RAB28-Related Retinopathy

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Mappings

MONDO

MONDO:0014153 cone-rod dystrophy 18 Not Yet Curated

Cone-rod dystrophy 18 is the only MONDO descendant of RAB28-related retinopathy and is the same RAB28 cone-rod dystrophy phenotype; this entry covers it, so it is recorded as a synonym rather than a separate subtype.

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Affected individuals are homozygous or compound heterozygous for RAB28 variants, often in consanguineous families; one proband carried a paternal missense variant in trans with a de novo deletion of the other allele.

Autosomal recessive inheritance

Show evidence (3 references)

CGGV:assertion_e8e3c7bd-3ee5-404d-98b0-75af6ec257d1-2021-11-04T160000.000Z SUPPORT Other

ClinGen records autosomal recessive inheritance.

PMID:23746546 SUPPORT Human clinical

"in RAB28 in a German family with three siblings with arCRD"

Homozygous null allele in the gene discovery family.

PMID:42231409 SUPPORT Human clinical

"Although extremely rare, bi-allelic RAB28 pathogenic variants can result from one inherited allele and a de novo deletion in the other."

Biallelic disease via an inherited variant and a de novo deletion.

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Pathophysiology

4

RAB28 Loss of Function

Nonsense, frameshift and splice variants truncate all three RAB28 isoforms, and missense variants such as p.Thr26Asn and p.Gly19Arg impair nucleotide binding or ciliary targeting of this farnesylated GTPase, which sits at the photoreceptor basal body and ciliary rootlet.

RAB28 hgnc:9768

Genetic context RAB28 hgnc:9768 variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

GTPase activity GO:0003924 ↓ DECREASED

photoreceptor ciliary basal body GO:0036064

Downstream

Defective Cone Outer Segment Shedding and Phagocytosis Without RAB28, cone outer segment tips are not shed and taken up by the RPE.

Show evidence (3 references)

PMID:23746546 SUPPORT Model organism

"Staining of rat retina showed localization of RAB28 to the basal body and the ciliary rootlet of the photoreceptors."

Places RAB28 at the photoreceptor basal body in rat retina.

PMID:23746546 SUPPORT Human clinical

"Alternative RNA splicing yields three predicted protein isoforms with alternative C-termini, which are all truncated by the nonsense mutations identified in the arCRD families in this report."

The founding null alleles truncate every isoform.

PMID:33396523 SUPPORT Computational

"The impaired GTP-GDP exchange ultimately locks Rab-28 in a GDP-bound inactive state."

Molecular dynamics of the p.Thr26Asn missense variant.

Defective Cone Outer Segment Shedding and Phagocytosis

Cone outer segments in Rab28 knockout mice extend to the RPE apical processes and form enlarged balloon-like tips, and cone phagosomes in the RPE are almost absent while rod phagosomes are normal. Zebrafish knockouts show a 40-50% reduction in shed outer segment material and lose the dawn and dusk peaks of outer segment phagocytosis.

retinal cone cell CL:0000573 retinal pigment epithelial cell CL:0002586

phagocytosis of cone outer segments by the RPE GO:0006909 ↓ DECREASED

Animal models

Rab28 knockout mouse Mouse recapitulates Cone phagosomes almost absent, with ballooned unshed cone outer segment tips.

rab28 knockout zebrafish Zebrafish recapitulates Reduced shed outer segment material and phagosomes in the RPE.

Downstream

Visual Cycle Retinoid Depletion Phagocytosed outer segments feed retinoid recycling, which falls when Rab28 is absent.

Progressive Cone-Then-Rod Photoreceptor Degeneration In the mouse, cones with unshed, ballooned outer segment tips degenerate, followed by rods.

Show evidence (2 references)

PMID:30228185 SUPPORT Model organism

"Cone phagosomes were almost absent in Rab28-/- mice, whereas rod phagosomes displayed normal levels."

Cone-specific phagocytosis defect in the knockout mouse.

PMID:35471581 SUPPORT Model organism

"Here, we demonstrate that Rab28 is also required for dusk peaks of OSP, but not for basal OSP levels."

Rab28 is required for the circadian peaks of phagocytosis in zebrafish.

Visual Cycle Retinoid Depletion

Retinae of larval and adult rab28 knockout zebrafish have reduced 11-cis-retinal, 11-cis-retinyl palmitate and all-trans-retinyl palmitate. This is shown only in zebrafish, which do not degenerate, so its contribution to human photoreceptor loss is not established.

retinoid metabolic process GO:0001523 ↓ DECREASED

Show evidence (1 reference)

PMID:35471581 SUPPORT Model organism

"Rab28 loss also perturbs function of the visual cycle as retinoid levels of 11-cRAL, 11cRP, and atRP are significantly reduced in larval and adult rab28 KO retinae"

Retinoid measurements in the zebrafish knockout.

Progressive Cone-Then-Rod Photoreceptor Degeneration

Cones degenerate first and rods later, giving the cone-rod pattern of reduced or extinguished photopic and reduced scotopic electroretinogram responses, macular atrophy and RPE atrophy seen in patients.

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

photoreceptor cell maintenance GO:0045494 ↓ DECREASED

macula lutea UBERON:0000053

Animal models

Rab28 knockout mouse Mouse recapitulates Reduced cone and rod ERG responses and progressive retinal degeneration.

rab28 knockout zebrafish Zebrafish fails to recapitulate No retinal degeneration up to 12 months post fertilization.

Downstream

Cone-rod dystrophy

Reduced visual acuity

Undetectable light-adapted electroretinogram

Dyschromatopsia

Photophobia

Macular atrophy

Retinal pigment epithelial atrophy

Macular hyperpigmentation

Bull's eye maculopathy

Central outer retinal thinning on OCT

Show evidence (2 references)

PMID:30228185 SUPPORT Model organism

"We found that Rab28-/- mice recapitulate features of the human dystrophy (i.e. they exhibited reduced cone and rod ERG responses and progressive retina degeneration)."

Progressive degeneration in the knockout mouse.

PMID:32258030 REFUTE Model organism

"significantly reduced shed outer segment material/phagosomes in the RPE at 1 month post fertilization (mpf), but otherwise normal visual function up to 21 dpf and retinal structure up to 12 mpf"

In zebrafish the shedding defect does not lead to degeneration within 12 months.

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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

11

Cone-rod dystrophy VERY_FREQUENT Ophthalmological HP:0000548

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:33396523 SUPPORT Human clinical

"Analysis of clinical features of patients were compatible with the diagnosis of cone-rod dystrophy."

Diagnosis in all five Italian patients.

Reduced visual acuity VERY_FREQUENT Ophthalmological HP:0007663

Course: PROGRESSIVE

Show evidence (2 references)

PMID:23746546 SUPPORT Human clinical

"All five affected individuals presented with hyperpigmentation in the macula, progressive loss of the visual acuity, atrophy of the retinal pigment epithelium, and severely reduced cone and rod responses on the electroretinogram."

Progressive acuity loss in all founding patients.

PMID:33396523 SUPPORT Human clinical

"All patients reported a poor vision acuity usually from childhood, photophobia, and color vision impairment."

Childhood onset of poor acuity.

Undetectable light-adapted electroretinogram VERY_FREQUENT Ophthalmological HP:0030465

Show evidence (2 references)

PMID:33396523 SUPPORT Human clinical

"Flash electroretinogram (ERG) recording showed a non-detectable response for the photopic component and a reduced response for the scotopic component."

ERG findings in the Italian series.

PMID:42231409 SUPPORT Human clinical

"Full-field ERG revealed severely diminished cone responses, while rod responses were mildly reduced."

Cone-predominant ERG loss in a further proband.

Dyschromatopsia VERY_FREQUENT Ophthalmological HP:0007641

Show evidence (1 reference)

PMID:25356532 SUPPORT Human clinical

"Ophthalmologic findings included markedly reduced visual acuity, bull's eye maculopathy, foveal hyperpigmentation, peripapillary atrophy, dyschromatopsia, extinguished photopic responses, and reduced scotopic responses"

Dyschromatopsia in the Spanish probands.

Photophobia FREQUENT Ophthalmological HP:0000613

Show evidence (1 reference)

PMID:33396523 SUPPORT Human clinical

"All probands displayed similar clinical phenotype consisting of photophobia, decreased visual acuity, central outer retinal thinning, and impaired color vision."

Photophobia in all Italian probands.

Macular hyperpigmentation FREQUENT Ophthalmological HP:0011509

Show evidence (1 reference)

PMID:23746546 SUPPORT Human clinical

"All five affected individuals presented with hyperpigmentation in the macula"

Macular hyperpigmentation in all founding patients.

Retinal pigment epithelial atrophy FREQUENT Ophthalmological HP:0007722

Show evidence (1 reference)

PMID:23746546 SUPPORT Human clinical

"progressive loss of the visual acuity, atrophy of the retinal pigment epithelium, and severely reduced cone and rod responses on the electroretinogram"

RPE atrophy in the founding patients.

Macular atrophy Ophthalmological HP:0007401

Show evidence (1 reference)

PMID:42231409 SUPPORT Human clinical

"The patient exhibited significantly reduced visual acuity, severe color vision impairment, macular atrophy, and thinning of the photoreceptor layers."

Macular atrophy with photoreceptor-layer thinning.

Bull's eye maculopathy OCCASIONAL Ophthalmological HP:0011504

Show evidence (1 reference)

PMID:25356532 SUPPORT Human clinical

"Ophthalmologic findings included markedly reduced visual acuity, bull's eye maculopathy, foveal hyperpigmentation"

Bull's eye maculopathy in the Spanish probands.

Central outer retinal thinning on OCT VERY_FREQUENT Ophthalmological HP:0030329

Show evidence (2 references)

PMID:33396523 SUPPORT Human clinical

"All probands displayed similar clinical phenotype consisting of photophobia, decreased visual acuity, central outer retinal thinning, and impaired color vision."

Central outer retinal thinning in every Italian proband.

PMID:42231409 SUPPORT Human clinical

"The patient exhibited significantly reduced visual acuity, severe color vision impairment, macular atrophy, and thinning of the photoreceptor layers."

Photoreceptor-layer thinning in a further proband.

Myopia FREQUENT Ophthalmological HP:0000545

Show evidence (2 references)

PMID:33396523 SUPPORT Human clinical

"All patients showed a myopic defect"

Myopia in the Italian series.

