The c.7409G>A (p.Cys2470Tyr) Variant of FBN1: Phenotypic Variability across Three Generations

Area of Science:

• Genetics
• Cardiovascular Medicine
• Molecular Biology

Background:

• Marfan syndrome is an autosomal dominant disorder of connective tissue, primarily linked to mutations in the FBN1 gene.
• Key features involve ocular, cardiovascular, and skeletal systems, with mutations often occurring in specific FBN1 exons.
• Missense mutations are common, but their phenotypic impact, especially in C-terminal regions, requires further elucidation.

Purpose of the Study:

• To investigate the clinical significance of a specific FBN1 missense variant (c.7409G>A, p.Cys2470Tyr) in exon 59.
• To evaluate the cardiovascular and systemic phenotype associated with C-terminal FBN1 mutations.
• To explore genotype-phenotype correlations in Marfan syndrome.

Main Methods:

• Clinical evaluation of five related individuals with a c.7409G>A FBN1 variant.
• Genetic analysis including identification of the missense variant and a de novo deletion on chromosome 5.
• Phenotypic assessment across skeletal, dermatological, neurological, ocular, and cardiovascular systems.

Main Results:

• A c.7409G>A (p.Cys2470Tyr) missense variant in FBN1 exon 59 was associated with significant cardiovascular features in five individuals.
• The family exhibited skeletal, dermatological, and neurological symptoms consistent with Marfan syndrome, but lacked major ophthalmological findings.
• Dural ectasia was observed, supporting previous associations with C-terminal FBN1 mutations.

Conclusions:

• FBN1 C-terminal missense mutations may not always lead to ophthalmological features of Marfan syndrome.
• These mutations can confer a greater risk of cardiovascular pathology than previously suggested.
• The findings underscore the importance of comprehensive cardiovascular assessment in patients with C-terminal FBN1 variants.