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

Abstract Purpose To establish a phenotype–genotype correlation of various autosomal–dominant corneal dystrophies among French subjects. Design Retrospective molecular genetic study and clinicopathologic correlation. Participants Forty-four subjects from 26 unrelated French families were included in this study, and 60 corneal buttons could be examined at the histologic and ultrastructural levels. Methods Light microscopy and transmission electron microscopy were performed on corneal specimens obtained during keratoplasty. Blood samples were collected for DNA analysis. Main outcome measures After genomic DNA extraction from peripheral blood leukocytes of each family member, exons of the TGFBI gene were amplified by polymerase chain reaction (PCR), and the PCR products were directly sequenced on both strands. Results Four different mutations were found to be responsible for dystrophy 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 ultrastructurally, specific characteristics that are easily recognizable. However, besides these stereotyped forms, differential histologic diagnosis of atypical forms remains difficult, and these forms could be misdiagnosed. Conclusions The characteristic biomicroscopic appearance and histopathologic features of each "classic" dystrophy present a significant degree of specificity and generally provide an accurate diagnosis. However, atypical forms in which clinical and histologic data alone could be misleading, are unequivocally diagnosed after DNA analysis.