EYS-related retinitis pigmentosa (RP25) is an autosomal recessive inherited retinal dystrophy caused by biallelic pathogenic variants in EYS (eyes shut homolog, also known as EGFL11/SPAM), the largest eye-specific gene in the human genome, spanning over 2 Mb on chromosome 6q12 and encoding a predicted 3,145–3,165 amino acid extracellular protein. EYS is an ortholog of Drosophila eyes shut (eys/spacemaker), a protein essential for maintaining the open rhabdom architecture of photoreceptors. The EYS protein contains multiple EGF-like domains and C-terminal laminin G (LamG) domains. In the vertebrate retinas in which it has been examined — zebrafish and primate — EYS localizes near the connecting cilium/transition zone and the photoreceptor ciliary axoneme, where it is thought to help maintain the integrity of the ciliary compartment and outer segment. Loss of EYS function disrupts photoreceptor ciliary architecture, leading to progressive rod photoreceptor degeneration followed by secondary cone loss, producing the classic retinitis pigmentosa triad of nyctalopia, peripheral visual field constriction, and eventual severe visual impairment. EYS is one of the most frequently mutated genes in autosomal recessive RP: EYS mutations were reported in at least 12% of a French cohort of sporadic and autosomal recessive RP cases and in 18% of a Japanese arRP cohort. Reported variant types include nonsense substitutions, frameshift and large intragenic deletions, and splice-site changes; truncating variants are predicted to undergo nonsense-mediated decay, while missense and splice variants of uncertain consequence have also been reported. No approved disease-modifying therapy exists; gene augmentation approaches are under development.
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name: EYS-Related Retinitis Pigmentosa
creation_date: "2026-06-30T00:00:00Z"
category: Mendelian
description: >-
EYS-related retinitis pigmentosa (RP25) is an autosomal recessive inherited retinal
dystrophy caused by biallelic pathogenic variants in EYS (eyes shut homolog, also
known as EGFL11/SPAM), the largest eye-specific gene in the human genome, spanning
over 2 Mb on chromosome 6q12 and encoding a predicted 3,145–3,165 amino acid
extracellular protein. EYS is an ortholog of Drosophila eyes shut (eys/spacemaker),
a protein essential for maintaining the open rhabdom architecture of photoreceptors.
The EYS protein contains multiple EGF-like domains and C-terminal laminin G (LamG)
domains. In the vertebrate retinas in which it has been examined — zebrafish and
primate — EYS localizes near the connecting cilium/transition zone and the
photoreceptor ciliary axoneme, where it is thought to help maintain the integrity
of the ciliary compartment and outer segment. Loss of EYS function disrupts
photoreceptor ciliary architecture, leading to progressive rod photoreceptor
degeneration followed by secondary cone loss, producing the classic retinitis
pigmentosa triad of nyctalopia, peripheral visual field constriction, and eventual
severe visual impairment. EYS is one of the most frequently mutated genes in
autosomal recessive RP: EYS mutations were reported in at least 12% of a French
cohort of sporadic and autosomal recessive RP cases and in 18% of a Japanese arRP
cohort. Reported variant types include nonsense substitutions, frameshift and large
intragenic deletions, and splice-site changes; truncating variants are predicted to
undergo nonsense-mediated decay, while missense and splice variants of uncertain
consequence have also been reported. No approved disease-modifying therapy exists;
gene augmentation approaches are under development.
disease_term:
preferred_term: retinitis pigmentosa 25
term:
id: MONDO:0011272
label: retinitis pigmentosa 25
synonyms:
- RP25
- EYS retinitis pigmentosa
- retinitis pigmentosa caused by mutation in EYS
- retinitis pigmentosa type 25
- EYS-associated retinal dystrophy
parents:
- Retinitis pigmentosa
- Inherited Retinal Dystrophy
notes: >-
EYS is independently disrupted or deleted in at least four mammalian lineages
(rodents, armadillo, bat, ruminants), which means conventional mouse models do not
recapitulate the disease; engineered zebrafish eys loss-of-function lines are the
principal in vivo vertebrate model cited here. Phenotype and diagnostic frequencies
in this entry are taken from the Orphanet record for retinitis pigmentosa overall
(ORPHA:791, all genetic forms) because no EYS-specific natural-history frequency
source is cited; they should be read as pooled-RP frequencies rather than as RP25
frequencies. The RP25 locus was the first major locus identified for
autosomal recessive RP. Variant analysis requires full-gene approaches because
large deletions affecting one or more exons are common. EYS has 43–44 exons
spanning the entire 2 Mb region; conventional panel sequencing may miss copy-number
variants and requires supplemental MLPA or array CGH. Vitamin A palmitate is
sometimes used empirically for RP in general, but specific evidence for EYS-RP is
limited and the intervention is controversial.
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Biallelic loss-of-function variants in EYS cause autosomal recessive retinitis
pigmentosa (RP25). Each parent of an affected child is an obligate heterozygous
carrier; each sibling has a 25% chance of being affected. The RP25 locus on
chromosome 6q12 was initially mapped in consanguineous Spanish families.
evidence:
- reference: PMID:18976725
reference_title: "Identification of a 2 Mb human ortholog of Drosophila eyes shut/spacemaker that is mutated in patients with retinitis pigmentosa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In patients with autosomal-recessive retinitis pigmentosa (arRP), homozygosity mapping was performed for detection of regions harboring genes that might be causative for RP."
explanation: >-
The discovery paper directly establishes EYS variants as the cause of
autosomal recessive retinitis pigmentosa through homozygosity mapping in
consanguineous families.
