Targeted Sequencing of 179 Genes Associated with Hereditary Retinal Dystrophies and 10 Candidate Genes Identifies Novel and Known Mutations in Patients with Various Retinal Diseases

PURPOSE. Hereditary retinal dystrophies (HRDs) are a group of monogenic diseases characterized by an irreversible loss of photoreceptors. HRDs exhibit significant genetic and clinical heterogeneities challenging traditional techniques for determining disease-causal mutations. This study aims to develop an efficient molecular diagnostic platform for HRDs, and to determine the genetic basis for 25 randomly collected Chinese families with a variety of HRDs. METHODS. We designed a high throughput sequence capture microarray targeting 179 genes associated with HRDs and 10 candidate genes. We combined sequence capture with next-generation sequencing (NGS) to screen for mutations in the cohort of Chinese families. Variants detected by NGS were filtered, validated, and prioritized by pathogenicity analysis. Genotypes and phenotypes were correlated. RESULTS. We identified four recurrent single mutations, two compound mutations, and eight novel putative causative mutations, including five putative pathogenic alleles (e. g., premature stop codons and frame shifts) and three novel missense variants that are very likely pathogenic. These findings provided specific genetic diagnoses in 14 of 25 families (56%). Among these, identification of a mutation in VCAN in a family with a complicated phenotype helped to finalize the clinical diagnosis as Wagner syndrome. In another five families, 11 potential novel pathogenic variants were identified. CONCLUSIONS. A substantial number of potential new genes and new mutations associated with HRDs remain to be discovered. Identification of the novel HRDs-causing mutations in our study not only provides a better understanding of genotype-phenotype relationships in these diseases, but also demonstrates that the approach described herein is an effective method for large scale mutation detection among diverse and complicated HRDs cases. (Invest Ophthalmol Vis Sci. 2013;54:2186-2197) DOI: 10.1167/iovs.12-10967