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X-Linked Juvenile Retinoschisis

Synonyms: Juvenile Retinoschisis, X-Linked Retinoschisis

, MD, PhD, , MD, CM, and , MSc.

Author Information

Initial Posting: ; Last Update: August 28, 2014.

Estimated reading time: 19 minutes


Clinical characteristics.

X-linked juvenile retinoschisis is characterized by symmetric bilateral macular involvement with onset in the first decade of life, in some cases as early as age three months. Fundus examination shows areas of schisis (splitting of the nerve fiber layer of the retina) in the macula, sometimes giving the impression of a spoke wheel pattern. Schisis of the peripheral retina, predominantly inferotemporally, occurs in approximately 50% of individuals. Affected males typically have vision of 20/60 to 20/120. Visual acuity often deteriorates during the first and second decades of life but then remains relatively stable until the fifth or sixth decade.


The diagnosis of X-linked juvenile retinoschisis is based on fundus findings, results of electrophysiologic testing, and molecular genetic testing. RS1 is the only gene known to be associated with X-linked juvenile retinoschisis.


Treatment of manifestations: Low-vision aids such as large-print textbooks; preferential seating in the front of the classroom; and use of handouts with high contrast. Surgery may be required to address the infrequent complications of vitreous hemorrhage and full-thickness retinal detachment.

Prevention of secondary complications: Ambylopia prevention therapy is indicated following surgical intervention for vitreous hemorrhage or retinal detachment or in cases of severe retinoschisis or hypermetropia.

Surveillance: Annual evaluation of children under age ten years by a pediatric ophthalmologist or retina specialist; patient education and close follow up may allow for early identification and treatment of vision-threatening complications.

Agents/circumstances to avoid: Head trauma and high-contact sports to reduce risk of retinal detachment and vitreous hemorrhage.

Genetic counseling.

X-linked juvenile retinoschisis is inherited in an X-linked manner. Carrier women have a 50% chance of transmitting the pathogenic variant in each pregnancy: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will nearly always have normal visual function and electrophysiology. Affected males pass the pathogenic variant to all of their daughters and none of their sons. Carrier testing for at-risk female relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant in the family is known.


Affected males. The diagnosis of X-linked juvenile retinoschisis is made in a young male with the following findings:

  • Bilaterally reduced visual acuity, typically between 20/60 and 20/120
  • The following findings on fundus examination:
    • Areas of schisis (splitting of the nerve fiber layer of the retina) in the macula, sometimes giving the impression of a spoke wheel pattern (Figure 1).
    • Schisis of the peripheral retina, predominantly inferotemporally, in approximately 50% of individuals [Eksandh et al 2000]. The associated elevation of the surface layer of the retina into the vitreous has been described as "vitreous veils" (Figure 2).
    • On occasion, more severe involvement of the macula (Figure 3)
    • On occasion, the Mizuo phenomenon, a color change in the retina after dark adaptation with the onset of light
  • Spectral domain optical coherence tomography (SD-OCT) that reveals characteristic signs, such as foveal schisis and thinning of the retina. This is currently the major diagnostic technique for X-linked juvenile retinoschisis [Molday et al 2012]
  • Increased fundus autofluorescence in the fovea, although this should be confirmed by SD-OCT [Renner et al 2008, Molday et al 2012]
  • A family history consistent with X-linked inheritance
Figure 1. . Fundus photo of a male with juvenile retinoschisis.

Figure 1.

Fundus photo of a male with juvenile retinoschisis. Arrow points to typical spoke-wheel pattern of foveal cysts.

Figure 2. . Fundus photo of the peripheral retina of a male with juvenile retinoschisis.

Figure 2.

Fundus photo of the peripheral retina of a male with juvenile retinoschisis. Area marked with arrows shows a partial-thickness retinal hole.

Figure 3.

Figure 3.