- reference: PMID:18836446
reference_title: "EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "identified a previously unreported gene, EYS, at the RP25 locus on chromosome 6q12 commonly mutated in autosomal recessive retinitis pigmentosa"
explanation: >-
The co-discovery paper independently establishes EYS as a major gene for
autosomal recessive RP at the RP25 locus.
genetic:
- name: EYS Biallelic Variants
association: Causative
gene_term:
preferred_term: EYS
term:
id: hgnc:21555
label: EYS
features: >-
Biallelic loss-of-function variants in EYS (eyes shut homolog), encoding an
approximately 3,145–3,165 amino acid extracellular protein with EGF-like and
LamG domains. The gene spans over 2 Mb of genomic DNA at chromosome 6q12 and
is the largest gene expressed in the human eye. Variant classes include nonsense
mutations, frameshift deletions, splice-site variants, and large intragenic
copy-number deletions. The six variants described in the original report all
created premature stop codons, predicted to undergo nonsense-mediated mRNA decay
and produce absence of functional protein; subsequent cohort screening also
identified missense, silent and splice-site changes, so truncation is the
best-characterized but not the only reported class of EYS sequence variant.
case_fractions:
- population: French cohort of 239 sporadic and autosomal recessive RP cases
case_fraction_percent: 12.0
cohort_size: 239
notes: >-
Minimum estimate reported by the authors ("12% or more") for the share of this
cohort explained by EYS.
evidence:
- reference: PMID:20333770
reference_title: "EYS is a major gene for rod-cone dystrophies in France."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "With a prevalence of 12% or more we provide evidence that EYS is a major gene for RP in France and probably elsewhere."
explanation: >-
Quantifies the EYS share of cases in a European (French) sporadic/arRP
cohort.
- population: Japanese cohort of 100 autosomal recessive RP patients
case_fraction_percent: 18.0
cohort_size: 100
notes: >-
Minimum observed prevalence of distinct EYS mutations; 9 of the 18 patients
carried two very likely pathogenic mutations and 9 carried only one.
evidence:
- reference: PMID:22363543
reference_title: "Two novel mutations in the EYS gene are possible major causes of autosomal recessive retinitis pigmentosa in the Japanese population."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The minimum observed prevalence of distinct EYS mutations in our study was 18%"
explanation: >-
Quantifies the EYS share of cases in a Japanese arRP cohort, supporting EYS
as a major arRP gene in an East Asian population.
evidence:
- reference: PMID:18976725
reference_title: "Identification of a 2 Mb human ortholog of Drosophila eyes shut/spacemaker that is mutated in patients with retinitis pigmentosa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a 10-kb transcript, starting with the annotated exons of EGFL11 and spanning 44 exons and 2 Mb of genomic DNA. The transcript is predicted to encode a 3165-aa extracellular protein containing 28 EGF-like and five laminin A G-like domains."
explanation: >-
Establishes the EYS gene structure: 44 exons, 2 Mb, encoding a 3165-aa
protein with EGF-like and laminin G domains.
- reference: PMID:18836446
reference_title: "EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "this is the largest gene identified to be expressed in the human eye and the fifth largest overall in the human genome"
explanation: >-
Establishes EYS as the largest eye-expressed gene in the human genome,
underlying its unique genomic characteristics as a disease gene.
- reference: PMID:18836446
reference_title: "EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we have identified six independent mutations, including four deletions and two nonsense substitutions, all leading to premature stop codons in five unrelated families"
explanation: >-
Establishes that the six variants reported in the original five families all
produced premature stop codons, consistent with a loss-of-function mechanism.
This is a statement about those six variants, not about the full EYS variant
spectrum.
- reference: PMID:20333770
reference_title: "EYS is a major gene for rod-cone dystrophies in France."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In addition, twenty missense, silent or splice-site mutations were detected."
explanation: >-
Shows that non-truncating (missense and splice-site) EYS sequence changes are
also found in patient cohorts, so premature termination is not the only
reported variant class.
pathophysiology:
- name: EYS Protein Deficiency
description: >-
Biallelic EYS variants lead to loss of the EYS protein, an extracellular
spacer/structural protein in the photoreceptor outer segment zone. EYS is
the human ortholog of Drosophila spacemaker (spam/eyes shut), a protein that
maintains the open rhabdom architecture between photoreceptors in insect eyes;
in the vertebrate retinas examined to date (zebrafish and primate), EYS localizes
near the connecting cilium/transition zone and the photoreceptor ciliary axoneme,
where it is believed to help maintain the structural integrity of the ciliary
compartment and outer segment. The protein contains at least 21
EGF-like domains and five C-terminal laminin G (LamG) domains. Unlike most RP
genes, EYS encodes an extracellular/secreted protein rather than an
intracellular component of the phototransduction cascade. Loss of EYS disrupts
photoreceptor outer segment morphology, likely through a structural scaffolding
role at the ciliary interface.
