A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3

Area of Science:

• Genetics
• Molecular Biology
• Human Pathology

Background:

• Loeys-Dietz syndrome (LDS) is a heritable connective tissue disorder.
• Cardiovascular, skeletal, and ocular systems are primarily affected in LDS.
• Mutations in TGF-β receptors (TGFBR1/2) were initially linked to LDS, causing impaired TGF-β signaling.

Purpose of the Study:

• To comprehensively review known and novel mutations in TGFB2, TGFB3, SMAD2, and SMAD3 genes associated with LDS.
• To detail clinical manifestations linked to TGFB2 and SMAD3 mutations.
• To highlight the expanding phenotypic spectrum of LDS.

Main Methods:

• Literature review of published LDS cases.
• Analysis of clinical data from previously described and newly reported patients.
• Compilation of mutation information, including variants in TGFB2, TGFB3, SMAD2, and SMAD3.

Main Results:

• Identified and reviewed numerous TGFB2, TGFB3, SMAD2, and SMAD3 mutations implicated in LDS.
• Detailed clinical phenotypes associated with TGFB2 and SMAD3 mutations.
• Confirmed that mutations in these genes contribute to a broad and evolving spectrum of LDS manifestations.

Conclusions:

• Disturbed TGF-β signaling due to mutations in TGFB2, TGFB3, SMAD2, and SMAD3 plays a crucial role in LDS pathogenesis.
• LDS is a disorder with a wide and still-emerging phenotypic spectrum.
• All discussed mutations are documented in the Leiden Open Variant Database.