Fundus photo of a male with juvenile retinoschisis showing atypical, more severe findings with arrows pointing to atrophic macular changes

Note: Electroretinogram (ERG) is no longer the primary diagnostic tool used in the diagnosis of X-linked juvenile retinoschisis. While ERG can show selective reduction of the amplitude of the dark-adapted b-wave amplitude with relative preservation of the a-wave amplitude in affected males [Nakamura et al 2001], recent studies have shown that the ERG response is much more variable than previously thought [Molday et al 2012]. Individuals with X-linked juvenile retinoschisis and an identified RS1 pathogenic variant can have a technically normal ERG in which the b-wave is still present [Sieving et al 1999a, Eksandh et al 2005, Renner et al 2008]. Therefore, this diagnosis cannot be excluded based on a normal ERG.

Carrier females. In most cases, carrier females cannot be identified by clinical examination. Carrier females nearly always have normal visual function and a normal ERG. Rarely, examination of the peripheral retina may show white flecks or areas of schisis.

  • In a study of nine obligate carriers, two had areas of retinal dysfunction detected by multifocal ERG testing. Both had normal-appearing fundi [Kim et al 2007].
  • An Australian study [Lamey et al 2010] identified an obligate carrier female with abnormal rod ERG and multifocal ERG. The authors attribute this finding to either skewed X-inactivation or another underlying condition.


Intravenous fluorescein angiogram appears normal in younger individuals, whereas older individuals may have atrophic changes in the retinal pigment epithelium (RPE).

Optical coherence tomography (OCT) shows small cystic-appearing spaces in the perifoveal region and larger cystic-like spaces within the fovea in most school-age individuals [Apushkin et al 2005]. Cystic spaces are not as evident after adolescence. OCT scans of older individuals may appear normal because of flattening of cysts with age.

Molecular Genetic Testing

Gene. RS1 is the only gene in which pathogenic variants are known to cause X-linked juvenile retinoschisis.

Table 1.

Molecular Genetic Testing Used in X-Linked Juvenile Retinoschisis

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
Affected MalesCarrier Females
RS1Targeted analysis for pathogenic variants 2, 3~95% 4
Sequence analysis for sequence variants 5~90% 6, 790% 8
Sequence analysis for partial- and whole-gene deletion 56% 90% 10
Deletion/duplication analysis 11~6% 12~6% 12

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.


p.Glu72Lys, p.Gly74Val, p.Gly109Arg [Huopaniemi et al 1999]


Pathogenic variants included in a panel may vary by laboratory.


In persons of Finnish heritage [Huopaniemi et al 1999]


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.


Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.


Gel sizing analysis can detect putative (multi)exon and whole-gene deletions in RS1 in affected males based on lack of amplification by PCR.


Sequence analysis of genomic DNA cannot detect deletion of one or more exons in RS1 in females.


Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Testing Strategy

Confirming the diagnosis in a proband. In general, the diagnosis in a proband can be made by ophthalmologic examination and confirmed by spectral domain optical coherence tomography.

To identify the pathogenic variant in an affected male:

One genetic testing strategy is molecular genetic testing of RS1.


In males of Finnish heritage, perform targeted analysis for the three common pathogenic variants.


If the pathogenic variant is not identified, or for males of non-Finnish heritage, perform sequence analysis of RS1.


In males in whom a pathogenic variant is not identified by sequence analysis, consider deletion/duplication analysis of RS1.

An alternative genetic testing strategy is use of a multigene panel that includes RS1 and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Characteristics

Clinical Description

X-linked juvenile retinoschisis is a symmetric bilateral macular disorder with onset in the first decade of life, in some cases as early as age three months. Affected males generally present with reduction in vision by early elementary school. Affected males typically have vision of 20/60 to 20/120 on first presentation.

Visual acuity may deteriorate during the first and second decades of life but then remain relatively stable, with only very slowly progressive reduction from macular atrophy, until the fifth or sixth decade [Eksandh et al 2000, Apushkin et al 2005]. Visual loss may progress to legal blindness (acuity <20/200) by the sixth or seventh decade. In individuals over age 50 years, macular pigmentary changes and some degree of atrophy of the RPE are common. The delayed B-wave onset seen in a study of 68 affected males suggests that photoreceptor synapse or bipolar cell dysfunction increases with age [Bowles et al 2011].

Variation in disease presentation and disease progression is observed even among members of the same family.