gene:
preferred_term: EYS
modifier: ABSENT
term:
id: hgnc:21555
label: EYS
cell_types:
- preferred_term: rod photoreceptor cell
term:
id: CL:0000604
label: retinal rod cell
- preferred_term: cone photoreceptor cell
term:
id: CL:0000573
label: retinal cone cell
biological_processes:
- preferred_term: photoreceptor cell maintenance
term:
id: GO:0045494
label: photoreceptor cell maintenance
modifier: DECREASED
- preferred_term: cilium assembly
term:
id: GO:0060271
label: cilium assembly
modifier: DECREASED
evidence:
- reference: PMID:18836446
reference_title: "EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "RP25 is predicted to be a multidomain protein containing 3,145 amino acids with at least 21 epidermal growth factor (EGF)-like domains in its N-terminus followed by five C-terminal LamG domains, interspersed by further EGF repeats"
explanation: >-
In silico domain prediction from the assembled coding sequence, defining the
EYS protein as an extracellular multidomain protein with EGF-like and LamG
scaffolding domains.
- reference: PMID:18836446
reference_title: "EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Information about the established function of insect orthologs suggests that EYS may possess similar functions in maintaining the integrity of the photoreceptor cells in human retina"
explanation: >-
A hedged inference from insect ortholog function ("may possess similar
functions"), not a direct human observation; it motivates but does not
establish the photoreceptor-maintenance role in human retina.
- reference: PMID:18836446
reference_title: "EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "RT-PCR analysis of cDNAs from a variety of normal tissues and cell lines using cDNA specific primers within RP25 (Supplementary Table 1 online) amplified the expected-size product only from the retina and from a photoreceptor-like cell line, Y79"
explanation: >-
Expression assay on tissue cDNA panels and a cultured photoreceptor-like cell
line demonstrating retina-restricted EYS expression, explaining why loss of
EYS function is restricted to photoreceptors.
downstream:
- target: Ciliary Structural Disruption
description: >-
Loss of EYS disrupts the structural integrity of the connecting cilium
and periciliary space, leading to ciliary structural disruption.
causal_link_type: DIRECT
- name: Ciliary Structural Disruption
conforms_to: "ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction"
description: >-
EYS localizes near the connecting cilium/transition zone of photoreceptors and to
the ciliary axoneme, shown by immunostaining in zebrafish and primate retina and
in ciliated human Y79 photoreceptor-like cells. The connecting cilium is the
narrow bridge linking the photoreceptor inner segment (biosynthetic compartment)
to the outer segment (disc-containing phototransduction compartment); it is
functionally equivalent to the transition zone of primary cilia. In zebrafish,
loss of EYS disrupts the ciliary pocket of cone photoreceptors and mislocalizes
outer segment proteins, indicating a requirement for EYS in maintaining this
compartment and in delivering outer segment components; the corresponding
localization and transport claims for human photoreceptors are inferred from
these non-human vertebrate and cell-line data rather than directly demonstrated.
On this basis EYS is treated as a photoreceptor-restricted ciliopathy gene. In
Drosophila, the ortholog spam/eyes shut maintains the physical separation between
rhabdomeric photoreceptors in the open rhabdom; without it, photoreceptors
collapse together.
cellular_components:
- preferred_term: connecting cilium
term:
id: GO:0035869
label: ciliary transition zone
cell_types:
- preferred_term: rod photoreceptor cell
term:
id: CL:0000604
label: retinal rod cell
biological_processes:
- preferred_term: cilium assembly
term:
id: GO:0060271
label: cilium assembly
modifier: DECREASED
- preferred_term: protein localization to cilium
term:
id: GO:0061512
label: protein localization to cilium
modifier: ABNORMAL
- preferred_term: intraflagellar transport
term:
id: GO:0042073
label: intraciliary transport
modifier: ABNORMAL
evidence:
- reference: PMID:18836446
reference_title: "EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The complete loss of eys (spam) converts an open rhabdom system to a closed one, whereas its targeted expression to photoreceptors of a closed system markedly reorganizes the architecture of the compound eyes to resemble an open system"
explanation: >-
The Drosophila ortholog experiments demonstrate that EYS/spam maintains
photoreceptor architectural integrity; loss of EYS collapses the
inter-photoreceptor space, directly analogous to outer segment disruption in RP25.
- reference: PMID:27737822
reference_title: "Eyes shut homolog is required for maintaining the ciliary pocket and survival of photoreceptors in zebrafish."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Immunostaining indicated that EYS localized near the connecting cilium/transition zone in photoreceptors."
explanation: >-
Provides the vertebrate localization data behind this node: EYS sits near the
connecting cilium/transition zone, the compartment the node is about.
- reference: PMID:27737822
reference_title: "Eyes shut homolog is required for maintaining the ciliary pocket and survival of photoreceptors in zebrafish."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Analysis of mutant EYS zebrafish revealed disruption of the ciliary pocket in cone photoreceptors, indicating that EYS is required for maintaining the integrity of the ciliary pocket lumen."
explanation: >-
Loss of EYS in a vertebrate retina disrupts the ciliary compartment, supporting
the structural-disruption claim of this node.
