Comprehensive analysis of genetic and clinical characteristics of 30 patients with X-linked juvenile retinoschisis in China.
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ABSTRACT: Purpose
To provides the clinical and genetic characteristics of a series of Chinese patients with X-linked juvenile retinoschisis (XLRS) through multimodal imaging and next-generation sequencing.Methods
Thirty patients (60 eyes) from 29 unrelated families of Chinese origin with XLRS were screened using multigene panel testing, and underwent a complete clinical evaluation. All variants identified in this study and reported in the Human Gene Mutation Database were analysed.Results
Twenty-five distinct variants in the retinoschisin gene were identified, of which eight were novel, and one was de novo. Missense mutations were the most prevalent type, and mutation hot spot was localized in the discoidin domain. The mean Snellen best-corrected visual acuity was 0.28 ± 0.17. Of all eyes presenting with schisis, 92.86% had lamellar schisis and 62.5% had peripheral schisis. Schisis changes mostly involved inner and outer nuclear layers. X-linked juvenile retinoschisis (XLRS) patients had a high incidence of complications, and peripheral schisis was a risk factor for it. No obvious genotype-phenotype association was observed.Conclusion
This study provides comprehensive analyses of the genetic and clinical characteristics of XLRS in a cohort of Chinese patients. The fourth de novo mutation in RS1 was identified. And we show that XLRS has a wide spectrum of clinical characteristics; hence, molecular diagnosis is crucial for its diagnosis, differential diagnosis and genetic counselling. Peripheral schisis is a risk factor for the high incidence of complications, and no clear genotype-phenotype correlations were found.
SUBMITTER: Gao FJ
PROVIDER: S-EPMC8359357 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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.
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Project description:X-linked juvenile retinoschisis (XLRS, MIM 312700) is a common early onset macular degeneration in males characterized by mild to severe loss in visual acuity, splitting of retinal layers, and a reduction in the b-wave of the electroretinogram (ERG). The RS1 gene (MIM 300839) associated with the disease encodes retinoschisin, a 224 amino acid protein containing a discoidin domain as the major structural unit, an N-terminal cleavable signal sequence, and regions responsible for subunit oligomerization. Retinoschisin is secreted from retinal cells as a disulphide-linked homo-octameric complex which binds to the surface of photoreceptors and bipolar cells to help maintain the integrity of the retina. Over 190 disease-causing mutations in the RS1 gene are known with most mutations occurring as non-synonymous changes in the discoidin domain. Cell expression studies have shown that disease-associated missense mutations in the discoidin domain cause severe protein misfolding and retention in the endoplasmic reticulum, mutations in the signal sequence result in aberrant protein synthesis, and mutations in regions flanking the discoidin domain cause defective disulphide-linked subunit assembly, all of which produce a non-functional protein. Knockout mice deficient in retinoschisin have been generated and shown to display most of the characteristic features found in XLRS patients. Recombinant adeno-associated virus (rAAV) mediated delivery of the normal RS1 gene to the retina of young knockout mice result in long-term retinoschisin expression and rescue of retinal structure and function providing a 'proof of concept' that gene therapy may be an effective treatment for XLRS.
| S-EPMC3334421 | biostudies-literature
Project description:Juvenile X-linked retinoschisis (XLRS, MIM#312700) belongs to a group of the vitreoretinal dystrophies. We aimed to describe the phenotype-genotype correlation of three XLRS cases in juveniles with different novel mutations from the Lithuanian population. The patients demonstrated macular retinoschisis and typical cyst-like cavities on spectral-domain optical coherence tomography (SD-OCT) images. The mean central foveal thickness was 569.7 µm. Two patients presented with peripheral retinoschisis. Flash electroretinogram demonstrated a reduced b/a ratio (<1.0) in all patients. RS1 (NM_000330.3) gene coding exons Sanger sequencing was performed. RS1 c.599G>T (p.R200L) mutation was detected in one case, showing to be pathogenic in silico analysis. c. (92_97) insC (p.W33fs) mutation was identified for another patient, indicating the variant is possibly damaging in silico analysis. The third case was identified with a pathogenic mutation c.422C>G (p.R141H), HGMD CM981753. These are the first cases of XLRS in the Lithuanian population confirmed by molecular genotyping. Presented patients had a different genotype but similar phenotypic traits.
