified in this region. Using array-comparative genomic hybridization, we identified two half-siblings with CoA with a 2.2 Mb deletion on 15q26.2, inherited from their mother, who was mosaic for this deletion. This interval contains an evolutionary conserved, protein-coding gene,  MCTP2  (multiple C2-domains with two transmembrane regions 2). Using gene-specific array screening in 146 individuals with non-syndromic LVOT obstructive defects, another individual with HLHS and CoA was found to have a  de novo  41 kb intragenic duplication within  MCTP2 , predicted to result in premature truncation, p.F697X. Alteration of  Mctp2  gene expression in  Xenopus laevis  embryos by morpholino knockdown and mRNA overexpression resulted in the failure of proper OT development, confirming the functional importance of this dosage-sensitive gene for cardiogenesis. Our results identify  MCTP2  as a novel genetic cause of CoA and related cardiac malformations.

MCTP2 is a dosage-sensitive gene required for cardiac outflow tract development