EYS-Related Retinitis Pigmentosa

Mendelian MONDO:0011272 Pathograph 9 Show in embeddings browser Retinitis pigmentosa Inherited Retinal Dystrophy

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, and localizes to the periciliary space and connecting cilium of vertebrate photoreceptors, where it acts as a structural spacer maintaining outer segment integrity. 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 variants account for 5–11% of autosomal recessive retinitis pigmentosa in European cohorts and are also a major cause in East Asian populations. Variant types include nonsense mutations, frameshift deletions, and splice-site alterations; all leading to premature termination and loss of functional protein. No approved disease-modifying therapy exists; gene augmentation approaches are under development.

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1
Inheritance
4
Pathophys.
9
Phenotypes
9
Pathograph
1
Genes
5
Medical Actions
3
References
👪

Inheritance

1
Autosomal recessive HP:0000007
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.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:18976725 SUPPORT Human Clinical
"In patients with autosomal-recessive retinitis pigmentosa (arRP), homozygosity mapping was performed for detection of regions harboring genes that might be causative for RP."
The discovery paper directly establishes EYS variants as the cause of autosomal recessive retinitis pigmentosa through homozygosity mapping in consanguineous families.
PMID:18836446 SUPPORT Human Clinical
"identified a previously unreported gene, EYS, at the RP25 locus on chromosome 6q12 commonly mutated in autosomal recessive retinitis pigmentosa"
The co-discovery paper independently establishes EYS as a major gene for autosomal recessive RP at the RP25 locus.
⚙

Pathophysiology

4
EYS Protein Deficiency
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 vertebrate photoreceptors, EYS localizes to the periciliary space and connecting cilium, where it is believed to maintain the structural integrity of the ciliary axoneme 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.
rod photoreceptor cell CL:0000604 cone photoreceptor cell CL:0000573
EYS hgnc:21555 ∅ ABSENT
photoreceptor cell maintenance GO:0045494 ↓ DECREASED cilium assembly GO:0060271 ↓ DECREASED
Downstream
Ciliary Structural Disruption Loss of EYS disrupts the structural integrity of the connecting cilium and periciliary space, leading to ciliary structural disruption.
Show evidence (3 references)
PMID:18836446 SUPPORT Human Clinical
"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"
Defines the structural domains of the EYS protein, establishing its extracellular nature with EGF-like and LamG scaffolding domains.
PMID:18836446 SUPPORT Human Clinical
"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"
Draws the functional inference that EYS maintains photoreceptor cell integrity based on the Drosophila ortholog function.
PMID:18836446 SUPPORT Human Clinical
"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"
Demonstrates retina-specific expression of EYS, explaining why loss of EYS function is restricted to photoreceptors.
Ciliary Structural Disruption
EYS localizes to the connecting cilium and periciliary space of photoreceptors. 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. Loss of EYS disrupts the structural integrity of this ciliary compartment, impeding the transport of newly synthesized membrane components into the outer segment. EYS is therefore a ciliopathy gene restricted to photoreceptors. In Drosophila, the ortholog spam/eyes shut maintains the physical separation between rhabdomeric photoreceptors in the open rhabdom; without it, photoreceptors collapse together.
rod photoreceptor cell CL:0000604
cilium assembly GO:0060271 ↓ DECREASED protein localization to cilium GO:0061512 ⚠ ABNORMAL intraflagellar transport GO:0042073 ⚠ ABNORMAL
connecting cilium GO:0035869
Downstream
Rod Photoreceptor Apoptosis Disruption of the ciliary structural zone prevents outer segment homeostasis and drives rod photoreceptor degeneration.
Show evidence (1 reference)
PMID:18836446 SUPPORT Model Organism
"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"
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.
Rod Photoreceptor Apoptosis
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.
rod photoreceptor cell CL:0000604
neuron apoptotic process GO:0051402 ↑ INCREASED
Downstream
Secondary Cone Degeneration Progressive rod loss leads to non-cell-autonomous secondary cone degeneration, converting nyctalopia and peripheral field loss to central vision impairment.
Show evidence (1 reference)
ORPHA:791 SUPPORT Human Clinical
"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."
Orphanet establishes progressive photoreceptor loss as the defining pathophysiological feature of retinitis pigmentosa including EYS-RP.
Secondary Cone Degeneration
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.
cone photoreceptor cell CL:0000573
neuron apoptotic process GO:0051402 ↑ INCREASED
Show evidence (1 reference)
ORPHA:791 SUPPORT Human Clinical
"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."
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.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for EYS-Related Retinitis Pigmentosa Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