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Project description:The aim of this study was to identify RS1 pathogenic variants in Czech patients with X-linked retinoschisis (XLRS) and to describe the associated phenotypes, including natural history, in some cases. Twenty-one affected males from 17 families were included. The coding region of RS1 was directly sequenced and segregation of the identified mutations was performed in available family members. In total, 12 disease-causing variants within RS1 were identified; of these c.20del, c.275G>A, c.[375_379del; 386A>T], c.539C>A and c.575_576insT were novel, all predicted to be null alleles. The c.539C>A mutation occurred de novo. Three patients (aged 8, 11 and 19 years) were misdiagnosed as having intermediate uveitis and treated with systemic steroids. Repeat spectral domain optical coherence tomography examinations in four eyes documented the transition from cystoid macular lesions to macular atrophy in the fourth decade of life. Four individuals were treated with topical dorzolamide and in two of them, complete resolution of the cystic macular lesions bilaterally was achieved, while one patient was noncompliant. Rebound phenomenon after discontinuation of dorzolamide for 7 days was documented in one case. Misdiagnosis of XLRS for uveitis is not uncommon; therefore, identification of disease-causing variants is of considerable benefit to the affected individuals.
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Project description:PURPOSE: X-linked retinoschisis (XLRS) is a recessively inherited disorder that causes macular degeneration and resultant visual defect in young males. Many genetic studies had focused on the patients in Western countries. We characterized the mutational spectrum of the RS1 gene in Korean patients with XLRS, and aimed to provide genetic information of XLRS in an Asian population. METHODS: This study enrolled 17 unrelated probands and their mothers for molecular genetic evaluation. All exons and the flanking intronic regions of RS1 were analyzed by direct sequencing. We performed gene dosage analysis by semiquantitative multiplex PCR to rule out the possibility of duplication in a patient without a sequence variation. We also tried RT-PCR analysis in a case with a putative splicing mutation. RESULTS: Genetic tests revealed 16 Korean patients (94.1%) had RS1 mutations. In one patient, neither sequence variation nor deletion or duplication in RS1 was detected. One case with de novo mutation was confirmed by familial analysis. Identified were 14 causative mutations, three of which were novel: one missense mutation (c.227T>G, p.V76G) and two splice-site mutations (c.78+1G>T and c.78+5G>A). No obvious genotype-phenotype relationship was observed. CONCLUSIONS: A missense mutation was the predominant type, and common or founder mutations were not observed in the Korean patients in this study who had XLRS. This study provides molecular genetic characteristics about an Asian population previously unexplored. The genetic characteristics of Korean XLRS will be helpful for understanding the worldwide spectrum of RS1 mutation.
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Project description:To investigate the clinical characteristics of X-linked retinoschisis (XLRS) and identify genetic mutations in Taiwanese patients with XLRS.This study included 23 affected males from 16 families with XLRS. Fundus photography, spectral domain optical coherent tomography (SD-OCT), fundus autofluorescence (FAF), and full-field electroretinograms (ERGs) were performed. The coding regions of the RS1 gene that encodes retinoschisin were sequenced.The median age at diagnosis was 18 years (range 4-58 years). The best-corrected visual acuity ranged from no light perception to 20/25. The typical spoke-wheel pattern in the macula was present in 61% of the patients (14/23) while peripheral retinoschisis was present in 43% of the patients (10/23). Four eyes presented with vitreous hemorrhage, and two eyes presented with leukocoria that mimics Coats' disease. Macular schisis was identified with SD-OCT in 82% of the eyes (31/38) while foveal atrophy was present in 18% of the eyes (7/38). Concentric area of high intensity was the most common FAF abnormality observed. Seven out of 12 patients (58%) showed electronegative ERG findings. Sequencing of the RS1 gene identified nine mutations, six of which were novel. The mutations are all located in exons 4-6, including six missense mutations, two nonsense mutations, and one deletion-caused frameshift mutation.XLRS is a clinically heterogeneous disease with profound phenotypic inter- and intrafamiliar variability. Genetic sequencing is valuable as it allows a definite diagnosis of XLRS to be made without the classical clinical features and ERG findings. This study showed the variety of clinical features of XLRS and reported novel mutations.