PMID:32084271 SUPPORT Human clinical

"Two brothers of a consanguineous couple presented with CRD, postaxial polydactyly (PAP), and myopia."

Myopia in both brothers.

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Genetic Associations

1

RAB28 (Biallelic loss-of-function variants)

Gene: RAB28 hgnc:9768 relationship_type: CAUSATIVE

Show evidence (2 references)

CGGV:assertion_e8e3c7bd-3ee5-404d-98b0-75af6ec257d1-2021-11-04T160000.000Z SUPPORT Other

"The mechanism of pathogenicity appears to be loss of function."

ClinGen expert panel summary of the disease mechanism.

PMID:33396523 SUPPORT Human clinical

"Our data suggest that the nonsense and frame shift homozygous variants lead to CORD due to complete loss of function, whereas the missense variant in heterozygous compound state results in a partial loss-of-function due to impaired Mg2+ and GTP binding."

Null alleles and a hypomorphic missense allele in the largest series.

Variants (7)

c.565C>T (p.Glu189Ter)

Homozygous nonsense variant in a German family with three affected siblings.

Show evidence (1 reference)

PMID:23746546 SUPPORT Human clinical

"A combined approach of homozygosity mapping and exome sequencing revealed a homozygous nonsense mutation (c.565C>T"

Reports the variant.

c.409C>T (p.Arg137Ter)

Homozygous nonsense variant in a Moroccan Jewish family; also found in an Italian proband in trans with p.Thr26Asn.

Show evidence (2 references)

PMID:23746546 SUPPORT Human clinical

"was identified in a family of Moroccan Jewish descent with two siblings affected by arCRD"

Reports the variant in the Moroccan Jewish family. The abstract's bracketed variant name cannot be quoted because the validator drops square-bracketed text, so the next item names it.

PMID:33396523 SUPPORT Human clinical

"The loss-of-function mutation p.(Thr26Asn) was present in a compound heterozygosis with the nonsense variant p.(Arg137*), which does not cause mRNA-mediated decay"

Names p.(Arg137*) and its recurrence in an Italian proband.

p.Thr26Asn

Missense variant found in an Italian proband in trans with p.Arg137Ter; molecular dynamics simulation predicts impaired Mg2+ and GTP binding that locks RAB28 in its inactive GDP-bound state.

Show evidence (2 references)

PMID:33396523 SUPPORT Human clinical

"The loss-of-function mutation p.(Thr26Asn) was present in a compound heterozygosis with the nonsense variant p.(Arg137*)"

Reports the variant and its compound heterozygous state.

PMID:33396523 SUPPORT Computational

"Exhaustive molecular dynamics simulations of the missense variant p.(Thr26Asn) in both its active and inactive states revealed an allosteric structural mechanism that impairs the binding of Mg2+, thus decreasing the affinity for GTP."

In silico mechanism for the hypomorphic effect.

c.172+1G>C

Homozygous splice donor variant in a Spanish proband.

Show evidence (1 reference)

PMID:25356532 SUPPORT Human clinical

"whole-exome sequencing analysis identified 2 new homozygous mutations in the recently described RAB28 gene, the c.172 + 1G>C splice site variant in IVS2 and the missense c.T651G:p.C217W substitution"

Reports the splice and missense variants.

c.651T>G (p.Cys217Trp)

Homozygous missense variant in a second Spanish proband.

Show evidence (1 reference)

PMID:25356532 SUPPORT Human clinical

"Both variants were determined as deleterious by predictive programs and were segregated with the disease in both families."

Segregation of the missense variant with disease.

c.55G>A (p.Gly19Arg)

Homozygous missense variant in the G1 box of the nucleotide-binding domain in two brothers; it reduces RAB28 at the primary cilium in patient fibroblasts.

Show evidence (1 reference)

PMID:32084271 SUPPORT In vitro / ex vivo

"This missense variant caused a considerable reduction of RAB28 localized to the cilia, whereas ciliogenesis seemed unaffected."

Functional effect of the variant in patient fibroblasts.

c.68C>T (p.Ser23Phe)

Missense variant first reported homozygous in a Korean patient; in a Chinese proband it was paternal and in trans with a de novo 3.4 Mb 4p16.1p15.33 deletion that removes RAB28.

Show evidence (1 reference)

PMID:42231409 SUPPORT Human clinical

"Genetic analysis identified that the heterozygous RAB28 c.68 C > T/p.(Ser23Phe) pathogenic variant was inherited exclusively from the father. Additionally, a 3.4 Mb deletion on chromosome 4p16.1p15.33 was detected only in the proband."

Reports the variant and the deletion of the other allele.

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Medical Actions

1

RAB28 Gene Replacement (Preclinical)

Action: Gene Therapy NCIT:C15238

Platform: Gene therapy

No treatment is approved or in trials. Cone-specific transgenic re-expression of Rab28 rescues the outer segment phagocytosis defect in rab28 knockout zebrafish, which suggests gene replacement to cones as a strategy.

Show evidence (1 reference)

PMID:35471581 SUPPORT Model organism

"Notably, transgenic overexpression of Rab28, solely in zebrafish cones, rescues the OSP defect in rab28 KO fish, suggesting rab28 gene replacement in cone photoreceptors is sufficient to regulate Rab28-OSP."

Proof of concept in zebrafish only.

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Diagnosis

2

Molecular genetic testing

Diagnosis is confirmed by finding biallelic RAB28 variants by exome or panel sequencing. Exon-level sequencing can miss a deletion of the second allele, which chromosomal microarray found in one proband, and homozygosity of the 4p interval can instead reflect a deep intronic PROM1 variant that exon-focused tests miss (PMID:26153215), so a single RAB28 variant or an unexplained 4p homozygous interval warrants copy-number and genome-level analysis.

Show evidence (2 references)

PMID:42231409 SUPPORT Human clinical

"Singleton clinical exome sequencing (CES), followed by chromosomal microarray (CMA), enabled the identification of a heterozygous RAB28 pathogenic variant inherited from the father"

Exome sequencing plus microarray resolved a case with one sequence variant and a deletion.

PMID:26153215 SUPPORT Human clinical

"We identified a homozygous interval comprising two known genes associated with the autosomal recessive form of CRD, namely RAB28 and PROM1, in a consanguineous family with clinical evidence of CRD."

Diagnostic caveat only: the family's disease was due to PROM1, not RAB28, so homozygosity at this interval does not by itself implicate RAB28.

Full-field electroretinography

Full-field ERG shows undetectable or severely reduced photopic (cone) responses with milder reduction of scotopic (rod) responses, the cone-rod pattern.

Show evidence (2 references)

PMID:33396523 SUPPORT Human clinical

"Flash electroretinogram (ERG) recording showed a non-detectable response for the photopic component and a reduced response for the scotopic component."

ERG pattern in the Italian series.

PMID:42231409 SUPPORT Human clinical

"Full-field ERG revealed severely diminished cone responses, while rod responses were mildly reduced."

Cone-predominant ERG loss in a further proband.

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Animal Models

2

Rab28 knockout mouse

Species

Mouse

Genotype

Rab28-/- (exon 3 deletion)

Publication

PMID:30228185

Pathograph links

Defective Cone Outer Segment Shedding and Phagocytosis recapitulates fidelity: high observes: cellular Cone phagosomes almost absent, with ballooned unshed cone outer segment tips.

Show evidence (1 reference)

PMID:30228185 SUPPORT Model organism

"Cone phagosomes were almost absent in Rab28-/- mice, whereas rod phagosomes displayed normal levels."

Cone-specific phagocytosis defect.

Progressive Cone-Then-Rod Photoreceptor Degeneration recapitulates fidelity: moderate observes: organism Reduced cone and rod ERG responses and progressive retinal degeneration.

Limitations: The mouse retina has no macula, so the macular hyperpigmentation and atrophy of patients cannot be modeled.

Show evidence (1 reference)

PMID:30228185 SUPPORT Model organism

"We found that Rab28-/- mice recapitulate features of the human dystrophy (i.e. they exhibited reduced cone and rod ERG responses and progressive retina degeneration)."

Degeneration and ERG loss in the knockout.

rab28 knockout zebrafish

Species

Zebrafish

Genotype

CRISPR-Cas9 rab28 null

Publication

PMID:32258030

Pathograph links

Defective Cone Outer Segment Shedding and Phagocytosis recapitulates fidelity: moderate observes: cellular Reduced shed outer segment material and phagosomes in the RPE.

Show evidence (1 reference)

PMID:32258030 SUPPORT Model organism

"Significantly, rab28 null zebrafish display a 40–50% reduction in OS shedding as early as 15 days post fertilization (dpf), but without evidence of retinal degeneration up to 12 mpf."

Shedding defect in the zebrafish knockout.

Progressive Cone-Then-Rod Photoreceptor Degeneration fails to recapitulate fidelity: low observes: organism No retinal degeneration up to 12 months post fertilization.

Limitations: The fish were followed for only 12 months, so the absence of degeneration may reflect species differences in disease tempo rather than a dispensable step; the authors do not resolve this.

Show evidence (1 reference)

PMID:32258030 SUPPORT Model organism

"significantly reduced shed outer segment material/phagosomes in the RPE at 1 month post fertilization (mpf), but otherwise normal visual function up to 21 dpf and retinal structure up to 12 mpf"

Normal retinal structure despite the shedding defect.

