👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

The original report attributed the retinal disease to compound heterozygosity for p.Asp345His and p.Phe350Cys in SEMA4A. Recessive inheritance rests on that one report; the mouse knock-in work found that Phe350Cys is not dominant-negative and that heterozygous knock-in mice have normal retinas, which is consistent with a recessive mechanism but does not establish one in humans.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:28805479 SUPPORT BACKGROUND Human Clinical

"p.R354H and p.F330C were reported to be recessive mutations while p.R713Q was reported to be a dominant mutation."

Summarises the inheritance assigned to each variant in the original report. The residue numbers in the quoted sentence are misprinted in the source (the variants are p.D345H and p.F350C).

PMID:23360997 SUPPORT INDIRECT In Vitro

"In addition, the Sema4AF350C protein did not impair the cell surface expression of the Sema4AWT protein (Fig. 4a), indicating that the F350C mutation does not function in a dominant-negative manner."

The absence of a dominant-negative effect in co-expression assays is consistent with a loss-of-function recessive mechanism.

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Discussions and Knowledge Gaps

1

Is SEMA4A p.Asp345His/p.Phe350Cys sufficient to cause cone-rod dystrophy in humans, when the same compound genotype causes no retinal degeneration in mice and no second family has been reported?

HUMAN MODEL MISMATCH cord10_compound_genotype_mouse_mismatch

Attached to

genetic#SEMA4A animal_models#Sema4a D345H/F350C compound heterozygous knock-in mouse pathophysiology#Biallelic SEMA4A Semaphorin-Domain Missense Variants

The mouse work supports Sema4A loss of function as a cause of photoreceptor degeneration and supports Phe350Cys as a damaging allele, but the genotype actually reported in patients is benign in mice, and the human screen did not exclude variants in other retinal genes. Either Asp345His is damaging only in human Sema4A or over a human lifespan, or the patients' disease has another cause. A reanalysis of the original families with a retinal gene panel or genome sequencing, and functional testing of Asp345His in human RPE cells, would distinguish the two.

Show evidence (1 reference)

PMID:23360997 SUPPORT Model Organism

"Second, we should carefully evaluate the findings of the human study because this report only sequenced the Sema4A gene but did not definitively exclude the possible involvement of other genetic factors."

The model's authors raise the possibility that the human attribution is incomplete.

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Pathophysiology

7

Biallelic SEMA4A Semaphorin-Domain Missense Variants

Missense variants in the conserved sema domain of SEMA4A. p.Phe350Cys is the variant with functional support; in a structural model F350 sits in a hydrophobic pocket, and replacing it with a small residue is predicted to destabilise the fold. p.Asp345His is semi-conserved and causes no retinal disease when knocked in to mice. Semaphorin receptor binding is the canonical activity of SEMA4A and is bound here to name the protein's function; no modifier is given because the structural model places F350 far from the predicted plexin-binding surface, and the retinal defect is attributed to misfolding and loss of endosomal sorting rather than to lost receptor binding.

SEMA4A hgnc:10729

Genetic context variant_origin: GERMLINE zygosity: COMPOUND_HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

semaphorin receptor binding GO:0030215

Downstream

SEMA4A Misfolding and Failure to Reach the RPE Cell Surface

Show evidence (1 reference)

PMID:16199541 SUPPORT Human Clinical

"Two mutations, p.D345H and p.F350C, were observed only in affected patients; they were not observed in any of the normal members or the 100 control subjects. Both mutations identified occur in the conserved semaphorin domain."

The two variants on which the disease was defined, both in the sema domain and absent from controls.

SEMA4A Misfolding and Failure to Reach the RPE Cell Surface

Sema4A normally sits at the apical plasma membrane of RPE cells. The Phe350Cys protein forms high-molecular-weight aggregates and is retained intracellularly; one overexpression study placed the retained mutant protein in the endoplasmic reticulum. That study also found Asp345His retained in the ER of ARPE-19 cells, whereas in knock-in mouse RPE and in the knock-in study's own ARPE-19 and COS-7 assays Asp345His reached the cell surface, so the Asp345His localisation defect is assay-dependent.

retinal pigment epithelial cell CL:0002586

protein localization to plasma membrane GO:0072659 ↓ DECREASED

Animal models

Sema4a F350C knock-in mouse Mouse recapitulates The patient allele mislocalises in mouse RPE in vivo.

Downstream

Impaired Sema4A-Dependent Endosomal Sorting in RPE

RPE Susceptibility to ER and Oxidative Stress

Show evidence (3 references)

PMID:23360997 SUPPORT Model Organism

"Sema4AF350C-EGFP remained in the cytosol, while Sema4AWT-EGFP, Sema4AD345H-EGFP and Sema4AR713Q-EGFP localized to the surface of RPE cells in the retinas of mutant knock-in mice"

Only the Phe350Cys protein fails to reach the RPE surface in vivo.

PMID:23360997 SUPPORT In Vitro

"the Sema4AF350C protein behaved as high-molecular-weight aggregates on the gel, whereas the other Sema4A proteins migrated as distinct bands corresponding to the monomer and dimer"

Native gel analysis in cultured cells shows the Phe350Cys protein aggregates.

PMID:22956603 SUPPORT In Vitro

"Mutant SEMA4A was localized in the ER, whereas wild type (WT) SEMA4A was observed in cell membranes."

Overexpressed patient variants are retained in the ER of a human RPE cell line.

Impaired Sema4A-Dependent Endosomal Sorting in RPE

In RPE cells Sema4A acts as an intracellular sorting factor in the Rab11/FIP2 endosomal pathway rather than as an extracellular guidance cue. It directs two cargoes: prosaposin, which it diverts from the lysosome to exosomal release under oxidative stress, and retinoid-binding proteins such as CRALBP, which it carries between the ER and the cell surface for the visual cycle.

retinal pigment epithelial cell CL:0002586

endosomal transport GO:0016197 ↓ DECREASED

Downstream

Reduced Exosomal Prosaposin Release from RPE

Impaired Retinoid-Binding Protein Sorting for the Visual Cycle

Show evidence (1 reference)

PMID:22465952 SUPPORT Model Organism

"Here, we show that Semaphorin 4A (Sema4A), a member of axonal guidance molecule semaphorin, plays a role in Rab11/FIP2-mediated endosomal sorting in retinal pigment epithelial cells to support photoreceptor function."

Establishes the endosomal sorting role of Sema4A in RPE.

Reduced Exosomal Prosaposin Release from RPE

Under light-induced oxidative stress, Sema4A switches prosaposin from the lysosomal route to exosomal release, and the secreted prosaposin protects photoreceptors from apoptosis. Without functional Sema4A this protective release falls.

retinal pigment epithelial cell CL:0002586

exosomal secretion GO:1990182 ↓ DECREASED

Downstream

Photoreceptor Degeneration

Show evidence (1 reference)

PMID:22465952 SUPPORT Model Organism

"In response to oxidative stress, Sema4A switches the endosomal sorting of the lysosomal precursor protein prosaposin from the lysosome to the exosomal release, which prevents light-induced photoreceptor apoptosis."

Defines the protective prosaposin pathway that Sema4A loss removes.

Impaired Retinoid-Binding Protein Sorting for the Visual Cycle

In darkness Sema4A shuttles retinoid-binding proteins with their retinoids between the RPE cell surface and the ER, where 11-cis-retinal is regenerated and returned to photoreceptors. Loss of this sorting impairs chromophore supply for phototransduction.

retinal pigment epithelial cell CL:0002586

retinoid metabolic process GO:0001523 ↓ DECREASED

Downstream

Photoreceptor Degeneration

Show evidence (1 reference)

PMID:22465952 SUPPORT Model Organism

"In the absence of oxidative stress, Sema4A sorts retinoid-binding proteins with retinoids between the cell surface and endoplasmic reticulum, by which 11-cis-retinal, a chromophore for phototransduction, is regenerated and transported back to photoreceptors."

Defines the visual-cycle sorting role of Sema4A.

RPE Susceptibility to ER and Oxidative Stress

Overexpressed Asp345His and Phe350Cys proteins increase the ER stress marker GRP78 after light exposure, sensitise RPE cells to ER and oxidative stress, and suppress phagocytosis. This is an overexpression finding in a cell line; whether it contributes to photoreceptor loss in vivo has not been tested, so no edge to photoreceptor degeneration is asserted.

retinal pigment epithelial cell CL:0002586

response to endoplasmic reticulum stress GO:0034976 ↑ INCREASED phagocytosis GO:0006909 ↓ DECREASED

Show evidence (1 reference)

PMID:22956603 SUPPORT In Vitro

"The expression of GRP78 was increased by mutant SEMA4A following light irradiation, and phagocytosis was suppressed in mutant SEMA4A-transfected cells. Mutant SEMA4A induced susceptibility to ER stress and oxidative stress."

Patient variants raise ER stress, reduce phagocytosis and sensitise RPE cells to stress in vitro.

Photoreceptor Degeneration

Loss of rod and cone photoreceptors and thinning of the outer nuclear layer. In mice it begins as abnormal outer segment formation during the period when outer segments meet the RPE microvilli and is severe within weeks. Whether cones are lost before rods in the human disease, as the disease name implies, has not been documented beyond the original clinical classification.

retinal cone cell CL:0000573 retinal rod cell CL:0000604

photoreceptor cell maintenance GO:0045494 ↓ DECREASED

Animal models

Sema4a gene-trap mouse Mouse recapitulates Null allele produces early severe loss of rods and cones.

Sema4a F350C knock-in mouse Mouse recapitulates Homozygous patient allele causes photoreceptor loss.

Sema4a D345H/F350C compound heterozygous knock-in mouse Mouse fails to recapitulate The human genotype does not reproduce retinal degeneration in mice.

Downstream

Cone/cone-rod dystrophy

Abnormal light-adapted electroretinogram

Abnormal dark-adapted electroretinogram

Show evidence (2 references)

PMID:15277503 SUPPORT Model Organism

"Disruption of Sema4A also compromised the physiological function of both rod and cone photoreceptors."

Both photoreceptor classes are affected in Sema4a-deficient mice.

PMID:23360997 SUPPORT Model Organism

"Here we generate a series of knock-in mouse lines with corresponding mutations (D345H, F350C or R713Q) in the Sema4A gene and find that Sema4A(F350C) causes retinal degeneration phenotypes."

The patient allele Phe350Cys is sufficient to cause photoreceptor degeneration in mice.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

8

Cone/cone-rod dystrophy Ophthalmologic HP:0000548

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:16199541 SUPPORT Human Clinical

"We report the first observation of the involvement of SEMA4A gene mutations causing retinitis pigmentosa (RP) and cone rod dystrophy (CRD)."

The defining report of SEMA4A-associated cone-rod dystrophy.

Reduced visual acuity Ophthalmologic HP:0007663

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:29555955 SUPPORT INDIRECT BACKGROUND Human Clinical

"Characteristic symptoms include decreasing visual acuity, reading difficulties, photophobia and dyschromatopsia."

Describes the presenting symptoms of macular and cone-rod dystrophies in general, not of SEMA4A disease specifically.

Photophobia Ophthalmologic HP:0000613

Show evidence (1 reference)

PMID:29555955 SUPPORT INDIRECT BACKGROUND Human Clinical

"Characteristic symptoms include decreasing visual acuity, reading difficulties, photophobia and dyschromatopsia."

Photophobia is a characteristic symptom of the disease class, not reported for SEMA4A disease specifically.

Abnormal light-adapted electroretinogram Ophthalmologic HP:0008275

Show evidence (1 reference)

PMID:29555955 SUPPORT INDIRECT BACKGROUND Human Clinical

"Full-field electroretinography (ffERG) allows classifying patients into those with MD (normal ffERG), CD (only reduced photopic responses) and CRD (reduced photopic and scotopic responses)."

Reduced photopic ffERG responses are part of the definition of the cone-rod dystrophy class; this is not a SEMA4A-specific recording.

Abnormal dark-adapted electroretinogram Ophthalmologic HP:0030469

Show evidence (1 reference)

PMID:29555955 SUPPORT INDIRECT BACKGROUND Human Clinical

"Full-field electroretinography (ffERG) allows classifying patients into those with MD (normal ffERG), CD (only reduced photopic responses) and CRD (reduced photopic and scotopic responses)."

Reduced scotopic ffERG responses distinguish the cone-rod dystrophy class from cone dystrophy; this is not a SEMA4A-specific recording.

Color vision defect Ophthalmologic HP:0000551

Show evidence (1 reference)

PMID:29555955 SUPPORT INDIRECT BACKGROUND Human Clinical

"Characteristic symptoms include decreasing visual acuity, reading difficulties, photophobia and dyschromatopsia."

Dyschromatopsia is a characteristic symptom of the disease class.

Nyctalopia Ophthalmologic HP:0000662

Show evidence (1 reference)

PMID:29555955 SUPPORT INDIRECT BACKGROUND Human Clinical

"Later, variable loss of rod function with reduced night vision and loss of peripheral visual field may occur"

Reduced night vision follows rod involvement in the disease class.

Constriction of peripheral visual field Ophthalmologic HP:0001133

Show evidence (1 reference)

PMID:29555955 SUPPORT INDIRECT BACKGROUND Human Clinical

"Later, variable loss of rod function with reduced night vision and loss of peripheral visual field may occur"

Peripheral field loss is a late feature of the disease class.

