FBN1 – Isolated Ectopia Lentis

Fibrillin-1 (FBN1) encodes a key extracellular matrix glycoprotein involved in microfibril formation within the ocular lens zonule. Heterozygous FBN1 variants can lead to isolated ectopia lentis (IEL; MONDO:0015998), presenting with lens subluxation and high myopia without systemic Marfan syndrome features. The inheritance is autosomal dominant, with multiple pedigrees demonstrating co-segregation of FBN1 mutations and IEL.

Clinical Validity

Based on ClinGen criteria, the FBN1–IEL association is classified as Strong. This determination is supported by segregation of pathogenic variants in at least 12 probands (PMID:33576469) and 6 affected relatives in a separate family (PMID:22950452), along with additional co-segregation in 4 members of intron 11 splicing families (PMID:39939800). Concordant functional data further reinforce the association.

Genetic Evidence

Inheritance mode: Autosomal dominant.
Segregation: 12 additional affected relatives across multiple families with segregating FBN1 variants.
Case reports & series: A recurrent missense variant c.184C>T (p.Arg62Cys) was identified in two independent Chinese pedigrees, affecting all 6 patients in one family (PMID:22950452) and in all affected members from an earlier study (PMID:16765689). In a cohort of 12 unrelated probands, targeted sequencing revealed 7 pathogenic FBN1 missense variants, including three novel alleles and the recurrent p.Arg62Cys (PMID:33576469). A novel intronic variant c.1327+3A>C co-segregated with IEL in 4 individuals and was shown by RT-PCR and minigene assays to cause in-frame skipping of exon 11 (PMID:39939800).

Variant spectrum: Predominantly heterozygous missense changes affecting cysteine residues within calcium-binding EGF-like domains (e.g., c.184C>T (p.Arg62Cys)), plus splice-region variants (c.1327+3A>C) leading to exon skipping.

Functional Evidence

The predominant mechanism is a dominant-negative effect on microfibril assembly. For c.1327+3A>C, patient cell RT-PCR and a minigene splicing assay confirmed skipping of exon 11, resulting in deletion of 60 amino acids from a hinge region critical for tensile properties of fibrillin-1 microfibrils (PMID:39939800). Missense substitutions of conserved cysteines disrupt disulfide bonding, likely impairing domain folding and lens zonule integrity.

Conflicting Evidence

No studies have refuted the association or reported high-frequency benign FBN1 variants in isolated ectopia lentis. All reported pathogenic alleles are absent in ethnically matched controls.

Integrated Conclusion

Autosomal dominant FBN1 variants, particularly missense changes targeting cysteine residues and splicing mutations causing exon skipping, are a robust cause of isolated ectopia lentis. Genetic testing for key recurrent variants such as c.184C>T (p.Arg62Cys) and splicing alleles like c.1327+3A>C is clinically informative for diagnosis and family counseling.

Key Take-home: Pathogenic FBN1 variants yield a reliable molecular diagnosis of autosomal dominant isolated ectopia lentis, enabling targeted genetic counseling and early ocular surveillance.

References

• American journal of ophthalmology • 2006 • Recurrent FBN1 mutation (R62C) in a Chinese family with isolated ectopia lentis. PMID:16765689
• Ophthalmic genetics • 2013 • Ophthalmic findings in a family with early-onset isolated ectopia lentis and the p.Arg62Cys mutation of the fibrillin-1 gene (FBN1). PMID:22950452
• Molecular medicine reports • 2021 • Genotype variant screening and phenotypic analysis of FBN1 in Chinese patients with isolated ectopia lentis. PMID:33576469
• Journal of human genetics • 2025 • Novel FBN1 intron variant causes isolated ectopia lentis via in-frame exon skipping. PMID:39939800

Evidence Based Scoring (AI generated)