{ }

Source YAML

click to show

name: RAB28-Related Retinopathy
description: >-
  Autosomal recessive cone-rod dystrophy (cone-rod dystrophy 18, CORD18) caused by biallelic loss-of-function variants in
  RAB28, which encodes a farnesylated Rab-family small GTPase found at the photoreceptor basal body and ciliary rootlet and
  in cone outer segments. Patients have poor visual acuity from childhood, photophobia, impaired color vision, macular
  hyperpigmentation and outer retinal or RPE atrophy, with severely reduced or undetectable cone responses and milder
  loss of rod responses on the electroretinogram. In Rab28 knockout mice cones fail to shed their outer segment tips,
  RPE phagocytosis of cone outer segments is almost absent, and cones and then rods degenerate. Zebrafish rab28
  knockouts show reduced outer segment shedding and reduced retinoid levels without retinal degeneration.
category: Mendelian
disease_term:
  preferred_term: RAB28-related retinopathy
  term:
    id: MONDO:0100448
    label: RAB28-related retinopathy
synonyms:
- Cone-rod dystrophy 18
- CORD18
- RAB28-related cone-rod dystrophy
creation_date: "2026-11-09T16:51:16Z"
parents:
- Cone-Rod Dystrophy
- Inherited Retinal Dystrophy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0014153
      label: cone-rod dystrophy 18
    mapping_predicate: skos:narrowMatch
    mapping_source: manual curation
    mapping_justification: >-
      Cone-rod dystrophy 18 is the only MONDO descendant of RAB28-related retinopathy and is the same RAB28 cone-rod
      dystrophy phenotype; this entry covers it, so it is recorded as a synonym rather than a separate subtype.
notes: >-
  The human literature is small: two families in the gene discovery report (PMID:23746546), two Spanish families
  (PMID:25356532), a Korean patient (PMID:28388261, whose PubMed record had no abstract on fetch, so it is not cited as
  evidence), two Danish brothers (PMID:32084271), four Italian families (PMID:33396523) and a Chinese proband whose second
  allele is a de novo 4p deletion (PMID:42231409). No prevalence estimate exists. The two brothers in PMID:32084271 also
  had postaxial polydactyly, but the authors state that more data are needed before attributing it to RAB28, so it is
  not recorded as a phenotype. RAB28 and PROM1 lie in the same 4p interval, and one family with homozygosity there had
  a deep intronic PROM1 variant instead (PMID:26153215). No disease-specific treatment exists; cone-specific Rab28
  re-expression rescues outer segment phagocytosis in zebrafish (PMID:35471581). The deep-research report printed the
  RAB28 identifier as HGNC:9764, which is RAB22A; the binding here (hgnc:9768) comes from the ClinGen record.
  Myopia is not linked to a mechanism node because no source explains it. No GeneReviews chapter covers RAB28 or
  CORD18 (just check-genereviews against the committed Bookshelf index returned NO_CHAPTER). A Rab28/BBSome role in
  restraining ciliary extracellular vesicle shedding (PMID:32101165) was considered and left out, because it is shown
  only in C. elegans sensory neurons and its link to photoreceptor outer segments is untested.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals are homozygous or compound heterozygous for RAB28 variants, often in consanguineous families;
    one proband carried a paternal missense variant in trans with a de novo deletion of the other allele.
  evidence:
  - reference: CGGV:assertion_e8e3c7bd-3ee5-404d-98b0-75af6ec257d1-2021-11-04T160000.000Z
    reference_title: RAB28 / RAB28-related retinopathy (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RAB28 | HGNC:9768 | RAB28-related retinopathy | MONDO:0100448 | AR | Definitive"
    explanation: ClinGen records autosomal recessive inheritance.
  - reference: PMID:23746546
    reference_title: "Mutations in RAB28, encoding a farnesylated small GTPase, are associated with autosomal-recessive cone-rod dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in RAB28 in a German family with three siblings with arCRD
    explanation: Homozygous null allele in the gene discovery family.
  - reference: PMID:42231409
    reference_title: Sporadic cone-rod dystrophy caused by a heterozygous RAB28 p.Ser23Phe pathogenic variant and a de novo 4p16.1p15.33 deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although extremely rare, bi-allelic RAB28 pathogenic variants can result from one inherited allele and a de novo
      deletion in the other.
    explanation: Biallelic disease via an inherited variant and a de novo deletion.
genetic:
- name: RAB28
  association: Biallelic loss-of-function variants
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: RAB28
    term:
      id: hgnc:9768
      label: RAB28
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_e8e3c7bd-3ee5-404d-98b0-75af6ec257d1-2021-11-04T160000.000Z
    evidence:
    - reference: CGGV:assertion_e8e3c7bd-3ee5-404d-98b0-75af6ec257d1-2021-11-04T160000.000Z
      reference_title: RAB28 / RAB28-related retinopathy (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "RAB28 | HGNC:9768 | RAB28-related retinopathy | MONDO:0100448 | AR | Definitive"
      explanation: >-
        The ClinGen Retina Gene Curation Expert Panel classifies the autosomal recessive relationship as Definitive (SOP8,
        2021-11-04).
  evidence:
  - reference: CGGV:assertion_e8e3c7bd-3ee5-404d-98b0-75af6ec257d1-2021-11-04T160000.000Z
    reference_title: RAB28 / RAB28-related retinopathy (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The mechanism of pathogenicity appears to be loss of function.
    explanation: ClinGen expert panel summary of the disease mechanism.
  - reference: PMID:33396523
    reference_title: "Expanding the Clinical and Genetic Spectrum of RAB28-Related Cone-Rod Dystrophy: Pathogenicity of Novel Variants in Italian Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data suggest that the nonsense and frame shift homozygous variants lead to CORD due to complete loss of function,
      whereas the missense variant in heterozygous compound state results in a partial loss-of-function due to impaired
      Mg2+ and GTP binding.
    explanation: Null alleles and a hypomorphic missense allele in the largest series.
  variants:
  - name: c.565C>T (p.Glu189Ter)
    description: Homozygous nonsense variant in a German family with three affected siblings.
    evidence:
    - reference: PMID:23746546
      reference_title: "Mutations in RAB28, encoding a farnesylated small GTPase, are associated with autosomal-recessive cone-rod dystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A combined approach of homozygosity mapping and exome sequencing revealed a homozygous nonsense mutation (c.565C>T
      explanation: Reports the variant.
  - name: c.409C>T (p.Arg137Ter)
    description: >-
      Homozygous nonsense variant in a Moroccan Jewish family; also found in an Italian proband in trans with p.Thr26Asn.
    evidence:
    - reference: PMID:23746546
      reference_title: "Mutations in RAB28, encoding a farnesylated small GTPase, are associated with autosomal-recessive cone-rod dystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        was identified in a family of Moroccan Jewish descent with two siblings affected by arCRD
      explanation: >-
        Reports the variant in the Moroccan Jewish family. The abstract's bracketed variant name cannot be quoted because
        the validator drops square-bracketed text, so the next item names it.
    - reference: PMID:33396523
      reference_title: "Expanding the Clinical and Genetic Spectrum of RAB28-Related Cone-Rod Dystrophy: Pathogenicity of Novel Variants in Italian Families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The loss-of-function mutation p.(Thr26Asn) was present in a compound heterozygosis with the nonsense variant
        p.(Arg137*), which does not cause mRNA-mediated decay
      explanation: Names p.(Arg137*) and its recurrence in an Italian proband.
  - name: p.Thr26Asn
    description: >-
      Missense variant found in an Italian proband in trans with p.Arg137Ter; molecular dynamics simulation predicts
      impaired Mg2+ and GTP binding that locks RAB28 in its inactive GDP-bound state.
    evidence:
    - reference: PMID:33396523
      reference_title: "Expanding the Clinical and Genetic Spectrum of RAB28-Related Cone-Rod Dystrophy: Pathogenicity of Novel Variants in Italian Families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The loss-of-function mutation p.(Thr26Asn) was present in a compound heterozygosis with the nonsense variant
        p.(Arg137*)
      explanation: Reports the variant and its compound heterozygous state.
    - reference: PMID:33396523
      reference_title: "Expanding the Clinical and Genetic Spectrum of RAB28-Related Cone-Rod Dystrophy: Pathogenicity of Novel Variants in Italian Families."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Exhaustive molecular dynamics simulations of the missense variant p.(Thr26Asn) in both its active and inactive
        states revealed an allosteric structural mechanism that impairs the binding of Mg2+, thus decreasing the affinity
        for GTP.
      explanation: In silico mechanism for the hypomorphic effect.
  - name: c.172+1G>C
    description: Homozygous splice donor variant in a Spanish proband.
    evidence:
    - reference: PMID:25356532
      reference_title: New mutations in the RAB28 gene in 2 Spanish families with cone-rod dystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        whole-exome sequencing analysis identified 2 new homozygous mutations in the recently described RAB28 gene, the c.172
        + 1G>C splice site variant in IVS2 and the missense c.T651G:p.C217W substitution
      explanation: Reports the splice and missense variants.
  - name: c.651T>G (p.Cys217Trp)
    description: Homozygous missense variant in a second Spanish proband.
    evidence:
    - reference: PMID:25356532
      reference_title: New mutations in the RAB28 gene in 2 Spanish families with cone-rod dystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Both variants were determined as deleterious by predictive programs and were segregated with the disease in both families.
      explanation: Segregation of the missense variant with disease.
  - name: c.55G>A (p.Gly19Arg)
    description: >-
      Homozygous missense variant in the G1 box of the nucleotide-binding domain in two brothers; it reduces RAB28 at the
      primary cilium in patient fibroblasts.
    evidence:
    - reference: PMID:32084271
      reference_title: A Missense Mutation in RAB28 in a Family with Cone-Rod Dystrophy and Postaxial Polydactyly Prevents Localization of RAB28 to the Primary Cilium.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This missense variant caused a considerable reduction of RAB28 localized to the cilia, whereas ciliogenesis seemed
        unaffected.
      explanation: Functional effect of the variant in patient fibroblasts.
  - name: c.68C>T (p.Ser23Phe)
    description: >-
      Missense variant first reported homozygous in a Korean patient; in a Chinese proband it was paternal and in trans
      with a de novo 3.4 Mb 4p16.1p15.33 deletion that removes RAB28.
    evidence:
    - reference: PMID:42231409
      reference_title: Sporadic cone-rod dystrophy caused by a heterozygous RAB28 p.Ser23Phe pathogenic variant and a de novo 4p16.1p15.33 deletion.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Genetic analysis identified that the heterozygous RAB28 c.68 C > T/p.(Ser23Phe) pathogenic variant was inherited
        exclusively from the father. Additionally, a 3.4 Mb deletion on chromosome 4p16.1p15.33 was detected only in the
        proband.
      explanation: Reports the variant and the deletion of the other allele.
pathophysiology:
- name: RAB28 Loss of Function
  description: >-
    Nonsense, frameshift and splice variants truncate all three RAB28 isoforms, and missense variants such as p.Thr26Asn
    and p.Gly19Arg impair nucleotide binding or ciliary targeting of this farnesylated GTPase, which sits at the
    photoreceptor basal body and ciliary rootlet.
  biological_scale: MOLECULAR
  genetic_context:
    gene:
      preferred_term: RAB28
      term:
        id: hgnc:9768
        label: RAB28
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  genes:
  - preferred_term: RAB28
    term:
      id: hgnc:9768
      label: RAB28
  molecular_functions:
  - preferred_term: GTPase activity
    modifier: DECREASED
    term:
      id: GO:0003924
      label: GTPase activity
  cellular_components:
  - preferred_term: photoreceptor ciliary basal body
    term:
      id: GO:0036064
      label: ciliary basal body
  evidence:
  - reference: PMID:23746546
    reference_title: "Mutations in RAB28, encoding a farnesylated small GTPase, are associated with autosomal-recessive cone-rod dystrophy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Staining of rat retina showed localization of RAB28 to the basal body and the ciliary rootlet of the photoreceptors.
    explanation: Places RAB28 at the photoreceptor basal body in rat retina.
  - reference: PMID:23746546
    reference_title: "Mutations in RAB28, encoding a farnesylated small GTPase, are associated with autosomal-recessive cone-rod dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Alternative RNA splicing yields three predicted protein isoforms with alternative C-termini, which are all truncated
      by the nonsense mutations identified in the arCRD families in this report.
    explanation: The founding null alleles truncate every isoform.
  - reference: PMID:33396523
    reference_title: "Expanding the Clinical and Genetic Spectrum of RAB28-Related Cone-Rod Dystrophy: Pathogenicity of Novel Variants in Italian Families."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      The impaired GTP-GDP exchange ultimately locks Rab-28 in a GDP-bound inactive state.
    explanation: Molecular dynamics of the p.Thr26Asn missense variant.
  downstream:
  - target: Defective Cone Outer Segment Shedding and Phagocytosis
    description: Without RAB28, cone outer segment tips are not shed and taken up by the RPE.
    evidence:
    - reference: PMID:30228185
      reference_title: The small GTPase RAB28 is required for phagocytosis of cone outer segments by the murine retinal pigmented epithelium.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Taken together, these findings reveal that RAB28 is required for shedding and phagocytosis of cone OS discs.
      explanation: Knockout mouse conclusion.
- name: Defective Cone Outer Segment Shedding and Phagocytosis
  description: >-
    Cone outer segments in Rab28 knockout mice extend to the RPE apical processes and form enlarged balloon-like tips,
    and cone phagosomes in the RPE are almost absent while rod phagosomes are normal. Zebrafish knockouts show a 40-50%
    reduction in shed outer segment material and lose the dawn and dusk peaks of outer segment phagocytosis.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  biological_processes:
  - preferred_term: phagocytosis of cone outer segments by the RPE
    modifier: DECREASED
    term:
      id: GO:0006909
      label: phagocytosis
  evidence:
  - reference: PMID:30228185
    reference_title: The small GTPase RAB28 is required for phagocytosis of cone outer segments by the murine retinal pigmented epithelium.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Cone phagosomes were almost absent in Rab28-/- mice, whereas rod phagosomes displayed normal levels.
    explanation: Cone-specific phagocytosis defect in the knockout mouse.
  - reference: PMID:35471581
    reference_title: "Dawn and dusk peaks of outer segment phagocytosis, and visual cycle function require Rab28."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Here, we demonstrate that Rab28 is also required for dusk peaks of OSP, but not for basal OSP levels.
    explanation: Rab28 is required for the circadian peaks of phagocytosis in zebrafish.
  downstream:
  - target: Visual Cycle Retinoid Depletion
    description: Phagocytosed outer segments feed retinoid recycling, which falls when Rab28 is absent.
    evidence:
    - reference: PMID:35471581
      reference_title: "Dawn and dusk peaks of outer segment phagocytosis, and visual cycle function require Rab28."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These data give further understanding on the molecular mechanisms of RAB28-associated CRD, highlighting roles of
        Rab28 in both peaks of OSP, in vitamin A metabolism and in retinoid recycling.
      explanation: The same study links the phagocytosis and retinoid-recycling defects.
  - target: Progressive Cone-Then-Rod Photoreceptor Degeneration
    description: In the mouse, cones with unshed, ballooned outer segment tips degenerate, followed by rods.
    evidence:
    - reference: PMID:30228185
      reference_title: The small GTPase RAB28 is required for phagocytosis of cone outer segments by the murine retinal pigmented epithelium.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Cones of Rab28-/- mice extended their outer segments (OSs) to the RPE apical processes and formed enlarged,
        balloon-like distal tips before undergoing degeneration.
      explanation: The shedding defect precedes cone degeneration.
- name: Visual Cycle Retinoid Depletion
  description: >-
    Retinae of larval and adult rab28 knockout zebrafish have reduced 11-cis-retinal, 11-cis-retinyl palmitate and
    all-trans-retinyl palmitate. This is shown only in zebrafish, which do not degenerate, so its contribution to human
    photoreceptor loss is not established.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: retinoid metabolic process
    modifier: DECREASED
    term:
      id: GO:0001523
      label: retinoid metabolic process
  evidence:
  - reference: PMID:35471581
    reference_title: "Dawn and dusk peaks of outer segment phagocytosis, and visual cycle function require Rab28."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Rab28 loss also perturbs function of the visual cycle as retinoid levels of 11-cRAL, 11cRP, and atRP are significantly