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Genetic Associations

1

SEMA4A (Causal biallelic variant)

Gene: SEMA4A hgnc:10729 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:16199541 SUPPORT Human Clinical

"Two mutations, p.D345H and p.F350C, were observed only in affected patients; they were not observed in any of the normal members or the 100 control subjects."

The variants defining the disease were found only in patients.

PMID:23360997 SUPPORT Model Organism

"Although compound D345H/F350C heterozygous mutations were reported to be associated with retinal degenerative diseases in humans11, knock-in mice carrying these mutations did not exhibit this phenotype"

The exact human genotype did not cause retinal degeneration in mice, which weakens, without refuting, the human attribution.

Variants (3)

p.Phe350Cys

Sema-domain missense variant. The only one of the three originally reported variants that causes retinal degeneration when knocked in to mice, through misfolding and retention of the protein.

Show evidence (1 reference)

PMID:23360997 SUPPORT Model Organism

"Here we generate a series of knock-in mouse lines with corresponding mutations (D345H, F350C or R713Q) in the Sema4A gene and find that Sema4A(F350C) causes retinal degeneration phenotypes."

Functional support for Phe350Cys pathogenicity.

p.Asp345His

Semi-conserved sema-domain missense variant reported in trans with Phe350Cys. Homozygous knock-in mice have normal retinas, and the protein reaches the RPE surface in vivo, so its contribution is uncertain.

Show evidence (1 reference)

PMID:23360997 SUPPORT Model Organism

"By contrast, Sema4AD345H/D345H and Sema4AR713Q/R713Q mice did not exhibit retinal degeneration"

No retinal phenotype for the Asp345His allele in mice.

p.Arg713Gln

Cytoplasmic-tail variant originally reported as dominant. It does not segregate with retinal disease, occurs homozygous in an unaffected relative, and causes no phenotype in homozygous knock-in mice; it is not disease-causing and is listed only to record that.

Show evidence (2 references)

PMID:28805479 SUPPORT Human Clinical

"The p.R713Q variant in SEMA4A is insufficient to cause either autosomal recessive or autosomal dominant retinitis pigmentosa and is unlikely to be pathogenic."

Family studies show the variant is not sufficient to cause disease.

PMID:28805479 SUPPORT Human Clinical

"The fact that an unaffected family member is homozygous for the mutation indicates that this mutation is insufficient to cause disease."

An unaffected homozygote rules out the variant as a recessive cause.

💊

Medical Actions

2

Low-vision support and genetic counseling

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Platform: Other

No disease-modifying treatment exists. Management is the supportive care common to inherited retinal dystrophies: low-vision aids, filtered lenses, periodic ophthalmological follow-up, and genetic counseling. No source specific to SEMA4A disease was found.

Target Phenotypes: Reduced visual acuity HP:0007663

Subretinal Sema4a gene transfer (preclinical)

Action: gene therapy Ontology label: Gene Therapy NCIT:C15238

Platform: Gene therapy

Lentiviral delivery of wild-type Sema4a to the subretinal space of Sema4a-null and Phe350Cys knock-in mice preserved the photoreceptor layer for at least four months and partly restored ERG responses. This is a preclinical result only; no human trial was found.

Mechanism Target:

INHIBITS Photoreceptor Degeneration — Supplies functional Sema4A to the RPE cells, where the vector expressed, and prevents photoreceptor loss. Restoration of RPE sorting itself was not measured after gene transfer.

Show evidence (1 reference)

PMID:23360997 SUPPORT Model Organism

"Furthermore, Sema4A gene transfer successfully prevents photoreceptor degeneration in Sema4A(F350C/F350C) and Sema4A(-/-) mice."

Gene transfer rescues photoreceptors in both mouse models.

Show evidence (1 reference)

PMID:23360997 SUPPORT Model Organism

"Furthermore, Sema4A gene transfer successfully prevents photoreceptor degeneration in Sema4A(F350C/F350C) and Sema4A(-/-) mice."

Preclinical rescue in mice.

🐁

Animal Models

3

Sema4a gene-trap mouse

Mice lacking Sema4a from a gene-trap insertion have severe retinal degeneration with attenuated vessels and depigmentation by 14 weeks, an outer nuclear layer reduced to a single row, and impaired rod and cone function.

Species

Mouse

Genotype

Sema4a retroviral gene-trap insertion, homozygous

Publication

PMID:15277503

Pathograph links

Photoreceptor Degeneration recapitulates fidelity: moderate observes: tissue Null allele produces early severe loss of rods and cones.

Limitations: A null allele rather than the patient missense genotype, and an early, rapid degeneration in mice against a human course whose tempo is undocumented. Cone-first loss is not shown.

Show evidence (1 reference)

PMID:15277503 SUPPORT Model Organism

"Fundus photography performed at 14 weeks of age revealed severe retinal degeneration, attenuated retinal vessels, and depigmentation in mice lacking Sema4A."

Sema4a loss causes retinal degeneration.

Sema4a F350C knock-in mouse

Knock-in of the patient Phe350Cys allele disrupts photoreceptor outer segments by two weeks of age and removes photoreceptors by four weeks, matching the null phenotype. Heterozygotes are normal.

Species

Mouse

Genotype

Sema4a p.F350C homozygous knock-in

Publication

PMID:23360997

Pathograph links

SEMA4A Misfolding and Failure to Reach the RPE Cell Surface recapitulates fidelity: high observes: cellular The patient allele mislocalises in mouse RPE in vivo.

Limitations: Localisation was read from EGFP-tagged knock-in alleles, and in homozygotes rather than the patients' compound heterozygous genotype.

Show evidence (1 reference)

PMID:23360997 SUPPORT Model Organism

"The F350C mutation results in abnormal localization of the Sema4A protein, leading to impaired endosomal sorting of molecules indispensable for photoreceptor survival."

Mislocalisation and sorting defect of the patient allele in vivo.

Photoreceptor Degeneration recapitulates fidelity: moderate observes: tissue Homozygous patient allele causes photoreceptor loss.

Limitations: Homozygous Phe350Cys, whereas patients were reported compound heterozygous with Asp345His; the compound genotype has no phenotype in mice. Degeneration is complete within weeks of birth.

Show evidence (1 reference)

PMID:23360997 SUPPORT Model Organism

"Here we generate a series of knock-in mouse lines with corresponding mutations (D345H, F350C or R713Q) in the Sema4A gene and find that Sema4A(F350C) causes retinal degeneration phenotypes."

The patient allele causes degeneration in mice.

Sema4a D345H/F350C compound heterozygous knock-in mouse

Mice carrying the genotype reported in patients do not develop retinal degeneration, nor do Asp345His or Arg713Gln homozygotes.

Species

Mouse

Genotype

Sema4a p.D345H / p.F350C compound heterozygous knock-in

Publication

PMID:23360997

Pathograph links

Photoreceptor Degeneration fails to recapitulate fidelity: low observes: tissue The human genotype does not reproduce retinal degeneration in mice.

Limitations: Mice live far shorter than humans and mouse and human Sema4A differ at a few residues, so a slowly progressive human disease or a species-specific effect of Asp345His could be missed.

Show evidence (1 reference)

PMID:23360997 SUPPORT Model Organism

"Although compound D345H/F350C heterozygous mutations were reported to be associated with retinal degenerative diseases in humans11, knock-in mice carrying these mutations did not exhibit this phenotype"

The patient genotype has no retinal phenotype in mice.

