RDH12-Related Dominant Retinopathy

Mendelian MONDO:0800100 Pathograph 21 Show in embeddings browser Retinitis Pigmentosa Inherited Retinal Dystrophy

RDH12-related dominant retinopathy is a rare, late-onset and comparatively mild rod-cone dystrophy (autosomal dominant retinitis pigmentosa) caused by a single heterozygous frameshift in the penultimate coding exon of RDH12. It is allelic to, and clinically very different from, the recessive RDH12 disease (Leber congenital amaurosis 13 / early-onset severe retinal dystrophy). Four families have been published, carrying three single-base deletions within 20 nucleotides of one another (c.759del, c.763del and c.778del, the last first reported as 776delG). Affected people present with night blindness and peripheral field loss, mid-peripheral bone-spicule pigmentation, attenuated vessels and disc pallor, while central acuity and macular structure are relatively preserved; expressivity varies within a family, and one carrier was recognised as affected only by adaptive optics imaging. RDH12 is an NADPH-dependent retinal reductase of the photoreceptor inner segment that clears all-trans-retinal and other aldehydes. Heterozygous carriers of recessive loss-of-function alleles are unaffected, so simple haploinsufficiency does not explain the dominant disease. All three dominant frameshifts are predicted to escape nonsense-mediated decay and to produce a truncated protein ending in the same novel C-terminal peptide. Whether that protein acts by a toxic gain of function or by dominant-negative interference with wild-type RDH12 is not settled; both are recorded here as alternative hypotheses, and neither has been tested directly. Patient iPSC-derived retinal organoids show fewer, shorter photoreceptors late in differentiation, with reduced RDH12 expression and disrupted vitamin A pathway and cone phototransduction gene expression.

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Inheritance

1
Autosomal dominant inheritance HP:0000006
A single heterozygous RDH12 frameshift segregates with disease through several generations in each published family. Expressivity is highly variable within a family: in the four-generation British pedigree one carrier with a normal fundus was recognised as affected only by adaptive optics imaging and autofluorescence, which the authors read as variable expressivity rather than non-penetrance.
Autosomal dominant inheritance
Show evidence (4 references)
PMID:18779497 SUPPORT Human clinical
"A frameshift mutation (776delG) was detected in all affected family members and was not detected in 158 control subjects."
Cosegregation of the heterozygous frameshift with disease in the founding dominant pedigree.
PMID:18779497 SUPPORT Human clinical
"Heterozygous mutations in RDH12 can cause autosomal dominant RP with a late onset and relatively mild severity."
The founding study's conclusion that a heterozygous RDH12 variant causes dominant disease.
PMID:34031043 SUPPORT Human clinical
"This novel heterozygous variant RDH12 c.763delG is associated with a rod-cone dystrophy with variable expression."
Dominant transmission with variable expression in a second, four-generation family.
+ 1 more reference
◈

