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Updated: Apr 23, 2026
A Pipeline to Characterize Structural Heart Defects in the Fetal Mouse
Published on: December 16, 2022
Disruption of the SEMA3D gene in a patient with congenital heart defects
Marta Sanchez-Castro1, Olivier Pichon, Annaig Briand
1INSERM, UMR1087, l'institut du thorax, Nantes, France; Université de Nantes, Nantes, France.
Insights
Genetic duplication in the SEMA3D gene is linked to congenital heart defects (CHD) in a child. This finding suggests a novel mechanism for human heart malformations involving disrupted neural crest cell migration.
Area of Science:
- Genetics
- Developmental Biology
- Cardiology
Background:
- Congenital heart defect (CHD) is the most common birth defect, yet its genetic underpinnings are largely unknown.
- Semaphorin3D (SEMA3D) is an axon guidance protein crucial for cardiac neural crest cell (CNCC) migration during heart development.
Observation:
- A patient presented with complex CHD, including transposition of the great arteries, ventricular septal defect, and coarctation of the aorta.
- Array comparative genomic hybridization revealed a tandem duplication in the 5' region of the SEMA3D gene in the patient.
- Increased SEMA3D mRNA levels and a truncated SEMA3D mRNA variant were detected in patient lymphoblasts.
Findings:
- The identified SEMA3D duplication led to abnormal transcription and a truncated mRNA.
- This truncated SEMA3D may impair the migration of CNCCs, a critical process for normal heart formation.
- Sema3D(-/-) mouse models exhibit CHD, but this study elucidates a potential human-specific mechanism.
Implications:
- This research implicates SEMA3D gene duplication as a potential cause of human CHD.
- Understanding the role of SEMA3D in CNCC migration offers new insights into heart development.
- Identifies a potential genetic target for future research into congenital heart malformations.
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.