- reference: PMID:27846257
reference_title: "EYS Is a Protein Associated with the Ciliary Axoneme in Rods and Cones."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "EYS was observed at the ciliary axoneme in Y79 ciliated cells"
explanation: >-
Human photoreceptor-like (Y79) cells place the human EYS protein at the ciliary
axoneme, the closest human-derived support for the ciliary localization claim.
- reference: PMID:28378834
reference_title: "Ablation of EYS in zebrafish causes mislocalisation of outer segment proteins, F-actin disruption and cone-rod dystrophy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "these results point to a novel role for EYS in maintaining the morphological structure of F-actin and in protein transport"
explanation: >-
Supports the protein-transport component of this node (annotated as abnormal
protein localization to cilium and intraciliary transport), on zebrafish data.
downstream:
- target: Rod Photoreceptor Apoptosis
description: >-
Disruption of the ciliary structural zone prevents outer segment homeostasis
and drives rod photoreceptor degeneration.
causal_link_type: DIRECT
- name: Rod Photoreceptor Apoptosis
conforms_to: "photoreceptor_degeneration#Rod Photoreceptor Apoptosis"
description: >-
Structural disruption of the photoreceptor outer segment and connecting cilium
resulting from EYS deficiency produces progressive rod photoreceptor death via
apoptosis, the final common pathway of rod-cone dystrophies. Rods are the
primary affected cell type because EYS is expressed in both rod and cone
photoreceptors but the initial rod-predominant degeneration produces the
characteristic nyctalopia and peripheral field loss of retinitis pigmentosa.
Secondary cone degeneration follows as rods are lost, converting night blindness
to broader visual field loss and ultimately severe central visual impairment.
cell_types:
- preferred_term: rod photoreceptor cell
term:
id: CL:0000604
label: retinal rod cell
biological_processes:
- preferred_term: neuron apoptotic process
term:
id: GO:0051402
label: neuron apoptotic process
modifier: INCREASED
evidence:
- reference: ORPHA:791
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: OTHER
snippet: "Retinitis pigmentosa (RP) is an inherited retinal dystrophy leading to progressive loss of the photoreceptors and retinal pigment epithelium and resulting in blindness usually after several decades."
explanation: >-
Orphanet establishes progressive photoreceptor loss as the defining
pathophysiological feature of retinitis pigmentosa including EYS-RP.
downstream:
- target: Secondary Cone Degeneration
description: >-
Progressive rod loss leads to non-cell-autonomous secondary cone degeneration,
converting nyctalopia and peripheral field loss to central vision impairment.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- loss of rod-derived trophic support for cones
- elevated outer retinal oxygen tension after rod loss
- name: Secondary Cone Degeneration
description: >-
Progressive loss of rod photoreceptors leads to non-cell-autonomous secondary
cone degeneration. Rods provide trophic support to cones and maintain normal
outer retinal oxygen tension; as rods are lost, elevated oxygen levels in the
outer retina and loss of rod-derived survival factors drive cone photoreceptor
death. This converts the initial rod-dominant disease (nyctalopia, peripheral
field loss) to central vision impairment and legal blindness.
cell_types:
- preferred_term: cone photoreceptor cell
term:
id: CL:0000573
label: retinal cone cell
biological_processes:
- preferred_term: neuron apoptotic process
term:
id: GO:0051402
label: neuron apoptotic process
modifier: INCREASED
evidence:
- reference: ORPHA:791
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: OTHER
snippet: "Retinitis pigmentosa (RP) is an inherited retinal dystrophy leading to progressive loss of the photoreceptors and retinal pigment epithelium and resulting in blindness usually after several decades."
explanation: >-
Progressive loss of both rod and cone photoreceptors is the established
natural history of retinitis pigmentosa; secondary cone degeneration following
rod loss explains the progression from nyctalopia to complete blindness.
phenotypes:
- category: Ophthalmologic
name: Progressive Night Blindness
description: >-
Progressive worsening of scotopic vision as rod photoreceptors are progressively
lost. This is among the most very frequent and earliest symptoms of RP in general.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Progressive night blindness
term:
id: HP:0007675
label: Progressive night blindness
evidence:
- reference: ORPHA:791
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0007675 | Progressive night blindness | Very frequent (99-80%)"
explanation: >-
Orphanet records progressive night blindness as a very frequent feature
of retinitis pigmentosa.
- category: Ophthalmologic
name: Peripheral Visual Field Loss
description: >-
Progressive constriction of the visual field beginning in the midperiphery and
advancing centrally as rods are lost from the peripheral retina. Patients develop
tunnel vision, often dramatically apparent on Goldmann or automated perimetry.
This is a cardinal feature of retinitis pigmentosa and is typically progressive
over decades.
frequency: FREQUENT
phenotype_term:
preferred_term: Peripheral visual field loss
term:
id: HP:0007994
label: Peripheral visual field loss
evidence:
- reference: ORPHA:791
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0007994 | Peripheral visual field loss | Frequent (79-30%)"
explanation: >-
Orphanet records peripheral visual field loss as a frequent phenotype of
retinitis pigmentosa.
