Disruption of the SEMA 3 D Gene in a Patient with Congenital Heart Defects

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 semaphorin3 D ( SEMA 3 D ) . Breakpoint sequencing and fiber fluorescent in situ hybridization showed tandem duplication. Expression studies showed a higher level of SEMA 3 D m RNA in patient's lymphoblasts versus controls. Moreover, we demonstrated the presence of a truncated SEMA 3 D poly‐ A tailed m RNA , resulting from an abnormal transcription of SEMA 3 D partial duplication. S ema3 D is an axon guidance protein essential for the correct migration of cardiac neural crest cells ( CNCC ) into the outflow tract. S ema3 D −/− mice present with CHD but its role in humans remains unclear. Our results suggest that truncated SEMA 3 D may have hampered the migration of CNCC during heart development, contributing to patient's CHD .