Dataset Information

Clinical findings and RS1 genotype in 90 Chinese families with X-linked retinoschisis.

ABSTRACT: Purpose:X-linked retinoschisis (XLRS) is an early-onset retinal degenerative disorder caused by mutations in the RS1 gene. The objective of this study was to describe the clinical and genetic findings in 90 unrelated Chinese patients with XLRS. Methods:All patients underwent clinical examination, including best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, fundus examination, and spectral domain-optical coherence tomography (SD-OCT). A combination of molecular screening methods, including Sanger-DNA sequencing of RS1 and targeted next-generation sequencing (TES), were used to detect mutations. In silico programs were used to analyze the pathogenicity of all the variants. Long-range PCR with subsequent DNA sequencing was employed to find the breakpoints of large deletions. Results:The 90 probands (mean age 17.29±12.94 years; 3-52 years) showed a variety of clinical phenotypes, and their average best correct visual acuity was 0.81±0.48 (logarithm of the minimal angle of resolution, 0-3). Of the 175 eyes analyzed, 140 (80%) had macular retinoschisis, 84 (48%) had peripheral retinoschisis, 28 (16%) had macular atrophy, and five (3%) had a normal macular structure. We identified 68 mutations in this cohort of patients, including 15 novel mutations. Most mutations (65%) were missense; the remaining null mutations included nonsense, splicing effect, frameshift indel, and large genomic DNA deletions. The 62 patients with missense mutations seemed to have relatively milder visual defects than the 28 patients with null mutations. Conclusions:Patients with RS1 mutations present profound phenotypic variability and show no clear genotype-phenotype correlations. Patients with null mutations tend to have more severe XLRS-related visual defects.

SUBMITTER: Chen C

PROVIDER: S-EPMC7155891 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Clinical findings and <i>RS1</i> genotype in 90 Chinese families with X-linked retinoschisis.

Chen Chunjie C Xie Yue Y Sun Tengyang T Tian Lu L Xu Ke K Zhang Xiaohui X Li Yang Y

Molecular vision 20200411

<h4>Purpose</h4>X-linked retinoschisis (XLRS) is an early-onset retinal degenerative disorder caused by mutations in the <i>RS1</i> gene. The objective of this study was to describe the clinical and genetic findings in 90 unrelated Chinese patients with XLRS.<h4>Methods</h4>All patients underwent clinical examination, including best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, fundus examination, and spectral domain-optical coherence tomography (SD-OCT). A combination of molecular sc ...[more]

PMID: 32300273

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Project description:PURPOSE: To determine the clinical features and to identify mutations in the retinoschisis gene (RS1) in ten patients with X-linked retinoschisis (XLRS). METHODS: Ten male patients from nine Polish families were included in this study. Ophthalmologic examinations, including optical coherence tomography (OCT) and full-field electroretinography (ERG), were performed in all affected boys. The entire coding region encompassing six exons of the RS1 gene was amplified with PCR and directly sequenced in all the patients. RESULTS: All affected individuals showed typical retinoschisis signs and symptoms, and all appeared to have a mutation in the RS1 gene. Seven different mutations were identified, including two novel missense substitutions: c.176G>C (p.Cys59Ser), c.451T>A (p.Tyr151Asp); one novel nonsense substitution: c.218C>A (p.Ser73*); and one novel frameshift mutation: c.354_355delCA (p.Asp118Glufs*2). We also found two missense substitutions that had been previously described: c.214G>A (p.Glu72Lys) and c.626G>T (p.Arg209Leu) and one known splice site mutation in intron 5: c.522+1G>T (IVS5+1G>T). CONCLUSIONS: This study provides the first molecular genetic characteristics of patients with juvenile retinoschisis from the previously unexplored Polish population. We investigated the molecular background of XLRS in ten boys. The present study reports for the first time four novel mutations, including two missense substitutions, one nonsense substitution, and one frameshift deletion. One of these substitutions and 2-bp deletion created stop codons. Moreover, we described three substitutions that had been previously reported (one is a splicing mutation). Further genetic characterization of Polish patients with XLRS will be helpful in understanding the worldwide spectrum of RS1 mutations. Despite the mutation heterogeneity found in a small group of our patients, they presented a relatively uniform clinical picture. Identifying the causative mutation is helpful in confirming diagnosis and counseling, but cannot provide prognostic data.