- category: Ophthalmologic
name: Bone Spicule Pigmentation of the Retina
description: >-
Characteristic intraretinal pigment clumping distributed around mid-peripheral
retinal vessels, resembling bone spicules on funduscopy. Represents migration
of retinal pigment epithelium cells into the inner retina following rod
photoreceptor degeneration. This is one of the hallmark funduscopic signs of
retinitis pigmentosa.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Bone spicule pigmentation of the retina
term:
id: HP:0007737
label: Spicular pigmentation of the retina
evidence:
- reference: ORPHA:791
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0007737 | Bone spicule pigmentation of the retina | Very frequent (99-80%)"
explanation: >-
Orphanet records bone spicule retinal pigmentation as a very frequent
finding in retinitis pigmentosa.
- category: Ophthalmologic
name: Attenuation of Retinal Blood Vessels
description: >-
Progressive narrowing of retinal arterioles, a classic funduscopic feature of
retinitis pigmentosa. Vascular attenuation reflects reduced metabolic demand
from the degenerating photoreceptor layer and is a useful clinical marker of
disease stage alongside bone spicule pigmentation and disc pallor.
frequency: FREQUENT
phenotype_term:
preferred_term: Attenuation of retinal blood vessels
term:
id: HP:0007843
label: Attenuation of retinal blood vessels
evidence:
- reference: ORPHA:791
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0007843 | Attenuation of retinal blood vessels | Frequent (79-30%)"
explanation: >-
Orphanet records retinal vascular attenuation as a frequent feature of RP.
- category: Ophthalmologic
name: Optic Disc Pallor
description: >-
Waxy pallor of the optic disc, resulting from loss of the nerve fiber layer
secondary to ganglion cell and photoreceptor degeneration. Together with bone
spicule pigmentation and vessel attenuation, optic disc pallor completes the
classic triad of funduscopic signs in advanced retinitis pigmentosa.
frequency: FREQUENT
phenotype_term:
preferred_term: Optic disc pallor
term:
id: HP:0000543
label: Optic disc pallor
evidence:
- reference: ORPHA:791
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0000543 | Optic disc pallor | Frequent (79-30%)"
explanation: >-
Orphanet records optic disc pallor as a frequent finding in RP.
- category: Ophthalmologic
name: Abnormal Electroretinogram
description: >-
Full-field electroretinography (ffERG) demonstrates reduced and eventually
extinguished rod responses (scotopic ERG) before cone-mediated (photopic) responses
are affected. In advanced EYS-RP, both rod and cone ERG responses are
non-recordable. The ffERG is the most sensitive functional measure and is required
for clinical diagnosis and monitoring in retinitis pigmentosa.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Abnormal electroretinogram
term:
id: HP:0000512
label: Abnormal electroretinogram
reports_on:
- target: Rod Photoreceptor Apoptosis
relationship: READOUT_OF
endpoint_context: DIAGNOSTIC
interpretation: Electroretinographic responses reflecting photoreceptor (rod then cone) degeneration.
evidence:
- reference: ORPHA:791
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0000512 | Abnormal electroretinogram | Very frequent (99-80%)"
explanation: >-
Orphanet records abnormal ERG as a very frequent finding in RP; consistent
with the role of ffERG as a diagnostic cornerstone in EYS-RP.
- category: Ophthalmologic
name: Posterior Subcapsular Cataract
description: >-
Posterior subcapsular cataract (PSC) is a frequent secondary complication in
retinitis pigmentosa, including EYS-RP. The mechanism is not fully established
but may involve altered ocular fluid dynamics and oxidative stress in the
degenerating retina. PSC can accelerate visual impairment and may benefit from
cataract surgery.
frequency: FREQUENT
phenotype_term:
preferred_term: Posterior subcapsular cataract
term:
id: HP:0007787
label: Posterior subcapsular cataract
evidence:
- reference: ORPHA:791
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0007787 | Posterior subcapsular cataract | Frequent (79-30%)"
explanation: >-
Orphanet records posterior subcapsular cataract as a frequent complication
of retinitis pigmentosa.
- category: Ophthalmologic
name: Cystoid Macular Edema
description: >-
Cystoid macular edema (CME) complicates retinitis pigmentosa in a subset of
patients and can further reduce central visual acuity. CME is visible on OCT
as intraretinal cystic spaces in the macula. Treatment with carbonic anhydrase
inhibitors (topical or oral) can reduce CME and partially preserve central
vision, making CME detection an important diagnostic consideration.
frequency: FREQUENT
phenotype_term:
preferred_term: Cystoid macular edema
term:
id: HP:0011505
label: Cystoid macular edema
evidence:
- reference: ORPHA:791
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0011505 | Cystoid macular edema | Frequent (79-30%)"
explanation: >-
Orphanet records cystoid macular edema as a frequent complication of RP
that warrants detection given available treatment with carbonic anhydrase
inhibitors.
