Comprehensive Molecular Diagnosis of a Large Chinese Patient Cohort With Autosomal Dominant Retinitis Pigmentosa

Abstract

Purpose : Retinitis pigmentosa (RP) is a group of clinically and genetically heterogeneous inherited retinal disease that can cause severe visual loss; therefore, an accurate molecular diagnosis is essential for appropriate disease treatment and family planning. The purpose of this study was to perform the comprehensive molecular diagnosis for a cohort of Chinese autosomal dominant RP (adRP) patients.

Methods : Totally, 55 well-characterized adRP families with 235 patients were recruited. First, we performed direct Sanger sequencing of 13 adRP disease genes in 34 adRP families. After identifying disease-causing mutations in 12 adRP pedigrees, the remaining 22 families were screened for deletions/duplications of one or more sequence in RHO, IMPDH1, RP1 and PRPF31 with multiplex ligation-dependent probe amplification (MLPA). Next, we developed a capture panel that enriches the entire coding exons and splicing sites of 163 known retinal disease genes and other candidate retinal disease genes. The capture panel allowed us to quickly identify disease-causing mutations in a large number of genes at a relatively low cost. Thus, this method was applied to the 20 adRP families that were unsolved by direct Sanger sequencing and MLPA testing of 13 adRP disease genes and an additional 21 adRP families. Systematic next-generation sequencing (NGS) data analysis, Sanger sequencing validation, and segregation analysis were used to identify pathogenic mutations.

Results : We identified disease-causing mutations in known adRP genes in 74.5 % (41) of our patients. Of these, PRPF31 mutations are the most common cause of disease, representing 26.8% (11/41) of the total. RHO mutations account for the second largest group, 24.4% (10/41), PRPF8 accounts for the third largest group, 14.6% (6/41), and TOPORS accounts for the forth largest group, 7.3% (3/41). Among the other genes, IMPDH1, NR2E3, and RP1 account for 4.9% each, and CA4, PRPF3, PRPH2, SNRNP200 and HMCN1 account for roughly 2.4% each. In particular, 78 % (32/41) of mutations found in this study have never been previously reported.

Conclusions : Our study provides a comprehensive genetic characterization of a large collection of Chinese adRP patients. Applying this tool on patients from different ethnic groups is essential for enhancing our knowledge of the global spectrum of adRP disease-causing mutations.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.