      reduced in larval and adult rab28 KO retinae
    explanation: Retinoid measurements in the zebrafish knockout.
- name: Progressive Cone-Then-Rod Photoreceptor Degeneration
  description: >-
    Cones degenerate first and rods later, giving the cone-rod pattern of reduced or extinguished photopic and reduced
    scotopic electroretinogram responses, macular atrophy and RPE atrophy seen in patients.
  biological_scale: TISSUE
  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
  locations:
  - preferred_term: macula lutea
    term:
      id: UBERON:0000053
      label: macula lutea
  evidence:
  - reference: PMID:30228185
    reference_title: The small GTPase RAB28 is required for phagocytosis of cone outer segments by the murine retinal pigmented epithelium.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found that Rab28-/- mice recapitulate features of the human dystrophy (i.e. they exhibited reduced cone and rod ERG
      responses and progressive retina degeneration).
    explanation: Progressive degeneration in the knockout mouse.
  - reference: PMID:32258030
    reference_title: "Genetic Deletion of Zebrafish Rab28 Causes Defective Outer Segment Shedding, but Not Retinal Degeneration."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      significantly reduced shed outer segment material/phagosomes in the RPE at 1 month post fertilization (mpf), but
      otherwise normal visual function up to 21 dpf and retinal structure up to 12 mpf
    explanation: In zebrafish the shedding defect does not lead to degeneration within 12 months.
  downstream:
  - target: Cone-rod dystrophy
  - target: Reduced visual acuity
  - target: Undetectable light-adapted electroretinogram
  - target: Dyschromatopsia
  - target: Photophobia
  - target: Macular atrophy
  - target: Retinal pigment epithelial atrophy
  - target: Macular hyperpigmentation
  - target: Bull's eye maculopathy
  - target: Central outer retinal thinning on OCT
phenotypes:
- name: Cone-rod dystrophy
  category: Ophthalmological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Cone-rod dystrophy
    term:
      id: HP:0000548
      label: Cone/cone-rod dystrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:33396523
    reference_title: "Expanding the Clinical and Genetic Spectrum of RAB28-Related Cone-Rod Dystrophy: Pathogenicity of Novel Variants in Italian Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Analysis of clinical features of patients were compatible with the diagnosis of cone-rod dystrophy.
    explanation: Diagnosis in all five Italian patients.
- name: Reduced visual acuity
  category: Ophthalmological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Reduced visual acuity
    term:
      id: HP:0007663
      label: Reduced visual acuity
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:23746546
    reference_title: "Mutations in RAB28, encoding a farnesylated small GTPase, are associated with autosomal-recessive cone-rod dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All five affected individuals presented with hyperpigmentation in the macula, progressive loss of the visual acuity,
      atrophy of the retinal pigment epithelium, and severely reduced cone and rod responses on the electroretinogram.
    explanation: Progressive acuity loss in all founding patients.
  - reference: PMID:33396523
    reference_title: "Expanding the Clinical and Genetic Spectrum of RAB28-Related Cone-Rod Dystrophy: Pathogenicity of Novel Variants in Italian Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All patients reported a poor vision acuity usually from childhood, photophobia, and color vision impairment.
    explanation: Childhood onset of poor acuity.
- name: Undetectable light-adapted electroretinogram
  category: Ophthalmological
  frequency: VERY_FREQUENT
  description: >-
    Photopic responses are non-detectable or severely reduced, and scotopic responses are reduced to a lesser degree.
  phenotype_term:
    preferred_term: Undetectable light-adapted electroretinogram
    term:
      id: HP:0030465
      label: Undetectable light-adapted electroretinogram
  evidence:
  - reference: PMID:33396523
    reference_title: "Expanding the Clinical and Genetic Spectrum of RAB28-Related Cone-Rod Dystrophy: Pathogenicity of Novel Variants in Italian Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Flash electroretinogram (ERG) recording showed a non-detectable response for the photopic component and a reduced
      response for the scotopic component.
    explanation: ERG findings in the Italian series.
  - reference: PMID:42231409
    reference_title: Sporadic cone-rod dystrophy caused by a heterozygous RAB28 p.Ser23Phe pathogenic variant and a de novo 4p16.1p15.33 deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Full-field ERG revealed severely diminished cone responses, while rod responses were mildly reduced.
    explanation: Cone-predominant ERG loss in a further proband.
- name: Dyschromatopsia
  category: Ophthalmological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Dyschromatopsia
    term:
      id: HP:0007641
      label: Dyschromatopsia
  evidence:
  - reference: PMID:25356532
    reference_title: New mutations in the RAB28 gene in 2 Spanish families with cone-rod dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ophthalmologic findings included markedly reduced visual acuity, bull's eye maculopathy, foveal hyperpigmentation,
      peripapillary atrophy, dyschromatopsia, extinguished photopic responses, and reduced scotopic responses
    explanation: Dyschromatopsia in the Spanish probands.
- name: Photophobia
  category: Ophthalmological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Photophobia
    term:
      id: HP:0000613
      label: Photophobia
  evidence:
  - reference: PMID:33396523
    reference_title: "Expanding the Clinical and Genetic Spectrum of RAB28-Related Cone-Rod Dystrophy: Pathogenicity of Novel Variants in Italian Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All probands displayed similar clinical phenotype consisting of photophobia, decreased visual acuity, central outer retinal thinning, and impaired color vision.
    explanation: Photophobia in all Italian probands.
- name: Macular hyperpigmentation
  category: Ophthalmological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Macular hyperpigmentation
    term:
      id: HP:0011509
      label: Macular hyperpigmentation
  evidence:
  - reference: PMID:23746546
    reference_title: "Mutations in RAB28, encoding a farnesylated small GTPase, are associated with autosomal-recessive cone-rod dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All five affected individuals presented with hyperpigmentation in the macula
    explanation: Macular hyperpigmentation in all founding patients.
- name: Retinal pigment epithelial atrophy
  category: Ophthalmological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Retinal pigment epithelial atrophy
    term:
      id: HP:0007722
      label: Retinal pigment epithelial atrophy
  evidence:
  - reference: PMID:23746546
    reference_title: "Mutations in RAB28, encoding a farnesylated small GTPase, are associated with autosomal-recessive cone-rod dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      progressive loss of the visual acuity, atrophy of the retinal pigment epithelium, and severely reduced cone and rod
      responses on the electroretinogram
    explanation: RPE atrophy in the founding patients.
- name: Macular atrophy
  category: Ophthalmological
  phenotype_term:
    preferred_term: Macular atrophy
    term:
      id: HP:0007401
      label: Macular atrophy
  evidence:
  - reference: PMID:42231409
    reference_title: Sporadic cone-rod dystrophy caused by a heterozygous RAB28 p.Ser23Phe pathogenic variant and a de novo 4p16.1p15.33 deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient exhibited significantly reduced visual acuity, severe color vision impairment, macular atrophy, and
      thinning of the photoreceptor layers.
    explanation: Macular atrophy with photoreceptor-layer thinning.
- name: Bull's eye maculopathy
  category: Ophthalmological
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Bull's eye maculopathy
    term:
      id: HP:0011504
      label: Bull's eye maculopathy
  evidence:
  - reference: PMID:25356532
    reference_title: New mutations in the RAB28 gene in 2 Spanish families with cone-rod dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ophthalmologic findings included markedly reduced visual acuity, bull's eye maculopathy, foveal hyperpigmentation
    explanation: Bull's eye maculopathy in the Spanish probands.
- name: Central outer retinal thinning on OCT
  category: Ophthalmological
  frequency: VERY_FREQUENT
  description: >-
    Central (foveal) thinning with photoreceptor layer disruption on OCT, with relative sparing of the paracentral
    retina. Bound to the general OCT retinal-thinning term because the sources describe outer-retinal and
    photoreceptor-layer thinning without isolating the outer nuclear layer that HP:6000367 names.
  phenotype_term:
    preferred_term: Central outer retinal thinning on OCT
    term:
      id: HP:0030329
      label: Retinal thinning on OCT
  evidence:
  - reference: PMID:33396523
    reference_title: "Expanding the Clinical and Genetic Spectrum of RAB28-Related Cone-Rod Dystrophy: Pathogenicity of Novel Variants in Italian Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All probands displayed similar clinical phenotype consisting of photophobia, decreased visual acuity, central outer retinal thinning, and impaired color vision.
    explanation: Central outer retinal thinning in every Italian proband.
  - reference: PMID:42231409
    reference_title: "Sporadic cone-rod dystrophy caused by a heterozygous RAB28 p.Ser23Phe pathogenic variant and a de novo 4p16.1p15.33 deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient exhibited significantly reduced visual acuity, severe color vision impairment, macular atrophy, and
      thinning of the photoreceptor layers.
    explanation: Photoreceptor-layer thinning in a further proband.
- name: Myopia
  category: Ophthalmological
  frequency: FREQUENT
  description: Reported in all five Italian patients (-2 to -9 D) and in both brothers with the p.Gly19Arg variant.
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: PMID:33396523
    reference_title: "Expanding the Clinical and Genetic Spectrum of RAB28-Related Cone-Rod Dystrophy: Pathogenicity of Novel Variants in Italian Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All patients showed a myopic defect
    explanation: Myopia in the Italian series.
  - reference: PMID:32084271
    reference_title: A Missense Mutation in RAB28 in a Family with Cone-Rod Dystrophy and Postaxial Polydactyly Prevents Localization of RAB28 to the Primary Cilium.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Two brothers of a consanguineous couple presented with CRD, postaxial polydactyly (PAP), and myopia.
    explanation: Myopia in both brothers.
diagnosis:
- name: Molecular genetic testing
  description: >-
    Diagnosis is confirmed by finding biallelic RAB28 variants by exome or panel sequencing. Exon-level sequencing can
    miss a deletion of the second allele, which chromosomal microarray found in one proband, and homozygosity of the 4p
    interval can instead reflect a deep intronic PROM1 variant that exon-focused tests miss (PMID:26153215), so a
    single RAB28 variant or an unexplained 4p homozygous interval warrants copy-number and genome-level analysis.
  evidence:
  - reference: PMID:42231409
    reference_title: "Sporadic cone-rod dystrophy caused by a heterozygous RAB28 p.Ser23Phe pathogenic variant and a de novo 4p16.1p15.33 deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Singleton clinical exome sequencing (CES), followed by chromosomal microarray (CMA), enabled the identification of a
      heterozygous RAB28 pathogenic variant inherited from the father
    explanation: Exome sequencing plus microarray resolved a case with one sequence variant and a deletion.
  - reference: PMID:26153215
    reference_title: Homozygosity mapping and whole-genome sequencing reveals a deep intronic PROM1 mutation causing cone-rod dystrophy by pseudoexon activation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a homozygous interval comprising two known genes associated with the autosomal recessive form of CRD,
      namely RAB28 and PROM1, in a consanguineous family with clinical evidence of CRD.
    explanation: >-
      Diagnostic caveat only: the family's disease was due to PROM1, not RAB28, so homozygosity at this interval does
      not by itself implicate RAB28.
- name: Full-field electroretinography
  description: >-
    Full-field ERG shows undetectable or severely reduced photopic (cone) responses with milder reduction of scotopic
    (rod) responses, the cone-rod pattern.
  evidence:
  - reference: PMID:33396523
    reference_title: "Expanding the Clinical and Genetic Spectrum of RAB28-Related Cone-Rod Dystrophy: Pathogenicity of Novel Variants in Italian Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Flash electroretinogram (ERG) recording showed a non-detectable response for the photopic component and a reduced
      response for the scotopic component.
    explanation: ERG pattern in the Italian series.
  - reference: PMID:42231409
    reference_title: "Sporadic cone-rod dystrophy caused by a heterozygous RAB28 p.Ser23Phe pathogenic variant and a de novo 4p16.1p15.33 deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Full-field ERG revealed severely diminished cone responses, while rod responses were mildly reduced.
    explanation: Cone-predominant ERG loss in a further proband.
treatments:
- name: RAB28 Gene Replacement (Preclinical)
  description: >-
    No treatment is approved or in trials. Cone-specific transgenic re-expression of Rab28 rescues the outer segment
    phagocytosis defect in rab28 knockout zebrafish, which suggests gene replacement to cones as a strategy.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: Gene Therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  evidence:
  - reference: PMID:35471581
    reference_title: "Dawn and dusk peaks of outer segment phagocytosis, and visual cycle function require Rab28."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Notably, transgenic overexpression of Rab28, solely in zebrafish cones, rescues the OSP defect in rab28 KO fish,
      suggesting rab28 gene replacement in cone photoreceptors is sufficient to regulate Rab28-OSP.
    explanation: Proof of concept in zebrafish only.
animal_models:
- name: Rab28 knockout mouse
  species: Mouse
  genotype: Rab28-/- (exon 3 deletion)
  publication: PMID:30228185
  modeled_mechanisms:
  - target: Defective Cone Outer Segment Shedding and Phagocytosis
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: Cone phagosomes almost absent, with ballooned unshed cone outer segment tips.
    evidence:
    - reference: PMID:30228185
      reference_title: The small GTPase RAB28 is required for phagocytosis of cone outer segments by the murine retinal pigmented epithelium.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Cone phagosomes were almost absent in Rab28-/- mice, whereas rod phagosomes displayed normal levels.
      explanation: Cone-specific phagocytosis defect.
  - target: Progressive Cone-Then-Rod Photoreceptor Degeneration
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Reduced cone and rod ERG responses and progressive retinal degeneration.
    limitations: The mouse retina has no macula, so the macular hyperpigmentation and atrophy of patients cannot be modeled.
    evidence:
    - reference: PMID:30228185
      reference_title: The small GTPase RAB28 is required for phagocytosis of cone outer segments by the murine retinal pigmented epithelium.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We found that Rab28-/- mice recapitulate features of the human dystrophy (i.e. they exhibited reduced cone and rod
        ERG responses and progressive retina degeneration).
      explanation: Degeneration and ERG loss in the knockout.
- name: rab28 knockout zebrafish
  species: Zebrafish
  genotype: CRISPR-Cas9 rab28 null
  publication: PMID:32258030
  modeled_mechanisms:
  - target: Defective Cone Outer Segment Shedding and Phagocytosis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Reduced shed outer segment material and phagosomes in the RPE.
    evidence:
    - reference: PMID:32258030
      reference_title: "Genetic Deletion of Zebrafish Rab28 Causes Defective Outer Segment Shedding, but Not Retinal Degeneration."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Significantly, rab28 null zebrafish display a 40–50% reduction in OS shedding as early as 15 days post fertilization
        (dpf), but without evidence of retinal degeneration up to 12 mpf.
      explanation: Shedding defect in the zebrafish knockout.
  - target: Progressive Cone-Then-Rod Photoreceptor Degeneration
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: No retinal degeneration up to 12 months post fertilization.
    limitations: >-
      The fish were followed for only 12 months, so the absence of degeneration may reflect species differences in
      disease tempo rather than a dispensable step; the authors do not resolve this.
    evidence:
    - reference: PMID:32258030
      reference_title: "Genetic Deletion of Zebrafish Rab28 Causes Defective Outer Segment Shedding, but Not Retinal Degeneration."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        significantly reduced shed outer segment material/phagosomes in the RPE at 1 month post fertilization (mpf), but
        otherwise normal visual function up to 21 dpf and retinal structure up to 12 mpf
      explanation: Normal retinal structure despite the shedding defect.

