Mutation spectrum in a large cohort of inherited retinal dystrophy patients revealed by next-generation sequencing

Abstract

Purpose: Inherited retinal dystrophy (IRD) is a leading cause of blindness worldwide. Due to an extremely genetic heterogeneity, the etiology and genotypic spectrum of IRD have not been clearly defined. The purpose of this study was to elucidate the mutational spectrum of IRD in Chinese population.

Methods: We started by developing a targeted panel of 164 known retinal-disease genes, 88possible candidate genes, and 32 retina-abundant microRNAs, which were used forexome sequencing. Total 335 Chinese families with IRD were recruited.

Results: In the 335 unrelated families, pathogenic mutations were identified in 191 patients, with a detection rate of 57% (191/335). The total 335 cases consist of 230 sporadic cases (69%, 230/335), 71 autosomal recessive cases (20%, 71/335), 25 autosomal dominant cases (7%, 25/335) and 9 X-Linked cases (4%, 9/335), with a detection rate of 56% (sporadic), 63% (AR), 52% (AD) and 56% (XL) respectively. Among the 230 sporadic patients, 128 cases (57%) were identified to harbor mutations, including 103 autosomal recessive cases (80%), fifteen de novo cases (12%) and ten X-linked (8%). In our mutation pool, the top three genes contributing to the IRD were USH2A, EYS andCRB1. Moreover, we identified AHI1 as a novel candidate gene for non-syndromic retinitis pigmentosa.

Conclusions: In summary, we have developed a paneled exome sequencing methodology for the molecular diagnosis of IRD and identified pathogenic mutations in 191 unrelated patients among the total 335 Chinese families, with a detection rate of 57% (191/335). Furthermore, novel genotype-phenotype correlations of IRD were uncovered, and we established a novel candidate gene for non-syndromic RP. To the best of our knowledge, this is the largest comprehensive genetic screening of Chinese IRD to date. This study expands the field of genotype-phenotype correlations and the mutational spectrum of the Chinese population with IRD, increasing our understanding of molecular mechanisms of the disease and aiding the clinical diagnosis and personalized treatment of patients with IRD.