Mechanistic Hypotheses

3
Toxic gain of function of the aberrant C-terminal peptide
rdh12_ad_toxic_c_terminal_gain ALTERNATIVE
Evidence balance 2 support
The NMD-escaping frameshift protein carries a novel C-terminal peptide that is itself toxic to photoreceptors, independently of RDH12 catalytic activity. Proposed by the authors of the British family and adopted by the ClinGen curation as gain of function; not tested experimentally.
Pathograph links
NMD-Escaping Transcript Encoding RDH12 With a Novel C-Terminus -> Toxic Gain of Function of the Aberrant C-Terminal Peptide DIRECT
Toxic Gain of Function of the Aberrant C-Terminal Peptide -> Photoreceptor Segment Shortening and Loss INDIRECT UNKNOWN INTERMEDIATES
Show evidence (2 references)
PMID:34031043 SUPPORT Human clinical
"This rare and specific heterozygous (dominant) variant is predicted to result in a gain of function"
The gain-of-function interpretation is a prediction, not a measurement.
CGGV:assertion_958d5e41-ea0c-4497-af02-56d6ed3cd341-2023-03-02T170000.000Z SUPPORT Other
"The mechanism of pathogenicity is reported to be gain-of-function, most likely due to the creation of an alternate reading frame predicted to escape NMD and lead to a truncated protein with altered C-terminus."
ClinGen records gain of function as the reported mechanism.
Dominant-negative interference with wild-type RDH12
rdh12_ad_dominant_negative ALTERNATIVE
Evidence balance 2 support
The truncated protein retains the cofactor-binding and catalytic regions and interferes with the wild-type enzyme, for example by sequestering it if RDH12 acts as a dimer, lowering total RDH12 activity below what one normal allele provides. Proposed from protein modelling and the organoid data; not tested experimentally.
Pathograph links
NMD-Escaping Transcript Encoding RDH12 With a Novel C-Terminus -> Dominant-Negative Interference With Wild-Type RDH12 DIRECT
Dominant-Negative Interference With Wild-Type RDH12 -> Disrupted Vitamin A Pathway and Cone Phototransduction Gene Expression INDIRECT UNKNOWN INTERMEDIATES
Show evidence (2 references)
PMID:40365019 SUPPORT In vitro / ex vivo
"The alternative C-terminus may function as a dominant-negative protein, sequestering WT protein to reduce its activity."
Stated as a possibility in the organoid study's discussion.
PMID:32322264 SUPPORT Human clinical
"This C-terminal peptide sequence produced by the dominant variants may be responsible for a protein interaction resulting in gain of function or a dominant negative effect, which may account for the milder phenotype."
The authors leave both mechanisms open.
Haploinsufficiency
rdh12_ad_haploinsufficiency ⚠ DEPRECATED
⚠ Overturned model — shown for reference, not as current mechanism

DisMech records superseded hypotheses explicitly rather than deleting them, so that claims still circulating in reviews, textbooks and older diagnostic criteria can be checked against an assessment. This model is not part of the disease mechanism DisMech asserts.

Citation volume does not decide standing here. A hypothesis may retain more supporting than refuting citations simply because the supporting literature accumulated for decades before the refutation landed; where the two conflict, DisMech follows the more recent and more direct evidence. Supporting citations below are retained for the historical record.

Evidence balance 3 refute
Loss of one functional RDH12 allele is not sufficient for disease: heterozygous parents of LCA13 patients are unaffected, heterozygous Rdh12 mice have no retinal phenotype, and other truncating variants that also escape NMD but do not create the shared C-terminal peptide have not been linked to dominant disease. No causal edge in this entry belongs to this hypothesis; it is recorded so that the reason for excluding it is visible.
Show evidence (3 references)
PMID:35994252 REFUTE Human clinical
"Most individuals with heterozygous RDH12 variants were disease-free, indicating that a single allele was sufficient to maintain the activity of retinol dehydrogenase, except for patients with RDH12-associated adRP."
One functional allele suffices outside the dominant families, which argues against haploinsufficiency.
PMID:34031043 REFUTE BACKGROUND Human clinical
"Importantly, heterozygous carriers of loss of function alleles are entirely asymptomatic, suggesting that a single functional allele is sufficient."
Carriers of recessive null alleles are unaffected.
PMID:40365019 REFUTE BACKGROUND Model organism
"The heterozygous Rdh12 mouse model does not exhibit any retinal phenotype"
Heterozygous loss in the mouse gives no retinal phenotype. The organoid paper states this as background, citing the original knockout studies.
?