Appearance of foveal lesions varies from largely radial striations (3%), microcystic lesions (34%), honeycomb-like cysts (8%), or their combinations (31%) to non-cystic-appearing foveal changes including pigment mottling (8%), loss of the foveal reflex (8%), or an atrophic-appearing lesion (8%) [Apushkin et al 2005].

X-linked juvenile retinoschisis progresses to retinal detachment in an estimated 5% to 22% of affected individuals. Retinal detachment can occur in infants with severe retinoschisis. About 4% to 40% of individuals with X-linked juvenile retinoschisis develop vitreous hemorrhage.

Genotype-Phenotype Correlations

Pathogenic missense, splice site, and frameshift variants; insertions; and deletions all result in the same phenotype. Some studies suggest that pathogenic variants that putatively cause protein truncation result in greater clinical severity [Sieving et al 1999b].

The possibility of meaningful genotype-phenotype correlations in X-linked juvenile retinoschisis is debated. On one hand, there can be variable phenotypic expression between sibs, other related individuals, and non-related individuals sharing the same pathogenic variant. However, milder phenotypic abnormalities are more commonly seen in males with missense pathogenic variants. This may be due to residual RS1 gene expression in such affected males compared to those with other types of pathogenic variants. Other as-yet unidentified factors are likely involved as well [Kim & Mukai 2013].


X-linked juvenile retinoschisis exhibits complete penetrance with variable expressivity.


Other terms correctly used in the past to refer to X-linked juvenile retinoschisis:

  • Juvenile retinoschisis
  • Congenital retinoschisis
  • Juvenile macular degeneration/dystrophy
  • Degenerative retinoschisis

Other terms incorrectly used in the past to refer to X-linked juvenile retinoschisis:

  • Cone dystrophy
  • Macular hole


Estimates of the prevalence of X-linked juvenile retinoschisis vary from one in 5,000 to one in 25,000 [The Retinoschisis Consortium 1998].

Differential Diagnosis

While the presence of retinoschisis in an individual with a positive family history of X-linked juvenile retinoschisis establishes the diagnosis in that person, making the diagnosis in a male with no known family history may be more difficult.

Cystoid macular edema may mimic foveal retinoschisis. Macular edema may be caused by diabetes mellitus, inflammatory conditions of the eye (uveitis), or intraocular surgery.

Amblyopia can be a referring diagnosis when foveal schisis changes are subtle. Suspicion of X-linked juvenile retinoschisis is raised if family history indicates other affected males in an X-linked inheritance pattern.

Goldmann-Favre vitreoretinal degeneration and enhanced S-cone syndrome (OMIM 268100), caused by pathogenic variants in NR2E3, may mimic X-linked juvenile retinoschisis. Onset occurs in infancy. Generally, affected individuals have severely impaired vision including marked visual field loss and severe night blindness. Coarse intraretinal cysts may be seen with peripheral retinoschisis; no vitreous veils are observed. The electroretinogram shows markedly reduced a-waves and b-waves with altered timing rather than simply the reduction in the b-wave amplitude found in X-linked juvenile retinoschisis. Inheritance is autosomal recessive.

Retinitis pigmentosa (RP) is the referring diagnosis in many persons with X-linked juvenile retinoschisis. Characteristics of RP that distinguish it from X-linked juvenile retinoschisis include some or all of the following: optic nerve gliotic pallor, narrowing of retinal vessels, and intraretinal pigment dispersion or clumping. The X-linked form of RP may cause confusion with X-linked juvenile retinoschisis, and other family members should be examined; the ERG in RP (particularly X-linked RP) is markedly diminished rather than having the selective reduction in b-wave amplitude seen in X-linked juvenile retinoschisis. Noble et al [1978] reported a family with rod-cone dystrophy and associated foveal schisis. For this reason, foveal retinoschisis alone does not make the diagnosis of X-linked juvenile retinoschisis.

VCAN-related vitreoretinopathy, which includes Wagner syndrome and erosive vitreoretinopathy (ERVR), is characterized by "optically empty vitreous" on slit-lamp examination and avascular vitreous strands and veils, mild or occasionally moderate to severe myopia, presenile cataract, night blindness of variable degree associated with progressive chorioretinal atrophy, retinal traction and retinal detachment at advanced stages of the disease, and reduced visual acuity. Optic nerve inversion has also been described. The first signs usually become apparent during early adolescence but onset can be as early as age two years. Pathogenic variants in VCAN (previously CSPG2) are causative. Inheritance is autosomal dominant.