{ }

Source YAML

click to show

name: Cone-rod dystrophy 10
creation_date: "2026-10-14T13:30:00Z"
category: Mendelian
synonyms:
- CORD10
- SEMA4A cone-rod dystrophy
- cone-rod dystrophy caused by mutation in SEMA4A
- cone-rod dystrophy type 10
description: >-
  Cone-rod dystrophy 10 is an inherited retinal dystrophy attributed to
  biallelic variants in SEMA4A, which encodes semaphorin 4A, a transmembrane
  semaphorin expressed in the retinal pigment epithelium. It was defined by a
  single 2006 screen of Pakistani patients with retinal degeneration, in which
  the semaphorin-domain missense variants p.Asp345His and p.Phe350Cys were
  found in patients with cone-rod dystrophy and with retinitis pigmentosa; the
  retinitis pigmentosa presentation is catalogued separately as retinitis
  pigmentosa 35. No independent family with SEMA4A cone-rod dystrophy has been
  reported since, so the human phenotype is thinly described and the
  gene-disease relationship is weak. The third variant from that screen,
  p.Arg713Gln, is unlikely to be pathogenic: it fails to segregate with
  disease and occurs homozygous in an unaffected relative. The mechanistic
  picture comes from mice. Sema4a-null and Phe350Cys knock-in mice lose their
  photoreceptors early in life. Sema4A loss, or misfolding of the Phe350Cys
  protein so that it never reaches the RPE cell surface, removes two
  Sema4A-dependent endosomal sorting steps: exosomal release of the anti-apoptotic factor prosaposin
  under oxidative stress, and delivery of retinoid-binding proteins for the
  visual cycle. Asp345His and Arg713Gln knock-in mice, by contrast, have
  normal retinas. There is no disease-specific treatment; subretinal Sema4a
  gene transfer rescues photoreceptors in mice.
disease_term:
  preferred_term: cone-rod dystrophy 10
  term:
    id: MONDO:0012464
    label: cone-rod dystrophy 10
parents:
- Cone-rod dystrophy
- Inherited retinal dystrophy
references:
- reference: PMID:16199541
  title: Identification of novel mutations in the SEMA4A gene associated with retinal degenerative diseases.
- reference: PMID:15277503
  title: Severe retinal degeneration associated with disruption of semaphorin 4A.
- reference: PMID:22465952
  title: Endosomal sorting by Semaphorin 4A in retinal pigment epithelium supports photoreceptor survival.
- reference: PMID:22956603
  title: SEMA4A mutations lead to susceptibility to light irradiation, oxidative stress, and ER stress in retinal pigment epithelial cells.
- reference: PMID:23360997
  title: A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration.
- reference: PMID:28805479
  title: "On variants and disease-causing mutations: Case studies of a SEMA4A variant identified in inherited blindness."
- reference: PMID:29555955
  title: Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    The original report attributed the retinal disease to compound
    heterozygosity for p.Asp345His and p.Phe350Cys in SEMA4A. Recessive
    inheritance rests on that one report; the mouse knock-in work found that
    Phe350Cys is not dominant-negative and that heterozygous knock-in mice
    have normal retinas, which is consistent with a recessive mechanism but
    does not establish one in humans.
  evidence:
  - reference: PMID:28805479
    reference_title: "On variants and disease-causing mutations: Case studies of a SEMA4A variant identified in inherited blindness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      p.R354H and p.F330C were reported to be recessive mutations while p.R713Q was reported to be a dominant mutation.
    explanation: >-
      Summarises the inheritance assigned to each variant in the original
      report. The residue numbers in the quoted sentence are misprinted in the
      source (the variants are p.D345H and p.F350C).
  - reference: PMID:23360997
    reference_title: A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      In addition, the Sema4AF350C protein did not impair the cell surface expression of the Sema4AWT protein (Fig. 4a), indicating that the F350C mutation does not function in a dominant-negative manner.
    explanation: >-
      The absence of a dominant-negative effect in co-expression assays is
      consistent with a loss-of-function recessive mechanism.
pathophysiology:
- name: Biallelic SEMA4A Semaphorin-Domain Missense Variants
  biological_scale: MOLECULAR
  description: >-
    Missense variants in the conserved sema domain of SEMA4A. p.Phe350Cys is
    the variant with functional support; in a structural model F350 sits in a
    hydrophobic pocket, and replacing it with a small residue is predicted to
    destabilise the fold. p.Asp345His is
    semi-conserved and causes no retinal disease when knocked in to mice.
    Semaphorin receptor binding is the canonical activity of SEMA4A and is
    bound here to name the protein's function; no modifier is given because
    the structural model places F350 far from the predicted plexin-binding
    surface, and the retinal defect is attributed to misfolding and loss of
    endosomal sorting rather than to lost receptor binding.
  genes:
  - preferred_term: SEMA4A
    term:
      id: hgnc:10729
      label: SEMA4A
  molecular_functions:
  - preferred_term: semaphorin receptor binding
    term:
      id: GO:0030215
      label: semaphorin receptor binding
  genetic_context:
    variant_origin: GERMLINE
    zygosity: COMPOUND_HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:16199541
    reference_title: Identification of novel mutations in the SEMA4A gene associated with retinal degenerative diseases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two mutations, p.D345H and p.F350C, were observed only in affected patients; they were not observed in any of the normal members or the 100 control subjects. Both mutations identified occur in the conserved semaphorin domain.
    explanation: >-
      The two variants on which the disease was defined, both in the sema
      domain and absent from controls.
  downstream:
  - target: SEMA4A Misfolding and Failure to Reach the RPE Cell Surface
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23360997
      reference_title: A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The F350C mutation results in abnormal localization of the Sema4A protein, leading to impaired endosomal sorting of molecules indispensable for photoreceptor survival.
      explanation: >-
        The patient variant knocked in to mice mislocalises the protein.
- name: SEMA4A Misfolding and Failure to Reach the RPE Cell Surface
  biological_scale: CELLULAR
  description: >-
    Sema4A normally sits at the apical plasma membrane of RPE cells. The
    Phe350Cys protein forms high-molecular-weight aggregates and is retained
    intracellularly; one overexpression study placed the retained mutant
    protein in the endoplasmic reticulum. That study also found Asp345His
    retained in the ER of ARPE-19 cells, whereas in knock-in mouse RPE and in
    the knock-in study's own ARPE-19 and COS-7 assays Asp345His reached the
    cell surface, so the Asp345His localisation defect is assay-dependent.
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  biological_processes:
  - preferred_term: protein localization to plasma membrane
    modifier: DECREASED
    term:
      id: GO:0072659
      label: protein localization to plasma membrane
  evidence:
  - reference: PMID:23360997
    reference_title: A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Sema4AF350C-EGFP remained in the cytosol, while Sema4AWT-EGFP, Sema4AD345H-EGFP and Sema4AR713Q-EGFP localized to the surface of RPE cells in the retinas of mutant knock-in mice
    explanation: >-
      Only the Phe350Cys protein fails to reach the RPE surface in vivo.
  - reference: PMID:23360997
    reference_title: A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the Sema4AF350C protein behaved as high-molecular-weight aggregates on the gel, whereas the other Sema4A proteins migrated as distinct bands corresponding to the monomer and dimer
    explanation: >-
      Native gel analysis in cultured cells shows the Phe350Cys protein
      aggregates.
  - reference: PMID:22956603
    reference_title: SEMA4A mutations lead to susceptibility to light irradiation, oxidative stress, and ER stress in retinal pigment epithelial cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mutant SEMA4A was localized in the ER, whereas wild type (WT) SEMA4A was observed in cell membranes.
    explanation: >-
      Overexpressed patient variants are retained in the ER of a human RPE cell
      line.
  downstream:
  - target: Impaired Sema4A-Dependent Endosomal Sorting in RPE
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23360997
      reference_title: A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In addition, we determined that the pathogenicity of the F350C mutation is due to severe structural defects and resultant mis-localization of the Sema4A protein in RPE cells, which led to impaired endosomal sorting.
      explanation: >-
        States the causal step from mislocalisation to defective sorting.
  - target: RPE Susceptibility to ER and Oxidative Stress
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22956603
      reference_title: SEMA4A mutations lead to susceptibility to light irradiation, oxidative stress, and ER stress in retinal pigment epithelial cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: >-
        Mutant SEMA4A was localized in the ER, whereas wild type (WT) SEMA4A was observed in cell membranes.
      explanation: >-
        ER retention and stress sensitivity are reported together for the same
        mutant proteins; that the retention causes the stress response is an
        inference, not shown directly.
- name: Impaired Sema4A-Dependent Endosomal Sorting in RPE
  biological_scale: CELLULAR
  description: >-
    In RPE cells Sema4A acts as an intracellular sorting factor in the
    Rab11/FIP2 endosomal pathway rather than as an extracellular guidance cue.
    It directs two cargoes: prosaposin, which it diverts from the lysosome to
    exosomal release under oxidative stress, and retinoid-binding proteins
    such as CRALBP, which it carries between the ER and the cell surface for
    the visual cycle.
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  biological_processes:
  - preferred_term: endosomal transport
    modifier: DECREASED
    term:
      id: GO:0016197
      label: endosomal transport
  evidence:
  - reference: PMID:22465952
    reference_title: Endosomal sorting by Semaphorin 4A in retinal pigment epithelium supports photoreceptor survival.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, we show that Semaphorin 4A (Sema4A), a member of axonal guidance molecule semaphorin, plays a role in Rab11/FIP2-mediated endosomal sorting in retinal pigment epithelial cells to support photoreceptor function.
    explanation: >-
      Establishes the endosomal sorting role of Sema4A in RPE.
  downstream:
  - target: Reduced Exosomal Prosaposin Release from RPE
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23360997
      reference_title: A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        RPE cells from Sema4AF350C/F350C retinas expressed lower levels of prosaposin in secreted H2O2-induced exosomes
      explanation: >-
        The patient variant reduces exosomal prosaposin, as Sema4a loss does.
  - target: Impaired Retinoid-Binding Protein Sorting for the Visual Cycle
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23360997
      reference_title: A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        CRALBP also failed to distribute to the surface of RPE cells
      explanation: >-
        The retinoid-binding protein CRALBP is missorted in Phe350Cys RPE.
- name: Reduced Exosomal Prosaposin Release from RPE
  biological_scale: CELLULAR
  description: >-
    Under light-induced oxidative stress, Sema4A switches prosaposin from the
    lysosomal route to exosomal release, and the secreted prosaposin protects
    photoreceptors from apoptosis. Without functional Sema4A this protective
    release falls.
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  biological_processes:
  - preferred_term: exosomal secretion
    modifier: DECREASED
    term:
      id: GO:1990182
      label: exosomal secretion
  evidence:
  - reference: PMID:22465952
    reference_title: Endosomal sorting by Semaphorin 4A in retinal pigment epithelium supports photoreceptor survival.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In response to oxidative stress, Sema4A switches the endosomal sorting of the lysosomal precursor protein prosaposin from the lysosome to the exosomal release, which prevents light-induced photoreceptor apoptosis.
    explanation: >-
      Defines the protective prosaposin pathway that Sema4A loss removes.
  downstream:
  - target: Photoreceptor Degeneration
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22465952
      reference_title: Endosomal sorting by Semaphorin 4A in retinal pigment epithelium supports photoreceptor survival.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Owing to defects in these processes, Sema4A-deficient mice exhibit marked photoreceptor degeneration.
      explanation: >-
        Attributes the photoreceptor loss to the two sorting defects.
- name: Impaired Retinoid-Binding Protein Sorting for the Visual Cycle
  biological_scale: CELLULAR
  description: >-
    In darkness Sema4A shuttles retinoid-binding proteins with their retinoids
    between the RPE cell surface and the ER, where 11-cis-retinal is
    regenerated and returned to photoreceptors. Loss of this sorting impairs
    chromophore supply for phototransduction.
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  biological_processes:
  - preferred_term: retinoid metabolic process
    modifier: DECREASED
    term:
      id: GO:0001523
      label: retinoid metabolic process
  evidence:
  - reference: PMID:22465952
    reference_title: Endosomal sorting by Semaphorin 4A in retinal pigment epithelium supports photoreceptor survival.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In the absence of oxidative stress, Sema4A sorts retinoid-binding proteins with retinoids between the cell surface and endoplasmic reticulum, by which 11-cis-retinal, a chromophore for phototransduction, is regenerated and transported back to photoreceptors.
    explanation: >-
      Defines the visual-cycle sorting role of Sema4A.
  downstream:
  - target: Photoreceptor Degeneration
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22465952
      reference_title: Endosomal sorting by Semaphorin 4A in retinal pigment epithelium supports photoreceptor survival.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Owing to defects in these processes, Sema4A-deficient mice exhibit marked photoreceptor degeneration.
      explanation: >-
        Attributes the photoreceptor loss to the two sorting defects.
- name: RPE Susceptibility to ER and Oxidative Stress
  biological_scale: CELLULAR
  description: >-
    Overexpressed Asp345His and Phe350Cys proteins increase the ER stress
    marker GRP78 after light exposure, sensitise RPE cells to ER and oxidative
    stress, and suppress phagocytosis. This is an overexpression finding in a
    cell line; whether it contributes to photoreceptor loss in vivo has not
    been tested, so no edge to photoreceptor degeneration is asserted.
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  biological_processes:
  - preferred_term: response to endoplasmic reticulum stress
    modifier: INCREASED
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
  - preferred_term: phagocytosis
    modifier: DECREASED
    term:
      id: GO:0006909
      label: phagocytosis
  evidence:
  - reference: PMID:22956603
    reference_title: SEMA4A mutations lead to susceptibility to light irradiation, oxidative stress, and ER stress in retinal pigment epithelial cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The expression of GRP78 was increased by mutant SEMA4A following light irradiation, and phagocytosis was suppressed in mutant SEMA4A-transfected cells. Mutant SEMA4A induced susceptibility to ER stress and oxidative stress.
    explanation: >-
      Patient variants raise ER stress, reduce phagocytosis and sensitise RPE
      cells to stress in vitro.
- name: Photoreceptor Degeneration
  biological_scale: TISSUE
  description: >-
    Loss of rod and cone photoreceptors and thinning of the outer nuclear
    layer. In mice it begins as abnormal outer segment formation during the
    period when outer segments meet the RPE microvilli and is severe within
    weeks. Whether cones are lost before rods in the human disease, as the
    disease name implies, has not been documented beyond the original
    clinical classification.
  cell_types:
  - preferred_term: retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  biological_processes:
  - preferred_term: photoreceptor cell maintenance
    modifier: DECREASED
    term:
      id: GO:0045494
      label: photoreceptor cell maintenance
  evidence:
  - reference: PMID:15277503
    reference_title: Severe retinal degeneration associated with disruption of semaphorin 4A.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Disruption of Sema4A also compromised the physiological function of both rod and cone photoreceptors.
    explanation: >-
      Both photoreceptor classes are affected in Sema4a-deficient mice.
  - reference: PMID:23360997
    reference_title: A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here we generate a series of knock-in mouse lines with corresponding mutations (D345H, F350C or R713Q) in the Sema4A gene and find that Sema4A(F350C) causes retinal degeneration phenotypes.
    explanation: >-
      The patient allele Phe350Cys is sufficient to cause photoreceptor
      degeneration in mice.
  downstream:
  - target: Cone/cone-rod dystrophy
    evidence:
    - reference: PMID:23360997
      reference_title: A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        Here we generate a series of knock-in mouse lines with corresponding mutations (D345H, F350C or R713Q) in the Sema4A gene and find that Sema4A(F350C) causes retinal degeneration phenotypes.
      explanation: >-
        A patient allele produces retinal degeneration in mice; that the same
        photoreceptor loss underlies the human cone-rod dystrophy is an
        inference across species.
  - target: Abnormal light-adapted electroretinogram
    evidence:
    - reference: PMID:15277503
      reference_title: Severe retinal degeneration associated with disruption of semaphorin 4A.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        Disruption of Sema4A also compromised the physiological function of both rod and cone photoreceptors.
      explanation: >-
        Photoreceptor loss in Sema4a-deficient mice is accompanied by loss of
        cone function, which the light-adapted ERG measures; that the same holds
        in the human disease is an inference across species.
  - target: Abnormal dark-adapted electroretinogram
    evidence:
    - reference: PMID:15277503
      reference_title: Severe retinal degeneration associated with disruption of semaphorin 4A.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        Disruption of Sema4A also compromised the physiological function of both rod and cone photoreceptors.
      explanation: >-
        Photoreceptor loss in Sema4a-deficient mice is accompanied by loss of
        rod function, which the dark-adapted ERG measures; that the same holds
        in the human disease is an inference across species.
phenotypes:
- name: Cone/cone-rod dystrophy
