title: Disruption of the SEMA3D gene 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.
authors.affiliation: INSERM, UMR1087, l'institut du thorax, Nantes, France; Université de Nantes, Nantes, France.
authors.forename: Marta
authors.initials: M
authors.lastname: Sanchez-Castro
authors.forename: Olivier
authors.initials: O
authors.lastname: Pichon
authors.forename: Annaig
authors.initials: A
authors.lastname: Briand
authors.forename: Damien
authors.initials: D
authors.lastname: Poulain
authors.forename: Véronique
authors.initials: V
authors.lastname: Gournay
authors.forename: Albert
authors.initials: A
authors.lastname: David
authors.forename: Cédric
authors.initials: C
authors.lastname: Le Caignec
mesh_terms: D000818:Animals; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D020440:Gene Duplication; D055785:Gene Knockdown Techniques; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D009432:Neural Crest / Q000196:embryology / Q000473:pathology; D010375:Pedigree; D039961:Semaphorins / Q000235:genetics*
chemical_list: C000592402:Sema3D protein, human; D039961:Semaphorins
keywords: CNV; Sema3D; aCGH; congenital heart defects; gene duplication