Genetic Characterization of 191 Probands with Inherited Retinal Dystrophy by Targeted NGS Analysis

Abstract

Inherited retinal diseases (IRDs) represent a frequent cause of blindness in children and adults. As a consequence of the phenotype and genotype heterogeneity of the disease, it is difficult to have a specific diagnosis without molecular testing. To date, over 340 genes and loci have been associated with IRDs. We present the molecular finding of 191 individuals with IRD, analyzed by targeted next-generation sequencing (NGS). For 67 of them, we performed a family segregation study, considering a total of 126 relatives. A total of 359 variants were identified, 44 of which were novel. Genetic diagnostic yield was 41%. However, after stratifying the patients according to their clinical suspicion, diagnostic yield was higher for well-characterized diseases such as Stargardt disease (STGD), at 65%, and for congenital stationary night blindness 2 (CSNB2), at 64%. Diagnostic yield was higher in the patient group where family segregation analysis was possible (68%) and it was higher in younger (55%) than in older patients (33%). The results of this analysis demonstrated that targeted NGS is an effective method for establishing a molecular genetic diagnosis of IRDs. Furthermore, this study underlines the importance of segregation studies to understand the role of genetic variants with unknow pathogenic role.

Keywords: IRDs; NGS; genetic diagnosis.

Figure 1

Distribution of patients according to their clinical diagnosis. “rod–cone dystrophy” (RCD), “cone and cone–rod dystrophy” (CRD), “retinitis pigmentosa” (RT), “Stargardt disease” (STGD), “best vitelliform macular dystrophy” (BVMD), “Usher syndrome” (USH), “generalized retinal dystrophy” (GRD), “congenital stationary night blindness 2” (CSNB2), “Leber congenital amaurosis” (LCA), “achromatopsia” (ACHM) and “retinoschisis” (XLRS).

Figure 2

Genetic diagnosis results: (A) diagnostic yield in total cohort; (B) diagnostic yield according to the disease type “rod–cone dystrophy” (RCD), “cone and cone–rod dystrophy” (CRD), “retinitis pigmentosa” (RT), “Stargardt disease” (STGD), “best vitelliform macular dystrophy” (BVMD), “Usher syndrome” (USH) (8.9%), “generalized retinal dystrophy” (GRD), “congenital stationary night blindness 2” (CSNB2), “Leber congenital amaurosis” (LCA), “achromatopsia” (ACHM) and “retinoschisis” (XLRS) and (C) diagnostic yield according to the patients’ ages.

Figure 3

Distribution of patients with genetic diagnosis according to the gene where variants were localized.