Charting the Phenotypic Landscape of FBN1 Variants in Marfan Syndrome With Ectopia Lentis Through Extreme Phenotype Sampling

Purpose: Phenotypic heterogeneity is a hallmark of Marfan syndrome (MFS) with ectopia lentis (EL), yet genotype-phenotype correlations for ocular traits remain incompletely understood. This study aimed to identify genomic determinants of extreme ocular phenotypes using a combined phenotype-first and genotype-first analytical strategy. Methods: A two-stage discovery-validation genotype-phenotype association study included 490 patients with MFS with FBN1 variants (246 retrospective and 244 prospective validation). Age-adjusted Z-scores were calculated for axial length (AL) and corneal curvature radius (CCR), whereas central corneal thickness (CCT) and white-to-white distance (WTW) were analyzed using raw measurements. Extreme phenotype sampling identified candidate associations, validated prospectively. A genotype score integrating mutational effect and genomic position was developed. Results: FBN1 genotype was significantly associated with Z-AL, with suggestive exploratory associations for WTW and CCT. Haploinsufficient (HI) variants correlated with higher Z-AL, whereas dominant-negative (DN) variants affecting non-critical residues (Others) were enriched among lower Z-AL individuals. Variants in the TGF-β regulatory region (exons 43-65) further distinguished higher Z-AL individuals from those carrying DN variants affecting critical residues (-Cys + CaB). The genotype score demonstrated a significant positive association with Z-AL (β = 0.724, 95% confidence interval [CI] = 0.371-1.077, P < 0.001), independent of age, sex, and EL severity. Higher scores were also associated with thinner CCT and larger WTW, likely secondary to progressive axial elongation. EL severity showed no significant correlation with genotype. Conclusions: Extreme phenotype sampling with independent validation reveals reproducible genotype-phenotype correlations in the MFS ocular system. The genotype score provides preliminary genotype-guided risk stratification for ocular biometric variability.