Project description:PURPOSE: To determine clinical phenotypes, examine the age dependency of X-linked juvenile retinoschisis (XLRS), and identify mutations in the retinoschisis1 gene (RS1) in 13 Hungarian (Caucasian) families with this disease. METHODS: This study included 72 members in 13 families. Complete ophthalmological examinations, including optical coherence tomography (OCT) and full-field and multifocal electroretinography (ERG), were performed on 20 affected males, 13 female carriers, and 27 healthy controls. The patients were divided into two age groups (Group I <25 years and Group II >25 years), retrospectively, to assess the possible effects of age. Correlations among genotype, age, best corrected visual acuity (BCVA), OCT, and ERG results were analyzed. A modified classification scheme was done to identify the different phenotypes of the disease. In each of the 72 family members and 100 age-matched male controls, all exons and introns of RS1 were amplified by polymerase chain reaction (PCR) and directly sequenced. RESULTS: Foveal retinoschisis was detected in 25 eyes (62.5%) of patients by funduscopy, and in 29 eyes (72.5%) by OCT, while macular lamellar schisis was recognizable only by OCT in 30 eyes (75%) of patients. Foveal thickness (FT) and total macular volume were significantly increased in younger (Group I) patients only. For patients younger than 26 years, large inner nuclear central cysts were observable by OCT, while after 26 years, foveas were atrophic. White flecks and dots, which were like that seen in fundus albipunctatus, were detected in both eyes of one patient. In both patient groups, characteristically decreased b-waves of standard combined ERG were recorded without any significant difference between the patient groups. The BCVA and ERG parameters of all patients and the OCT of younger patients were significantly worse (p<0.05) than those of age-matched controls. A significant difference between the two age groups was found in case FT, total macular volume, and amplitudes of rod b-wave only. Moderate negative correlation (r=-0.54, p<0.001) was detected between age and FT, while only low negative correlation (r=-0.33, p<0.05) was detected between age and standard combined b-wave amplitudes of full-field ERG. BCVA LogMAR did not show any obvious correlation with age (r=-0.14, p=0.39) or with the type of mutation. Nine different mutations were identified in 25 male patients and 31 female carriers of 13 families: six known and one novel missense mutation (c.575C>T, p.Pro192Leu), one insertion mutation (c.579dupC, p.Ile194Hisfs29ext43), and one frameshift, causing splice site mutation (c.78+1G>C) were detected. These mutations were absent in the 100 age-matched male control samples. CONCLUSIONS: Foveal cystic schisis was found more often by OCT than by funduscopy (+10%), while flat macular lamellar schisis was recognizable only by OCT. Advancing age inversely influenced the size of cavities (FT), and standard combined b-wave amplitudes of full-field ERG, while BCVA, response density, and implicit times of multifocal electroretinography did not show any obvious correlation with age. The atrophic stage of the disease was observable after 26 years of age. The lesions that appeared to be indicative of fundus albipunctatus were proven to be palisades between the splitted retinal layers. Our modified classification scheme was helpful in assessing the prevalence of disease types. In these Hungarian patients, one novel and eight known mutations were detected. The distribution of mutations in RS1 was different to that reported in the literature, because the greatest number of different mutations was in exon 6 instead of exon 4. Two mutation hot spots were found: between c.418-422 in exon 5 and between c.574-579 in exon 6. Genotype-phenotype correlation was not demonstrable.

Dataset Information

Clinical findings and RS1 genotype in 90 Chinese families with X-linked retinoschisis.

Publications

Clinical findings and <i>RS1</i> genotype in 90 Chinese families with X-linked retinoschisis.

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