Abstract
To describe a novel pathogenic TGFBI variant identified in a Greek family and investigate its structural impact on the TGFBI protein, focusing on clinical significance and genotype-phenotype correlations.
Single-family case-control study with computational structural analysis.
Three generations of a Greek family, including the proband, her brother, and their mother were clinically evaluated using slit-lamp examination and anterior segment optical coherence tomography. Whole exome sequencing was performed on the proband, followed by targeted sequencing of family members. Bioinformatics tools, including DynaMut2, PROVEAN, and AlphaFold2, were used to predict the mutation's impact on protein structure and stability.
A novel heterozygous variant, c.1517_1518insCCCCCCCAAGGG, was identified. This 12-nucleotide insertion replaces methionine at position 506 with isoleucine, proline, proline, lysine, and glycine (p.M506delinsIPPKG). Clinically, this mutation was associated with geographic subepithelial and anterior stromal opacities without discernible lattice lines and presented as recurrent corneal erosions in the second decade. Structural analysis revealed disruption of the first α-helix of the FAS1-4 domain, destabilizing the protein and potentially exposing amyloidogenic regions. Previously reported mutations within this α-helix consistently produce a phenotype of geographic subepithelial opacities and a similar age of onset.
M506delinsIPPKG represents a novel pathogenic TGFBI variant associated with an autosomal dominant lattice corneal dystrophies variant. The structural disruption of the FAS1-4 domain's α-helix likely underlies the disease mechanism and links structural changes to specific phenotypic traits. These findings contribute to our understanding of genotype-phenotype correlations in TGFBI-related corneal dystrophies and highlight the importance of structural analysis in such cases.