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Background <p>This study aimed to investigate genotype–phenotype correlations within families affected by <i>TGFBI</i>-associated corneal dystrophies (CDs) and to describe the clinical implications of phenotypic heterogeneity, specifically regarding pre-operative screening for corneal refractive surgery.</p> Methods <p>Comprehensive ophthalmic evaluations were performed on four probands and their available family members. Genomic DNA was extracted from peripheral venous blood samples. Candidate pathogenic variants were identified utilizing high-throughput whole-exome sequencing coupled with rigorous bioinformatic filtering. Pathogenicity was validated through Sanger sequencing and familial co-segregation analysis.</p> Results <p>Two pathogenic mutational hotspots within the <i>TGFBI</i> gene—p.R555W and p.R124H—were identified from four unrelated pedigrees. The p.R555W variant co-segregated with the Granular Corneal Dystrophy Type 1 (GCD1) phenotype in a multi-generational family, characterized by progressive "crushed breadcrumbs" stromal deposits that gradually coalesced, and encroached upon the visual axis, resulting in severe visual impairment. On anterior segment optical coherence tomography (AS-OCT) these lesions manifested as distinct punctate and granular hyper-reflective foci within the anterior corneal stroma. The p.R124H variant, the established genetic etiology for Granular Corneal Dystrophy Type 2 (GCD2), was isolated in the remaining three pedigrees. In GCD2 patients, corneal deposits primarily manifested as discrete granular or discoid opacities, with coalescence typically absent until advanced disease stages. On AS-OCT, these lesions corresponded to punctate, linear, or granular hyper-reflective foci exhibiting variable anatomical penetration across the corneal epithelium, Bowman’s layer, and the underlying stroma. Notably, one p.R124H carrier presented as entirely asymptomatic, identified incidentally only during a routine pre-operative screening for refractive surgery—a procedure known to trigger severe iatrogenic exacerbation in latent <i>TGFBI</i> variant carriers.</p> Conclusions <p>This family-based case series confirms previously reported genotype–phenotype correlations for <i>TGFBI</i> p.R555W and p.R124H variants and illustrates the wide phenotypic spectrum, including subclinical carriers. The incidental detection of an asymptomatic carrier scheduled for refractive surgery highlights the importance of careful multimodal corneal evaluation in individuals with a family history of corneal dystrophy. These findings support a cautious approach to pre-operative assessment and suggest that targeted molecular testing may be considered as an optional adjunct when routine clinical examinations are inconclusive, particularly in individuals with a family history of corneal dystrophy.</p>

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Clinical and genotypic profiling of TGFBI-associated corneal dystrophies: phenotypic variability and implications for pre-operative evaluation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月22日

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  • Junwen Wang,
  • Pan Yin,
  • Yunxi Ma,
  • Yang Liu,
  • Die Lv,
  • Lan Yu,
  • Xiaoqin Yang,
  • Kunming Cui,
  • Yin Li,
  • Xufang Sun

摘要

Background

This study aimed to investigate genotype–phenotype correlations within families affected by TGFBI-associated corneal dystrophies (CDs) and to describe the clinical implications of phenotypic heterogeneity, specifically regarding pre-operative screening for corneal refractive surgery.

Methods

Comprehensive ophthalmic evaluations were performed on four probands and their available family members. Genomic DNA was extracted from peripheral venous blood samples. Candidate pathogenic variants were identified utilizing high-throughput whole-exome sequencing coupled with rigorous bioinformatic filtering. Pathogenicity was validated through Sanger sequencing and familial co-segregation analysis.

Results

Two pathogenic mutational hotspots within the TGFBI gene—p.R555W and p.R124H—were identified from four unrelated pedigrees. The p.R555W variant co-segregated with the Granular Corneal Dystrophy Type 1 (GCD1) phenotype in a multi-generational family, characterized by progressive "crushed breadcrumbs" stromal deposits that gradually coalesced, and encroached upon the visual axis, resulting in severe visual impairment. On anterior segment optical coherence tomography (AS-OCT) these lesions manifested as distinct punctate and granular hyper-reflective foci within the anterior corneal stroma. The p.R124H variant, the established genetic etiology for Granular Corneal Dystrophy Type 2 (GCD2), was isolated in the remaining three pedigrees. In GCD2 patients, corneal deposits primarily manifested as discrete granular or discoid opacities, with coalescence typically absent until advanced disease stages. On AS-OCT, these lesions corresponded to punctate, linear, or granular hyper-reflective foci exhibiting variable anatomical penetration across the corneal epithelium, Bowman’s layer, and the underlying stroma. Notably, one p.R124H carrier presented as entirely asymptomatic, identified incidentally only during a routine pre-operative screening for refractive surgery—a procedure known to trigger severe iatrogenic exacerbation in latent TGFBI variant carriers.

Conclusions

This family-based case series confirms previously reported genotype–phenotype correlations for TGFBI p.R555W and p.R124H variants and illustrates the wide phenotypic spectrum, including subclinical carriers. The incidental detection of an asymptomatic carrier scheduled for refractive surgery highlights the importance of careful multimodal corneal evaluation in individuals with a family history of corneal dystrophy. These findings support a cautious approach to pre-operative assessment and suggest that targeted molecular testing may be considered as an optional adjunct when routine clinical examinations are inconclusive, particularly in individuals with a family history of corneal dystrophy.