Mutations of 60 known causative genes in 157 families with retinitis pigmentosa based on exome sequencing

Abstract

Retinitis pigmentosa (RP) is the most common and highly heterogeneous form of hereditary retinal degeneration. This study was to identify mutations in the 60 genes that were known to be associated with RP in 157 unrelated Chinese families with RP. Genomic DNA from probands was initially analyzed by whole exome sequencing. Sanger sequencing was used to confirm potential candidate variants affecting the encoded residues in the 60 genes, including heterozygous variants from genes that are related to autosomal dominant RP, homozygous or compound heterozygous variants from genes that are related to autosomal recessive RP, and hemizygous variants from genes that are related to X-linked RP. Synonymous and intronic variants were also examined to confirm whether they could affect splicing. A total of 244 candidate variants were detected by exome sequencing. Sanger sequencing confirmed 240 variants out of the 244 candidates. Informatics and segregation analyses suggested 110 potential pathogenic mutations in 28 out of the 60 genes involving 79 of the 157 (50%) families, including 31 (39%, 31/79) families with heterozygous mutations in autosomal dominant genes, 37 (47%, 37/79) families with homozygous (9) or compound heterozygous (28) mutations in autosomal recessive genes, and 11 (14%, 11/79) families with hemizygous mutations in X-linked genes. Of the 110 identified variants, 74 (67%) were novel. The genetic defects in approximately half of the 157 studies families were detected by exome sequencing. A comprehensive analysis of the 60 known genes not only expanded the mutation spectrum and frequency of the 60 genes in Chinese patients with RP, but also provided an overview of the molecular etiology of RP in Chinese patients. The analysis of the known genes also supplied the foundation and clues for discovering novel causative RP genes.

High Diagnostic Yield of Whole Exome Sequencing in Participants With Retinal Dystrophies in a Clinical Ophthalmology Setting

“…Previous studies have shown the effectiveness of exome sequencing and targeted gene panels in determining the molecular etiology of retinal dystrophies. 7-10 Here we demonstrate its high diagnostic yield, feasibility and acceptability of exome sequencing for retinal dystrophy patients enrolled in a clinical setting.…”

Inner segment ellipsoid band length is a prognostic factor in retinitis pigmentosa associated with EYS mutations: 5-year observation of retinal structure

“…2,3 Sixty RP causative gene mutations were found. 4 EYS is an important and common cause of RP in the Japanese, Spanish, British, Chinese, Israelis, and Palestinians. [5][6][7][8][9] Furthermore, a report has described that EYS-associated RP patients share a relatively uniform phenotype with near-normal central visual function up to their 20s.…”

Genome-Wide Detection of Copy Number Variations in Unsolved Inherited Retinal Disease

“…5,6 Among these identified IRD genes, the top leading ones include USH2A, EYS, ABCA4, PDE6B, RPGR, and RHO. [7][8][9][10][11][12][13] However, a definitive molecular diagnosis of IRD remains extremely complex and challenging because mutations are only detected in 40% to 60% of cases. 4,8,[14][15][16] Most of the previous studies of IRDs have focused on single-base substitution mutations or small insertions/deletions; however, it is reasonable to speculate that large duplications or deletions can also contribute to IRDs.…”