- category: Ophthalmologic
name: Progressive Visual Loss
description: >-
Progressive reduction of overall visual function, ultimately leading to
significant visual impairment and blindness after several decades. The
progression rate varies between patients but EYS-RP typically follows the
rod-first pattern with peripheral field loss preceding central vision loss.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Progressive visual loss
term:
id: HP:0000529
label: Progressive visual loss
evidence:
- reference: ORPHA:791
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: OTHER
snippet: "Retinitis pigmentosa (RP) is an inherited retinal dystrophy leading to progressive loss of the photoreceptors and retinal pigment epithelium and resulting in blindness usually after several decades."
explanation: >-
Orphanet establishes progressive blindness as the natural history endpoint
of retinitis pigmentosa.
diagnosis:
- name: Full-Field Electroretinography (ERG)
description: >-
Full-field electroretinography (ffERG) is the cornerstone diagnostic test for
EYS-related retinitis pigmentosa. In early disease, scotopic (rod-mediated)
responses are reduced while photopic (cone-mediated) responses are relatively
preserved. As the disease progresses, both rod and cone responses are severely
attenuated and eventually non-recordable. The ERG is essential for establishing
the rod-cone dystrophy pattern and for staging disease severity.
diagnosis_term:
preferred_term: electroretinogram procedure
term:
id: NCIT:C101217
label: Retinal Examination
evidence:
- reference: ORPHA:791
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0000512 | Abnormal electroretinogram | Very frequent (99-80%)"
explanation: >-
The very high frequency of abnormal ERG in RP supports ffERG as a core
diagnostic investigation for EYS-RP.
- name: Fundus Examination and Retinal Imaging
description: >-
Ophthalmologic examination documents the classic triad of bone spicule
pigmentation in the mid-periphery, attenuation of retinal blood vessels, and
waxy optic disc pallor. Fundus photography provides a permanent record for
monitoring progression. Multimodal retinal imaging including fundus
autofluorescence helps characterize the zone of preserved photoreceptors and
may inform prognosis.
diagnosis_term:
preferred_term: ophthalmologist evaluation
term:
id: NCIT:C38060
label: Eye Examination
evidence:
- reference: ORPHA:791
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0007737 | Bone spicule pigmentation of the retina | Very frequent (99-80%)"
explanation: >-
Bone spicule pigmentation is a very frequent funduscopic finding used to
recognize and monitor RP including EYS-RP.
- name: Optical Coherence Tomography (OCT)
description: >-
OCT documents outer retinal thinning and progressive loss of the
photoreceptor inner/outer segment junction, outer nuclear layer, and retinal
pigment epithelium. OCT-derived measures (ellipsoid zone width, outer nuclear
layer thickness) serve as structural endpoints in natural history studies and
clinical trials. OCT also detects cystoid macular edema as intraretinal cystic
spaces.
diagnosis_term:
preferred_term: optical coherence tomography
term:
id: NCIT:C20828
label: Optical Coherence Tomography
evidence:
- reference: ORPHA:791
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0030610 | Photoreceptor outer segment loss on macular OCT | Frequent (79-30%)"
explanation: >-
Orphanet records photoreceptor outer segment loss on macular OCT as a
frequent finding in RP, confirming OCT as a diagnostic and monitoring tool.
- name: Visual Field Testing (Perimetry)
description: >-
Kinetic (Goldmann) or automated static perimetry documents the extent and
progression of peripheral visual field loss. The characteristic ring scotoma
of early RP progresses to a constricted central island and eventual complete
loss. Serial perimetry tracks disease progression and is used as a functional
endpoint in gene therapy trials.
diagnosis_term:
preferred_term: visual field testing (perimetry)
term:
id: NCIT:C156778
label: Vision Assessment
evidence:
- reference: ORPHA:791
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0007994 | Peripheral visual field loss | Frequent (79-30%)"
explanation: >-
Peripheral visual field loss is a cardinal feature of RP; perimetry is
the primary method to quantify and track this deficit.
- name: Molecular Genetic Testing
description: >-
Panel-based or exome sequencing identifies biallelic pathogenic variants in
EYS. Given the large size of EYS (2 Mb, 43–44 exons), copy-number variant
analysis (MLPA or array CGH) must supplement sequencing because large
intragenic deletions are common. Molecular diagnosis confirms RP25, enables
cascade family testing, and is required for gene therapy trial eligibility.
diagnosis_term:
preferred_term: genetic testing
term:
id: NCIT:C15709
label: Genetic Testing
evidence:
- reference: PMID:18836446
reference_title: "EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We then used a combination of methods incorporating direct sequence analysis, array CGH and the multiplex ligation-dependent probe amplification (MLPA) techniques to ensure comprehensive mutation screening of the coding regions and splice sites of the 43 exons comprising RP25"
explanation: >-
Demonstrates the need for combined sequencing and copy-number analysis
to comprehensively screen the 43-exon EYS gene, including MLPA and array CGH
for large deletion detection.
treatments:
- name: Low Vision Rehabilitation
description: >-
Low vision aids including magnification devices, high-contrast displays,
adaptive lighting, and orientation and mobility training are the mainstay of
management for patients with EYS-RP. As progressive field constriction and
visual acuity loss develop, low-vision services help patients maintain
functional independence, educational participation, and occupational activities.
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
target_phenotypes:
- preferred_term: Progressive visual loss
term:
id: HP:0000529
label: Progressive visual loss
evidence:
- reference: ORPHA:791
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: OTHER
snippet: "Retinitis pigmentosa (RP) is an inherited retinal dystrophy leading to progressive loss of the photoreceptors and retinal pigment epithelium and resulting in blindness usually after several decades."
explanation: >-
Progressive visual impairment in RP justifies ongoing low-vision
rehabilitation as the primary symptomatic management strategy.