Discussions and Knowledge Gaps

1
Does the shared C-terminal peptide of the dominant RDH12 frameshift protein act through a toxic gain of function or by interfering with wild-type RDH12?
KNOWLEDGE GAP OPEN rdh12_ad_gain_vs_dominant_negative
Attached to
pathophysiology#NMD-Escaping Transcript Encoding RDH12 With a Novel C-Terminus pathophysiology#Toxic Gain of Function of the Aberrant C-Terminal Peptide pathophysiology#Dominant-Negative Interference With Wild-Type RDH12
Both mechanisms are proposed in the same small literature and neither has been tested: the mutant protein has not been detected separately from wild type, RDH12 dimerisation is inferred from a Drosophila ortholog, and the organoid transcriptome cannot separate the two. The answer decides the therapy. Allele-specific silencing of the mutant transcript, proposed by the British family's authors, would suffice under a toxic gain of function, because one normal allele is enough; under a dominant-negative mechanism silencing would also help, but gene supplementation could too.
Proposed experiments
Isogenic organoids and co-expression assays for the dominant RDH12 allele
rdh12_ad_isogenic_organoid_coexpression
Correct c.759del in the patient iPSC line, and introduce it into a control line, then compare photoreceptor number, retinoid reductase activity and mutant protein level in the organoids. In parallel, co-express wild-type and frameshift RDH12 in cells to test whether the mutant protein binds wild-type RDH12 or reduces its activity, and whether the C-terminal peptide is toxic when fused to an unrelated protein.
Would support
pathophysiology#Dominant-Negative Interference With Wild-Type RDH12
Would refute
pathophysiology#Toxic Gain of Function of the Aberrant C-Terminal Peptide
Supporting outcome
  • The frameshift protein binds wild-type RDH12 and lowers its activity, while the peptide alone is not toxic, and correction restores photoreceptor number.
Refuting outcome
  • The peptide is toxic on its own and wild-type activity is unchanged by co-expression, favouring a gain of function.
Show evidence (2 references)
PMID:34031043 SUPPORT Human clinical
"being able to switch off the dominant gain-of-function mutant allele using AON targeting would leave affected patients expressing 50% of normal RDH12 like an unaffected parent of an RDH12 LCA child."
The proposed allele-specific antisense strategy and its rationale.
PMID:32322264 SUPPORT Human clinical
"However, further functional studies into the differences in disease mechanisms between autosomal recessive and autosomal dominant mutations are required."
The authors state that the mechanism needs functional study.
⚙

