Background:
Truncus arteriosus accounts for 0.67% of congenital heart defects. The genetic basis of isolated nonsyndromic truncus arteriosus is largely unknown.
Methods:
In order to identify the underlying molecular defect in a consanguineous family with recurrent tuncus arteriosus, homozygosity mapping followed by whole exome sequencing was performed.
Results:
We identified a homozygous mutation, Arg1299Cys, in the PLXND1 gene. The mutation affected a highly conserved residue, segregated with the disease in the family and was absent from available SNP databases and ethnic matched controls. in silico comparative modeling revealed that the mutation resides in the N-terminal segment of the human plexin-D1 intracellular region which interacts with the catalytic GTPase-activating protein homology region. The phenotype in human PLXND1 mutation is closely related to that of knockout mice for PLXND1, its co-receptor neuropilin-1 or its ligand SEMA3C.
Conclusion:
SEMA3C signaling, propagated through the heterodimer receptor plexin-D1/neuropilin, is important for truncus arteriosus septation.
Exome analysis is recommended in selected patients for molecular investigation of congenital heart defects.
PLXND1 is the first gene to be associated with isolated TA in human and determination of its sequence is warranted in similar patients.
