X-linked retinoschisis

Summary

X-linked retinoschisis (MONDO:0010725) is a disease caused by RS1 (GenCC Definitive), with 2 cohort genes and 7 clinical trials. Top therapeutic interventions include dorzolamide.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal gene: RS1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 208
• Phenotypes (HPO): 16
• Clinical trials: 7

Clinical features

Epidemiology

Prevalence records

5 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	5	Worldwide	Validated
Point prevalence	1-9 / 100 000	4.5	Europe	Validated
Point prevalence	1-9 / 100 000	3.6	France	Validated
Point prevalence	1-9 / 100 000	5	Denmark	Not yet validated
Point prevalence	1-9 / 100 000	5	Netherlands	Not yet validated

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0000496	Abnormality of eye movement	Very frequent (80-99%)
HP:0000501	Glaucoma	Very frequent (80-99%)
HP:0000504	Abnormality of vision	Very frequent (80-99%)
HP:0000512	Abnormal electroretinogram	Very frequent (80-99%)
HP:0000529	Progressive visual loss	Very frequent (80-99%)
HP:0030502	Retinoschisis	Very frequent (80-99%)
HP:0000493	Abnormal foveal morphology	Frequent (30-79%)
HP:0007722	Retinal pigment epithelial atrophy	Frequent (30-79%)
HP:0007902	Vitreous hemorrhage	Frequent (30-79%)
HP:0007984	Electronegative electroretinogram	Frequent (30-79%)
HP:0025158	Hyperautofluorescent retinal lesion	Frequent (30-79%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000541	Retinal detachment	Occasional (5-29%)
HP:0000662	Nyctalopia	Occasional (5-29%)
HP:0030824	Mizuo phenomenon	Occasional (5-29%)
HP:0030825	Absent foveal reflex	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked retinoschisis
Mondo ID	MONDO:0010725
OMIM	312700
Orphanet	792
DOID	DOID:0060763
ICD-11	2074506458
NCIT	C75483
SNOMED CT	86923008
UMLS	C3714753
MedGen	811458
GARD	0004690
NORD	1864
Is cancer (heuristic)	no

Also known as: juvenile retinoschisis · juvenile X-linked retinoschisis · retinoschisis 1, X-linked, juvenile · retinoschisis juvenile X chromosome-linked · retinoschisis X-linked · retinoschisis, X-linked · retinoschisis, X-linked recessive · RS · RS1 · X-linked juvenile retinoschisis · X-linked juvenile retinoschisis type 1 · X-linked retinoschisis · XJR · XLRS · XLRS1

Data availability: 208 ClinVar variants · 95 ClinGen variant curations · 5 GenCC gene-disease records · 11 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › X-linked retinoschisis

Related subtypes (49): X-linked Opitz G/BBB syndrome, X-linked immunoneurologic disorder, X-linked adrenal hypoplasia congenita, X-linked lissencephaly with abnormal genitalia, X-linked severe congenital neutropenia, X-linked distal spinal muscular atrophy type 3, epilepsy, X-linked 1, with variable learning disabilities and behavior disorders, Aland island eye disease, X-linked erythropoietic protoporphyria, X-linked central congenital hypothyroidism with late-onset testicular enlargement, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, X-linked acrogigantism due to Xq26 microduplication, Wiskott-Aldrich syndrome, X-linked Alport syndrome, X-linked mandibulofacial dysostosis, X-linked chondrodysplasia punctata, choroideremia, cone dystrophy, X-linked, with tapetal-like sheen, diabetes insipidus, nephrogenic, X-linked, Dyggve-Melchior-Clausen syndrome, X-linked, dyskeratosis congenita, X-linked, X-linked hypohidrotic ectodermal dysplasia, X-linked Ehlers-Danlos syndrome, epidermodysplasia verruciformis, X-linked, exudative vitreoretinopathy 2, X-linked, Aarskog-Scott syndrome, X-linked, hemophilia A, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius, hyper-IgM syndrome type 1, X-linked lymphoproliferative syndrome, macular dystrophy, X-linked, X-linked Emery-Dreifuss muscular dystrophy, X-linked myotubular myopathy, X-linked lethal multiple pterygium syndrome, spondyloepiphyseal dysplasia tarda, X-linked, X-linked cerebellar ataxia, adrenoleukodystrophy, Charcot-Marie-Tooth disease type X, X-linked dominant disease, X-linked recessive disease, X-linked hypophosphatemic rickets, X-linked sideroblastic anemia 1, X-linked deafness, X-linked cone-rod dystrophy, X-linked congenital stationary night blindness, X-linked congenital hemolytic anemia, X-linked complex neurodevelopmental disorder, X-linked intellectual disability, leukemia, acute, X-linked