📚

References & Deep Research

Deep Research

1

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)

Record notes

The human literature is small: two families in the gene discovery report (PMID:23746546), two Spanish families (PMID:25356532), a Korean patient (PMID:28388261, whose PubMed record had no abstract on fetch, so it is not cited as evidence), two Danish brothers (PMID:32084271), four Italian families (PMID:33396523) and a Chinese proband whose second allele is a de novo 4p deletion (PMID:42231409). No prevalence estimate exists. The two brothers in PMID:32084271 also had postaxial polydactyly, but the authors state that more data are needed before attributing it to RAB28, so it is not recorded as a phenotype. RAB28 and PROM1 lie in the same 4p interval, and one family with homozygosity there had a deep intronic PROM1 variant instead (PMID:26153215). No disease-specific treatment exists; cone-specific Rab28 re-expression rescues outer segment phagocytosis in zebrafish (PMID:35471581). The deep-research report printed the RAB28 identifier as HGNC:9764, which is RAB22A; the binding here (hgnc:9768) comes from the ClinGen record. Myopia is not linked to a mechanism node because no source explains it. No GeneReviews chapter covers RAB28 or CORD18 (just check-genereviews against the committed Bookshelf index returned NO_CHAPTER). A Rab28/BBSome role in restraining ciliary extracellular vesicle shedding (PMID:32101165) was considered and left out, because it is shown only in C. elegans sensory neurons and its link to photoreceptor outer segments is untested.

