Disruption of the SEMA3D Gene in a Patient with Congenital Heart Defects

• Published in: Human mutation Vol. 36; no. 1; pp. 30 - 33
• Main Authors: Sanchez-Castro, Marta, Pichon, Olivier, Briand, Annaig, Poulain, Damien, Gournay, Véronique, David, Albert, Caignec, Cédric Le
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-01-2015; Hindawi Limited; Wiley
• Series: Equipe 3
• Subjects: aCGH; Animals; Cardiovascular disease; Child, Preschool; CNV; Comparative Genomic Hybridization; Congenital diseases; congenital heart defects; Gene Duplication; Gene Knockdown Techniques; Genomics; Heart Defects, Congenital - genetics; Heart Defects, Congenital - pathology; Humans; Life Sciences; Male; Mice; Mutation; Neural Crest - embryology; Neural Crest - pathology; Pedigree; Sema3D; Semaphorins - genetics; CNV; Sema3D; gene duplication; aCGH; congenital heart defects
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.22702

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.