Genotype–phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing

Abstract

Purpose: Inherited retinal dystrophy (IRD) is a leading cause of blindness worldwide. Because of extreme genetic heterogeneity, the etiology and genotypic spectrum of IRD have not been clearly defined, and there is limited information on genotype-phenotype correlations. The purpose of this study was to elucidate the mutational spectrum and genotype-phenotype correlations of IRD. Methods:We developed a targeted panel of 164 known retinal disease genes, 88 candidate genes, and 32 retina-abundant microRNAs, used for exome sequencing. A total of 179 Chinese families with IRD were recruited. Results:In 99 unrelated patients, a total of 124 mutations in known retinal disease genes were identified, including 79 novel mutations (detection rate, 55.3%). Moreover, novel genotype-phenotype correlations were discovered, and phenotypic trends noted. Three cases are reported, including the identification of AHI1 as a novel candidate gene for nonsyndromic retinitis pigmentosa. Conclusion:This study revealed novel genotype-phenotype correlations, including a novel candidate gene, and identified 124 genetic defects within a cohort with IRD . The identification of novel genotype-phenotype correlations and the spectrum of mutations greatly enhance the current knowledge of IRD phenotypic and genotypic heterogeneity, which will assist both clinical diagnoses and personalized treatments of IRD patients.

Identification of false-negative mutations missed by next-generation sequencing in retinitis pigmentosa patients: a complementary approach to clinical genetic diagnostic testing

“…Table S1 online), and 1 patient was previously screened using WES. 16 No deleterious mutations were found in any of the 164 known genes, however, suggesting either that pathogenic mutations might have been missed by exome sequencing or that the clinical phenotype was caused by previously undescribed, novel RP genes.…”

“…This strategy was validated in 50 unrelated patients with either simplex RP or XLRP, all of whom previously tested negative for pathogenic mutations by exome sequencing. 16 We assessed and compared the sequencing quality of entire targeted regions and ORF15, which demonstrated that ORF15 lies in a region of very low sequencing depth. Subsequent screening of ORF15 directly by Sanger sequencing resulted in the identification of pathogenic mutations in 7 of 50 patients (14%).…”

“…Using a capture panel including 164 known retinal disease-causing genes, we previously identified pathogenic mutations in 99 patients. 16 Among the remaining 80 unrelated patients with unknown genetic causes, 49 male patients with either simplex RP or XLRP were included in this study. Another patient (A-1; Table 1) was previously screened using WES, which failed to discover any disease-causing variants.…”

Response to Heller and Bolz

“…5 We also reexamined the pathogenicity using multiple other databases. 2 Our analyses indicate that this variant is predicted to be damaging by MutationTaster 6 (score 0.999) and PolyPhen-2 (ref. 7) (score 0.994).…”

“…Our study was a large-scale screening investigation of patients with inherited retinal dystrophy. 2 We considered the two variants as damaging for the following reasons. (i) The first variant, E1086G, was reported as a known disease mutation in a previous study 3 and in the RetinoGenetics database 4 as well as the Human Gene Mutation Database (CM080033), the major database for human mutation repositories.…”