Genotype-Guided Risk Stratification of Mitral Valve Surgery in Marfan Syndrome.

BACKGROUND

Although genotype-based risk stratification for aortic disease has been extensively studied in Marfan syndrome (MFS), mitral valve disease has received less attention despite being a major cardiovascular complication requiring surgery in up to 16% of cases.

OBJECTIVES

The authors aimed to evaluate genotype-specific differences in mitral valve disease progression and surgical intervention to inform precision medicine approaches in MFS.

METHODS

This retrospective cohort study included 437 MFS patients with pathogenic FBN1 variants (2006-2024). Variants were classified by molecular mechanism (premature termination codon [PTC] variants vs in-frame variants [IFVs]) and genomic location. Time-to-event cause-specific analysis assessed genotype-specific risks for mitral valve surgery.

RESULTS

Among 437 patients, 206 (47.1%) had PTC variants and 231 (52.9%) IFVs. Mitral valve surgery was performed in 38 patients (8.7%) at median age of 25.0 years. Among IFVs, those within the DNCD region (Dominant Negative variants affecting Cysteine residues and in-frame Deletions; exons 26-37 and 44-50) showed markedly higher 30-year cumulative incidence of mitral valve surgery (23.8% [95% CI: 11.7%-35.9%] vs 1.24% [95% CI: 0.0%-2.96%] in other IFVs and 3.20% [95% CI: 0.66%-5.77%] in PTC variants). IFVs within the DNCD region showed the earliest onset of mitral valve surgery in childhood/adolescence, whereas PTC variants demonstrated delayed risk beginning around age 30 years. Cox analysis confirmed IFVs within the DNCD region had highest risk of mitral valve surgery for patients aged ≤30 years (HR: 7.83 vs PTC variants; 95% CI: 3.14-19.57; P < 0.001) with robust discrimination (C-index = 0.725).

CONCLUSIONS

IFVs within the DNCD region confer the highest risk for mitral valve surgery with distinct age-dependent patterns. These findings enable genotype-guided risk stratification with age-specific surveillance protocols, potentially transforming clinical management in MFS.