9
Eye 2
Abnormal Electroretinogram VERY_FREQUENT Abnormal electroretinogram HP:0000512
Show evidence (1 reference)
ORPHA:791 SUPPORT Human Clinical
"HP:0000512 | Abnormal electroretinogram | Very frequent (99-80%)"
Orphanet records abnormal ERG as a very frequent finding in RP; consistent with the role of ffERG as a diagnostic cornerstone in EYS-RP.
Progressive Visual Loss VERY_FREQUENT Progressive visual loss HP:0000529
Show evidence (1 reference)
ORPHA:791 SUPPORT Human Clinical
"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."
Orphanet establishes progressive blindness as the natural history endpoint of retinitis pigmentosa.
Other 7
Progressive Night Blindness VERY_FREQUENT Progressive night blindness HP:0007675
Show evidence (1 reference)
ORPHA:791 SUPPORT Human Clinical
"HP:0007675 | Progressive night blindness | Very frequent (99-80%)"
Orphanet records progressive night blindness as a very frequent feature of retinitis pigmentosa.
Peripheral Visual Field Loss FREQUENT Peripheral visual field loss HP:0007994
Show evidence (1 reference)
ORPHA:791 SUPPORT Human Clinical
"HP:0007994 | Peripheral visual field loss | Frequent (79-30%)"
Orphanet records peripheral visual field loss as a frequent phenotype of retinitis pigmentosa.
Bone Spicule Pigmentation of the Retina VERY_FREQUENT Spicular pigmentation of the retina HP:0007737
Show evidence (1 reference)
ORPHA:791 SUPPORT Human Clinical
"HP:0007737 | Bone spicule pigmentation of the retina | Very frequent (99-80%)"
Orphanet records bone spicule retinal pigmentation as a very frequent finding in retinitis pigmentosa.
Attenuation of Retinal Blood Vessels FREQUENT Attenuation of retinal blood vessels HP:0007843
Show evidence (1 reference)
ORPHA:791 SUPPORT Human Clinical
"HP:0007843 | Attenuation of retinal blood vessels | Frequent (79-30%)"
Orphanet records retinal vascular attenuation as a frequent feature of RP.
Optic Disc Pallor FREQUENT Optic disc pallor HP:0000543
Show evidence (1 reference)
ORPHA:791 SUPPORT Human Clinical
"HP:0000543 | Optic disc pallor | Frequent (79-30%)"
Orphanet records optic disc pallor as a frequent finding in RP.
Posterior Subcapsular Cataract FREQUENT Posterior subcapsular cataract HP:0007787
Show evidence (1 reference)
ORPHA:791 SUPPORT Human Clinical
"HP:0007787 | Posterior subcapsular cataract | Frequent (79-30%)"
Orphanet records posterior subcapsular cataract as a frequent complication of retinitis pigmentosa.
Cystoid Macular Edema FREQUENT Cystoid macular edema HP:0011505
Show evidence (1 reference)
ORPHA:791 SUPPORT Human Clinical
"HP:0011505 | Cystoid macular edema | Frequent (79-30%)"
Orphanet records cystoid macular edema as a frequent complication of RP that warrants detection given available treatment with carbonic anhydrase inhibitors.
🧬

Genetic Associations

1
EYS Biallelic Variants (Causative)
Gene: EYS hgnc:21555
Show evidence (3 references)
PMID:18976725 SUPPORT Human Clinical
"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."
Establishes the EYS gene structure: 44 exons, 2 Mb, encoding a 3165-aa protein with EGF-like and laminin G domains.
PMID:18836446 SUPPORT Human Clinical
"this is the largest gene identified to be expressed in the human eye and the fifth largest overall in the human genome"
Establishes EYS as the largest eye-expressed gene in the human genome, underlying its unique genomic characteristics as a disease gene.
PMID:18836446 SUPPORT Human Clinical
"we have identified six independent mutations, including four deletions and two nonsense substitutions, all leading to premature stop codons in five unrelated families"
Establishes that EYS pathogenic variants produce premature stop codons consistent with loss-of-function disease mechanism.
💊