Pathophysiology

7
Heterozygous RDH12 Penultimate-Exon Frameshift
Mechanism confidence: Established
The initiating lesion is one of three single-base deletions clustered in the penultimate coding exon of RDH12: c.759del p.(Phe254Leufs*24), c.763del p.(Val255Serfs*23) and c.778del p.(Glu260Argfs*18). Each was found heterozygous and segregating with disease. The frameshifts lie downstream of the conserved cofactor-binding (residues 46 to 52) and catalytic (200 to 204) regions, which are left intact.
RDH12 hgnc:19977 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RDH12 (hgnc:19977). hgnc:19977 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context allele_type: frameshift variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: UNKNOWN
Functional impact is left UNKNOWN on purpose. The sources agree that the alleles are not simple loss of function, and disagree on whether they act as a toxic gain of function or as dominant negatives (see mechanistic_hypotheses).
all-trans-retinol dehydrogenase (NADP+) activity GO:0052650 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal all-trans-retinol dehydrogenase (NADP+) activity (GO:0052650). GO:0052650 is a molecular function from the Gene Ontology.
Downstream
NMD-Escaping Transcript Encoding RDH12 With a Novel C-Terminus
Show evidence (3 references)
PMID:32322264 SUPPORT Human clinical
"Both heterozygous variants are associated with a late onset RP phenotype, suggesting a possible genotype-phenotype correlation."
The c.759del and c.776del (c.778del) frameshifts share a late-onset dominant phenotype.
PMID:32322264 SUPPORT Human clinical
"the two highly conserved catalytic domains: the cofactor binding site at positions 46–52, and the active site at 200–204, possibly accounting for the relatively mild phenotype"
The frameshift leaves the conserved cofactor-binding and active sites in place.
PMID:35994252 SUPPORT Human clinical
"These three adRP-related variants were located downstream of the domain on the penultimate exon of RDH12"
Places all three dominant variants in the penultimate exon.
NMD-Escaping Transcript Encoding RDH12 With a Novel C-Terminus
Mechanism confidence: Provisional
The premature stop codon falls within about 20 nucleotides of the last exon-exon junction, so the mutant transcript is predicted to escape nonsense-mediated decay. All three dominant frameshifts enter the same alternative reading frame and end in an identical novel C-terminal peptide (RGRRPACTAPWLRAWSP), replacing roughly 60 wild-type residues. Recessive truncations further downstream, such as c.806_810del, also escape NMD but do not create this peptide and are not dominant, which is why the peptide rather than truncation itself is suspected. In patient-derived organoids the mutant mRNA is present while total RDH12 expression is reduced by about 45 per cent, suggesting partial degradation; the mutant protein itself has not been detected separately from the wild-type protein.
Dominant-negative interference with wild-type RDH12 Toxic gain of function of the aberrant C-terminal peptide
RDH12 hgnc:19977 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RDH12 (hgnc:19977). hgnc:19977 is a gene from the HUGO Gene Nomenclature Committee.
all-trans-retinol dehydrogenase (NADP+) activity GO:0052650 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal all-trans-retinol dehydrogenase (NADP+) activity (GO:0052650). GO:0052650 is a molecular function from the Gene Ontology.
photoreceptor inner segment layer UBERON:0003925 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in photoreceptor inner segment layer (UBERON:0003925). UBERON:0003925 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Toxic Gain of Function of the Aberrant C-Terminal Peptide Toxic gain of function of the aberrant C-terminal peptide
Dominant-Negative Interference With Wild-Type RDH12 Dominant-negative interference with wild-type RDH12
Show evidence (5 references)
PMID:35994252 SUPPORT Computational
"they all produced an identical terminal peptide (RGRRPACTAPWLRAWSP; see Fig. 2F)"
Sequence analysis shows the three dominant variants converge on one terminal peptide.
PMID:34031043 SUPPORT Human clinical
"we therefore propose that this variant will lead to an aberrant transcript that may survive NMD and lead to a protein product with a mutant 23 amino acid residue C-terminal sequence, replacing 62 residues of the wild-type protein."
Predicted NMD escape and C-terminal replacement for c.763del.
PMID:35994252 SUPPORT Human clinical
"However, these variants have not been causally linked to RDH12-associated adRP."
Other NMD-escaping truncations downstream are not dominant, pointing to the shared peptide rather than truncation.
+ 2 more references
Toxic Gain of Function of the Aberrant C-Terminal Peptide
Mechanism confidence: Hypothetical
Hypothesis: the novel C-terminal peptide confers a toxic property on the protein that damages rod photoreceptors, analogous to the toxic C-terminal frameshift proposed for dominant RGR chorioretinopathy. On this model, silencing the mutant allele would leave patients with the half dose of normal RDH12 that unaffected LCA13 carriers have. The toxic activity has not been identified or measured.
Toxic gain of function of the aberrant C-terminal peptide
Downstream
Photoreceptor Segment Shortening and Loss Toxic gain of function of the aberrant C-terminal peptide
Show evidence (2 references)
PMID:34031043 SUPPORT Human clinical
"all act as dominant alleles, with a toxic effect on the rod photoreceptors"
The toxic-allele hypothesis as stated by its authors.
PMID:34031043 SUPPORT Human clinical
"we believe that this represents the most likely mechanism of disease, although this remains to be molecularly evaluated."
The authors state the hypothesis is untested.
Dominant-Negative Interference With Wild-Type RDH12
Mechanism confidence: Hypothetical
Hypothesis: the truncated protein binds or sequesters wild-type RDH12 and lowers total retinal reductase activity in the inner segment below the level one normal allele supplies. It rests on the suggestion, from the Drosophila photoreceptor ortholog, that RDH12 may act as a dimer; RDH12 dimerisation and mutant-wild-type interaction have not been shown. Normal RDH12 function, which this hypothesis would reduce, is well characterised: the purified human enzyme has its highest catalytic efficiency for all-trans-retinal, and in rod inner segments it protects organelles against aldehyde toxicity from all-trans-retinal leaking out of the outer segment and from other aldehydes.
Dominant-negative interference with wild-type RDH12
photoreceptor cell CL:0000210 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves photoreceptor cell (CL:0000210). CL:0000210 is a cell type from the Cell Ontology.
all-trans-retinol dehydrogenase (NADP+) activity GO:0052650 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased all-trans-retinol dehydrogenase (NADP+) activity (GO:0052650). GO:0052650 is a molecular function from the Gene Ontology.