Degenerative retinoschisis is an idiopathic, degenerative disease of the peripheral retina. No evidence suggests genetic etiology [Lewis 2003]. In degenerative or age-related peripheral retinoschisis, splitting occurs in the outer retina through the outer nuclear layer and plexiform layer, whereas in X-linked juvenile retinoschisis, splitting is found in the nerve fiber layer and the ganglion cell layer [Sieving 1998].

Retinal detachment, in which the full-thickness retina elevates and lifts off from the underlying ocular support, differs from retinoschisis, in which the retina splits through the nerve fiber layer. Retinal detachment in an otherwise normal eye can be surgically repaired, whereas retinal detachment associated with retinoschisis usually cannot.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with X-linked juvenile retinoschisis, the following evaluations are recommended:

  • Visual acuity
  • Goldmann visual field
  • Family history
  • Electroretinogram
  • Funduscopic examination
  • Optical coherence tomography
  • Genetic counseling

Treatment of Manifestations

Low-vision services are designed to benefit those whose ability to function is compromised by vision impairment. Low-vision specialists, often optometrists, help optimize the use of remaining vision. Services provided vary based on age and needs.

Public school systems are mandated by federal law to provide appropriate education for children who have vision impairment. Assistance may include larger print textbooks, preferential seating in the front of the classroom, and use of handouts with higher contrast.

Many individuals with X-linked juvenile retinoschisis are able to obtain a restricted driver's license. Some individuals have found specially designed telescopic lenses useful when driving; legal use of telescopic lenses may vary by locale.

Retinoschisis affects primarily the inner retinal layers; hence, retinoschisis alone (without retinal detachment) is at best difficult to treat surgically.

Treatment of retinoschisis may require the care of a retinal surgeon to address the infrequent complications of vitreous hemorrhage and full-thickness retinal detachment. The clinical presentation of a large area of peripheral retinoschisis may mask a true retinal detachment. Advice from an ophthalmologist or retinal surgeon should be sought when in doubt.

Prevention of Secondary Complications

Ambylopia prevention therapy is indicated following surgical intervention to treat vitreous hemorrhage or retinal detachment, or in cases of severe retinoschisis or hypermetropia [Medscape, accessed 8-21-14].


Annual evaluation of children under age ten years by a pediatric ophthalmologist or retina specialist is recommended.

Patient education and close follow-up are the only clinical options that may allow for early identification and treatment of vision-threatening complications [Orphanet, accessed 8-21-14].

Older children and adults need less frequent monitoring.

Agents/Circumstances to Avoid

Although retinal detachment and vitreous hemorrhage occur in a minority of affected individuals (5%-22% and 4%-40%, respectively), general avoidance of head trauma and high-contact sports is recommended.

Evaluation of Relatives at Risk

It is appropriate to evaluate at-risk male relatives of an affected individual in order to identify as early as possible those who would benefit from institution of treatment and preventive measures.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

A mouse model of human X-linked juvenile retinoschisis was studied to determine whether supplementation with functional normal retinoschisin protein can produce improvement in ERG function and retina morphology [Zeng et al 2004, Min et al 2005]. Subsequent evaluation of the mouse model confirmed that it appropriately mimics structural features of human X-linked juvenile retinoschisis. Replacements of the deficient protein through use of a neomycin resistance cassette or through use of an AAV vector were both successful, suggesting that, with additional study, gene therapy could become a viable strategy for therapeutic intervention [Kjellstrom et al 2007].

