Extreme phenotype sampling with independent validation reveals reproducible genotype-phenotype correlations in the MFS ocular system, and a genotype score provides preliminary genotype-guided risk stratification for ocular biometric variability.
Key Findings
Results
FBN1 genotype was significantly associated with age-adjusted axial length Z-scores (Z-AL) in Marfan syndrome patients with ectopia lentis.
Study included 490 patients with MFS with FBN1 variants: 246 retrospective (discovery) and 244 prospective (validation) patients.
Age-adjusted Z-scores were calculated for axial length (AL) and corneal curvature radius (CCR) to control for age-related variation.
Central corneal thickness (CCT) and white-to-white distance (WTW) were analyzed using raw measurements.
The association was identified through a two-stage discovery-validation genotype-phenotype association study using a combined phenotype-first and genotype-first analytical strategy.
Results
Haploinsufficient (HI) FBN1 variants were correlated with higher Z-AL, while dominant-negative variants affecting non-critical residues (Others) were enriched among individuals with lower Z-AL.
FBN1 variants were classified by mutational mechanism: haploinsufficient (HI) versus dominant-negative (DN).
DN variants were further subdivided based on whether they affected critical residues (such as cysteine or calcium-binding residues, designated -Cys + CaB) or non-critical residues (Others).
HI variants associated with greater axial elongation compared to DN variants affecting non-critical residues.
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).
Results
A genotype score integrating mutational effect and genomic position showed a significant positive association with Z-AL, independent of age, sex, and ectopia lentis severity.
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.
The association was independent of age, sex, and EL severity.
The genotype score was developed by integrating mutational effect (HI vs. DN and critical residue involvement) and genomic position (TGF-β regulatory region, exons 43–65).
The score provides 'preliminary genotype-guided risk stratification for ocular biometric variability.'
Results
Higher genotype scores were associated with thinner central corneal thickness (CCT) and larger white-to-white distance (WTW), likely secondary to progressive axial elongation.
CCT and WTW associations with genotype score were described as 'likely secondary to progressive axial elongation.'
These associations were identified as suggestive exploratory associations rather than primary confirmed findings.
CCT and WTW were analyzed using raw measurements rather than age-adjusted Z-scores.
The paper notes these as suggestive associations with prospective validation performed.
Results
Ectopia lentis severity showed no significant correlation with FBN1 genotype.
EL severity was assessed and included as a covariate in analyses.
No significant genotype-EL severity correlation was found despite significant correlations between genotype and ocular biometric traits.
This finding indicates that the genotype-phenotype correlations identified are specific to ocular biometric parameters (axial length, corneal measurements) rather than lens dislocation severity.
Phenotypic heterogeneity of EL severity does not appear to be explained by FBN1 variant type or genomic location in this cohort.
Background
Phenotypic heterogeneity of ocular traits in Marfan syndrome with ectopia lentis remains incompletely understood, motivating the use of extreme phenotype sampling as an analytical strategy.
Extreme phenotype sampling was used to identify candidate genotype-phenotype associations, which were then validated prospectively in a separate cohort.
The study design combined a 'phenotype-first and genotype-first analytical strategy.'
The retrospective discovery cohort included 246 patients and the prospective validation cohort included 244 patients.
The approach was chosen specifically because standard association methods may have limited power in rare disease cohorts with heterogeneous presentations.
What This Means
Marfan syndrome is a genetic connective tissue disorder caused by variants in the FBN1 gene, and it commonly affects the eyes, including causing lens dislocation (ectopia lentis) and changes in eye shape. However, patients with Marfan syndrome vary widely in how severely their eyes are affected, and scientists have not fully understood why. This study examined 490 patients with Marfan syndrome and ectopia lentis to determine whether specific types or locations of FBN1 gene variants could predict which patients would have more extreme eye measurements, particularly in axial length (the front-to-back length of the eye, which affects vision quality and risk for complications).
The researchers found that the type of FBN1 variant matters for predicting eye shape. Patients with 'haploinsufficient' variants — where one copy of the gene is essentially nonfunctional — tended to have longer eyes, while patients with certain 'dominant-negative' variants (where the abnormal protein actively interferes with normal function but does not affect critical structural residues) tended to have shorter eyes. Variants located in a specific region of the gene (exons 43–65, involved in regulating a growth factor called TGF-β) were associated with particularly long eyes. By combining information about variant type and gene location into a single 'genotype score,' the researchers could significantly predict axial length even after accounting for age, sex, and lens dislocation severity. Higher scores were also linked to thinner corneas and wider eyes, likely as consequences of increased eye elongation. Notably, the severity of lens dislocation itself was not predicted by genotype.
This research suggests that for patients with Marfan syndrome, knowing the specific type and location of their FBN1 gene variant could help clinicians anticipate which individuals are at greater risk for progressive eye elongation and related complications such as high myopia or retinal problems. The genotype score developed in this study represents a potential tool for personalized monitoring and risk stratification, though further research in larger cohorts will be needed to validate its clinical utility.
Huo Q, Chen Z, Shen X, Zhang L, Zhang Y, Jia W, et al.. (2026). Charting the Phenotypic Landscape of FBN1 Variants in Marfan Syndrome With Ectopia Lentis Through Extreme Phenotype Sampling.. Investigative ophthalmology & visual science. https://doi.org/10.1167/iovs.67.11.29