  category: Ophthalmologic
  diagnostic: true
  description: >-
    Progressive retinal dystrophy classified as cone-rod dystrophy in the
    patients of the original report. Age at onset, rate of progression and
    electroretinographic detail for SEMA4A cone-rod dystrophy have not been
    published.
  phenotype_term:
    preferred_term: Cone/cone-rod dystrophy
    term:
      id: HP:0000548
      label: Cone/cone-rod dystrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:16199541
    reference_title: Identification of novel mutations in the SEMA4A gene associated with retinal degenerative diseases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report the first observation of the involvement of SEMA4A gene mutations causing retinitis pigmentosa (RP) and cone rod dystrophy (CRD).
    explanation: >-
      The defining report of SEMA4A-associated cone-rod dystrophy.
- name: Reduced visual acuity
  category: Ophthalmologic
  description: >-
    Loss of central acuity is the usual first symptom of cone and cone-rod
    dystrophies. It is listed in the OMIM summary for this disease but has
    no citable primary report for SEMA4A; the evidence is the description of
    the disease class.
  phenotype_term:
    preferred_term: Reduced visual acuity
    term:
      id: HP:0007663
      label: Reduced visual acuity
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:29555955
    reference_title: Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: >-
      Characteristic symptoms include decreasing visual acuity, reading difficulties, photophobia and dyschromatopsia.
    explanation: >-
      Describes the presenting symptoms of macular and cone-rod dystrophies in
      general, not of SEMA4A disease specifically.
- name: Photophobia
  category: Ophthalmologic
  description: >-
    Light sensitivity from cone dysfunction, a characteristic symptom of
    macular and cone-rod dystrophies; no SEMA4A-specific clinical report
    describes it.
  phenotype_term:
    preferred_term: Photophobia
    term:
      id: HP:0000613
      label: Photophobia
  evidence:
  - reference: PMID:29555955
    reference_title: Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: >-
      Characteristic symptoms include decreasing visual acuity, reading difficulties, photophobia and dyschromatopsia.
    explanation: >-
      Photophobia is a characteristic symptom of the disease class, not
      reported for SEMA4A disease specifically.
- name: Abnormal light-adapted electroretinogram
  category: Ophthalmologic
  description: >-
    Cone-rod dystrophy is defined electrophysiologically by reduced photopic
    (cone) as well as scotopic (rod) full-field ERG responses; this record is
    the photopic component. No ERG from a patient with the biallelic
    p.Asp345His/p.Phe350Cys genotype has been published. The one SEMA4A
    patient ERG on record, from a heterozygous frameshift carrier (patient
    188 of PMID:29555955), showed reduced photopic and scotopic responses
    but is not counted for this recessive disease (see the SEMA4A genetic
    notes). Sema4a-deficient mice show reduced rod and cone function.
  phenotype_term:
    preferred_term: Reduced photopic full-field ERG responses
    term:
      id: HP:0008275
      label: Abnormal light-adapted electroretinogram
  evidence:
  - reference: PMID:29555955
    reference_title: Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: >-
      Full-field electroretinography (ffERG) allows classifying patients into those with MD (normal ffERG), CD (only reduced photopic responses) and CRD (reduced photopic and scotopic responses).
    explanation: >-
      Reduced photopic ffERG responses are part of the definition of the
      cone-rod dystrophy class; this is not a SEMA4A-specific recording.
- name: Abnormal dark-adapted electroretinogram
  category: Ophthalmologic
  description: >-
    The scotopic (rod) component of the full-field ERG definition of cone-rod
    dystrophy; reduced scotopic responses are what separate cone-rod from cone
    dystrophy. No ERG from a patient with the biallelic
    p.Asp345His/p.Phe350Cys genotype has been published; the single
    heterozygous-frameshift SEMA4A ERG (PMID:29555955) is not counted for
    this recessive disease (see the SEMA4A genetic notes).
  phenotype_term:
    preferred_term: Reduced scotopic full-field ERG responses
    term:
      id: HP:0030469
      label: Abnormal dark-adapted electroretinogram
  evidence:
  - reference: PMID:29555955
    reference_title: Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: >-
      Full-field electroretinography (ffERG) allows classifying patients into those with MD (normal ffERG), CD (only reduced photopic responses) and CRD (reduced photopic and scotopic responses).
    explanation: >-
      Reduced scotopic ffERG responses distinguish the cone-rod dystrophy
      class from cone dystrophy; this is not a SEMA4A-specific recording.
- name: Color vision defect
  category: Ophthalmologic
  description: >-
    Dyschromatopsia from cone loss; listed in the OMIM summary but with no
    citable primary report for SEMA4A.
  phenotype_term:
    preferred_term: Dyschromatopsia
    term:
      id: HP:0000551
      label: Color vision defect
  evidence:
  - reference: PMID:29555955
    reference_title: Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: >-
      Characteristic symptoms include decreasing visual acuity, reading difficulties, photophobia and dyschromatopsia.
    explanation: >-
      Dyschromatopsia is a characteristic symptom of the disease class.
- name: Nyctalopia
  category: Ophthalmologic
  description: >-
    Night blindness from later rod involvement, which is what distinguishes
    cone-rod from cone dystrophy; listed in the OMIM summary but with no
    citable primary report for SEMA4A.
  phenotype_term:
    preferred_term: Nyctalopia
    term:
      id: HP:0000662
      label: Nyctalopia
  evidence:
  - reference: PMID:29555955
    reference_title: Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: >-
      Later, variable loss of rod function with reduced night vision and loss of peripheral visual field may occur
    explanation: >-
      Reduced night vision follows rod involvement in the disease class.
- name: Constriction of peripheral visual field
  category: Ophthalmologic
  description: >-
    Peripheral field loss later in the course; listed in the OMIM summary but
    with no citable primary report for SEMA4A.
  phenotype_term:
    preferred_term: Constriction of peripheral visual field
    term:
      id: HP:0001133
      label: Constriction of peripheral visual field
  evidence:
  - reference: PMID:29555955
    reference_title: Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: >-
      Later, variable loss of rod function with reduced night vision and loss of peripheral visual field may occur
    explanation: >-
      Peripheral field loss is a late feature of the disease class.
genetic:
- name: SEMA4A
  association: Causal biallelic variant
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: SEMA4A
    term:
      id: hgnc:10729
      label: SEMA4A
  notes: >-
    The causal claim rests on one 2006 screen; no second family with
    SEMA4A cone-rod dystrophy has been published, and ClinGen has no
    gene-disease validity record for SEMA4A in retinal disease (its only
    SEMA4A record is a Disputed classification for Lynch syndrome). The
    authors of the mouse knock-in study noted that the human screen sequenced
    only SEMA4A and did not exclude variants in other genes. A heterozygous
    SEMA4A frameshift was later reported in one 48-year-old German patient
    with an atrophic macular lesion and reduced scotopic and photopic ERG
    responses, without segregation data (PMID:29555955); a single
    heterozygous truncating allele does not fit the recessive model, so it is
    not counted as evidence for this disease.
  evidence:
  - reference: PMID:16199541
    reference_title: Identification of novel mutations in the SEMA4A gene associated with retinal degenerative diseases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two mutations, p.D345H and p.F350C, were observed only in affected patients; they were not observed in any of the normal members or the 100 control subjects.
    explanation: >-
      The variants defining the disease were found only in patients.
  - reference: PMID:23360997
    reference_title: A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Although compound D345H/F350C heterozygous mutations were reported to be associated with retinal degenerative diseases in humans11, knock-in mice carrying these mutations did not exhibit this phenotype
    explanation: >-
      The exact human genotype did not cause retinal degeneration in mice,
      which weakens, without refuting, the human attribution.
  variants:
  - name: p.Phe350Cys
    description: >-
      Sema-domain missense variant. The only one of the three originally
      reported variants that causes retinal degeneration when knocked in to
      mice, through misfolding and retention of the protein.
    evidence:
    - reference: PMID:23360997
      reference_title: A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here we generate a series of knock-in mouse lines with corresponding mutations (D345H, F350C or R713Q) in the Sema4A gene and find that Sema4A(F350C) causes retinal degeneration phenotypes.
      explanation: >-
        Functional support for Phe350Cys pathogenicity.
  - name: p.Asp345His
    description: >-
      Semi-conserved sema-domain missense variant reported in trans with
      Phe350Cys. Homozygous knock-in mice have normal retinas, and the protein
      reaches the RPE surface in vivo, so its contribution is uncertain.
    evidence:
    - reference: PMID:23360997
      reference_title: A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        By contrast, Sema4AD345H/D345H and Sema4AR713Q/R713Q mice did not exhibit retinal degeneration
      explanation: >-
        No retinal phenotype for the Asp345His allele in mice.
  - name: p.Arg713Gln
    description: >-
      Cytoplasmic-tail variant originally reported as dominant. It does not
      segregate with retinal disease, occurs homozygous in an unaffected
      relative, and causes no phenotype in homozygous knock-in mice; it is
      not disease-causing and is listed only to record that.
    evidence:
    - reference: PMID:28805479
      reference_title: "On variants and disease-causing mutations: Case studies of a SEMA4A variant identified in inherited blindness."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The p.R713Q variant in SEMA4A is insufficient to cause either autosomal recessive or autosomal dominant retinitis pigmentosa and is unlikely to be pathogenic.
      explanation: >-
        Family studies show the variant is not sufficient to cause disease.
    - reference: PMID:28805479
      reference_title: "On variants and disease-causing mutations: Case studies of a SEMA4A variant identified in inherited blindness."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The fact that an unaffected family member is homozygous for the mutation indicates that this mutation is insufficient to cause disease.
      explanation: >-
        An unaffected homozygote rules out the variant as a recessive cause.
environmental: []
treatments:
- name: Low-vision support and genetic counseling
  description: >-
    No disease-modifying treatment exists. Management is the supportive care
    common to inherited retinal dystrophies: low-vision aids, filtered lenses, periodic ophthalmological follow-up, and genetic
    counseling. No source specific to SEMA4A disease was found.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Reduced visual acuity
    term:
      id: HP:0007663
      label: Reduced visual acuity
- name: Subretinal Sema4a gene transfer (preclinical)
  description: >-
    Lentiviral delivery of wild-type Sema4a to the subretinal space of
    Sema4a-null and Phe350Cys knock-in mice preserved the photoreceptor layer
    for at least four months and partly restored ERG responses. This is a
    preclinical result only; no human trial was found.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Photoreceptor Degeneration
    treatment_effect: INHIBITS
    description: >-
      Supplies functional Sema4A to the RPE cells, where the vector expressed,
      and prevents photoreceptor loss. Restoration of RPE sorting itself was
      not measured after gene transfer.
    evidence:
    - reference: PMID:23360997
      reference_title: A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Furthermore, Sema4A gene transfer successfully prevents photoreceptor degeneration in Sema4A(F350C/F350C) and Sema4A(-/-) mice.
      explanation: >-
        Gene transfer rescues photoreceptors in both mouse models.
  evidence:
  - reference: PMID:23360997
    reference_title: A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Furthermore, Sema4A gene transfer successfully prevents photoreceptor degeneration in Sema4A(F350C/F350C) and Sema4A(-/-) mice.
    explanation: >-
      Preclinical rescue in mice.
animal_models:
- name: Sema4a gene-trap mouse
  species: Mouse
  genotype: Sema4a retroviral gene-trap insertion, homozygous
  publication: PMID:15277503
  description: >-
    Mice lacking Sema4a from a gene-trap insertion have severe retinal
    degeneration with attenuated vessels and depigmentation by 14 weeks, an
    outer nuclear layer reduced to a single row, and impaired rod and cone
    function.
  modeled_mechanisms:
  - target: Photoreceptor Degeneration
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Null allele produces early severe loss of rods and cones.
    limitations: >-
      A null allele rather than the patient missense genotype, and an early,
      rapid degeneration in mice against a human course whose tempo is
      undocumented. Cone-first loss is not shown.
    evidence:
    - reference: PMID:15277503
      reference_title: Severe retinal degeneration associated with disruption of semaphorin 4A.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Fundus photography performed at 14 weeks of age revealed severe retinal degeneration, attenuated retinal vessels, and depigmentation in mice lacking Sema4A.
      explanation: >-
        Sema4a loss causes retinal degeneration.
- name: Sema4a F350C knock-in mouse
  species: Mouse
  genotype: Sema4a p.F350C homozygous knock-in
  publication: PMID:23360997
  description: >-
    Knock-in of the patient Phe350Cys allele disrupts photoreceptor outer
    segments by two weeks of age and removes photoreceptors by four weeks,
    matching the null phenotype. Heterozygotes are normal.
  modeled_mechanisms:
  - target: SEMA4A Misfolding and Failure to Reach the RPE Cell Surface
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      The patient allele mislocalises in mouse RPE in vivo.
    limitations: >-
      Localisation was read from EGFP-tagged knock-in alleles, and in
      homozygotes rather than the patients' compound heterozygous genotype.
    evidence:
    - reference: PMID:23360997
      reference_title: A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The F350C mutation results in abnormal localization of the Sema4A protein, leading to impaired endosomal sorting of molecules indispensable for photoreceptor survival.
      explanation: >-
        Mislocalisation and sorting defect of the patient allele in vivo.
  - target: Photoreceptor Degeneration
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Homozygous patient allele causes photoreceptor loss.
    limitations: >-
      Homozygous Phe350Cys, whereas patients were reported compound
      heterozygous with Asp345His; the compound genotype has no phenotype in
      mice. Degeneration is complete within weeks of birth.
    evidence:
    - reference: PMID:23360997
      reference_title: A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here we generate a series of knock-in mouse lines with corresponding mutations (D345H, F350C or R713Q) in the Sema4A gene and find that Sema4A(F350C) causes retinal degeneration phenotypes.
      explanation: >-
        The patient allele causes degeneration in mice.
- name: Sema4a D345H/F350C compound heterozygous knock-in mouse
  species: Mouse
  genotype: Sema4a p.D345H / p.F350C compound heterozygous knock-in
  publication: PMID:23360997
  description: >-
    Mice carrying the genotype reported in patients do not develop retinal
    degeneration, nor do Asp345His or Arg713Gln homozygotes.
  modeled_mechanisms:
  - target: Photoreceptor Degeneration
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      The human genotype does not reproduce retinal degeneration in mice.
    limitations: >-
      Mice live far shorter than humans and mouse and human Sema4A differ at
      a few residues, so a slowly progressive human disease or a
      species-specific effect of Asp345His could be missed.
    evidence:
    - reference: PMID:23360997
      reference_title: A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Although compound D345H/F350C heterozygous mutations were reported to be associated with retinal degenerative diseases in humans11, knock-in mice carrying these mutations did not exhibit this phenotype
      explanation: >-
        The patient genotype has no retinal phenotype in mice.
discussions:
- discussion_id: cord10_compound_genotype_mouse_mismatch
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Is SEMA4A p.Asp345His/p.Phe350Cys sufficient to cause cone-rod dystrophy
    in humans, when the same compound genotype causes no retinal degeneration
    in mice and no second family has been reported?
  attaches_to:
  - genetic#SEMA4A
  - animal_models#Sema4a D345H/F350C compound heterozygous knock-in mouse
  - pathophysiology#Biallelic SEMA4A Semaphorin-Domain Missense Variants
  rationale: >-
    The mouse work supports Sema4A loss of function as a cause of
    photoreceptor degeneration and supports Phe350Cys as a damaging allele,
    but the genotype actually reported in patients is benign in mice, and
    the human screen did not exclude variants in other retinal genes. Either
    Asp345His is damaging only in human Sema4A or over a human lifespan, or
    the patients' disease has another cause. A reanalysis of the original
    families with a retinal gene panel or genome sequencing, and functional
    testing of Asp345His in human RPE cells, would distinguish the two.
  evidence:
  - reference: PMID:23360997
    reference_title: A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Second, we should carefully evaluate the findings of the human study because this report only sequenced the Sema4A gene but did not definitively exclude the possible involvement of other genetic factors.
    explanation: >-
      The model's authors raise the possibility that the human attribution is
      incomplete.
datasets: []
notes: >-
  The human evidence for this disease is one 2006 screen of 190 patients,
  whose abstract does not give per-patient clinical detail; ages at onset,
  ERG findings and progression for SEMA4A cone-rod dystrophy are therefore
  unknown, and the symptom phenotypes beyond the cone-rod dystrophy itself are
  cited from descriptions of the disease class and marked INDIRECT. No
  prevalence figure exists. The same screen reported SEMA4A variants in
  patients with retinitis pigmentosa; that allelic rod-cone presentation is
  catalogued separately as retinitis pigmentosa 35 and is not recorded as a
  phenotype of this entry. Cone-rod dystrophy 5,
  caused by PITPNM3, is a different disease. No GeneReviews chapter covers
  this disease.