Other researchers showed that older mice had significantly reduced benefit from AAV Rs1h cDNA (the mouse ortholog of human RS1) gene transfer compared to younger mice that had rescue of retinal structure and function. These benefits along with retinoschisin expression persisted for more than 15 months. Other studies showed that intravitreal injection of a rAAV8 vector containing the mouse Rs1h cDNA under the control of a human retinoschisin promoter in Rs1h knockout mice yielded strong retinoschisin expression and structural and functional improvements. Wildtype retinoschisin delivered and expressed in human retinal culture cells has been shown to undergo protein folding, subunit assembly, and secretion mostly independent of endogenously expressed, defective retinoschisin protein. This suggests that gene therapy could be possible for affected individuals who have residual, pathogenic RS1 protein expression [Molday et al 2012].

Byrne et al [2014] explained that cell targeting and appropriate vector choice are very important to the success of retinal gene therapy. This group demonstrated that different cell types were able to secrete retinoschisin, transporting the protein across the retina. Photoreceptor cell secretion of this protein produced the best long-term rescue.

Another therapeutic approach involves in vivo directed evolution of AAV variants to deliver the wildtype gene to the outer retina after injection to the vitreous humor of the eye. The authors suggested that this has the potential to be a broadly applicable gene delivery method for inherited retinal diseases [Dalkara et al 2013].

Possible drawbacks of using viral vectors (e.g., the risks of oncogenicity, immunogenicity, and the possible persistence of such vectors in the brain after intravitreal injection) have triggered an interest in non-viral systems. A combination of solid lipid nanoparticles, dextran, and protamine as well as EGFP and RS1 plasmids have been used to develop non-viral vectors for X-linked juvenile retinoschisis treatment. Researchers studied the in vitro transfection capacity, cellular uptake, and intracellular trafficking of these vectors in ARPE-19 cells. In vivo intravitreal, subretinal, and topical forms of vector administration in Wistar rat eyes were also evaluated. EGFP expression in various cell types depended on the administration route. This work suggests that these non-viral vectors may be useful in treating X-linked juvenile retinoschisis, other degenerative retinal diseases, and ocular surface diseases as well [Delgado et al 2012].

Search in the US and in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

X-linked juvenile retinoschisis is inherited in an X-linked recessive manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother is a carrier, the chance of transmitting the RS1 pathogenic variant in each pregnancy is 50%. Male sibs who inherit the pathogenic variant will be affected; female sibs who inherit the pathogenic variant will be carriers. Carriers nearly always have normal visual function and normal electrophysiology (i.e., ERG).
  • If the mother is not a carrier, the risk to sibs is low but may be higher than that of the general population (the risk of germline mosaicism in mothers is not known).

Offspring of a proband. Males will pass the pathogenic variant to all of their daughters and none of their sons.

Other family members of a proband. The proband's maternal aunts may be at risk of being carriers and the aunt's offspring, depending on their gender, may be at risk of being carriers or of being affected.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Heterozygote (Carrier) Detection

Carrier testing for at-risk females requires prior identification of the pathogenic variant in the family.

Related Genetic Counseling Issues

See Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the RS1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Foundation Fighting Blindness
    7168 Columbia Gateway Drive
    Suite 100
    Columbia MD 21046
    Phone: 800-683-5555 (toll-free); 800-683-5551 (toll-free TDD); 410-423-0600
  • Retina International
    Retina Suisse
    Ausstellungsstrasse 36
    Zurich CH-8005
    Phone: +41 (0) 44 444 1077
    Fax: +41 (0) 44 444 1070
  • eyeGENE - National Ophthalmic Disease Genotyping Network Registry
    Phone: 301-435-3032

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

X-Linked Juvenile Retinoschisis: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for X-Linked Juvenile Retinoschisis (View All in OMIM)


Molecular Pathogenesis

For many years, X-linked juvenile retinoschisis has been thought of as a possible defect in the Muller cell, acting as a cellular scaffold within the retinal architecture. Studies on gene expression and immunolocalization of the normal protein, retinoschisin, indicate that it is expressed within the photoreceptors and has a complex interaction within cells of the retina. Retinoschisin is most highly expressed in the inner segments of the photoreceptors in human eye sections [Mooy et al 2002] and other mammals including mice [Molday et al 2001]. The protein was secreted by differentiated retinoblastoma cells (Weri-Rb1) [Grayson et al 2000]. From expression studies, it remains unclear whether the protein product of mutated disease-causing alleles is secreted properly [Wang et al 2002, Wu & Molday 2003].

