X-linked retinoschisis (XLR) is a rare medical condition that involves in the splitting of neurosensory layers and the impairment of vision in the retina. In majority of the XLR cases, pathogenic variants in Retinoschisin 1 (RS1) gene have been implicated in males with an early age of onset during early childhood. In the present study, we have recruited two North Indian families having multiple affected male members, who were diagnosed with XLR. The entire protein-coding region of RS1 was screened by PCR-Sanger sequencing and two recurrent pathogenic variants (p.I81N and p.R102Q) were unraveled. The in vitro study of these variants demonstrated the aggregation of mutant RS1 within the endoplasmic reticulum. Furthermore, mutant forms of this protein showed significant intracellular retention, which was evident by the absence of retinoschisin protein fractions in the extracellular media. These inferences were also supported by extensive bioinformatics analysis of the mutants, which showed dramatic conformational changes in the local structure of retinoschisin. Thus, our study suggests that the identified pathogenic variants interfere with proper protein folding, leading to anomalous structural changes ultimately resulting in intracellular retention of retinoschisin within the retina.

The inheritance pattern of genetically confirmed hereditary juvenile retinoschisis reported so far is X-linked recessive with limited number of female cases. We identified a female patient with retinoschisis, and this study reports the clinical features as well as the underlying genetic defect of this family.
Detailed family history and pedigree analysis were performed. All affected subjects underwent detailed ophthalmic examinations, including best corrected visual acuity (BCVA), dilated fundoscopy, optical coherent tomography (OCT) and fundus autofluorescence (FAF). DNA sample of the proband was sequenced by next-generation sequencing (NGS). Sanger sequencing was performed for validation and segregation.
Three affected subjects including one female and two males were confirmed in this consanguineous family. The BCVA ranged from 20/50 to hand motion. Foveoschisis, hyperopia, subcapsular cataracts, vitreous opacity, retinal pigmentation, and macular atrophy were present in all three patients, with variable severity. Nystagmus, esotropia, and retinal vessels transposition were noted in the female patient. Retinal detachment occurred in the female patient and her affected brother. A small deletion in RS1 gene c.97delT (p.W33Gfs*93) (NM_000330.3) was found, which was co-segregated in the pedigree.
Consanguineous family having XLRS female patient could manifest as pseudo-dominant inheritance. Significant intrafamilial phenotypic variation was revealed.

UNASSIGNED: X-linked retinoschisis is an inherited retinal disease caused by mutations in the RS1 gene; however, a genotype-phenotype correlation regarding the mutation type or location within the RS1 gene and clinical characteristics of the patients has not been established yet. This is the first report documenting the genotypes and ophthalmological findings in a Turkish population with confirmed RS1 mutations.
UNASSIGNED: Fifty eyes of 25 male patients were included in the study. RS1 mutation analysis was performed by DNA sequencing. Retrospective analysis of ocular examinations and SD-OCT scans were applied.
UNASSIGNED: The major mutation was c.422 G > A (p.Arg141His, exon 5) affecting 14 patients (56%) and c.531 T > G was the only non-sense mutation out of 7 pathogenic variants. At presentation; the mean age was 24.6 ± 16.2 (4-72) years, mean visual acuity (VA) was 0.61 ± 0.32 (logMAR, 0.10-1.30). Forty-six (92%) eyes had macular, 16 eyes (32%) had peripheral retinoschisis. None of the eyes had macular scar, whereas 7 eyes (14%) had macular atrophy. The most frequent location of schisis was inner nuclear layer (37.5%). The eyes with disruption of ellipsoid zone (EZ) or external limiting membrane (ELM) had worse VA (for EZ, 0.65 ± 0.25 versus 0.45 ± 0.34, logMAR, 31 versus 17 eyes, p = .013; for ELM, 0.66 ± 0.27 versus 0.45 ± 0.31, logMAR, 30 versus 18 eyes, p = .008).
UNASSIGNED: Seven different pathogenic variants in the RS1 gene were identified; with c.422 G > A (p.Arg141His) as the most frequent variant and c.531 T > G as only non-sense mutation. Having EZ or ELM disruption were the significant factors affecting VA.

The aim of the present study was to report a novel mutation in the retinoschisin 1 (RS1) gene in a Caucasian family affected by X-linked juvenile retinoschisis (XLRS) and to describe the long-term modification of retinal structure. Two brothers with an early onset maculopathy were diagnosed with XLRS. Fundus photography, fluorescein angiography, spectral domain optical coherence tomography and electroretinogram analyses were performed. Their sister was also examined. All subjects were screened for mutations in the RS1 gene. XLRS patients demonstrated a marked reduction of best-corrected visual acuity. SD-OCT scans reported a cystic degeneration primarily involving the inner nuclear layer, though some cysts were detected in the outer plexiform layer and in the ganglion cell layer. During the ten-year follow-up, a progressive retinal thickening and coalescence of the cysts was observed. Genetic testing revealed a novel mutation (p.Ile212Asn) in the RS1 gene in both XLRS patients, whereas their sister was not a genetic carrier. Several mutations of the RS1 gene were recognized to be responsible for XLRS. Although the correspondence between genotype and phenotype is still under debate, is reasonable that siblings affected by XLRS could share other genetic and/or epigenetic factors capable to influence clinical course of the disease.

OBJECTIVE: To identify the mutations in RS1 gene associated with typical phenotype of X-linked juvenile retinoschisis (XLRS) and a rare condition of concomitant glaucoma.
METHODS: Complete ophthalmic examinations were performed in the proband. The coding regions of the RS1 gene that encode retinoschisin were amplified by polymerase chain reaction and directly sequenced.
RESULTS: The proband showed a typical phenotype of XLRS with large peripheral retinal schisis in both eyes, involving the macula and combined with foveal cystic change, reducing visual acuity. A typical phenotype of recurrent glaucoma with high intraocular pressure (IOP) and reduced visual field was also demonstrated with the patient. Mutation analysis of RS1 gene revealed R102W (c.304C>T) mutations in the affected male, and his mother was proved to be a carrier with the causative mutation and another synonymous polymorphism (c.576C>CT).
CONCLUSIONS: We identified the genetic variations of a Chinese family with typical phenotype of XLRS and glaucoma. The severe XLRS phenotypes associated with R102W mutations reveal that the mutation determines a notable alteration in the function of the retinoschisin protein. Identification of the disease-causing mutation is beneficial for future clinical references.