OVERVIEW OF RB GENE-MUTATIONS IN PATIENTS WITH RETINOBLASTOMA - IMPLICATIONS FOR CLINICAL GENETIC SCREENING

Objective: This study aimed to determine the distribution of germline mutations in the retinoblastoma (RB) gene in patients with retinoblast oma to design more effective genetic testing. Design: A meta-analysis. Participants: 192 cases identified from literature. Methods: All iden tifiable reported cases of bilateral retinoblastoma, which included DN A sequence analysis of the RB gene, were reviewed. Main Outcome Measur e: Type of genetic mutation. Results: Among 192 patients with retinobl astoma with identifiable germline mutations in the RB gene, the DNA al teration was a nonsense mutation in 83 (43%), frameshift in 67 (35%), intron mutation in 23 (12%), missense mutation in 11 (6%), in-frame de letion in 5 (3%), and promoter mutation in 3 (2%). Mutations were dist ributed throughout 24 of the 27 exons of the RB gene with no single mu tational ''hotspot.'' Exons 8, 17, 18, and 23 were involved most often , and 189 (98%) of the mutations were predicted to affect the RB large pocket domain.Conclusions: A single genetic test is unlikely to detec t all germline RB gene mutations in patients with retinoblastoma becau se of the variety of types and locations of mutations that occur. Howe ver, a series of complementary tests may be able to rapidly detect mut ations based on the observation that most mutations alter the protein size and disrupt the large pocket domain.