In studying the mouse model of retinoschisis created by gene knockout, Weber et al [2002] noted disruption of the normal retinal cellular organization and the appearance of schisis-like cavities in the inner retina. The electroretinogram showed selective reduction of the ERG b-wave and a severe effect on the cone ERG. Atypical photoreceptor synapses were also observed, implicating a role for retinoschisin in the normal maintenance of the photoreceptor-bipolar synapse.

Gene structure. The transcript is 3040 bp in length NM_000330.3) and comprises six exons. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. A comprehensive list of benign variants (sequence polymorphisms) is maintained through the RetinoschisisDB© of the Retinoschisis Consortium.

Pathogenic variants. More than 196 pathogenic variants in RS1 have been associated with X-linked juvenile retinoschisis [Kim & Mukai 2013]. Most pathogenic variants occur in the discoidin domain of RS1, exons 4-6. An up-to-date listing of these pathogenic variants is maintained by the Retinoschisis Consortium; see RetinoschisisDB©.

Normal gene product. Retinoschisin is a 224-amino acid protein (NP_000321.1). Retinoschisin is an extracellular protein that exists as a novel disulfide-linked octamer. While it is expected to play a crucial role in cellular organization of the retina, the function of retinoschisin is as yet unknown [Wu et al 2005].

Abnormal gene product. The abnormal gene product may be sequestered in the cell and degraded or secreted [Wang et al 2002, Wu & Molday 2003].


Published Guidelines / Consensus Statements

  • AAO Task Force on Genetic Testing. American Academy of Ophthalmology Recommendations for 2014 genetic testing guidelines. Available online. 2014. Accessed 1-23-19.

Literature Cited

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  • Bowles K, Cukras C, Turriff A, Sergeev Y, Vitale S, Bush RA, Sieving PA. X-linked retinoschisis: RS1 mutation severity and age affect the ERG phenotype in a cohort of 68 affected male subjects. Invest Ophthalmol Vis Sci. 2011;52:9250–6. [PMC free article: PMC3302432] [PubMed: 22039241]
  • Byrne LC, Oztürk BE, Lee T, Fortuny C, Visel M, Dalkara D, Schaffer DV, Flannery JG. Retinoschisin gene therapy in photoreceptors, Müller glia or all retinal cells in the Rs1h-/- mouse. Gene Ther. 2014;21:585–92. [PMC free article: PMC4047144] [PubMed: 24694538]
  • Dalkara D, Byrne LC, Klimczak RR, Visel M, Yin L, Merigan WH, Flannery JG, Schaffer DV. In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous. Sci Transl Med. 2013;5:189ra76. [PubMed: 23761039]
  • Delgado D, del Pozo-Rodríguez A, Solinís MÁ, Avilés-Triqueros M, Weber BH, Fernández E, Gascón AR. Dextran and protamine-based solid lipid nanoparticles as potential vectors for the treatment of X-linked juvenile retinoschisis. Hum Gene Ther. 2012;23:345–55. [PubMed: 22295905]
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  • Gehrig A, Weber BH, Lorenz B, Andrassi M. First molecular evidence for a de novo mutation in RS1 (XLRS1) associated with X linked juvenile retinoschisis. J Med Genet. 1999;36:932–4. [PMC free article: PMC1734280] [PubMed: 10636740]
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Chapter Notes

Author History

Stephanie Chan, MSc (2014-present)
Ian M MacDonald, MD, CM (2003-present)
Paul A Sieving, MD, PhD (2003-present)
Meira Rina Meltzer, MA, MS; National Institutes of Health (2003-2014)
Nizar Smaoui, MD, FACMG; GeneDx (2003-2014)

Revision History

  • 28 August 2014 (me) Comprehensive update posted live
  • 12 May 2009 (me) Comprehensive update posted live
  • 18 June 2007 (cd) Revision: MLPA used for carrier testing for female relatives, as current PCR methodologies detect deletions in affected males only
  • 18 January 2006 (me) Comprehensive update posted live
  • 28 June 2004 (cd) Revision: change in test availability
  • 24 October 2003 (me) Review posted live
  • 1 July 2003 (ps) Original submission
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