Allelic variation in the VMD2 gene in best disease and age-related maculardegeneration

PURPOSE. To assess the allelic variation of the VMD2 gene in patients with Best disease and age-related macular degeneration (AMD). METHODS. Three hundred twenty-one AMD patients, 192 ethnically similar cont rol subjects, 39 unrelated probands with familial Best disease, and 57 unre lated probands with the ophthalmoscopic findings of Best disease but no fam ily history were screened for sequence variations in the VMD2 gene by singl e-strand conformation polymorphism (SSCP) analysis. Amplimers showing a ban dshift were reamplified and sequenced bidirectionally. In addition, the cod ing regions of the VMD2 gene were completely sequenced in six probands with familial Best disease who showed no SSCP shift. RESULTS. Forty different probable or possible disease-causing mutations wer e found in one or more Best disease or AMD patients. Twenty-nine of these v ariations are novel. Of the 39 probands with familial Best disease, mutatio ns were detected in all 39 (33 by SSCP and 6 by DNA sequencing). SSCP scree ning of the 57 probands with a clinical diagnosis of Best disease but no fa mily history revealed 16 with mutations. Mutations were found in 5 of 321 A MD patients (1.5%), a fraction that was not significantly greater than in c ontrol individuals (0/192, 0%). CONCLUSIONS. Patients with the clinical diagnosis of Best disease are signi ficantly more likely to have a mutation in the VMD2 gene if they also have a positive family history. These findings suggest that a small fraction of patients with the clinical diagnosis of AMD may actually have a late-onset variant of Best disease, whereas at the same time, a considerable fraction of isolated patients with the ophthalmoscopic features of Best disease are probably affected with some other macular disease.