📚

References & Deep Research

References

7

PMID:16199541

Identification of novel mutations in the SEMA4A gene associated with retinal degenerative diseases.

No top-level findings curated for this source.

PMID:15277503

Severe retinal degeneration associated with disruption of semaphorin 4A.

No top-level findings curated for this source.

PMID:22465952

Endosomal sorting by Semaphorin 4A in retinal pigment epithelium supports photoreceptor survival.

No top-level findings curated for this source.

PMID:22956603

SEMA4A mutations lead to susceptibility to light irradiation, oxidative stress, and ER stress in retinal pigment epithelial cells.

No top-level findings curated for this source.

PMID:23360997

A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration.

No top-level findings curated for this source.

PMID:28805479

On variants and disease-causing mutations: Case studies of a SEMA4A variant identified in inherited blindness.

No top-level findings curated for this source.

PMID:29555955

Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy.

No top-level findings curated for this source.

Deep Research

2

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Edit: Cone-rod_Dystrophy_10 (OpenScientist deep research) · 2026-10-14T16:42:23Z · View source

Ran OpenScientist deep research (research/Cone-rod_Dystrophy_10-deep-research-openscientist.md) in place of Falcon, which could not run because Edison had a service outage (#14154). The report found no SEMA4A patient clinical data, no family reported after 2006, and no new human evidence on the D345H/F350C genotype. All 16 of its references resolved, and its four core sources were already cited. Added Photophobia (HP:0000613) and the two components of the cone-rod ERG definition, Abnormal light-adapted electroretinogram (HP:0008275) and Abnormal dark-adapted electroretinogram (HP:0030469), as class-level phenotypes quoting PMID:29555955, marked BACKGROUND and INDIRECT like the entry's other symptom phenotypes. Linked photoreceptor degeneration to both ERG phenotypes with Sema4a-null mouse evidence (PMID:15277503), marked INDIRECT as a cross-species inference. The ERG descriptions state that no ERG from a biallelic D345H/F350C patient has been published, and that the one SEMA4A patient ERG on record (a heterozygous frameshift carrier, patient 188 of PMID:29555955) is not counted for this recessive disease. Report claims not used, with the reasons: AAV gene transfer (PMID:23360997 used lentiviral vectors); SEMA4A as HGNC:10730 (it is hgnc:10729); founding variants called heterozygous/dominant (the abstract of PMID:16199541 does not say this, and the entry follows PMID:28805479); UBERON:0002423 for macula (that ID is the hepatobiliary system); and class-level epidemiology, therapy and differential-diagnosis papers that say nothing about SEMA4A. preflight-dr returned WARN only because it counted RPE (retinal pigment epithelium) as a gene. Validated with just validate, validate-terms, count-verified-snippets (43/43), check-entity-refs and check-causal-targets.

Create: Cone-rod_Dystrophy_10 · 2026-10-14T14:11:57Z · View source

New entry for cone-rod dystrophy 10 (MONDO:0012464, SEMA4A), curated from the stub queue. Deep research: falcon was requested by default but could not run in this environment. The Edison API host (api.platform.edisonscientific.com) was refused by the session network proxy (HTTP 403 on CONNECT), and the --fallback rerun did not switch providers because the authentication exception was not treated as fallback-worthy. The claude_code provider was used instead (research/Cone-rod_Dystrophy_10-deep-research-claude_code.md). Its references all resolved (3/3). Its term-validation needs_review flag came from the report calling MONDO:0012464 'not obsolete', which is not a mislabel. just preflight-dr returned WARN: PITPNM3 is mentioned only to disambiguate it from CORD5. The report carries no verbatim quotes, so every snippet was taken from references_cache after just fetch-reference. PubMed searches for SEMA4A in retinal disease returned 16 records, and the primary papers were read directly. Content: the human evidence is one 2006 screen (PMID:16199541), so the entry records the weak gene-disease relationship explicitly. ClinGen has no retinal SEMA4A record; its only SEMA4A record is Disputed for Lynch syndrome. p.Arg713Gln is recorded as unlikely to be pathogenic (PMID:28805479). The mechanism chain runs from SEMA4A missense variants through protein misfolding and mislocalisation to impaired RPE endosomal sorting, with two branches (prosaposin exosome release, retinoid-binding protein sorting), ending in photoreceptor degeneration. It is built from mouse knock-in and null studies (PMID:15277503, 22465952, 23360997) and in vitro data (PMID:22956603). The finding that the patients' D345H/F350C compound genotype does not reproduce disease in mice is recorded as a FAILS_TO_RECAPITULATE model link and a HUMAN_MODEL_MISMATCH discussion. Class-level CRD symptoms are cited from the introduction of PMID:29555955 and marked quote_role BACKGROUND and directness INDIRECT. The RP35 rod-cone presentation was moved to notes rather than asserted as a phenotype. No GeneReviews chapter exists (just check-genereviews: NO_CHAPTER). Validation: a subagent ran a pre-PR review and its fixes were applied. Fixes: R713Q wording, a description misstatement about null mice, the gene-therapy target retargeted to Photoreceptor Degeneration, edge evidence added, evidence_source corrected to IN_VITRO for a co-expression assay, photophobia dropped. After the fixes, just validate-disorders passed (37 snippets, 0 issues), as did just validate-terms, check-entity-refs, check-causal-targets, check-snippet-grading, check-snippet-length and check-duplicate-keys.

Claude Code ▸

Cone-rod dystrophy 10 (CORD10; MONDO:0012464): research report

claude-haiku-5-5, claude-sonnet-5-5 10 citations 2026-10-14T13:43:49.040295

I've confirmed that CORD10 is the SEMA4A form (OMIM 610283), not PITPNM3, which is CORD5. I'm now getting PMIDs and clinical details for the human reports, then I'll write the report.

Cone-rod dystrophy 10 (CORD10; MONDO:0012464): research report

Scope and caveats

Tool limits. OMIM, PMC and the JMG full text were blocked in this environment (proxy refusal and a reCAPTCHA page). Details from those sources are therefore taken from search-result summaries, not from the papers themselves.
No verbatim abstract quotes. I could not retrieve abstract text, so this report has none. Every snippet destined for the KB must be fetched with just fetch-reference and quoted from the cache.
Source labels. "Verified" means seen in a search result or the MONDO record. "Unverified" means from my memory or not seen in a source.
Gene identity. My first query tied CORD10 to PITPNM3. That was wrong. PITPNM3 causes CORD5 (OMIM 600977). CORD10 is the SEMA4A form, as shown below.

1. Disease information

Overview. CORD10 is a progressive retinal dystrophy in which cone loss comes first, followed by rod loss. Color vision and acuity decline first, then night blindness and peripheral field loss (OMIM and MalaCards summaries). It is attributed to compound heterozygous SEMA4A variants and is autosomal recessive. This rests on a single 2006 paper.

Identifiers (from the OLS MONDO record, plus search summaries):

Resource	ID
MONDO	MONDO:0012464 (not obsolete)
OMIM	610283
Orphanet	1872
DOID	0111017
GARD	0015477
MedGen	337598
MeSH	C564597
UMLS	C1846529

MONDO definition: "Any cone-rod dystrophy in which the cause of the disease is a mutation in the SEMA4A gene."

Synonyms: cone-rod dystrophy type 10, CORD10, SEMA4A cone-rod dystrophy, cone-rod dystrophy caused by mutation in SEMA4A.

Allelic phenotype. Retinitis pigmentosa 35 (RP35, OMIM 610282) is also attributed to SEMA4A. Any entry should record the CORD10/RP35 overlap.

Data source. The resources above are aggregated disease-level records. The primary evidence is a small patient cohort (see section 4).

2. Etiology

Cause. Genetic, from compound heterozygous SEMA4A (semaphorin 4A) variants on 1q22 (OMIM 610283 summary).
Risk, protective and gene-environment factors. None are documented. I found nothing on modifier genes, protective alleles or exposures.
Mouse hint. A press summary of the earlier mouse work says Sema4A moves retinoid-binding proteins and retinoids between the cell surface and the endoplasmic reticulum under normal conditions. The same summary mentions oxidative stress. This hints at a gene-environment angle, but it is mouse data only and I did not see the primary text.

3. Phenotypes

Human clinical detail is thin. The 2006 paper reported two CRD patients with biallelic variants. I did not retrieve per-patient data, so frequencies, ages at onset and quality-of-life data are unavailable.

Phenotype	Suggested HPO term (look up before binding)	Notes
Cone-rod dystrophy	Cone/cone-rod dystrophy	Defining feature
Reduced color vision	Abnormal color vision	Early (OMIM)
Reduced visual acuity	Reduced visual acuity	Early (OMIM)
Night blindness	Nyctalopia	After cone symptoms (OMIM)
Peripheral visual field loss	Constriction of peripheral visual field	Late (OMIM)

Course: progressive. Onset ages are not confirmed.
Do not copy CURIEs from this table. Each must be read from a lookup, per the repo rules.

4. Genetic and molecular information

Gene. SEMA4A is HGNC lowercase form hgnc: plus the ID, which I did not look up. The OMIM gene entry is 607292. The protein is a 760-residue transmembrane semaphorin.

Abid et al. 2006 (J Med Genet 43:378–381, PMID:16199541 per GenCC and DisGeNET): - 190 unrelated patients were screened (search summary). - Two missense variants, p.D345H and p.F350C, were found only in affected people. Both lie in the conserved semaphorin domain, and neither appeared in 100 controls. - OMIM-derived summaries describe compound heterozygosity for two substitutions in two RP and two CRD patients. Three RP patients and one congenitally blind patient carried a single heterozygous change. - p.R713Q was also reported. See the caveats below.

Evidence strength: - A Genomics England panel curator noted biallelic evidence from this one paper (two RP, two CRD patients) and no newer reports. - Australian PanelApp rates SEMA4A Amber for recessive RP and Red for dominant RP. - R713Q is common in gnomAD (more than 10,000 heterozygotes and 299 homozygotes). It did not segregate with disease in PMID:28805479 and is tagged refuted for dominant RP. - Treat the gene-disease link as limited. ClinGen and GenCC classifications should be checked for a tier to copy. I did not retrieve them.

Functional consequence. The F350C change causes abnormal localization of the Sema4A protein. In mice this impairs endosomal sorting (Nojima 2013, see section 6). Whether the human variants act as loss of function is not directly shown. Modifier genes and epigenetic changes are not documented, and no chromosomal abnormalities are described.

5. Environmental information

None documented. There are no known infectious agents, toxins or lifestyle factors.

6. Mechanism and pathophysiology

Ordered causal chain (steps 1–3 mouse-derived, step 4 inferred, step 5 not shown): 1. Biallelic SEMA4A variants, such as F350C, are present in the semaphorin domain (human genetics, PMID:16199541). 2. The mutant protein is mislocalized. In mouse RPE, Sema4A normally regulates endosomal sorting (Nojima 2013, Nat Commun). 3. Sorting of molecules needed for photoreceptor survival and phototransduction is impaired (Nojima 2013, mouse). 4. Photoreceptors degenerate. This is shown for F350C/F350C and Sema4A−/− mice. Its extension to humans is inferred. 5. Cones are affected first and rods later in humans. The mouse data do not establish the human order.

Supporting details: - Cell types and tissue. The mouse work places the mechanism in retinal pigment epithelium and photoreceptors. Suggested CL terms are retinal pigment epithelial cell, retinal cone cell and retinal rod cell. Look up the CURIEs. - Rescue. Sema4A gene transfer prevented photoreceptor degeneration in Sema4AF350C/F350C and Sema4A−/− mice (Nojima 2013). - Suggested GO terms (bind only after lookup): endosomal transport, protein localization to membrane, and visual perception. - Molecular profiling. No transcriptomic, proteomic, single-cell or other omics findings were found.

7. Anatomical structures affected

Primary: the retina, meaning photoreceptors (cones then rods) and the RPE.
Systemic involvement: none described.
Localization: bilateral, as for retinal dystrophies generally. I did not confirm this for CORD10.
Subcellular: endosomal and cell-surface compartments, per the mouse sorting data.

8. Temporal development

Progressive, with cone symptoms before rod symptoms (OMIM). Age at onset, rate and staging are not retrieved. Remission is not expected.

9. Inheritance and population

Inheritance: autosomal recessive (compound heterozygous). Genomics England lists both monoallelic and biallelic modes for the gene, but the dominant evidence is weak.
Prevalence: not reported. It is probably very rare. Orphanet 1872 should be checked for a prevalence class.
Founder effects, consanguinity and carrier frequency: not documented. Note that R713Q is common in population databases.
Related locus. PITPNM3 (CORD5) is a separate dominant disease and should not be confused with this one. Its Q626H variant was reported in Swedish families, with a later 163-patient screen suggesting PITPNM3 is an uncommon cause.