Create: RAB28-Related Retinopathy · 2026-11-09T17:49:50Z · View source

New entry for RAB28-related retinopathy (MONDO:0100448) from one OpenScientist deep-research report (research/RAB28-Related_Retinopathy-deep-research-openscientist.md; 12/12 citations verified). preflight-dr flagged that the report gives HGNC:9764 (RAB22A) for RAB28; the entry binds hgnc:9768 from the ClinGen Definitive assertion. Claims were re-sourced from cached abstracts or PMC full text of PMID:23746546, 25356532, 33396523, 32084271, 42231409, 30228185, 32258030 and 35471581. Cone-rod dystrophy 18 (MONDO:0014153), the only MONDO descendant, is recorded as a synonym and a skos:narrowMatch mapping rather than a subtype. Validated with just validate (schema, terms, 40 snippets) and the offline pre-PR gates.

OpenScientist ▸

Key Findings

openscientist-autonomous 12 citations 2026-11-09T17:26:53.458117

Key Findings

Finding 1 — RAB28 loss-of-function causes autosomal-recessive cone-rod dystrophy (CORD18)

RAB28-related retinopathy was defined by a combined homozygosity-mapping and exome-sequencing study that identified recessive nonsense mutations segregating with arCRD in two unrelated families. In a German family with three affected siblings, a homozygous c.565C>T (p.Glu189*) variant was found; in a family of Moroccan-Jewish descent with two affected siblings, a homozygous c.409C>T (p.Arg137*) variant was found. As the original report states: "A combined approach of homozygosity mapping and exome sequencing revealed a homozygous nonsense mutation (c.565C>T [p.Glu189*]) in RAB28 in a German family with three siblings with arCRD. Another homozygous nonsense mutation (c.409C>T [p.Arg137*]) was identified in a family of Moroccan Jewish descent with two siblings affected by arCRD" (PMID: 23746546).

All five affected individuals shared a consistent clinical picture: "All five affected individuals presented with hyperpigmentation in the macula, progressive loss of the visual acuity, atrophy of the retinal pigment epithelium, and severely reduced cone and rod responses on the electroretinogram" (PMID: 23746546). The recessive inheritance, the nonsense nature of the variants (predicted null alleles), and the shared phenotype together establish RAB28 loss-of-function as the disease cause. Disease OMIM is 615374 (CORD18); gene OMIM is *612994; MONDO:0100448.

Phenotype (HPO) annotations: Cone-rod dystrophy (HP:0000548), abnormal electroretinogram (HP:0000512), abnormality of macular pigmentation (HP:0008061), retinal pigment epithelial atrophy (HP:0007894), reduced visual acuity (decreased), progressive visual loss (HP:0000529), dyschromatopsia (HP:0000551), photophobia (HP:0000613).

Finding 2 — RAB28 is a farnesylated ciliary GTPase at the basal body / connecting cilium, associated with IFT and the BBSome

Unlike most Rab GTPases, RAB28 carries an atypical prenylation signal: "Opposed to other Rab GTPases that are generally geranylgeranylated, RAB28 is predicted to be farnesylated. Staining of rat retina showed localization of RAB28 to the basal body and the ciliary rootlet of the photoreceptors" (PMID: 23746546). This farnesyl (C15) lipid anchor is mechanistically relevant because it governs membrane association and trafficking of the GTPase.

Developmental expression profiling in C. elegans confirmed a dedicated ciliary role: "this small GTPase is exclusively expressed in ciliated neurons where it dynamically associates with IFT trains" (PMID: 27930654). RAB28's distribution along the cilium depends on its GTP/GDP nucleotide state and on BBSome association, placing it within the ciliary intraflagellar transport machinery that is essential for photoreceptor outer-segment maintenance.

Ontology annotations: GTPase activity (GO:0003924), small GTPase mediated signal transduction (GO:0007264), protein farnesylation (GO:0018343), ciliary basal body (GO:0036064), photoreceptor connecting cilium (GO:0032391), intraflagellar transport (GO:0042073), BBSome (GO:0034464). Cell types: retinal cone cell (CL:0000573), retinal rod cell (CL:0000604), ciliated sensory neuron.

Finding 3 — RAB28 is required for RPE phagocytosis of (cone) outer segments and for visual-cycle retinoid recycling

The downstream cellular consequence of RAB28 loss is a defect in the daily renewal of photoreceptor outer segments. In rodent and zebrafish models, "the absence of Rab28 results in diminished dawn, photoreceptor, outer segment phagocytosis (OSP)" (PMID: 35471581). The circadian peaks of OSP (dawn for rods, with dusk contributions) are selectively blunted, while basal phagocytosis is preserved — implicating RAB28 in the regulated, high-throughput component of outer-segment turnover rather than constitutive clearance.

This OSP defect is coupled to a measurable disruption of the retinoid (visual) cycle: "retinoid levels of 11-cRAL, 11cRP, and atRP are significantly reduced in larval and adult rab28 KO retinae (p < .05)" (PMID: 35471581). Reduced 11-cis-retinal (11-cRAL, the chromophore of opsin) directly compromises phototransduction capacity.

The requirement is especially pronounced for cones. In mouse, "The small GTPase RAB28 is required for phagocytosis of cone outer segments by the murine retinal pigmented epithelium" (PMID: 30228185), consistent with the cone-predominant ERG deficit seen in patients. In zebrafish, "Genetic Deletion of Zebrafish Rab28 Causes Defective Outer Segment Shedding, but Not Retinal Degeneration" (PMID: 32258030) — a key model limitation indicating that the primary molecular lesion (defective OS shedding/phagocytosis) can be dissociated from overt degeneration in the fish, highlighting species differences in disease tempo.

Ontology annotations: photoreceptor outer segment (GO:0001750), retina homeostasis (GO:0001895), photoreceptor cell maintenance (GO:0045494), visual perception (GO:0007601), retinoid metabolic process (GO:0001523), phagocytosis (GO:0006909). Cell types: retinal pigment epithelial cell (CL:0002586). CHEBI: 11-cis-retinal (CHEBI:16066), retinoid.

Finding 4 — Ciliary Rab28 and the BBSome negatively regulate extracellular-vesicle (EV) shedding

A parallel mechanistic branch emerged from C. elegans sensory cilia: "the ciliary G-protein Rab28, associated with human autosomal recessive cone-rod dystrophy, negatively regulates EV levels in the sensory organs" (PMID: 32101165). Working with the BBSome, Rab28 restrains the production/shedding of ciliary extracellular vesicles. Because photoreceptor outer-segment disc morphogenesis and shedding share machinery with ciliary EV biogenesis, dysregulated EV shedding offers a complementary explanation for how RAB28 loss perturbs outer-segment homeostasis. This is an inferred bridge between the invertebrate EV finding and the vertebrate OSP defect rather than a directly demonstrated pathway in human retina.

Ontology annotations: extracellular vesicle biogenesis (GO:0140112), ciliary membrane (GO:0060170), negative regulation of extracellular exosome assembly.

Finding 5 — An ultra-rare, non-syndromic, childhood-onset, progressive condition with no approved therapy

RAB28-CRD is genetically homogeneous: "RAB28-associated CRD is genetically homogeneous and results from pathogenic variants in the RAB28 gene, which is essential for photoreceptor function" (PMID: 42231409). The characteristic electrophysiology is cone-predominant: "Full-field ERG revealed severely diminished cone responses, while rod responses were mildly reduced" (PMID: 42231409). Reported patients span European, North-African/Middle-Eastern (Moroccan-Jewish), Italian, and Korean backgrounds, with childhood-to-early-adult onset, progressive central/color-vision loss, macular hyperpigmentation, RPE/macular atrophy, and photoreceptor-layer thinning on OCT (PMID: 23746546, PMID: 33396523, PMID: 42231409). The condition is non-syndromic with normal life expectancy. No formal prevalence, incidence, penetrance, or natural-history figures are established, owing to the disease's rarity (fewer than ~20 reported families worldwide).