Downstream
Disrupted Vitamin A Pathway and Cone Phototransduction Gene Expression Dominant-negative interference with wild-type RDH12
Show evidence (4 references)
PMID:35994252 SUPPORT Human clinical
"produce aberrant proteins carrying toxic peptides (RGRRPACTAPWLRAWSP) at the C-terminal, and interrupt the function of wild-type proteins via dominant-negative effects"
Proposed dominant-negative action of the shared peptide, stated as speculation.
PMID:40365019 SUPPORT In vitro / ex vivo
"RDH12 was suggested to function as a dimer based on the ortholog photoreceptor retinal dehydrogenase in Drosophila melanogaster"
The structural premise of the dominant-negative model, itself inferred from an ortholog.
PMID:15865448 SUPPORT In vitro / ex vivo
"The enzyme exhibits the highest catalytic efficiency for all-trans-retinal"
The normal activity a dominant-negative protein would reduce.
+ 1 more reference
Disrupted Vitamin A Pathway and Cone Phototransduction Gene Expression
Mechanism confidence: Provisional
Mature (week 44) patient-derived organoids show broad transcriptional change: 2,446 differentially expressed genes, with disruption of the retinol biosynthesis and vitamin A pathways and downregulation of cone-specific phototransduction markers, which the authors take as a sign that cones are preferentially affected. The data come from one patient line against one unrelated control without isogenic correction, and the cause of the change (reduced RDH12 activity or something else) is not established; it is attached to the dominant-negative branch only because that is the branch that predicts reduced RDH12 activity.
retinal cone cell CL:0000573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal cone cell (CL:0000573). CL:0000573 is a cell type from the Cell Ontology.
retinol metabolic process GO:0042572 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated retinol metabolic process (GO:0042572). GO:0042572 is a biological process from the Gene Ontology. cone phototransduction GO:0007602 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cone phototransduction, annotated with phototransduction (GO:0007602). GO:0007602 is a biological process from the Gene Ontology.
Experimental models
RDH12 c.759del patient iPSC-derived retinal organoids ORGANOID Bulk RNA sequencing of week-44 organoids, the only source for this node.
Downstream
Photoreceptor Segment Shortening and Loss
Show evidence (2 references)
PMID:40365019 SUPPORT In vitro / ex vivo
"Visual cone function, retinol biosynthesis, and the vitamin A pathway were also highly disrupted at week 44."
Transcriptomic disruption of the retinoid and cone pathways in patient organoids.
PMID:40365019 SUPPORT In vitro / ex vivo
"suggesting cones are preferentially affected in RDH12-AD models"
Downregulated cone markers point to cone involvement.
Photoreceptor Segment Shortening and Loss
Mechanism confidence: Provisional
In patient-derived organoids photoreceptors develop normally to week 18, then by weeks 37 to 44 are fewer and have shorter segments, which the authors read as loss after differentiation rather than a developmental defect; no increase in cell death was detected at the time points sampled, so the mode of death is unknown. In patients, adaptive optics imaging shows reduced cone density, most marked away from the fovea.
retinal rod cell CL:0000604 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal rod cell (CL:0000604). CL:0000604 is a cell type from the Cell Ontology. retinal cone cell CL:0000573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal cone cell (CL:0000573). CL:0000573 is a cell type from the Cell Ontology.
photoreceptor cell maintenance GO:0045494 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased photoreceptor cell maintenance (GO:0045494). GO:0045494 is a biological process from the Gene Ontology.
Experimental models
RDH12 c.759del patient iPSC-derived retinal organoids ORGANOID Patient organoids develop normally and then show fewer photoreceptors with shorter segments late in differentiation, in keeping with the late onset of the human disease.
Downstream
Late-Onset Rod-Cone Degeneration
Show evidence (4 references)
PMID:40365019 SUPPORT In vitro / ex vivo
"however, transmission electron microscopy at week 37 showed that photoreceptors were less abundant and shorter in length."
Fewer, shorter photoreceptors in patient-derived organoids.
PMID:40365019 SUPPORT In vitro / ex vivo
"the percentage of photoreceptors (CRX-positive cells) in RDH12-AD retinal organoids was significantly decreased compared to the unaffected control at week 44"
Quantified photoreceptor reduction at week 44.
PMID:40365019 SUPPORT In vitro / ex vivo
"immunostaining at various time points failed to detect a significant increase in cell death in RDH12-AD organoids"
No detected increase in cell death, so the death mechanism is unresolved.
+ 1 more reference
Late-Onset Rod-Cone Degeneration
Mechanism confidence: Established
The clinical retinal disease: a rod-cone dystrophy that is milder and later in onset than recessive RDH12 disease. Rod function is affected first on electroretinography, and degeneration starts in the periphery, with bone spicules and vessel attenuation, while an island of central photoreceptors and good acuity persist. In the founding family the mean age at diagnosis was 28.5 years; in the British family the index patient had signs at about age 10. The circular autofluorescence ring around a residual foveal island resembles typical retinitis pigmentosa rather than the variegated macular atrophy of LCA13.
retinal rod cell CL:0000604 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal rod cell (CL:0000604). CL:0000604 is a cell type from the Cell Ontology.
Downstream
Nyctalopia
Constriction of peripheral visual field
Rod-cone dystrophy
Abnormal electroretinogram
Spicular pigmentation of the retina
Attenuation of retinal blood vessels
Optic disc pallor
Perifoveal ring of hyperautofluorescence
Central thinning of the outer nuclear layer
Show evidence (3 references)
PMID:34031043 SUPPORT Human clinical
"Full-field electroretinography demonstrated a rod-cone pattern of dysfunction and large-field pattern electroretinography identified peripheral macular dysfunction."
Rod-cone pattern of dysfunction on ERG.
PMID:32322264 SUPPORT BACKGROUND Human clinical
"Affected individuals displayed a milder late onset (average age of diagnosis was 28.5 years) retinitis pigmentosa (RP) phenotype, with intraretinal bone spicule pigmentation and attenuation of retinal arterioles"
Sarkar et al. summarise the founding family's late onset and fundus findings.
PMID:32322264 SUPPORT Human clinical
"The cases presented here are in stark contrast to this classical representation with relatively intact macular structure and visual acuity."
Relative preservation of macula and acuity compared with recessive disease.
⬡

