Isolated truncus arteriosus associated with a mutation in the plexin-D1 gene.

Area of Science:

• Genetics
• Developmental Biology
• Cardiology

Background:

• Truncus arteriosus is a rare congenital heart defect, accounting for 1% of cases, with largely unknown causes for isolated non-syndromic forms.
• Identifying the genetic basis of congenital heart defects is crucial for understanding their development and potential treatments.

Purpose of the Study:

• To identify the molecular defect responsible for recurrent truncus arteriosus in a consanguineous family.
• To investigate the role of the PLXND1 gene in the etiology of truncus arteriosus.

Main Methods:

• Homozygosity mapping and whole exome sequencing were employed to analyze affected family members.
• In silico comparative modeling was used to predict the functional impact of the identified mutation.

Main Results:

• A homozygous mutation, Arg1299Cys, was identified in the PLXND1 gene, segregating with the disease in the family.
• The mutation is predicted to destabilize the intracellular region of plexin-D1, affecting its function.
• The observed phenotype aligns with findings in PLXND1 knockout mouse models, suggesting a conserved role.

Conclusions:

• SEMA3C signaling, mediated by the plexin-D1/neuropilin receptor complex, is implicated in truncus arteriosus septation.
• Mutations in PLXND1 represent a potential cause of isolated non-syndromic truncus arteriosus.
• Whole exome sequencing is a valuable tool for investigating congenital heart defects in sporadic cases after excluding copy number variants.