Genotype Profile of Global EYS-Associated Inherited Retinal Dystrophy and Clinical Findings in a Large Chinese Cohort.

PURPOSE: The aim of this study was to probe the global profile of the EYS-associated genotype-phenotype trait in the worldwide reported IRD cases and to build a model for predicting disease progression as a reference for clinical consultation. METHODS: This retrospective study of 420 well-documented IRD cases with mutations in the EYS gene included 39 patients from a genotype-phenotype study of inherited retinal dystrophy (IRD) conducted at the Beijing Institute of Ophthalmology and 381 cases retrieved from global reports. All patients underwent ophthalmic evaluation. Mutations were revealed using next-generation sequencing, followed by Sanger DNA sequencing and real-time quantitative PCR analysis. Multiple regression models and statistical analysis were used to assess the genotype and phenotype characteristics and traits in this large cohort. RESULTS: A total of 420 well-defined patients with 841 identified mutations in the EYS gene were successfully obtained. The most common pathogenic variant was a frameshift c.4957dupA (p.S1653Kfs∗2) in exon 26, with an allele frequency of 12.7% (107/841), followed by c.8805C > A (p.Y2935X) in exon 43, with an allele frequency of 5.9% (50/841). Two new hot spots were identified in the Chinese cohort, c.1750G > T (p.E584X) and c.7492G > C (p.A2498P). Several EYS mutation types were identified, with CNV being relatively common. The mean age of onset was 20.54 ± 11.33 (4-46) years. Clinical examinations revealed a typical progression of RPE atrophy from the peripheral area to the macula. CONCLUSION: This large global cohort of 420 IRD cases, with 262 distinct variants, identified genotype-phenotype correlations and mutation spectra with hotspots in the EYS gene.

Genotype-Phenotype Analysis and Mutation Spectrum in a Cohort of Chinese Patients With Congenital Nystagmus.

Purpose: Congenital nystagmus (CN) is a genetically and clinically heterogeneous ocular disorder that manifests as involuntary, periodic oscillations of the eyes. To date, only FRMD7 and GPR143 have been reported to be responsible for causing CN. Here, we aimed to identify the disease-causing mutations and describe the clinical features in the affected members in our study. Methods: All the subjects underwent a detailed ophthalmic examination. Direct sequencing of all coding exons and splice site regions in FRMD7 and GPR143 and a mutation assessment were performed in each patient. Results: We found 14 mutations in 14/37 (37.8%) probands, including nine mutations in the FRMD7 gene and five mutations in the GPR143 gene, seven of which are novel, including c.284G>A(R95K), c.964C>T(P322S), c.284+10T>G, c.901T>C (Y301H), and c.2014_2023delTCACCCATGG(S672Pfs*12) in FRMD7, and c.250+1G>C, and c.485G>A (W162*) in GPR143. The mutation detection rate was 87.5% (7/8) of familial vs. 24.1% (7/29) of sporadic cases. Ten mutations in 24 (41.7%) non-syndromic subjects and 4 mutations in 13(30.8%) syndromic subjects were detected. A total of 77.8% (7/9) of mutations in FRMD7 were concentrated within the FERM and FA domains, while all mutations in GPR143 were located in exons 1, 2, 4 and 6. We observed that visual acuity tended to be worse in the GPR143 group than in the FRMD7 group, and no obvious difference in other clinical manifestations was found through comparisons in different groups of patients. Conclusions: This study identified 14 mutations (seven novel and seven known) in eight familial and 29 sporadic patients with congenital nystagmus, expanding the mutational spectrum and validating FRMD7 and GPR143 as mutation hotspots. These findings also revealed a significant difference in the screening rate between different groups of participants, providing new insights for the strategy of genetic screening and early clinical diagnosis of CN.

Mutation spectrum and genotype-phenotype correlation of inherited retinal dystrophy in Taiwan.

BACKGROUND: Inherited retinal dystrophy (IRD) is a group of irreversible retinal degenerative disorders with significant genotypic and phenotypic heterogeneity, which cause difficulty in making a precise clinical diagnosis. Furthermore, the mutation spectrum of IRD in Taiwan remains unknown. Therefore, our study focused on investigating the spectrum of mutations among Taiwanese families with IRD using targeted exome sequencing (TES) technology. METHODS: We recruited a total of 60 unrelated Taiwanese families with IRD; most of them were retinitis pigmentosa. We employed TES to investigate 284 candidate genes. Bioinformatics analysis, Sanger sequencing-based co-segregation testing, and computational assessment were performed to validate each mutation and its pathogenicity. The genotype-phenotype correlation was analysed in all patients with mutations defined in the guidelines provided by the American College of Medical Genetics. RESULTS: We successfully identified genetic causes in 32 families (detection rate of 53.3%). Among them, 16 had a sporadic inheritance (16/36, 44.4%); eight had an autosomal recessive inheritance (8/14, 57.1%); four had an autosomal dominant inheritance (4/5, 80%); four had an X-linked inheritance (4/5, 80%). Among 38 pathological mutations in 19 known genes, 20 mutations are reported here for the first time. Novel mutation spectrum and genotype-phenotype correlations were revealed as well. CONCLUSION: Here we achieved a detection rate of 53.3% and elucidated the mutation spectrum in Taiwanese families with IRD for the first time. The results indicated that CYP4V2 and USH2A might be the most common pathogenic genes in IRD patients in Taiwan.