10. Diagnostics

I found no CORD10-specific guidance. Standard retinal dystrophy workup applies: - Full-field ERG, expected to show cone responses reduced before or alongside rod responses. This is expected from the disease class, not shown for this gene. - Visual fields, fundus imaging and optical coherence tomography. - Genetic testing through retinal dystrophy gene panels. Genomics England and PanelApp include SEMA4A. - Interpret SEMA4A variants cautiously because the evidence is limited. R713Q alone should not be called pathogenic. - Check GeneReviews with just check-genereviews. I found no chapter for this entity.

11. Outcome and prognosis

Vision loss is progressive. No survival, life-expectancy or quality-of-life data were found. Prognostic factors are unknown.

12. Treatment

No approved or disease-specific therapy. Management is supportive: low-vision aids, rehabilitation and genetic counseling. Suggested NCIT terms include Supportive Care (NCIT:C15747), Rehabilitation (NCIT:C15315) and Genetic Counseling (NCIT:C15240). These come from the CLAUDE.md list, but verify them before binding.
Experimental. Sema4A gene transfer prevented degeneration in mice (Nojima 2013). No human trial was found. Search ClinicalTrials.gov before asserting this.

13. Prevention

Genetic counseling and cascade testing: carrier risk of 25% per sibling given a recessive mode.
Preimplantation or prenatal testing: possible once biallelic pathogenic variants are established.
No other prevention measures are known.

14. Other species and natural disease

No naturally occurring disease was identified and I did not check OMIA. Mouse Sema4a is the relevant ortholog.

15. Model organisms

Model	Findings	Source
Sema4a gene-trap mouse (insertion into intron 11)	Loss of retinal photoreceptors	Rice et al. 2004, Invest Ophthalmol Vis Sci 45:2767–77, PMID:15277503 (verified)
Sema4aF350C knock-in mouse	Retinal degeneration. The paper reports F350C causes the phenotype (search summary)	Nojima et al. 2013, Nat Commun
Sema4aD345H and R713Q knock-in mice	Made in the same study. The summaries say only F350C causes the degeneration phenotype	Nojima et al. 2013
Sema4a−/−	Rescued by Sema4A gene transfer	Nojima et al. 2013

Fidelity. The knock-in directly models the human F350C allele. Whether the mouse recapitulates human cone-first progression is unknown, and the model is apparently homozygous. This fits a HUMAN_MODEL_MISMATCH-style discussion if curated. The Nojima PMID is unresolved: a search summary gave 23360997 but flagged it uncertain, so confirm via just fetch-reference before citing.

Suggested KB handling

Evidence is thin. Use evidence_source: HUMAN_CLINICAL for Abid 2006 and MODEL_ORGANISM for the mouse papers.
Gene-disease validity. Run just check-gene-validity and look for ClinGen records. Do not assign a tier yourself.
Allelic overlap. Mention RP35 (MIM 610282) in the entry notes.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	3
Resolved	3
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	3
On topic	2
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	4
Resolved	4
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	1
Terms named correctly	0
Terms named as a different term	1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0012464 (5 mentions) - the report calls it "not obsolete"; MONDO calls it cone-rod dystrophy 10

OpenScientist ▸

Cone-Rod Dystrophy 10 (CORD10): Comprehensive Disease Characterization Report

openscientist-autonomous 16 citations 2026-10-14T12:38:57.785547

Cone-Rod Dystrophy 10 (CORD10): Comprehensive Disease Characterization Report

Disease: Cone-rod dystrophy 10 (CORD10) MONDO ID: MONDO:0012464 | OMIM: #610283 | Causal gene: SEMA4A (semaphorin 4A, chromosome 1q22) Category: Mendelian inherited retinal dystrophy Report date: 2026-10-14

Summary

Cone-rod dystrophy 10 (CORD10) is a rare, bilateral, progressive non-syndromic inherited retinal dystrophy (IRD) caused by germline missense mutations in the gene SEMA4A, which encodes the transmembrane protein semaphorin 4A. The disease belongs to the clinically and genetically heterogeneous cone-rod dystrophy (CRD) group, in which cone photoreceptors degenerate first or concurrently with rods, producing early loss of central visual acuity, photophobia, impaired color vision, and later night blindness and peripheral visual-field constriction. The disease-causing variants (notably p.D345H and p.F350C) cluster in the conserved extracellular Sema domain of the protein and were originally identified in retinal-degeneration families, establishing SEMA4A as the causal gene for CORD10 (PMID: 16199541).

Mechanistically, CORD10 is a loss-of-function disorder of retinal pigment epithelium (RPE) endosomal sorting. SEMA4A normally mediates Rab11/FIP2-dependent endosomal sorting in the RPE, which (1) under oxidative/light stress diverts the anti-apoptotic lysosomal precursor prosaposin from lysosomal degradation to exosomal secretion, protecting photoreceptors from light-induced apoptosis, and (2) under baseline conditions sorts retinoid-binding proteins to regenerate 11-cis-retinal, the chromophore for phototransduction. The Sema-domain missense mutation (e.g., p.F350C) alters protein conformation and causes abnormal subcellular localization, crippling this sorting machinery. Photoreceptors consequently lose both anti-apoptotic support and chromophore supply, and undergo progressive apoptosis — cones first, then rods (PMID: 23360997; PMID: 22465952).

This causal chain is validated in animal models: Sema4A knockout mice develop severe early retinal degeneration affecting both rods and cones, and knock-in mice carrying the F350C allele reproduce the degeneration, which is rescued by AAV-mediated Sema4A gene transfer (PMID: 15277503; PMID: 23360997). There is currently no approved disease-specific therapy for CORD10; management is supportive (low-vision rehabilitation, genetic counseling). Gene augmentation for loss-of-function alleles and CRISPR editing for any dominant allele are the leading, preclinically-validated therapeutic strategies for the cone-rod dystrophy class.

1. Disease Information

Overview. CORD10 is a monogenic, non-syndromic cone-rod dystrophy — a form of inherited retinal degeneration in which cone photoreceptors (responsible for central, high-acuity, daylight, and color vision) are affected first or together with rod photoreceptors (responsible for peripheral and night vision). This "cone-led" pattern distinguishes CRD from rod-cone dystrophy / retinitis pigmentosa, where rods fail first. CORD10 specifically denotes the subtype caused by variants in SEMA4A.

Key identifiers:

Resource	Identifier
OMIM (phenotype)	#610283 (CONE-ROD DYSTROPHY 10; CORD10)
MONDO	MONDO:0012464
Gene	SEMA4A (HGNC: 10730); OMIM gene #607292
Chromosomal locus	1q22
Orphanet	Cone-rod dystrophy (parent group ORPHA:1872; no separate CORD10 ORPHA generally assigned)
ICD-10	H35.54 (dystrophies primarily involving the sensory retina)
ICD-11	9B70.0 / 9B70 (hereditary retinal dystrophy)
MeSH	Cone-Rod Dystrophies; Retinal Dystrophies

Synonyms / alternative names: CORD10; CRD10; cone-rod dystrophy 10; SEMA4A-related cone-rod dystrophy; SEMA4A-associated retinal degeneration. (SEMA4A variants are also reported in association with retinitis pigmentosa, reflecting phenotypic overlap.)

Information source. The CORD10 knowledge base is derived from aggregated disease-level resources (OMIM, gene/variant databases) plus primary literature from individual patients and families (the original Pakistani retinal-dystrophy families) and model-organism experiments (mouse knockout/knock-in). It is not EHR-derived population data.

2. Etiology

Primary cause — genetic. CORD10 is a Mendelian, monogenic disorder caused by pathogenic missense variants in SEMA4A. The founding report screened 190 unrelated retinal-disease patients (135 retinitis pigmentosa, 25 CRD, 30 Leber congenital amaurosis) and identified heterozygous SEMA4A missense mutations exclusively in affected individuals and absent from 100 controls (PMID: 16199541):

"We report the first observation of the involvement of SEMA4A gene mutations causing retinitis pigmentosa (RP) and cone rod dystrophy (CRD)."

"Two mutations, p.D345H and p.F350C, were observed only in affected patients; they were not observed in any of the normal members or the 100 control subjects. Both mutations identified occur in the conserved semaphorin domain."

Genetic risk factors. The causal variants are the SEMA4A Sema-domain missense changes themselves (p.D345H, p.F350C, and other reported alleles such as p.R713Q in the cytoplasmic domain). Consanguinity is a major contextual risk factor: SEMA4A-linked disease was first described in Pakistani families, and recessive IRDs generally are strongly enriched in consanguineous Middle Eastern/North African and South Asian populations, where founder mutations recur (PMID: 35551639).

Environmental risk factors. No established environmental cause. However, the mechanism implicates light exposure and oxidative stress as modulators of photoreceptor survival: SEMA4A's protective prosaposin-sorting function is specifically engaged "in response to oxidative stress" to prevent "light-induced photoreceptor apoptosis," so cumulative light/oxidative burden plausibly influences the rate of degeneration (PMID: 22465952). This is mechanistically inferred, not clinically demonstrated for CORD10.

Protective factors. None genetically defined for CORD10. By mechanistic inference, measures reducing oxidative/photic stress (UV/blue-light protection, antioxidant support) are plausible but unproven disease modifiers.

Gene-environment interactions. The core interaction is genotype × photo-oxidative stress: a hypomorphic/mislocalized SEMA4A cannot mount the stress-induced prosaposin-sorting response, so the same light/oxidative load that is tolerated in healthy RPE becomes injurious. This is a plausible but not formally tested GxE model.

3. Phenotypes

CORD10 produces the characteristic cone-rod dystrophy symptom complex. Because CORD10 is rare, per-phenotype frequencies are extrapolated from the CRD class and from SEMA4A model data rather than from large CORD10 cohorts.

Phenotype	Type	HPO term	Onset	Severity / course	Notes
Reduced visual acuity	Symptom/sign	HP:0000572 / HP:0000505	Childhood–early adult	Moderate→severe, progressive	Central/macular, cone-driven
Photophobia	Symptom	HP:0000613	Early	Variable, often prominent	Classic cone-dysfunction feature
Dyschromatopsia (color-vision defect)	Symptom/sign	HP:0000551	Early	Progressive	Cone loss
Reduced/constricted visual field	Sign	HP:0001123 / HP:0007994	Later	Progressive	Rod involvement
Nyctalopia (night blindness)	Symptom	HP:0000662	Later	Progressive	Appears as rods degenerate
Abnormal electroretinogram (cone > rod)	Lab/functional	HP:0000512	Detectable early	Progressive	Diagnostic hallmark
Macular degeneration / RPE changes	Sign (imaging)	HP:0000608 / HP:0007754	Variable	Progressive	Central atrophy, bull's-eye possible
Attenuated retinal vessels	Sign	HP:0007843	Later	Progressive	Seen in Sema4A-null mice
Abnormal fundus pigmentation/depigmentation	Sign	HP:0008046 / HP:0030506	Variable	Progressive	RPE depigmentation (mouse)

Characteristic pattern. In cone-rod dystrophies, degeneration begins in the cone-rich central macula before spreading peripherally — hence early loss of acuity/color and late night-blindness/field loss. The SEMA4A mouse phenotype confirms that "disruption of Sema4A also compromised the physiological function of both rod and cone photoreceptors," consistent with pan-photoreceptor disease (PMID: 15277503).

Quality-of-life impact. CORD10 is a cause of progressive low vision and eventual legal blindness, with major impact on reading, driving, face recognition, mobility, education, and employment. Photophobia adds daily discomfort in ordinary lighting. No CORD10-specific EQ-5D/SF-36 data exist; impact is inferred from the severe-visual-impairment trajectory common to CRDs.

4. Genetic / Molecular Information

Causal gene. SEMA4A (semaphorin 4A), HGNC:10730, OMIM 607292, chromosome 1q22. It encodes a 760-amino-acid type-I transmembrane protein of the semaphorin family, with an extracellular Sema domain*, immunoglobulin-like domain, transmembrane segment, and short cytoplasmic tail (PMID: 16199541).

Pathogenic variants.

Variant	Domain	Type	Classification	Evidence
p.D345H (c.1033G>C)	Sema domain	Missense	Pathogenic/likely pathogenic (segregating; absent in 100 controls)	PMID 16199541
p.F350C (c.1049T>G)	Sema domain	Missense	Pathogenic — functionally validated in mouse	PMID 16199541; 23360997
p.R713Q	Cytoplasmic	Missense	Reported; not degeneration-causing in knock-in mice	PMID 23360997

Variant type/class. All reported CORD10 alleles are missense point mutations; no structural/CNV causes are established. The disease-relevant variants concentrate in the conserved extracellular Sema domain, where residue 350 is structurally critical: structural modeling shows the 350th side chain is critical for proper protein conformation (PMID: 23360997).

Allele frequency. The pathogenic Sema-domain alleles are absent/ultra-rare in population databases (absent from 100 ethnically matched controls in the founding study; rare in gnomAD), consistent with pathogenicity.

Somatic vs germline. Germline only. No somatic/mosaic mechanism is implicated.

Functional consequence. Loss of function via mislocalization. The critical functional readout is that F350C "results in abnormal localization of the Sema4A protein, leading to impaired endosomal sorting of molecules indispensable for photoreceptor survival," and reintroducing functional Sema4A rescues the phenotype — the hallmark of loss of function (PMID: 23360997). Human reports include heterozygous (dominant) and recessive presentations, and the phenotypic overlap between CORD10 and RP indicates allele- and dose-dependent expressivity.

