LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections

Area of Science:

• Genetics
• Cardiovascular Medicine
• Developmental Biology

Background:

• Heritable thoracic aortic disease (HTAD) is primarily linked to pathogenic variants in 11 known genes.
• Many families with HTAD lack identified alterations in these established genes, suggesting other genetic factors are involved.

Purpose of the Study:

• To investigate novel genetic causes of thoracic aortic disease (TAD) in families without known genetic defects.
• To identify and characterize the role of LTBP3 gene variants in the pathogenesis of TAD.

Main Methods:

• Exome sequencing was performed on families with a history of TAD.
• Rare variants in aorta-expressed genes were assessed, focusing on LTBP3.
• Segregation analysis and in vivo mouse models (Ltbp3-/-) were used to validate findings.

Main Results:

• Compound rare heterozygous variants and a homozygous variant in LTBP3 were identified in affected individuals from two families.
• LTBP3 variants were associated with thoracic and abdominal aortic aneurysms/dissections, dental abnormalities, and short stature.
• Ltbp3-/- mice exhibited aortic enlargement, supporting LTBP3's role in aortic integrity.

Conclusions:

• Pathogenic variants in LTBP3 are a novel cause of heritable thoracic aortic disease.
• LTBP3 mutations contribute to a spectrum of vascular abnormalities and connective tissue defects.
• This finding expands the genetic landscape of aortopathies and highlights LTBP-3's critical function in vascular health.