Disruption of theSEMA3DGene in a Patient with Congenital Heart Defects

Abstract

Congenital heart defect (CHD) is the leading malformation among newborns. However, its genetic basis remains mostly unknown. We report a child with transposition of the great arteries, ventricular septal defect, and coarctation of the aorta. By array comparative genomic hybridization, we identified a duplication of the 5' half of semaphorin3D (SEMA3D). Breakpoint sequencing and fiber fluorescent in situ hybridization showed tandem duplication. Expression studies showed a higher level of SEMA3D mRNA in patient's lymphoblasts versus controls. Moreover, we demonstrated the presence of a truncated SEMA3D poly-A tailed mRNA, resulting from an abnormal transcription of SEMA3D partial duplication. Sema3D is an axon guidance protein essential for the correct migration of cardiac neural crest cells (CNCC) into the outflow tract. Sema3D(-/-) mice present with CHD but its role in humans remains unclear. Our results suggest that truncated SEMA3D may have hampered the migration of CNCC during heart development, contributing to patient's CHD.

Sema3d controls collective endothelial cell migration by distinct mechanisms via Nrp1 and PlxnD1

“…Collective cell migration is a highly important process during embryogenesis and organogenesis (Scarpa and Mayor, 2016); it also drives processes during tissue repair, immune responses, tissue vascularization, and cancer metastasis (Friedl and Gilmour, 2009). Patients with congenital heart defects and anomalous pulmonary veins have been shown to have disruptions in the Sema3d gene (Silversides et al, 2012;Degenhardt et al, 2013;Sanchez-Castro et al, 2015). Recently, Sema3d autocrine signaling has been shown to promote tumor cell migration (Foley et al, 2015).…”

“…Recently, SEMA3D has been shown to be necessary for pulmonary vein development and pulmonary venous connections in mice (Degenhardt et al, 2013). In addition, disruptions in the SEMA3D gene in human patients resulted in congenital heart defects and anomalous pulmonary vein formations (Degenhardt et al, 2013;Sanchez-Castro et al, 2015). These analyses of SEMA3D deficiencies in mice and humans, however, were confined to phenotypic descriptions and failed to elucidate the mechanisms by which SEMA3D fulfills its diverse functions.…”

Role of Semaphorin Signaling During Cardiovascular Development

“…Human: partial anomalous pulmonary venous connection, transposition of the great arteries, ventricular septal defect, coarctation of the aorta…”

“…70 In addition to the loss-of-function allele, a gain-of-function allele was also identified in a human patient who carried a duplication of the 5 0 half of SEMA3D. 71 This patient displayed transposition of the great arteries, ventricular septal defect, and coarctation of the aorta. The authors speculated that migration of cardiac NCCs into the OFT is impaired in patients.…”

“…Zebrafish: dysmorphic hearts, absence of atrioventricular valves and trabeculation 67 Mouse: total anomalous pulmonary venous connection, cardiomegaly 70 Human: partial anomalous pulmonary venous connection, transposition of the great arteries, ventricular septal defect, coarctation of the aorta 70,71 SEMA3E Notochord, lateral plate mesoderm, caudal region of somites 72,73 Mouse: disorganized intersomitic vessels, paired dorsal aortas, fusion of a large plexus of blood vessels [72][73][74] SEMA5A Atrium septum, endocardial cells, cushion mesenchymal cells, mesoderm surrounding cranial vessels 77…”