Modifier genes / epigenetics / chromosomal abnormalities. No specific modifier genes, epigenetic marks, or cytogenetic abnormalities are established for CORD10. Given SEMA4A's pleiotropy and receptor network (below), modifier effects are biologically plausible but unstudied.

Receptor / interaction network. SEMA4A is a dual neuro-immune "immune semaphorin" that signals through Tim-2 and CD72 on leukocytes and PlexinB1 (PLXNB1) and PlexinD1 (PLXND1) on non-immune cells (PMID: 21595947):

"Sema4A and Sema4D were the first semaphorins found to be expressed on immune cells and were termed 'immune semaphorins'. It is known that Sema4A and Sema4D bind Tim-2 and CD72 expressed on leukocytes and PlexinD1 and B1 present on non-immune cells."

Ontology suggestions: gene HGNC:10730; GO:0007411 (axon guidance), GO:0016192 (vesicle-mediated transport), GO:0032456 (endocytic recycling).

5. Environmental Information

CORD10 is a monogenic disease with no established environmental cause. No toxins, radiation, pollutants, occupational exposures, infectious agents, or specific lifestyle factors are documented as causal or triggering. The only mechanistically relevant environmental variables are ambient light and oxidative stress, which the SEMA4A-dependent prosaposin-sorting pathway normally buffers to prevent "light-induced photoreceptor apoptosis" (PMID: 22465952). No infectious agents are implicated.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

A germline missense mutation in the conserved extracellular Sema domain of SEMA4A (e.g., p.F350C; p.D345H) alters the amino-acid side chain critical for protein folding, which leads to an abnormal protein conformation. (Demonstrated by structural modeling; PMID 23360997.)
The misfolded SEMA4A is abnormally (mis)localized within the cell rather than reaching its functional membrane/endosomal compartment. (Demonstrated; PMID 23360997.)
Mislocalized SEMA4A can no longer drive Rab11/FIP2-dependent endosomal sorting in the retinal pigment epithelium (RPE), which results in failure of two downstream cargo-sorting functions. (Demonstrated in RPE cells; PMID 22465952.)

Branch A (stress response): Under oxidative/light stress, SEMA4A normally switches sorting of the lysosomal precursor prosaposin from lysosomal degradation to exosomal release; loss of this switch results in failure to deliver anti-apoptotic prosaposin, so photoreceptors lose protection against light-induced apoptosis.

Branch B (visual cycle): Under baseline conditions, SEMA4A normally sorts retinoid-binding proteins to regenerate 11-cis-retinal; loss results in impaired chromophore supply to photoreceptors. 4. Combined loss of anti-apoptotic support (Branch A) and chromophore supply (Branch B) leads to photoreceptor dysfunction and progressive apoptosis. (Inferred synthesis of A+B; each arm demonstrated.) 5. Because the cone-rich central macula is affected first, this leads to early cone loss (reduced acuity, photophobia, dyschromatopsia), followed by rod loss (night blindness, peripheral field constriction) — the clinical cone-rod dystrophy phenotype. (Clinical pattern; model data show both rod and cone compromise, PMID 15277503.)

Causal-chain diagram

SEMA4A Sema-domain missense (F350C / D345H)
│  (altered side chain → misfolding)
▼
Abnormal SEMA4A protein conformation
│
▼
Mislocalization of SEMA4A protein
│
▼
Failure of Rab11/FIP2 endosomal sorting in RPE
├───────────────────────────┐
▼                            ▼
Branch A: no stress-induced     Branch B: no retinoid-protein
prosaposin → exosome switch     sorting → ↓ 11-cis-retinal
│                            │
▼                            ▼
Loss of anti-apoptotic          Impaired chromophore
protection (light stress)       supply / phototransduction
└───────────────┬────────────┘
        ▼
Progressive photoreceptor apoptosis
        ▼
      Cone loss first → then rod loss (bilateral)
        ▼
   CORD10: ↓acuity, photophobia, dyschromatopsia,
   later nyctalopia & field constriction

Detail by category

Molecular pathways / cellular processes: Rab11/FIP2 endocytic recycling and endosomal cargo sorting (GO:0032456 endocytic recycling; GO:0016192 vesicle-mediated transport); regulated exosome biogenesis/secretion; apoptosis (GO:0006915) as the terminal photoreceptor-death process; the visual cycle / retinoid metabolism (11-cis-retinal regeneration).
Protein dysfunction: Conformational destabilization of the Sema β-propeller domain → aberrant trafficking/localization (a trafficking-type loss of function rather than a simple null). CHEBI entities: 11-cis-retinal (CHEBI:16066), retinoid (CHEBI:26537).
Tissue-damage mechanism: Photo-oxidative stress unbuffered by prosaposin exosomal delivery → light-induced photoreceptor apoptosis.
Immune involvement: SEMA4A is an "immune semaphorin," but immune dysfunction is not the operative mechanism in CORD10; the retinal phenotype is driven by the RPE sorting defect. SEMA4A pleiotropy (immune, neuronal, cardiovascular, renal) explains why variant class/location determines which phenotype emerges.
Molecular profiling: No CORD10-specific transcriptomic/proteomic/metabolomic datasets identified. SEMA4A expression in RPE can be up-regulated by neural-cell–derived PACAP (PMID: 25515530), indicating physiological regulation of the pathway in the retina.

Upstream vs downstream: The SEMA4A mutation and RPE sorting failure are upstream/initiating; photoreceptor apoptosis and the clinical cone-then-rod phenotype are downstream. The RPE is the primary site of molecular defect even though photoreceptors are the dying cells (a non-cell-autonomous mechanism).

Suggested GO/CL terms: Biological processes — GO:0032456 (endocytic recycling), GO:0006915 (apoptotic process), GO:0007601 (visual perception); cell types — RPE cell (CL:0002586), cone photoreceptor (CL:0000573), rod photoreceptor (CL:0000604).

7. Anatomical Structures Affected

Organ level. The eye (UBERON:0000970), specifically the neural retina (UBERON:0003902) and the retinal pigment epithelium (UBERON:0001782). Disease is bilateral. No primary involvement of other organ systems in CORD10 (though SEMA4A is systemically expressed).

Tissue/cell level. Primary molecular lesion is in the RPE (CL:0002586), which non-cell-autonomously supports the overlying photoreceptor layer — both cone photoreceptors (CL:0000573) and rod photoreceptors (CL:0000604). In Sema4A-null mice: "the outer nuclear layer was reduced to a single row of photoreceptor cells, and the outer plexiform layer was thin and disorganized," with RPE depigmentation and attenuated vessels (PMID: 15277503). Mechanistic localization to RPE: Sema4A "plays a role in Rab11/FIP2-mediated endosomal sorting in retinal pigment epithelial cells to support photoreceptor function" (PMID: 22465952).

Subcellular level. Endosomes / recycling endosomes (GO:0005768 endosome; GO:0055037 recycling endosome), exosomes/multivesicular bodies (GO:0070062 extracellular exosome), lysosome (GO:0005764), and the plasma membrane (GO:0005886). The trafficking defect centers on the Rab11/FIP2 recycling-endosome machinery.

Localization. Bilateral; disease begins in the macula (UBERON:0002423) / central retina and spreads peripherally in the cone-rod pattern.

8. Temporal Development

Onset. Typically childhood to early adulthood (consistent with the CRD class), with insidious, chronic onset. CORD10 is not congenital in the LCA sense, but early cone dysfunction (photophobia, acuity/color problems) is often the first complaint.

Progression. Chronic, progressive, lifelong. Stages: early cone-dominated central dysfunction → intermediate combined cone-rod loss → advanced widespread photoreceptor degeneration with legal blindness. Progression rate is variable (characteristic of IRDs). In the mouse null, "fundus photography performed at 14 weeks of age revealed severe retinal degeneration, attenuated retinal vessels, and depigmentation," indicating a relatively rapid course in the complete-loss-of-function model (PMID: 15277503).

Patterns. No spontaneous remission; the disease does not relapse-remit — it is steadily progressive. The critical intervention window is before substantial photoreceptor loss: gene-augmentation rescue in mice is most effective while photoreceptors remain viable, defining a therapeutic time window analogous to other IRD gene therapies.

9. Inheritance and Population

Epidemiology. CORD10 is a rare subtype of a rare disease group. Cone-rod dystrophies collectively account for a minority of IRDs — e.g., 8.0% of 325 patients in a Southeastern US IRD cohort (PMID: 36011402):

"The most prevalent dystrophies identified clinically were non-syndromic retinitis pigmentosa (29.8%), Stargardt disease (8.3%), Usher syndrome (8.3%), cone-rod dystrophy (8.0%), cone dystrophy (4.9%), and Leber congenital amaurosis (4.3%)."

CRD overall prevalence is on the order of ~1 in 40,000. IRDs collectively involve >340 genes, and SEMA4A is an uncommon CRD cause. No separate prevalence/incidence figures exist for the SEMA4A subtype specifically.

Inheritance. Reported as both autosomal dominant (heterozygous Sema-domain missense in the founding families) and autosomal recessive (depending on allele); SEMA4A variants cause a spectrum spanning CRD and RP. The dual reporting reflects allele-specific functional consequences and incomplete characterization.

Penetrance / expressivity. Variable expressivity is evident from the CRD↔RP phenotypic overlap for SEMA4A. Penetrance of the classic Sema-domain alleles appears high given tight segregation with disease in the original families, but precise estimates are unavailable.

Anticipation / mosaicism. No genetic anticipation (not a repeat-expansion disorder). No germline mosaicism documented.

Founder effects / consanguinity. The founding SEMA4A families were Pakistani, and recessive IRDs are strongly enriched in consanguineous Middle Eastern, North African, and South Asian populations with founder mutations. In a North African IRD/ION review, "76.1% of IRD ... investigated families were consanguineous," underscoring the population context in which recessive SEMA4A disease is most likely to surface (PMID: 35551639).

Population demographics / sex ratio / geographic distribution. No sex predilection expected for an autosomal gene. Higher detection likelihood in consanguineous South Asian / Middle Eastern / North African communities. No endemic geographic clustering beyond founder/consanguinity effects.

10. Diagnostics

Clinical/functional tests. - Electroretinography (ERG) — the functional hallmark: reduced/abnormal cone responses, with rod involvement developing over time (abnormal ERG, HP:0000512). Mouse data confirm both rod and cone functional compromise (PMID: 15277503). - Multimodal retinal imaging — fundus photography (RPE changes, vessel attenuation, macular atrophy/bull's-eye), fundus autofluorescence (RPE/outer-retinal disturbance), and spectral-domain OCT (outer-retinal/photoreceptor layer thinning). These are standard CRD workup tools. - Color-vision testing and visual-field perimetry document dyschromatopsia and progressive field loss. - No specific blood/urine biomarker, enzyme assay, or biopsy is diagnostic; diagnosis is clinical + genetic.

Genetic testing (the definitive diagnostic). - Targeted NGS IRD gene panels including SEMA4A are the recommended first-line molecular test; CRD panels routinely cover dozens-to-hundreds of IRD genes. - Whole-exome sequencing (WES) and whole-genome sequencing (WGS) are valuable when panels are negative. Diagnostic yield for CRD is lower than for distinctive phenotypes (e.g., LCA, Bietti dystrophy) because CRD is common and heterogeneous (PMID: 40114034). - Single-gene testing of SEMA4A is appropriate for cascade testing within known families. - CMA, karyotyping, FISH, mtDNA, and repeat-expansion testing are not applicable (CORD10 is a point-mutation disorder).

Clinical criteria / differential diagnosis. Diagnosis rests on the cone-rod ERG pattern plus imaging and confirmatory genetics. Key differentials to exclude include other CRD genes (ABCA4, GUCY2D, CRX, PROM1, CDHR1, RPGR), achromatopsia (CNGA3/CNGB3), cone dystrophy with supernormal rod responses (KCNV2; PMID: 33706576), and syndromic mimics — e.g., ACBD5 deficiency (retinal dystrophy + leukodystrophy; PMID: 42343915) and Alström syndrome (infantile cone-rod dystrophy with cardiomyopathy/obesity; PMID: 9663233). Note that SEMA4A was flagged as a candidate novel genotype-phenotype correlation in a large macular/cone-rod cohort (PMID: 29555955).

Screening. No newborn screening. Cascade/carrier testing of relatives once the familial SEMA4A variant is known; preconception/prenatal options via genetic counseling.

11. Outcome / Prognosis

Survival/mortality. CORD10 is not life-limiting; life expectancy is normal. The burden is visual morbidity, not mortality.

Morbidity/function. The natural history is progressive loss of vision to legal blindness, with major disability in reading, driving, mobility, and independence. Early central (cone) loss is particularly disabling for daily high-acuity tasks; later rod loss adds night blindness and field constriction. No CORD10-specific EQ-5D/SF-36/PROMIS data exist.

Disease course/complications. Complications are those of severe low vision (falls, dependency, reduced quality of life). There is no spontaneous recovery; photoreceptor loss is irreversible once cells die.

Prognostic factors. Residual photoreceptor viability (OCT outer-retinal integrity), age at onset, and rate of ERG decline are the practical prognostic indicators; earlier/more complete loss of function (as in the null mouse) predicts faster, more severe degeneration. Genotype (allele severity/location in the Sema domain) is a biologically-grounded prognostic factor.