Medical Actions

5
Low Vision Rehabilitation
Action: supportive care MAXO:0000950
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.
Target Phenotypes: Progressive visual loss HP:0000529
Show evidence (1 reference)
ORPHA:791 SUPPORT Human Clinical
"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."
Progressive visual impairment in RP justifies ongoing low-vision rehabilitation as the primary symptomatic management strategy.
Carbonic Anhydrase Inhibitor Therapy for CME
Action: Pharmacotherapy NCIT:C15986
Oral or topical carbonic anhydrase inhibitors (e.g., acetazolamide, dorzolamide) can reduce cystoid macular edema in RP patients with CME, and may partially preserve central visual acuity. OCT-guided diagnosis of CME is required before initiating this treatment.
Target Phenotypes: Cystoid macular edema HP:0011505
Show evidence (1 reference)
ORPHA:791 PARTIAL Human Clinical
"HP:0011505 | Cystoid macular edema | Frequent (79-30%)"
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.
Gene Augmentation Therapy (EYS, Investigational)
Action: gene therapy MAXO:0001001
Adeno-associated virus (AAV)-mediated delivery of wild-type EYS cDNA to photoreceptors is under preclinical and early clinical investigation as a disease-modifying therapy for EYS-RP. The large size of the EYS coding sequence (approximately 9.5 kb) exceeds the capacity of standard AAV vectors and requires dual-vector or large-capacity vector strategies. No approved gene therapy for EYS-RP exists as of mid-2026; investigational programs are ongoing.
Show evidence (1 reference)
PMID:18836446 PARTIAL Human Clinical
"EYS is independently disrupted in four other mammalian lineages, including that of rodents"
The absence of functional EYS in rodents is cited here to highlight a critical translational barrier: conventional mouse knockout models do not exist, necessitating non-rodent models for gene therapy development.
Genetic Counseling
Action: genetic counseling MAXO:0000079
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.
Show evidence (1 reference)
PMID:18976725 SUPPORT Human Clinical
"The same mutation was identified homozygously in three arRP siblings of an unrelated family."
Identification of homozygous mutations in siblings establishes the autosomal recessive inheritance requiring genetic counseling for families.
Ophthalmologic Surveillance
Action: eye examination MAXO:0001155
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.
Show evidence (1 reference)
ORPHA:791 SUPPORT Human Clinical
"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."
The progressive nature of RP establishes the rationale for regular ophthalmologic surveillance to track disease course and manage complications.
{ }

Source YAML

click to show 
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, and localizes to the periciliary space and connecting cilium of vertebrate
  photoreceptors, where it acts as a structural spacer maintaining outer segment
  integrity. 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 variants account
  for 5–11% of autosomal recessive retinitis pigmentosa in European cohorts and are
  also a major cause in East Asian populations. Variant types include nonsense
  mutations, frameshift deletions, and splice-site alterations; all leading to
  premature termination and loss of functional protein. 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; zebrafish (eys-morphant/mutant) and pig models have been
  used for preclinical work. 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. All described pathogenic variants lead to premature stop
    codons, predicted to undergo nonsense-mediated mRNA decay and produce complete
    absence of functional protein.
  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 EYS pathogenic variants produce premature stop codons
      consistent with loss-of-function disease mechanism.

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 vertebrate photoreceptors, EYS localizes to the periciliary space and
    connecting cilium, where it is believed to maintain the structural integrity
    of the ciliary axoneme 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: HUMAN_CLINICAL
    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: >-
      Defines the structural domains of the EYS protein, establishing its
      extracellular nature 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: HUMAN_CLINICAL
    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: >-
      Draws the functional inference that EYS maintains photoreceptor cell
      integrity based on the Drosophila ortholog function.
  - 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: "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: >-
      Demonstrates retina-specific expression of EYS, 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 to the connecting cilium and periciliary space of photoreceptors.
    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. Loss of EYS disrupts the structural integrity of this
    ciliary compartment, impeding the transport of newly synthesized membrane
    components into the outer segment. EYS is therefore a ciliopathy gene restricted
    to photoreceptors. 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.
  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: HUMAN_CLINICAL
    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: HUMAN_CLINICAL
    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: HUMAN_CLINICAL
    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: HUMAN_CLINICAL
    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: HUMAN_CLINICAL
    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: HUMAN_CLINICAL
    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: HUMAN_CLINICAL
    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
  evidence:
  - reference: ORPHA:791
    reference_title: "Retinitis pigmentosa"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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: HUMAN_CLINICAL
    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: HUMAN_CLINICAL
    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: HUMAN_CLINICAL
    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: MAXO:0035099
      label: electroretinogram procedure
  evidence:
  - reference: ORPHA:791
    reference_title: "Retinitis pigmentosa"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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: MAXO:0000703
      label: ophthalmologist evaluation
  evidence:
  - reference: ORPHA:791
    reference_title: "Retinitis pigmentosa"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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: MAXO:0000969
      label: optical coherence tomography
  evidence:
  - reference: ORPHA:791
    reference_title: "Retinitis pigmentosa"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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: MAXO:0000971
      label: vision assessment
  evidence:
  - reference: ORPHA:791
    reference_title: "Retinitis pigmentosa"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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: MAXO:0000127
      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: MAXO:0000950
      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: HUMAN_CLINICAL
    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) can reduce cystoid macular edema in RP patients with CME, and
    may partially preserve central visual acuity. OCT-guided diagnosis of CME
    is required before initiating this treatment.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Cystoid macular edema
    term:
      id: HP:0011505
      label: Cystoid macular edema
  evidence:
  - reference: ORPHA:791
    reference_title: "Retinitis pigmentosa"
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    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 under preclinical and early clinical investigation as a
    disease-modifying therapy for EYS-RP. The large size of the EYS coding
    sequence (approximately 9.5 kb) exceeds the capacity of standard AAV vectors
    and requires dual-vector or large-capacity vector strategies. No approved
    gene therapy for EYS-RP exists as of mid-2026; investigational programs
    are ongoing.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: MAXO:0001001
      label: gene therapy
  evidence:
  - reference: PMID:18836446
    reference_title: "EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "EYS is independently disrupted in four other mammalian lineages, including that of rodents"
    explanation: >-
      The absence of functional EYS in rodents is cited here to highlight a
      critical translational barrier: conventional mouse knockout models do not
      exist, necessitating non-rodent models for gene therapy development.

