PURPOSE. To describe the clinical and pathologic characteristics of a family with a congenital stromal dystrophy of the cornea and to identify the genetic basis for this disorder. METHODS. All family members in three generations underwent ophthalmic examination. Stored corneal buttons were examined by transmission electron microscopy. Molecular genetic studies, including a genome- wide scan with microsatellite markers, linkage analysis, and DNA sequencing, were performed. RESULTS. The dystrophy was inherited in an autosomal dominant pattern and was seen as clouded corneas shortly after birth. No associated systemic abnormalities or congenital diseases were present. After penetrating keratoplasty (PK), the grafts remained completely clear in 56% of the eyes with amean (range) observation period of 19.5 years (3- 36). Transmission electron microscopy of corneal buttons revealed lamellae with normal arrangement of collagen fibrils separated by abnormal fibrillar layers. Genome- wide screening revealed linkage to chromosome 12q22, with a maximum LOD score of4.68 at D12S351. Subsequent sequencing of candidate genes revealed a frameshift mutation in the DCN gene (c.967delT) that encodes for decorin, predicting a C- terminal truncation of the decorin protein (p.S323fsX5). CONCLUSIONS. The authors hypothesize that truncated decorin binds to collagen in a suboptimal way, disturbing the regularity of corneal collagen fibril formation and thereby causing corneal opacities. To the best of the authors’ knowledge, this is the first description of a disorder associated with an inherited alteration in the decorin gene in humans. To describe the clinical and pathologic characteristics of a family with a congenital stromal dystrophy of the cornea and to identify the genetic basis for this disorder. METHODS. All family members in three generations underwent ophthalmic examination. Stored corneal buttons were examined by transmission electron RESULTS: Molecular genetic studies, including a genome-wide scan with microsatellite markers, linkage analysis, and DNA sequencing, were performed. RESULTS. The dystrophy was inherited in an autosomal dominant pattern and was seen as clouded corneas shortly after birth. After penetrating keratoplasty (PK), the grafts were completely completely clear in 56% of the eyes with a mean (range) observation period of 19.5 years (3-36). Transmission electron microscopy of corneal buttons revealed lamellae with normal arrangement of collagen fibrils separated by abnormal fibrillar layers. Genome-wide scree ning revealed linkage to chromosome 12q22, with a maximum LOD score of 4.68 at D12S351. Subsequent sequencing of candidate genes revealed a frameshift mutation in the DCN gene (c.967delT) that encodes for decorin, predicting a C- terminal truncation of the decorin The authors hypothesize that truncated decorin binds to collagen in a suboptimal way, disturbing the regularity of corneal collagen fibril formation and thereby causing corneal opacities. To the best of the authors’ knowledge, this is the first description of a disorder associated with an inherited alteration in the decorin gene in humans.