Histologic phenotype-genotype correlation of corneal dystrophies associated with eight distinct mutations in the TGFBI gene

Purpose: To establish a phenotype-genotype correlation of various autosomal -dominant corneal dystrophies among French subjects. Design: Retrospective molecular genetic study and clinicopathologic correla tion. Participants: Forty-four subjects from 26 unrelated French families were in cluded in this study, and 60 corneal buttons could be examined at the histo logic and ultrastructural levels. Methods: Light microscopy and transmission electron microscopy were perform ed on corneal specimens obtained during keratoplasty. Blood samples were co llected for DNA analysis. Main Outcome Measures: After genomic DNA extraction from peripheral blood l eukocytes of each family member, exons of the TGFBI gene were amplified by polymerase chain reaction (PCR), and the PCR products were directly sequenc ed on both strands. Results: Four different mutations were found to be responsible for dystroph y of granular type (R555W, R124L, R124H, and R124L+delT125-delE126), three other different mutations produced a lattice type (R124C, H626R, and A546T) , and the last mutation identified was associated with the honeycomb-shaped dystrophy (R555Q). Each subtype of dystrophy showed, histologically and ul trastructurally, specific characteristics that are easily recognizable. How ever, besides these stereotyped forms, differential histologic diagnosis of atypical forms remains difficult, and these forms could be misdiagnosed. Conclusions: The characteristic biomicroscopic appearance and histopatholog ic features of each "classic" dystrophy present a significant degree of spe cificity and generally provide an accurate diagnosis. However, atypical for ms in which clinical and histologic data alone could be misleading, are une quivocally diagnosed after DNA analysis. (C) 2001 by the American Academy o f Ophthalmology.