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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.
| S-EPMC3534142 | biostudies-literature
Project description:To identify mutations in the retinoschisin (RS1) gene in families with X-linked retinoschisis (XLRS). Twenty families with XLRS were enrolled in this study. All six coding exons and adjacent intronic regions of RS1 were amplified by polymerase chain reaction (PCR). The nucleotide sequences of the amplicons were determined by Sanger sequencing. Ten hemizygous mutations in RS1 were detected in patients from 14 of the 20 families. Four of the ten mutations were novel, including c:176G>A (p:Cys59Tyr) in exon 3, c:531T>G (p:Tyr177X), c:607C>G (p:Pro203Ala) and c:668G>A (p:Cys223Tyr) in exon 6. These four novel mutations were not present in 176 normal individuals. The remaining six were recurrent mutations, including c:214G>A (p:Glu72Lys), c:304C>T (p:Arg102Trp), c:436G>A (p:Glu146Lys), c:544C>T (p:Arg182Cys), c:599G>A (p:Arg200His) and c:644A>T (p:Glu215Val). Our study expanded the mutation spectrum of RS1 and enriches our understanding of the molecular basis of XLRS.
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Project description:X-linked juvenile retinoschisis (XLRS) is a hereditary retinal degeneration affecting young males caused by mutations in the retinoschisin (RS1) gene. We generated human induced pluripotent stem cells (hiPSCs) from XLRS patients and established three-dimensional retinal organoids (ROs) for disease investigation. This disease model recapitulates the characteristics of XLRS, exhibiting defects in RS1 protein production and photoreceptor cell development. XLRS ROs also revealed dysregulation of Na/K-ATPase due to RS1 deficiency and increased ERK signaling pathway activity. Transcriptomic analyses of XLRS ROs showed decreased expression of retinal cells, particularly photoreceptor cells. Furthermore, relevant recovery of the XLRS phenotype was observed when co-cultured with control ROs derived from healthy subject during the early stages of differentiation. In conclusion, our in vitro XLRS RO model presents a valuable tool for elucidating the pathophysiological mechanisms underlying XLRS, offering insights into disease progression. Additionally, this model serves as a robust platform for the development and optimization of targeted therapeutic strategies, potentially improving treatment outcomes for patients with XLRS.
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Project description:X-linked juvenile retinoschisis (RS) is a recessively inherited disorder resulting in poor visual acuity. Affected males typically show retinal degeneration and intraretinal splitting. The prevalence of RS is 1:15,000-1:30,000. Elsewhere we have mapped the RS gene between the markers DXS43 and DXS274 in Xp22.1-p22.2. To narrow the RS region, we analyzed 31 Finnish RS families with the markers DXS418, DXS999, DXS7161, and DXS365 and a new polymorphic microsatellite marker, HYAT1. Multipoint linkage analysis allowed us to localize the RS gene between the markers DXS418 and DXS7161 (LOD score = 31.3). We have covered this region with nine YAC clones. On the basis of the sizes of the YACs, sequence-tagged site (STS) content mapping, and restriction mapping, the physical distance between DXS418 and DXS7161 is approximately 0.9 Mb. A total of five potential CpG islands could be identified. For haplotype analysis, eight additional Finnish RS families were analyzed with the markers DXS1195, DXS418, HYAT1, DXS999, DXS7161, and DXS365. On the basis of the linkage-disequilibrium data that were derived from the genetically isolated Finnish population, the critical region for RS could be narrowed to 0.2-0.3 cM, between the markers DXS418 and HYAT1.
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