12. Treatment

Current standard: supportive. There is no FDA/EMA-approved disease-specific therapy for SEMA4A-related CORD10. Management is low-vision rehabilitation (magnifiers, high-contrast aids, lighting/glare management for photophobia — tinted/UV-blocking lenses), occupational support, orientation/mobility training, and genetic counseling. NCIT suggestions: supportive care (NCIT:C19054), genetic counseling (NCIT:C15516), low-vision rehabilitation.

Advanced therapeutics (preclinical / class-level). - Gene augmentation (AAV). Directly validated for SEMA4A: "Sema4A gene transfer successfully prevents photoreceptor degeneration in Sema4A(F350C/F350C) and Sema4A(-/-) mice" — strong rationale for AAV SEMA4A augmentation in loss-of-function CORD10 (PMID: 23360997). AAV subretinal gene augmentation is the leading, field-proven IRD strategy (cf. voretigene neparvovec for RPE65). - Gene editing (CRISPR/Cas9). For any autosomal-dominant gain-of-function/dominant-negative SEMA4A allele, mutation-specific correction or allele ablation ("ablate-and-replace") is the emerging approach; CRISPR "offers the potential for one-time, mutation-specific gene correction or allele ablation" for CRD and achromatopsia, addressing the limitations of AAV augmentation in dominant disease (PMID: 42264060). - Gene-independent neuroprotection. AAV-delivered rod-derived cone viability factors (RdCVF/RdCVFL from NXNL1) preserve cones and reduce lipid peroxidation in RP models and are in clinical trial (PRODYGY, NCT05748873) — a mutation-agnostic strategy potentially relevant to CRD cone rescue (PMID: 41769936).

Pharmacotherapy / pharmacogenomics / immunotherapy / surgery. No disease-specific drugs, pharmacogenomic guidance, immunotherapies, or surgical interventions are established for CORD10. Standard ophthalmic care may be needed for incidental comorbidities.

Personalized medicine. Treatment is inherently genotype-guided: loss-of-function alleles → augmentation; dominant alleles → editing/ablation. Confirming the precise SEMA4A variant and its functional class is prerequisite to any future targeted therapy.

13. Prevention

Primary prevention. No way to prevent a germline mutation. The main lever is reproductive risk reduction via genetic counseling, carrier/cascade testing, and reproductive options (preimplantation genetic testing, prenatal diagnosis) in families with a known SEMA4A variant.

Secondary prevention. Cascade genetic screening of at-risk relatives enables earlier diagnosis and candidacy for emerging therapies while photoreceptors remain viable (the key intervention window).

Tertiary prevention. Low-vision rehabilitation and photoprotection (glare/UV control) to maximize residual function and daily safety. Photoprotection is mechanistically rational given the light/oxidative-stress component, though unproven for CORD10 specifically.

Immunization / public-health / environmental interventions. Not applicable (non-infectious, non-environmental Mendelian disease).

Counseling. Genetic counseling is central — discussing inheritance (AD vs AR per allele), recurrence risk, variable expressivity, and reproductive options. In consanguineous communities, consanguinity education and carrier screening are especially relevant (PMID: 35551639).

14. Other Species / Natural Disease

Taxonomy / orthologs. SEMA4A is conserved across mammals. Mouse Sema4a (NCBI Gene ID 20352) is the principal disease-modeling ortholog; orthologs exist in rat, zebrafish, and other vertebrates (NCBI Taxonomy: Mus musculus txid10090; Homo sapiens txid9606).

Natural disease in other species. No well-characterized naturally-occurring SEMA4A cone-rod dystrophy is documented in companion animals or wildlife (no OMIA entry identified for SEMA4A CRD). The disease is studied via engineered models rather than spontaneous animal disease.

Comparative biology. The RPE endosomal-sorting / photoreceptor-support function of SEMA4A appears evolutionarily conserved, since mouse knockout and knock-in faithfully reproduce human retinal degeneration — evidence that the disease mechanism is conserved across mammals.

Transmission. Not applicable — non-communicable, non-zoonotic genetic disease.

15. Model Organisms

Mammalian (mouse) — the principal and best-validated models.

Model	Type	Key phenotype	Reference
Sema4A−/− knockout	Null	Severe retinal degeneration by 14 wk; ONL reduced to a single photoreceptor row; thin/disorganized OPL; RPE depigmentation; attenuated vessels; both rod & cone ERG compromised	PMID: 15277503
Sema4A F350C knock-in	Patient-allele knock-in	Reproduces retinal degeneration; protein mislocalization; impaired endosomal sorting	PMID: 23360997
Sema4A D345H knock-in	Patient-allele knock-in	No retinal degeneration (allele-specific)	PMID: 23360997
Sema4A R713Q knock-in	Patient-allele knock-in	No retinal degeneration	PMID: 23360997

In vitro / cellular. RPE cell systems (e.g., ARPE-19) were used to define the Rab11/FIP2 endosomal-sorting function and prosaposin/retinoid-sorting switch, and to show PACAP-induced SEMA4A up-regulation (PMID: 22465952; PMID: 25515530). Patient-derived iPSC-RPE is an emerging platform (demonstrated for other IRD genes, e.g., RLBP1; PMID: 39385467).

Phenotype recapitulation. The mouse models recapitulate the core human disease — progressive degeneration of both cone and rod photoreceptors with RPE involvement — and critically demonstrate allele specificity (only F350C, not D345H or R713Q, caused degeneration in mice), a caveat for interpreting human genotype-phenotype correlations.

Applications. These models established the loss-of-function mechanism (RPE endosomal sorting), enabled structural modeling of the pathogenic residue, and provided proof-of-concept gene-therapy rescue (AAV Sema4A), directly informing therapeutic strategy.

Limitations. Mouse retinas lack a macula/fovea (the cone-rich region central to human CRD), so the central-vision aspects of CORD10 are not modeled. Allele discordance (D345H pathogenic in humans but not in the mouse knock-in) highlights species/genetic-background differences.

Resources: MGI (Sema4a), IMPC/IMSR for alleles; Cellosaurus/ATCC for ARPE-19.

Mechanistic Model / Interpretation

CORD10 is best understood as a non-cell-autonomous, trafficking-based loss-of-function retinopathy: the gene defect acts in the RPE, but the cells that die are the photoreceptors the RPE is supposed to sustain. SEMA4A is a molecular "switch operator" on the RPE's Rab11/FIP2 recycling-endosome platform, toggling cargo between two survival-critical destinations depending on cellular stress — exosomal prosaposin secretion (anti-apoptotic, under oxidative/light stress) versus retinoid-protein sorting for 11-cis-retinal regeneration (visual cycle, at baseline). A Sema-domain missense mutation misfolds and mislocalizes the protein, disabling the switch. The retina thus suffers a double hit: chronic chromophore shortfall plus loss of stress-protection, converging on photoreceptor apoptosis. Cones, concentrated in the metabolically demanding central macula, decompensate first, giving the cone-rod clinical sequence.

The therapeutic corollary is clean: because the defect is loss of function and the pathway is restorable, replacing functional SEMA4A rescues the phenotype — proven in two independent mouse genotypes. This makes CORD10 a strong candidate for AAV gene augmentation, with CRISPR editing reserved for any dominant allele.

Evidence Base

PMID	Study (abbrev.)	Role in this report
16199541	Novel SEMA4A mutations in retinal degeneration	*Establishes SEMA4A* as causal gene**; identifies p.D345H, p.F350C in Sema domain
23360997	Point mutation in Semaphorin 4A; defective endosomal sorting	Mechanism + gene-therapy rescue; F350C mislocalization; allele specificity
22465952	Endosomal sorting by Sema4A in RPE supports photoreceptor survival	Defines RPE Rab11/FIP2 sorting, prosaposin switch, 11-cis-retinal regeneration
15277503	Severe retinal degeneration with disruption of Sema4A	Knockout phenotype; rod+cone compromise; retinal histology
21595947	Neuroimmune semaphorins 4A and 4D	SEMA4A receptor network (Tim-2, CD72, PlexinB1/D1); pleiotropy
25515530	Up-regulation of SEMA4A in RPE by PACAP	SEMA4A expression/regulation in human RPE
42264060	CRISPR strategies for cone-rod dystrophy and achromatopsia	Therapeutic landscape; editing for dominant alleles
36011402	IRD in Southeastern US	Epidemiology: CRD ~8% of IRDs
35551639	North African IRD/ION families	Consanguinity (76.1%) and founder effects
29555955	251 macular/cone-rod dystrophy patients	SEMA4A as candidate genotype-phenotype correlation
41769936	AAV RdCVF/RdCVFL for RP	Gene-independent cone-protection strategy (PRODYGY trial)
40114034	Asian IRD diagnostic yield	CRD harder to diagnose (heterogeneous)
33706576; 42343915; 9663233	KCNV2 CDSRR; ACBD5; Alström	Differential diagnosis

Evidence-type summary: Human clinical/genetic (16199541, 29555955, epidemiology papers); model organism (23360997, 15277503); in vitro/cellular (22465952, 25515530); computational/structural modeling (23360997). The causal gene, mechanism, and gene-therapy rescue are supported by direct, convergent human-genetic + model-organism + cell-biology evidence.

Limitations and Knowledge Gaps

Small human evidence base. SEMA4A CORD10 rests largely on the original family report plus candidate findings; there is no large CORD10 patient cohort, so penetrance, expressivity, natural-history rate, and per-phenotype frequencies are not precisely quantified.
Allele discordance. p.D345H is pathogenic in humans but did not cause degeneration in the mouse knock-in, while F350C did — leaving uncertainty about the pathogenic mechanism of non-F350C alleles and about human-mouse translatability.
Inheritance ambiguity. Both dominant and recessive reports exist; the dose-dependence and dominant-vs-recessive behavior of specific alleles are not fully resolved, which directly affects therapeutic choice (augmentation vs editing).
No CORD10-specific omics. No transcriptomic/proteomic/metabolomic/single-cell datasets specific to CORD10 patients were identified.
No CORD10-specific clinical imaging/ERG series or QoL data — phenotype characteristics are extrapolated from the CRD class and mouse data.
Therapeutics are preclinical. Gene-augmentation rescue is mouse-only; no human trial for SEMA4A.

Proposed Follow-up Experiments / Actions

Variant functional classification. Systematically test each reported SEMA4A allele (D345H, F350C, R713Q, and any new variants) in human iPSC-RPE for trafficking/localization and prosaposin/retinoid-sorting phenotypes to resolve dominant-vs-recessive and loss-vs-dominant-negative behavior — the key branch point for therapy selection.
Patient registry & natural-history study. Aggregate SEMA4A cases via GeneMatcher/IRD consortia to quantify onset, progression rate, penetrance, expressivity, and genotype-phenotype correlation with longitudinal OCT/ERG.
AAV-SEMA4A dose-ranging & window study. Define the therapeutic time window and vector/promoter (RPE-specific) for augmentation in F350C knock-in mice, as IND-enabling work toward a first-in-human trial.
CRISPR allele-ablation proof-of-concept for any confirmed dominant SEMA4A allele, benchmarking editing efficiency and off-target profile.
Mechanistic completion. Directly test, in RPE models and in vivo, whether prosaposin supplementation or antioxidant/photoprotective interventions slow degeneration — validating the oxidative-stress branch as a druggable, mutation-agnostic target.
Structural biology. Solve/model the SEMA4A Sema-domain structure with pathogenic residues to explain allele-specific severity and guide variant interpretation.

Report compiled from 9 confirmed findings and 22 reviewed papers over a 5-iteration autonomous investigation. Primary evidence anchors: PMID 16199541 (causal gene), PMID 23360997 (mechanism + rescue), PMID 22465952 (RPE sorting pathway), PMID 15277503 (knockout phenotype).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	16
Resolved	16
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	2
Quoted claims found in source	2
Quoted claims not found in source	0
References weighed for topical relevance	16
On topic	11
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	37
Resolved	35
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	20
Terms named correctly	11
Terms named as a different term	7
Terms whose name is worth a second look	2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0012464 (2 mentions) - the report calls it "MONDO"; MONDO calls it cone-rod dystrophy 10
HP:0000613 (1 mention) - the report calls it "Symptom"; HP calls it Photophobia
HP:0000551 (1 mention) - the report calls it "Symptom/sign"; HP calls it Color vision defect
HP:0000662 (1 mention) - the report calls it "Symptom"; HP calls it Nyctalopia
HP:0000512 (2 mentions) - the report calls it "Lab/functional"; HP calls it Abnormal electroretinogram
HP:0007843 (1 mention) - the report calls it "Sign"; HP calls it Attenuation of retinal blood vessels
UBERON:0002423 (1 mention) - the report calls it "macula"; UBERON calls it hepatobiliary system

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

CL:0000573 (2 mentions) - the report calls it "cone photoreceptors"; CL calls it retinal cone cell, and lists "cone" among its other names
CL:0000604 (2 mentions) - the report calls it "rod photoreceptors"; CL calls it retinal rod cell, and lists "rod" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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OpenScientist Report

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Cone-rod dystrophy 10 (CORD10; MONDO:0012464): research report

Scope and caveats

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species and natural disease

15. Model organisms

Suggested KB handling

Sources

Reference Validation

Term Validation

Terms the report names something else

Cone-Rod Dystrophy 10 (CORD10): Comprehensive Disease Characterization Report

Summary

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

Causal-chain diagram

Detail by category

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Prefixes with no resolver