- 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: MAXO:0000079
      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: MAXO:0001155
      label: eye examination
  evidence:
  - reference: ORPHA:791
    reference_title: "Retinitis pigmentosa"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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: General European population
  percentage: 0.0005-0.0014%
  notes: >-
    EYS-related RP (RP25) affects approximately 1 in 70,000–200,000 individuals
    in the general population, derived from the overall RP prevalence of ~1 in
    4,000 and the estimated 5–11% contribution of EYS variants to autosomal
    recessive RP cases in European cohorts. EYS is also a major cause of ARRP
    in East Asian populations.
  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: "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, indicating a prevalence substantially above the 1–5% seen
      for most other ARRP loci.

animal_models:
- species: Zebrafish
  genotype: eys morphant/mutant (eys knockout or morpholino knockdown)
  description: >-
    Zebrafish express eys in photoreceptors, unlike rodents in which the gene is
    pseudogenized. Morpholino-mediated knockdown or CRISPR knockout of zebrafish
    eys produces photoreceptor structural defects, validating the ciliary spacer
    function of EYS. These models are the primary in vivo experimental system
    for EYS biology and for preclinical gene therapy evaluation.
  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: "EYS is independently disrupted in four other mammalian lineages, including that of rodents"
    explanation: >-
      Establishes that rodents lack functional EYS, explaining why zebrafish and
      other non-rodent vertebrates must be used as animal models for EYS-RP.

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 pseudogenization in multiple mammalian lineages limits mouse
      modeling but supports zebrafish as the preferred experimental organism for EYS.
    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: HUMAN_CLINICAL
      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: >-
        Co-discovery paper with additional functional evidence from the Drosophila
        ortholog and evolutionary analysis of EYS pseudogenization across mammals.
- 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: HUMAN_CLINICAL
      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.
📚

References & Deep Research

References

3
PMID:18976725
Identification of a 2 Mb human ortholog of Drosophila eyes shut/spacemaker that is mutated in patients with retinitis pigmentosa.
1 finding
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).
"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."
Show evidence (1 reference)
PMID:18976725 SUPPORT Human Clinical
"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."
Original discovery paper establishing EYS as the RP25 gene, describing gene structure and protein domain architecture.
PMID:18836446
EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa.
1 finding
EYS/SPAM is the largest eye-specific human gene and the fifth largest overall; its independent pseudogenization in multiple mammalian lineages limits mouse modeling but supports zebrafish as the preferred experimental organism for EYS.
"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."
Show evidence (1 reference)
PMID:18836446 SUPPORT Human Clinical
"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"
Co-discovery paper with additional functional evidence from the Drosophila ortholog and evolutionary analysis of EYS pseudogenization across mammals.
ORPHA:791
Retinitis pigmentosa
1 finding
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.
"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."
Show evidence (1 reference)
ORPHA:791 SUPPORT Human Clinical
"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."
Orphanet provides authoritative clinical overview of retinitis pigmentosa including EYS-RP as a major genetic subtype.