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

208 retrieved; paginated sample, class counts are floors:

64 pathogenic, 54 likely pathogenic, 36 uncertain significance, 21 pathogenic/likely pathogenic, 14 likely benign, 11 benign, 8 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066419	NM_000330.4(RS1):c.227T>A (p.Val76Asp)	CDKL5	Pathogenic	reviewed by expert panel
1184473	NM_000330.4(RS1):c.287G>A (p.Trp96Ter)	CDKL5	Pathogenic	no assertion criteria provided
1459515	NM_000330.4(RS1):c.461A>G (p.Gln154Arg)	CDKL5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1517929	NM_000330.4(RS1):c.187T>C (p.Cys63Arg)	CDKL5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1687609	NM_000330.4(RS1):c.531T>G (p.Tyr177Ter)	CDKL5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2113491	NM_000330.4(RS1):c.188G>T (p.Cys63Phe)	CDKL5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2574303	NM_000330.4(RS1):c.185-1G>T	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
2637975	NM_000330.4(RS1):c.377A>G (p.Asp126Gly)	CDKL5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279886	NM_000330.4(RS1):c.520del (p.Arg174fs)	CDKL5	Pathogenic	reviewed by expert panel
2982432	NM_000330.4(RS1):c.505C>T (p.Gln169Ter)	CDKL5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3249744	NM_000330.4(RS1):c.206T>C (p.Leu69Pro)	CDKL5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3339552	NM_000330.4(RS1):c.365G>A (p.Trp122Ter)	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
370754	NM_000330.4(RS1):c.498C>A (p.Tyr166Ter)	CDKL5	Pathogenic	reviewed by expert panel
372496	NM_000330.4(RS1):c.208G>A (p.Gly70Ser)	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
372497	NM_000330.4(RS1):c.668G>A (p.Cys223Tyr)	CDKL5	Pathogenic	reviewed by expert panel
3775403	NM_000330.4(RS1):c.362del (p.Gln121fs)	CDKL5	Pathogenic	criteria provided, single submitter
3899908	NC_000023.11:g.18644511C>T	CDKL5	Pathogenic	reviewed by expert panel
4081778	NM_000330.4(RS1):c.354delinsGGTGTGCCTGGCTCTCCA (p.Asp118fs)	CDKL5	Pathogenic	criteria provided, single submitter
4279580	NM_000330.4(RS1):c.581T>A (p.Ile194Asn)	CDKL5	Pathogenic	reviewed by expert panel
429436	NM_000330.4(RS1):c.452A>C (p.Tyr151Ser)	CDKL5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449509	NM_000330.4(RS1):c.221_237delinsTCCCCTGACCGGGTTAGAGT (p.Gly74_Asp79delinsValProTer)	CDKL5	Pathogenic	reviewed by expert panel
4818179	NM_000330.4(RS1):c.238C>T (p.Gln80Ter)	CDKL5	Pathogenic	criteria provided, single submitter
4849233	NM_000330.4(RS1):c.206_207del (p.Leu69fs)	CDKL5	Pathogenic	criteria provided, single submitter
547067	NM_000330.4(RS1):c.366G>A (p.Trp122Ter)	CDKL5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68072	NM_000330.4(RS1):c.349C>T (p.Gln117Ter)	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
68076	NM_000330.4(RS1):c.579del (p.Ile194fs)	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
813235	NM_000330.4(RS1):c.199_206dup (p.Gly70fs)	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
9886	NM_000330.4(RS1):c.286T>C (p.Trp96Arg)	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
9887	NM_000330.4(RS1):c.304C>T (p.Arg102Trp)	CDKL5	Pathogenic	reviewed by expert panel
9888	NM_000330.4(RS1):c.214G>A (p.Glu72Lys)	CDKL5	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RS1	Definitive	X-linked	X-linked retinoschisis	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RS1	Orphanet:792	X-linked retinoschisis
CDKL5	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
CDKL5	Orphanet:3095	Atypical Rett syndrome
CDKL5	Orphanet:505652	CDKL5-deficiency disorder
CDKL5	Orphanet:697160	Infantile epileptic spasms syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RS1	HGNC:10457	ENSG00000102104	O15537	Retinoschisin	gencc,clinvar
CDKL5	HGNC:11411	ENSG00000008086	O76039	Cyclin-dependent kinase-like 5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RS1	Retinoschisin	Binds negatively charged membrane lipids, such as phosphatidylserine and phosphoinositides.
CDKL5	Cyclin-dependent kinase-like 5	Mediates phosphorylation of MECP2.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RS1	Other/Unknown	no		FA58C, Galactose-bd-like_sf, Neuropilin_MCO_CoagFactor
CDKL5	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	1
oocyte	1
secondary oocyte	1
Brodmann (1909) area 23	1
cortical plate	1
frontal pole	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RS1	34	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, oocyte, secondary oocyte
CDKL5	257	ubiquitous	marker	frontal pole, Brodmann (1909) area 23, cortical plate

