Survey of patients with granular, lattice, avellino, and Reis-Bucklers corneal dystrophies for mutations in the BIGH3 and gelsolin genes

Objectives: To search for novel mutations that cause corneal stromal dystro phies and to confirm or revise the clinical diagnosis of patients with thes e mutations. Patients: Through review of the records of the Cogan Eye Pathology Laborato ry at the Massachusetts Eye and Ear Infirmary, Boston, and of clinical reco rds, we ascertained 14 unrelated patients with the clinical or histopatholo gic diagnosis of granular (3 cases), Avellino (5 cases), lattice (5 cases), or Reis-Bucklers (1 case) corneal dystrophy. Methods: Clinical records and histopathologic findings of the index patient s and their relatives were reviewed. Patients and selected relatives donate d a blood sample from which leukocyte DNA was purified and assayed for muta tions in the BIGH3 gene and, in 2 patients, the gelsolin gene, using the po lymerase chain reaction and direct genomic sequencing. Results: All index patients with the diagnosis of granular dystrophy or Ave llino dystrophy had the missense mutation Arg555Trp or Arg124His, respectiv ely, previously reported in the BIGH3 gene. Of the 5 index patients with a prior diagnosis of lattice dystrophy, 2 had the originally reported lattice mutation (Arg124Cys) in the BIGH3 gene, 1 had a more recently reported mis sense mutation (His626Arg) in the same gene, 1 had the missense mutation As p187Asn in the gelsolin gene, and 1 had no detected mutation in either gene . Affected members of the family with Reis-Bucklers dystrophy did not carry the previously reported mutations Arg555Gln or Arg124Leu but instead carri ed a novel missense mutation Gly623Asp in the BIGH3 gene. Conclusions: Molecular genetic analysis can improve the accuracy of diagnos is of patients with corneal dystrophies. Two patients with a prior diagnosi s of lattice corneal dystrophy had their diagnosis changed to gelsolin-rela ted amyloidosis (1 case) or secondary, nonhereditary localized amyloidosis (1 case). A novel mutation in the BIGH3 gene that causes Reis-Bucklers dyst rophy was uncovered through this analysis, and another recently reported no vel mutation was encountered. These findings serve to expand our knowledge of the spectrum of pathogenic mutations in BIGH3.