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

Biallelic loss-of-function variant in RAB28 (nonsense/frameshift predominantly; rare missense) leads to absent or non-functional RAB28 GTPase protein (predicted null alleles such as p.Glu189* and p.Arg137*). [Demonstrated in human families, PMID 23746546.]
Loss of the farnesylated ciliary RAB28 GTPase results in disrupted RAB28 function at the photoreceptor basal body, connecting cilium and ciliary rootlet, and loss of its nucleotide-state-dependent association with IFT trains and the BBSome. [Demonstrated: localization PMID 23746546; IFT/BBSome PMID 27930654.]
Impaired ciliary RAB28/BBSome function branches into two coupled consequences:
Branch A: leads to diminished circadian (dawn/dusk) peaks of RPE phagocytosis of photoreceptor — especially cone — outer segments (OSP), with basal OSP preserved. [Demonstrated: PMID 35471581, 30228185.]
Branch B: leads to dysregulated (increased) ciliary extracellular-vesicle shedding, since Rab28/BBSome normally negatively regulate EV levels. [Demonstrated in C. elegans; PMID 32101165. Link to vertebrate photoreceptor is inferred.]
Defective OSP results in failure to recycle outer-segment retinoids, leading to significantly reduced 11-cis-retinal (11-cRAL), 11-cis-retinyl palmitate (11cRP) and all-trans-retinyl palmitate (atRP) — i.e., visual-cycle disruption. [Demonstrated: PMID 35471581.]
Reduced chromophore availability plus accumulating/unrenewed outer-segment material results in progressive cone (then rod) photoreceptor dysfunction, leading to macular RPE stress and hyperpigmentation, RPE atrophy, and photoreceptor-layer thinning. [Demonstrated clinically: PMID 23746546, 42231409.]
Photoreceptor and RPE degeneration results in the clinical phenotype: progressive loss of visual acuity and color vision, macular atrophy, and a cone-predominant ERG deficit. [Demonstrated: PMID 23746546, 42231409.]

Schematic

 RAB28 biallelic LoF (p.Glu189*, p.Arg137*, ...)
     │
     ▼
 Loss of farnesylated ciliary RAB28 GTPase
 (basal body / connecting cilium / rootlet; IFT + BBSome)
     │
     ┌───────┴────────────────────────┐
     ▼                                 ▼
 Branch A                         Branch B
 ↓ dawn/dusk RPE OSP of           dysregulated ciliary
 (cone) outer segments            EV shedding (BBSome)
     │                                 │
     ▼                                 │
 Visual-cycle disruption              │ (inferred link to
 (↓11-cRAL, 11cRP, atRP)             │  OS disc homeostasis)
     │                                 │
     └───────────────┬─────────────────┘
             ▼
     Progressive cone→rod photoreceptor dysfunction
     + macular hyperpigmentation, RPE atrophy, OCT thinning
             ▼
     Cone-rod dystrophy: ↓acuity, ↓color vision,
     cone>>rod ERG reduction (CORD18)

Upstream vs downstream

Upstream / initiating: RAB28 LoF variant → loss of ciliary GTPase function (molecular).
Midstream: OSP failure and EV dysregulation (cellular, RPE-photoreceptor interface).
Downstream: visual-cycle depletion → photoreceptor degeneration → clinical cone-rod dystrophy.

Cell types involved: retinal cone cell (CL:0000573, primary), retinal rod cell (CL:0000604), retinal pigment epithelial cell (CL:0002586). Anatomy: retina (UBERON:0000966), macula lutea (UBERON:0005388), photoreceptor outer segment, retinal pigment epithelium (UBERON:0001782). Subcellular: connecting cilium / basal body (GO:0032391, GO:0036064), ciliary rootlet, ciliary membrane.

Section-by-Section Reference Content

1. Disease Information

Overview: Non-syndromic autosomal-recessive cone-rod dystrophy with childhood/early-adult onset, progressive central and color vision loss, macular pigmentary changes and RPE atrophy.
Identifiers: OMIM disease 615374 (Cone-Rod Dystrophy 18, CORD18); OMIM gene RAB28 *612994; MONDO:0100448; HGNC:9764 (RAB28). ICD-11: 9B70.0 (cone and cone-rod dystrophies) / ICD-10 H35.5 (hereditary retinal dystrophy). Orphanet: within the inherited cone-rod dystrophy group. MeSH: Cone-Rod Dystrophies / Retinal Dystrophies.
Synonyms: RAB28 retinopathy; RAB28-related cone-rod dystrophy; CORD18; arCRD due to RAB28.
Data source: Aggregated from individual-patient case reports/series and model-organism functional studies — not EHR-derived population data.

2. Etiology

Causal factor: Purely genetic — biallelic (homozygous or compound-heterozygous) loss-of-function variants in RAB28. No environmental or infectious etiology.
Genetic risk factors: The RAB28 pathogenic variants themselves are causal (not susceptibility loci). Consanguinity increases homozygous-variant risk (families reported from consanguineous/isolated populations).
Protective factors: None identified. No modifier alleles or protective variants reported.
Gene-environment interactions: None documented. The circadian light cycle is biologically relevant (OSP peaks are light/dark-entrained) but not established as a modifiable disease modifier.

3. Phenotypes

Phenotype	Type	HPO	Onset	Severity	Progression	Frequency
Cone-rod dystrophy	Clinical sign (ERG)	HP:0000548	Childhood–early adult	Severe (cone)	Progressive	~All
Reduced visual acuity	Symptom	decreased acuity	Childhood on	Moderate–severe	Progressive	~All
Macular hyperpigmentation	Physical sign	HP:0008061	Variable	Variable	Progressive	High
RPE atrophy / macular atrophy	Clinical sign	HP:0007894	Childhood on	Variable	Progressive	High
Photoreceptor-layer thinning (OCT)	Imaging sign	abnormal OCT	Childhood on	Variable	Progressive	High
Dyschromatopsia (color-vision loss)	Symptom	HP:0000551	Early	Variable	Progressive	Common
Photophobia	Symptom	HP:0000613	Variable	Mild–moderate	Stable/progressive	Variable

Quality-of-life impact: Progressive central and color-vision loss impairs reading, driving, and fine visual tasks; low-vision aids and rehabilitation partially mitigate. No disease-specific QOL instrument data (EQ-5D/SF-36) published.

4. Genetic / Molecular Information

Causal gene: RAB28 (HGNC:9764; OMIM *612994), chromosome 4p15.33; encodes a farnesylated Rab-family small GTPase.
Pathogenic variants: Predominantly nonsense/null — c.565C>T (p.Glu189*), c.409C>T (p.Arg137*) (PMID: 23746546); additional alleles expanded the spectrum (PMID: 33396523). A rare missense p.Ser23Phe was reported in a sporadic case alongside a de novo 4p16.1p15.33 deletion (PMID: 42231409).
Classification: Null variants are pathogenic (ACMG PVS1 + segregation). Missense/VUS require functional support.
Allele frequency: Pathogenic alleles are ultra-rare/absent-to-very-rare in gnomAD.
Origin: Germline. Functional consequence: loss of function (null alleles; hypomorphic for some).
Chromosomal abnormalities: A de novo 4p16.1p15.33 deletion unmasking a RAB28 variant was reported (PMID: 42231409) — relevant because RAB28 lies on 4p.
Diagnostic caveat: RAB28 and PROM1 sit in the same homozygous 4p interval; a deep-intronic PROM1 pseudoexon mutation caused CRD in a family initially suspected of RAB28 involvement (PMID: 26153215). Both must be sequenced (including deep intronic regions) when this interval maps.
Modifier genes / epigenetics: None identified.

5. Environmental Information

Not applicable. No environmental, lifestyle, or infectious contributors; disease is monogenic recessive.

6. Mechanism / Pathophysiology

See Mechanistic Model above. Pathways/processes: ciliary trafficking (IFT/BBSome), RPE phagocytosis (GO:0006909), retinoid/visual cycle (GO:0001523), extracellular-vesicle biogenesis (GO:0140112). No canonical Wnt/MAPK/mTOR involvement reported. Protein dysfunction = loss of GTPase function at the cilium. No immune or metabolic-systemic involvement.

7. Anatomical Structures Affected

Organ: Eye/retina (UBERON:0000966); macula (UBERON:0005388) predominantly affected; RPE (UBERON:0001782).
Tissue/cell: Neural retina photoreceptors — cones (CL:0000573) > rods (CL:0000604); RPE cells (CL:0002586).
Subcellular: Connecting cilium/basal body (GO:0032391/GO:0036064), ciliary rootlet, outer-segment membranes.
Localization: Bilateral, macula-predominant (central), symmetric.

8. Temporal Development

Onset: Childhood to early adulthood; insidious, chronic.
Progression: Slowly progressive; cone dysfunction precedes/exceeds rod. Lifelong, no remission.
Critical period: Therapeutic window exists while photoreceptors survive (pre-end-stage atrophy) — relevant to gene-replacement timing.

9. Inheritance and Population

Inheritance: Autosomal recessive; biallelic. Penetrance appears complete in reported homozygotes; expressivity variable.
Epidemiology: Ultra-rare; no formal prevalence/incidence. <~20 families reported.
Populations: European, North-African/Middle-Eastern (Moroccan-Jewish), Italian, Korean. Consanguinity contributes. No established founder variant. Sex ratio ~1:1 (autosomal recessive).

10. Diagnostics

Clinical/functional: Full-field ERG (cone >> rod reduction), color-vision testing, visual-field testing. OCT (photoreceptor/ONL thinning, RPE changes), fundus autofluorescence, fundus photography (macular hyperpigmentation/atrophy).
Genetic testing (definitive): IRD gene panels including RAB28, whole-exome (WES) or whole-genome sequencing (WGS). WGS adds value because deep-intronic variants (e.g., the PROM1 pseudoexon in the same interval, PMID: 26153215) and CNVs (4p deletion, PMID: 42231409) are missed by exon-focused assays. Chromosomal microarray detects 4p deletions. Homozygosity mapping aids consanguineous families.
Differential diagnosis: Other autosomal-recessive cone-rod dystrophies (ABCA4, PROM1, CDHR1, ADAM9, C8orf37, etc.), Stargardt disease, achromatopsia. Distinguished by gene testing; the shared 4p RAB28/PROM1 interval is the key pitfall.

11. Outcome / Prognosis

Survival/mortality: Normal life expectancy; non-lethal, non-systemic.
Morbidity: Progressive low vision / visual disability; central and color vision most affected.
Disease course: Chronic, progressive, no spontaneous remission. Legal blindness possible in advanced disease.
Prognostic factors: Residual photoreceptor survival and macular integrity; earlier/larger atrophy portends worse function. No validated molecular prognostic biomarkers.

12. Treatment

Current standard: No approved disease-modifying therapy. Supportive low-vision rehabilitation, optical aids, UV/glare protection, and genetic counseling.
Experimental — gene therapy: AAV-mediated RAB28 gene supplementation is the leading strategy. Cone-specific wild-type Rab28 re-expression rescued the OSP defect in zebrafish rab28 mutants (PMID: 37321111). Small gene size and cone-targeting feasibility are favorable for AAV.
Gene-agnostic option: Optogenetic therapy is a universal approach for late-stage degeneration regardless of causal gene (PMID: 33262683), potentially applicable once photoreceptors are lost.
NCIT suggestions: Gene Therapy (NCIT:C15431), AAV Vector-based therapy, Supportive Care (NCIT:C15277), Low Vision Rehabilitation. No pharmacotherapy or pharmacogenomics established.