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CDKL5	1,357
RS1	1,317

Intra-cohort edges

A	B	Sources
CDKL5	RS1	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CDKL5	O76039	3
RS1	O15537	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of dendrite development	1	495.6×	0.007	CDKL5
positive regulation of dendrite morphogenesis	1	443.5×	0.007	CDKL5
retina layer formation	1	324.1×	0.007	RS1
positive regulation of Rac protein signal transduction	1	324.1×	0.007	CDKL5
regulation of cilium assembly	1	300.9×	0.007	CDKL5
regulation of postsynapse organization	1	263.3×	0.007	CDKL5
positive regulation of axon extension	1	255.3×	0.007	CDKL5
eye development	1	175.5×	0.009	RS1
modulation of chemical synaptic transmission	1	91.6×	0.016	CDKL5
neuron migration	1	66.9×	0.019	CDKL5
protein homooligomerization	1	61.1×	0.019	RS1
visual perception	1	39.8×	0.027	RS1
cell adhesion	1	18.7×	0.053	RS1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CDKL5	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDKL5	14	4
RS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	CDKL5
CAPMATINIB	4	CDKL5
DEFACTINIB	3	CDKL5
ALVOCIDIB	3	CDKL5
LESTAURTINIB	3	CDKL5
RUBOXISTAURIN	3	CDKL5
FORETINIB	2	CDKL5
RG-547	2	CDKL5
AT-7519	2	CDKL5
TOZASERTIB	2	CDKL5
BMS-387032	1	CDKL5
PF-03758309	1	CDKL5
5-(6-BENZOTHIAZOLYLMETHYLENE)-3,5-DIHYDRO-2-(((1S)-1-(METHOXYMETHYL)-3-METHYLBUTYL)AMINO)-4H-IMIDAZOL-4-ONE, (5Z)-	1	CDKL5
AST-487	1	CDKL5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CDKL5	74	Binding:74

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CDKL5	2.7.11.22	cyclin-dependent kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

14 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
FEDRATINIB	4	CDKL5
CAPMATINIB	4	CDKL5
DEFACTINIB	3	CDKL5
ALVOCIDIB	3	CDKL5
LESTAURTINIB	3	CDKL5
RUBOXISTAURIN	3	CDKL5
FORETINIB	2	CDKL5
RG-547	2	CDKL5
AT-7519	2	CDKL5
TOZASERTIB	2	CDKL5
BMS-387032	1	CDKL5
PF-03758309	1	CDKL5
5-(6-BENZOTHIAZOLYLMETHYLENE)-3,5-DIHYDRO-2-(((1S)-1-(METHOXYMETHYL)-3-METHYLBUTYL)AMINO)-4H-IMIDAZOL-4-ONE, (5Z)-	1	CDKL5
AST-487	1	CDKL5

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CDKL5
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	RS1

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
RS1	0	CDKL5

Clinical trials & evidence

Clinical trials

Clinical trials: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
EARLY_PHASE1	2
PHASE3	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05878860	PHASE3	RECRUITING	ATSN-201 Gene Therapy in RS1-Associated X-linked Retinoschisis
NCT02416622	PHASE1/PHASE2	COMPLETED	Safety and Efficacy of rAAV-hRS1 in Patients With X-linked Retinoschisis (XLRS)
NCT06345898	EARLY_PHASE1	RECRUITING	Safety and Efficacy of a Single Subretinal Injection of JWK002 Gene Therapy in Subjects With X-linked Retinoschisis(XLRS)
NCT06066008	EARLY_PHASE1	COMPLETED	Safety and Efficacy Study of Novel Gene Therapy ZM-01 for X-linked Retinoschisis Patients
NCT05814952	Not specified	RECRUITING	Safety and Efficacy Study of LX103 Treatment of X-Linked Retinoschisis (XLRS)
NCT07502664	Not specified	RECRUITING	Development and Evaluation of Functional Visual Field and Navigation Endpoints in Moderate to Profound Inherited Retinal Disease (DEFINE-IRD)
NCT02331173	Not specified	COMPLETED	Clinical Evaluation of Patients With X-linked Retinoschisis

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DORZOLAMIDE	4	1