- name: Carbonic Anhydrase Inhibitor Therapy for CME
description: >-
Oral or topical carbonic anhydrase inhibitors (e.g., acetazolamide,
dorzolamide) are used for cystoid macular edema complicating retinitis
pigmentosa. The efficacy evidence comes from the general RP literature and is not
cited in this entry; no EYS-specific CAI study is cited, so this entry records
only that CME is a frequent, potentially treatable RP complication and that
OCT-guided diagnosis of CME precedes treatment.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: acetazolamide
term:
id: CHEBI:27690
label: acetazolamide
- preferred_term: dorzolamide
term:
id: CHEBI:4702
label: dorzolamide
target_phenotypes:
- preferred_term: Cystoid macular edema
term:
id: HP:0011505
label: Cystoid macular edema
evidence:
- reference: ORPHA:791
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0011505 | Cystoid macular edema | Frequent (79-30%)"
explanation: >-
CME is a frequent and potentially treatable complication of RP; this reference
establishes the target phenotype. Specific CAI evidence is from the broader
RP literature.
- name: Gene Augmentation Therapy (EYS, Investigational)
description: >-
Adeno-associated virus (AAV)-mediated delivery of wild-type EYS cDNA to
photoreceptors is the obvious disease-modifying strategy for EYS-RP, but it faces
two constraints documented here rather than a cited clinical program. The EYS
coding region is approximately 9 kb, well beyond the packaging capacity of a
standard AAV vector, so any augmentation approach would need a dual-vector or
large-capacity system; and rodents lack an intact EYS gene, so the conventional
mouse-knockout preclinical route is unavailable. No approved gene therapy for
EYS-RP exists, and no specific investigational program is cited in this entry.
therapeutic_modality: GENE_THERAPY
treatment_term:
preferred_term: gene therapy
term:
id: NCIT:C15238
label: Gene Therapy
evidence:
- reference: PMID:18836446
reference_title: "EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "EYS is independently disrupted in four other mammalian lineages, including that of rodents"
explanation: >-
Comparative-genomics analysis of mammalian genomes; the absence of functional
EYS in rodents is cited here as a translational barrier, because conventional
mouse knockout models cannot be made.
- reference: PMID:18836446
reference_title: "EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa."
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "The full coding region of the RP25 gene (~9 kb) was amplified in two overlapping fragments"
explanation: >-
Sources the ~9 kb coding-region size behind the AAV packaging-capacity
constraint stated in the description; it does not itself address vector
design, so the treatment-relevant constraint follows only by comparing that
size against standard AAV capacity.
- name: Genetic Counseling
description: >-
Genetic counseling explains the autosomal recessive inheritance pattern,
the 25% recurrence risk for future pregnancies in carrier-carrier couples,
carrier testing for at-risk relatives, and reproductive options including
preimplantation genetic testing. Molecular confirmation of biallelic EYS
variants is required before counseling.
treatment_term:
preferred_term: genetic counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:18976725
reference_title: "Identification of a 2 Mb human ortholog of Drosophila eyes shut/spacemaker that is mutated in patients with retinitis pigmentosa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The same mutation was identified homozygously in three arRP siblings of an unrelated family."
explanation: >-
Identification of homozygous mutations in siblings establishes the
autosomal recessive inheritance requiring genetic counseling for families.
- name: Ophthalmologic Surveillance
description: >-
Regular ophthalmologic follow-up with ERG, perimetry, OCT, and acuity testing
monitors disease progression, detects treatable complications (CME, cataract),
and enables timely low-vision rehabilitation. Children and young adults with
EYS-RP should be seen annually; adults with stable disease may be followed
every 1–2 years.
treatment_term:
preferred_term: eye examination
term:
id: NCIT:C38060
label: Eye Examination
evidence:
- reference: ORPHA:791
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: OTHER
snippet: "Retinitis pigmentosa (RP) is an inherited retinal dystrophy leading to progressive loss of the photoreceptors and retinal pigment epithelium and resulting in blindness usually after several decades."
explanation: >-
The progressive nature of RP establishes the rationale for regular
ophthalmologic surveillance to track disease course and manage complications.
prevalence:
- population: Worldwide
measure_type: UNKNOWN
prevalence_class: NOT_YET_DOCUMENTED
notes: >-
No population prevalence has been measured for EYS-related RP (RP25)
specifically in the sources cited here. Orphanet reports a point prevalence of
1-5 / 10,000 for retinitis pigmentosa as a whole (all genetic forms), which
bounds but does not measure the EYS-specific rate; the EYS share of cases is
recorded as cohort case fractions under `genetic` rather than converted into a
derived population rate.
evidence:
- reference: ORPHA:791
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
directness: INDIRECT
evidence_source: OTHER
snippet: "1-5 / 10 000 | Worldwide | Point prevalence | EXPERT"
explanation: >-
Orphanet's worldwide point prevalence for retinitis pigmentosa overall; EYS-RP
is one genetic subset of that total, so this bounds rather than states the
RP25 prevalence.
- reference: PMID:18836446
reference_title: "EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "RP25 as the first major locus for recessive retinitis pigmentosa"
explanation: >-
Abd El-Aziz et al. identify RP25 as the first major locus for autosomal
recessive RP, a qualitative statement of relative importance; the paper gives
no EYS case fraction or population rate.
animal_models:
- species: Zebrafish
genotype: eys loss-of-function alleles (TALEN-generated EYS knockout line; engineered mutant alleles)
description: >-
Zebrafish retain a functional eys gene, unlike mouse and rat in which it is
disrupted, and are the vertebrate system in which EYS loss of function has been
studied in vivo. A TALEN-generated EYS-knockout line shows early visual
impairment and progressive, cone-predominant retinal degeneration with
mislocalization of outer segment proteins; engineered mutant alleles disrupt the
ciliary pocket of cone photoreceptors and cause progressive loss of both cones
and rods. No gene-therapy efficacy study in this model is cited in this entry.
evidence:
- reference: PMID:28378834
reference_title: "Ablation of EYS in zebrafish causes mislocalisation of outer segment proteins, F-actin disruption and cone-rod dystrophy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We constructed an EYS-knockout zebrafish-line by TALEN technology which showed visual impairment at an early age, while the histological and immunofluorescence assays indicated the presence of progressive retinal degeneration with a cone predominately affected pattern."
explanation: >-
Documents the engineered zebrafish knockout and the progressive retinal
degeneration phenotype attributed to it here.
- reference: PMID:27737822
reference_title: "Eyes shut homolog is required for maintaining the ciliary pocket and survival of photoreceptors in zebrafish."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Mutant zebrafish exhibited progressive loss of cone and rod photoreceptors."
explanation: >-
Independent zebrafish loss-of-function alleles reproduce progressive
photoreceptor loss, the disease-relevant endpoint.
- reference: PMID:18836446
reference_title: "EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa."
supports: SUPPORT
directness: INDIRECT
evidence_source: COMPUTATIONAL
snippet: "EYS is independently disrupted in four other mammalian lineages, including that of rodents"
explanation: >-
Comparative-genomics analysis showing that rodents lack an intact EYS gene,
which is why a non-rodent vertebrate model is needed; it says nothing about
zebrafish phenotypes, so it supports this model entry only through the
rationale for choosing a non-rodent system.
references:
- reference: PMID:18976725
title: "Identification of a 2 Mb human ortholog of Drosophila eyes shut/spacemaker that is mutated in patients with retinitis pigmentosa."
findings:
- statement: >-
EYS (eyes shut homolog) is a 2 Mb, 44-exon retina-specific gene on
chromosome 6 encoding a 3165-aa extracellular protein with EGF-like and
laminin A G-like domains; biallelic EYS variants cause autosomal recessive
retinitis pigmentosa (RP25).
supporting_text: >-
We identified a gene, coined eyes shut homolog (EYS), consisting of EGFL11
and the human ortholog of Drosophila eys, which is mutated in patients with
arRP. With a size of 2 Mb, it is one of the largest human genes, and it is
by far the largest retinal dystrophy gene.
evidence:
- reference: PMID:18976725
reference_title: "Identification of a 2 Mb human ortholog of Drosophila eyes shut/spacemaker that is mutated in patients with retinitis pigmentosa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we identified a gene, coined eyes shut homolog (EYS), consisting of EGFL11 and the human ortholog of Drosophila eys, which is mutated in patients with arRP. With a size of 2 Mb, it is one of the largest human genes, and it is by far the largest retinal dystrophy gene."
explanation: >-
Original discovery paper establishing EYS as the RP25 gene, describing
gene structure and protein domain architecture.
- reference: PMID:18836446
title: "EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa."
findings:
- statement: >-
EYS/SPAM is the largest eye-specific human gene and the fifth largest overall;
its independent disruption in multiple mammalian lineages, including rodents,
rules out conventional mouse models.
supporting_text: >-
Spanning over 2 Mb, this is the largest eye-specific gene identified so far.
EYS is independently disrupted in four other mammalian lineages, including
that of rodents.
evidence:
- reference: PMID:18836446
reference_title: "EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "Spanning over 2 Mb, this is the largest eye-specific gene identified so far. EYS is independently disrupted in four other mammalian lineages, including that of rodents"
explanation: >-
Comparative-genomics analysis of mammalian genome sequences establishing the
gene's size and its repeated loss across mammalian lineages.
- reference: "ORPHA:791"
title: "Retinitis pigmentosa"
findings:
- statement: >-
Retinitis pigmentosa is a rare inherited retinal dystrophy with multiple
causative genes including EYS; core clinical features include nyctalopia,
bone spicule pigmentation, vessel attenuation, abnormal ERG, posterior
subcapsular cataract, and cystoid macular edema.
supporting_text: >-
Retinitis pigmentosa (RP) is an inherited retinal dystrophy leading to
progressive loss of the photoreceptors and retinal pigment epithelium and
resulting in blindness usually after several decades.
evidence:
- reference: "ORPHA:791"
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: OTHER
snippet: "Retinitis pigmentosa (RP) is an inherited retinal dystrophy leading to progressive loss of the photoreceptors and retinal pigment epithelium and resulting in blindness usually after several decades."
explanation: >-
Orphanet provides authoritative clinical overview of retinitis pigmentosa
including EYS-RP as a major genetic subtype.