13. Prevention

Primary: Not preventable (monogenic). Genetic counseling, carrier testing in at-risk families, and reproductive options (preimplantation/prenatal genetic diagnosis) for known familial variants.
Secondary: Cascade testing of relatives; early ophthalmologic surveillance in at-risk children.
Tertiary: Low-vision rehabilitation to limit disability. No immunization or public-health measures apply.

14. Other Species / Natural Disease

Orthologs: Mouse Rab28 (NCBI Gene 211548), zebrafish rab28, C. elegans rab-28. Highly conserved ciliary GTPase.
Natural disease: No naturally occurring RAB28 retinopathy documented in companion animals/wildlife (OMIA search negative). All animal data are engineered models.
Comparative biology: Mechanism (ciliary GTPase, OSP) conserved; zebrafish shows OSP defect without overt degeneration (PMID: 32258030), a notable cross-species difference. No zoonotic/transmission relevance.

15. Model Organisms

Model	Type	Key phenotype	Recapitulation	Reference
Mouse Rab28 KO	Mammalian, knockout	Loss of cone outer-segment phagocytosis by RPE; blunted dawn/dusk OSP; ↓retinoids	Recapitulates OSP/visual-cycle defect	PMID: 30228185, PMID: 35471581
Zebrafish rab28 KO	Teleost, genetic deletion	Defective OS shedding; no overt retinal degeneration	Partial — molecular defect without degeneration	PMID: 32258030
Zebrafish rab28 + cone transgene	Rescue model	Cone-specific WT Rab28 rescues OSP	Proof-of-concept for gene therapy	PMID: 37321111
C. elegans rab-28	Invertebrate	Dysregulated ciliary EV shedding; IFT/BBSome association	Models ciliary/EV mechanism	PMID: 27930654, PMID: 32101165

Limitations: Zebrafish lacks overt degeneration (tempo/species difference); no model fully reproduces human progressive macular atrophy. Resources: MGI, ZFIN, WormBase.

Evidence Base

PMID	Title (abbrev.)	Evidence type	Supports
23746546	Mutations in RAB28 … cause arCRD	Human clinical + IHC	F1 (causal variants, phenotype), F2 (farnesylation, localization)
33396523	Expanding the clinical/genetic spectrum	Human clinical	F5 (variant/phenotype spectrum)
42231409	Sporadic CRD: RAB28 p.Ser23Phe + 4p deletion	Human clinical	F5 (homogeneity, cone>rod ERG), missense + CNV
30228185	RAB28 required for cone OS phagocytosis (mouse)	Mouse model	F3 (RPE phagocytosis)
35471581	Dawn/dusk OSP & visual cycle require Rab28	Mouse + zebrafish	F3 (OSP, retinoids)
32258030	Zebrafish Rab28 KO: OS shedding defect, no degeneration	Zebrafish model	F3 (model limitation)
27930654	RAB-28 ciliary GTPase, BBSome/IFT	C. elegans	F2 (IFT/BBSome)
32101165	Ciliary Rab28 & BBSome regulate EV shedding	C. elegans	F4 (EV shedding)
37321111	Gene therapy for RAB28: zebrafish	Zebrafish rescue	Treatment (gene therapy)
26153215	Deep-intronic PROM1 pseudoexon mimics RAB28 CRD	Human clinical	Diagnostic caveat (RAB28/PROM1 interval)
33262683	Optogenetic gene therapy for degenerate retina	Review	Gene-agnostic therapy option
40869487	Genetic therapies for retinitis pigmentosa	Review	IRD gene-therapy landscape

How papers challenge findings: PMID: 32258030 is the main internal tension — zebrafish Rab28 loss produces the molecular OS-shedding defect but not degeneration, indicating the OSP lesion is necessary but perhaps not sufficient for rapid photoreceptor death, or that species differ in resilience/tempo. PMID: 26153215 does not challenge RAB28 causation but warns that the co-localized PROM1 gene can masquerade as RAB28 disease.

Limitations and Knowledge Gaps

Epidemiology unquantified: No formal prevalence, incidence, penetrance, or natural-history figures — disease too rare; estimates rely on <~20 reported families.
Human mechanism inferred from models: OSP/visual-cycle and EV-shedding mechanisms are demonstrated in mouse, zebrafish, and C. elegans; direct human retinal mechanistic data are absent.
Model-human discordance: Zebrafish lacks degeneration, so disease tempo and the sufficiency of the OSP defect for human photoreceptor loss remain uncertain.
EV branch under-validated: The EV-shedding pathway (Finding 4) is established only in C. elegans; its contribution to vertebrate photoreceptor pathology is an inference.
Genotype-phenotype correlations: With so few patients and a mix of null and rare missense alleles, severity/progression correlations are not established.
No therapy in humans: Gene-replacement efficacy is shown only in zebrafish; no human trials, dosing, or safety data.
No validated biomarkers for progression or treatment response.

Proposed Follow-up Experiments / Actions

Establish a RAB28-CRD patient registry to capture natural history, age-of-onset distribution, progression rate, and genotype-phenotype correlations across the reported populations.
Generate a mammalian degeneration model (e.g., aged/stressed Rab28-KO mouse, or cone-rich model) to test whether the OSP/visual-cycle defect is sufficient for progressive macular-type degeneration, resolving the zebrafish discordance.
Patient iPSC-derived retinal organoids / RPE to directly test the OSP, visual-cycle, and EV-shedding mechanisms in human cells and validate cross-species inferences.
Preclinical AAV-RAB28 gene-supplementation study in the mouse model with functional (ERG) and structural (OCT/histology) endpoints, defining the therapeutic window relative to photoreceptor survival.
Dissect the EV-shedding branch in vertebrates — test whether RAB28/BBSome-dependent EV dysregulation occurs in mammalian photoreceptor cilia and contributes to outer-segment disc defects.
Deep-sequencing diagnostic protocol for the 4p RAB28/PROM1 interval (WGS + CNV analysis) to avoid misattribution and capture deep-intronic and structural variants.
Biomarker discovery — longitudinal OCT/autofluorescence and retinoid-related measures as progression/treatment-response surrogates.

References

Roosing S, et al. Mutations in RAB28, encoding a farnesylated small GTPase, are associated with autosomal-recessive cone-rod dystrophy. PMID: 23746546
Expanding the Clinical and Genetic Spectrum of RAB28-related retinopathy. PMID: 33396523
Sporadic cone-rod dystrophy caused by a heterozygous RAB28 p.Ser23Phe pathogenic variant and a de novo 4p16.1p15.33 deletion. PMID: 42231409
The small GTPase RAB28 is required for phagocytosis of cone outer segments by the murine retinal pigmented epithelium. PMID: 30228185
Dawn and dusk peaks of outer segment phagocytosis, and visual cycle function require Rab28. PMID: 35471581
Genetic Deletion of Zebrafish Rab28 Causes Defective Outer Segment Shedding, but Not Retinal Degeneration. PMID: 32258030
Whole-Organism Developmental Expression Profiling Identifies RAB-28 as a Novel Ciliary GTPase Associated with the BBSome and Intraflagellar Transport. PMID: 27930654
Ciliary Rab28 and the BBSome negatively regulate extracellular vesicle shedding. PMID: 32101165
Gene therapy for RAB28: What can we learn from zebrafish? PMID: 37321111
Homozygosity mapping and whole-genome sequencing reveals a deep intronic PROM1 mutation causing cone-rod dystrophy by pseudoexon activation. PMID: 26153215
Optogenetic Gene Therapy for the Degenerate Retina: Recent Advances. PMID: 33262683
Genetic Therapies for Retinitis Pigmentosa: Current Breakthroughs and Future Directions. PMID: 40869487

Evidence source legend: Human clinical (PMIDs 23746546, 33396523, 42231409, 26153215); Mouse model (30228185, 35471581); Zebrafish model (32258030, 35471581, 37321111); C. elegans (27930654, 32101165); Review (33262683, 40869487).

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Term Validation

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

Outcome	Count
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Terms whose name was checked	9
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Terms whose name is worth a second look	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:0100448 (5 mentions) - the report calls it "MONDO"; MONDO calls it RAB28-related retinopathy
HP:0000548 (2 mentions) - the report calls it "Clinical sign (ERG)"; HP calls it Cone/cone-rod dystrophy
HP:0008061 (2 mentions) - the report calls it "Physical sign"; HP calls it Aplasia/Hypoplasia of the retina
HP:0007894 (2 mentions) - the report calls it "Clinical sign"; HP calls it Fundus hypopigmentation
HP:0000551 (2 mentions) - the report calls it "Symptom"; HP calls it Color vision defect
HP:0000613 (2 mentions) - the report calls it "Symptom"; HP calls it Photophobia
CL:0000573 (3 mentions) - the report calls it "Tissue/cell: Neural retina photoreceptors — cones"; CL calls it retinal cone cell**
NCIT:C15431 (1 mention) - the report calls it "NCIT suggestions: Gene Therapy"; NCIT calls it Hematopoietic Cell Transplantation**

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:

UBERON:0000966 (2 mentions) - the report calls it "Organ: Eye/retina"; UBERON calls it retina**

Terms named inconsistently

The report gives these identifiers more than one name of its own:

HGNC:9764 - called "chromosome 4p15.33", "RAB28"

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Mappings

Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Animal Models

Source YAML

References & Deep Research

Deep Research

Key Findings

Finding 1 — RAB28 loss-of-function causes autosomal-recessive cone-rod dystrophy (CORD18)

Finding 2 — RAB28 is a farnesylated ciliary GTPase at the basal body / connecting cilium, associated with IFT and the BBSome

Finding 3 — RAB28 is required for RPE phagocytosis of (cone) outer segments and for visual-cycle retinoid recycling

Finding 4 — Ciliary Rab28 and the BBSome negatively regulate extracellular-vesicle (EV) shedding

Finding 5 — An ultra-rare, non-syndromic, childhood-onset, progressive condition with no approved therapy

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

Schematic

Upstream vs downstream

Section-by-Section Reference Content

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

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

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

References

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently