Study of Retinoblastoma Penetrance and Phenotype

Abstract

In this study we characterized hereditary forms of retinoblastoma (RB). Mutational analysis was conducted among 85 RB patients and 156 their relatives. Using a combination of NGS (next generation sequencing) and MLPA (Multiplex Ligation-dependent Probe Amplification) assays we found RB1 germinal mutations in majority of RB patients (96,4% - 27/28) with binocular disease and in 21% (12/57) with monocular RB.A relationship between different types of RB1 germline mutations and clinical manifestation was analyzed. Mainly., hereditary RB developed into severe binocular clinical form with high penetrance. However in some families low penetrance was observed (when patients carrying germline mutation didn’t develop RB). We confirmed that 3 mutations at splice sites: с.607 + 1G>T (intron 6); c.1422-8delT (exon 16); g.61807 G>A (exon 9); and 2 missense mutations: p. 1364 G>C (14 exon); с.1981 C>T (20 exon) were inherited from not affected fathers. These RB cases were less severe (unilateral RB developed later in life). Of the 85 tested RB patients, germline mutations were detected in 45.8% (39/85), 41% (16/39) among which were localized in exons 12-18, 19-23. Hence, different RB mutations were associated with various phenotype. We suggest conducting genetic testing among all RB patients. This will allow identification of asymptomatic carriers with low penetrance mutations, germline mosaicism, lead to early diagnosis, facilitate development of individual treatment plans and determine genetic risk among affected families.