Retinoschisis

Summary

Retinoschisis (MONDO:0004579) is a disease (an umbrella term covering 5 Mondo subtypes) caused by RS1 (GenCC Definitive), with 2 cohort genes (5 GWAS associations across 4 studies) and 10 clinical trials. Top therapeutic interventions include acetazolamide, bupivacaine, and triamcinolone.

At a glance

• Causal gene: RS1 (GenCC Definitive)
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 2
• GWAS associations: 5
• ClinVar variants: 11
• Clinical trials: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	retinoschisis
Mondo ID	MONDO:0004579
MeSH	D041441
DOID	DOID:8465
ICD-11	1118046584
NCIT	C85046
SNOMED CT	44268007
UMLS	C0152439
MedGen	56292
GARD	0027687
Is cancer (heuristic)	no

Data availability: 11 ClinVar variants · 5 GWAS associations (4 studies) · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal degeneration › retinoschisis

Related subtypes (5): peripheral retinal degeneration, macular degeneration, inherited retinal dystrophy, cone dystrophy 5, X-linked, cone dystrophy 1, X-linked

Subtypes (5): bullous retinoschisis, flat retinoschisis, retinoschisis, autosomal dominant, retinoschisis of fovea, X-linked retinoschisis

Genetics & variants

GWAS landscape

5 GWAS associations across 4 studies. Top hits map to 2 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs115803211	1e-32	MIR9-2HG	T	0.64
rs1054266228	2e-12	CELF2	C	3.31
rs1313237	1e-11	LINC02322 - C14orf39	A	0.24
chr14:61072875	2e-11		T	0.23

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90475846	Verma A	2024	1,704	448,821	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90480041	Verma A	2024	430	121,162	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90481901	Verma A	2024	430	121,162	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90435963	Zhou W	2018	68	397,761	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	4

MAF distribution

Bucket	Variants
common (>=0.05)	3
low_freq (0.01-0.05)	0
rare (<0.01)	1
unknown	0

Functional consequences

Consequence	Count
intron_variant	2
intergenic_variant	1
unknown	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs115803211	5	88611619	T>C,G	0.059	intron_variant	MIR9-2HG	1e-32	Tier 4: intronic/intergenic
rs1054266228	10	11109377	C>T	0	intron_variant	CELF2	2e-12	Tier 4: intronic/intergenic
rs1313237	14	60381506	A>C,G	0.473	intergenic_variant	LINC02322 - C14orf39	1e-11	Tier 4: intronic/intergenic
chr14:61072875				0.402			2e-11	Tier 4: intronic/intergenic

ClinVar germline variants

11 retrieved; paginated sample, class counts are floors:

8 pathogenic, 2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
812429	NM_000330.4(RS1):c.632C>T (p.Ala211Val)	CDKL5	Pathogenic	no assertion criteria provided
9887	NM_000330.4(RS1):c.304C>T (p.Arg102Trp)	CDKL5	Pathogenic	reviewed by expert panel
98937	NM_000330.4(RS1):c.326G>A (p.Gly109Glu)	CDKL5	Pathogenic	criteria provided, single submitter
98938	NM_000330.4(RS1):c.329G>A (p.Cys110Tyr)	CDKL5	Pathogenic	reviewed by expert panel
9895	NM_000330.4(RS1):c.608C>T (p.Pro203Leu)	CDKL5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
98956	NM_000330.4(RS1):c.418G>A (p.Gly140Arg)	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
98959	NM_000330.4(RS1):c.421C>T (p.Arg141Cys)	CDKL5	Pathogenic	reviewed by expert panel
98982	NM_000330.4(RS1):c.523-2A>G	CDKL5	Pathogenic	criteria provided, single submitter
98994	NM_000330.4(RS1):c.578C>T (p.Pro193Leu)	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
3220934	NM_000330.4(RS1):c.395T>G (p.Val132Gly)	CDKL5	Likely pathogenic	criteria provided, single submitter
1301833	NM_000330.4(RS1):c.52+3A>G	RS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts

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

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Acetazolamide.

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: 10.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	6
PHASE4	1
PHASE1/PHASE2	1
PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01995045	PHASE4	COMPLETED	Postoperative Pain Control Following Vitreoretinal Surgery
NCT02317887	PHASE1/PHASE2	COMPLETED	Study of RS1 Ocular Gene Transfer for X-linked Retinoschisis
NCT06114537	PHASE2	COMPLETED	The AXIS Study: the Efficacy of Acetazolamide for the Treatment of Cystoid Fluid Collections in Retinoschisis
NCT06289452	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Safety and Efficacy Study of IVB102 Injection in Subjects With X-linked Retinoschisis
NCT00055029	Not specified	ACTIVE_NOT_RECRUITING	Clinical and Genetic Studies of X-Linked Juvenile Retinoschisis
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT02317354	Not specified	COMPLETED	People s Expectations When Enrolling in a Phase I/II RS1 Ocular Gene Transfer Clinical Trial
NCT02682797	Not specified	COMPLETED	Optical Coherence Tomography Evaluation of Retinoschisis and Retinal Detachment
NCT03023800	Not specified	COMPLETED	Effects of Macular Buckle Versus Vitrectomy on Macular Schisis and Macular Detachment in Highly Myopic Eyes
NCT03354403	Not specified	COMPLETED	Mothers Experiences With X-linked Retinoschisis Compared to Fathers Experiences

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ACETAZOLAMIDE	4	1
BUPIVACAINE	4	1
TRIAMCINOLONE	4	1