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.
Pathograph: causal mechanism network for RDH12-Related Dominant Retinopathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

10
Cardiovascular 1
Attenuation of retinal blood vessels HP:0007843 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retinal vessel attenuation, annotated with Attenuation of retinal blood vessels (HP:0007843). HP:0007843 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32322264 SUPPORT Human clinical
"fundus examination showed mild waxy disc pallor with retinal vessel attenuation and mid-peripheral bone-spicules."
Vessel attenuation in the first c.759del proband; the second proband's fundus was described as similar.
Eye 9
Nyctalopia HP:0000662 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Night blindness, annotated with Nyctalopia (HP:0000662). HP:0000662 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32322264 SUPPORT Human clinical
"who presented with nyctalopia and field loss, but preserved central vision."
Presenting symptoms of the first c.759del proband.
CGGV:assertion_958d5e41-ea0c-4497-af02-56d6ed3cd341-2023-03-02T170000.000Z SUPPORT Other
"RDH12-related dominant retinopathy is associated with late onset cases typically diagnosed as retinitis pigmentosa with a milder phenotype, characterized by nyctalopia and visual field loss, but relatively preserved central vision."
ClinGen summary of the presentation across the curated probands.
Constriction of peripheral visual field HP:0001133 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Constricted visual fields, annotated with Constriction of peripheral visual field (HP:0001133). HP:0001133 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34031043 SUPPORT Human clinical
"Visual acuity ranged from -0.1 to 0.2 logMAR. Affected individuals had constricted visual fields."
Constricted fields with good acuity in the British family.
PMID:32322264 SUPPORT Human clinical
"After this he began to notice nyctalopia and progressive visual field loss. He maintains good central and color vision."
Progressive field loss with preserved central vision in the second c.759del proband.
Rod-cone dystrophy HP:0000510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rod-cone dystrophy (retinitis pigmentosa), annotated with Rod-cone dystrophy (HP:0000510). HP:0000510 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:18779497 SUPPORT Human clinical
"Nineteen family members had a mild form of RP."
Mild retinitis pigmentosa in all affected members of the founding family.
PMID:34031043 SUPPORT Human clinical
"This novel heterozygous variant RDH12 c.763delG is associated with a rod-cone dystrophy with variable expression."
Rod-cone dystrophy in the British family.
Abnormal electroretinogram HP:0000512 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rod-cone pattern of ERG dysfunction, annotated with Abnormal electroretinogram (HP:0000512). HP:0000512 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34031043 SUPPORT Human clinical
"Full-field electroretinography demonstrated a rod-cone pattern of dysfunction and large-field pattern electroretinography identified peripheral macular dysfunction."
Full-field and pattern ERG abnormalities.
Spicular pigmentation of the retina HP:0007737 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bone-spicule pigmentation, annotated with Spicular pigmentation of the retina (HP:0007737). HP:0007737 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32322264 SUPPORT Human clinical
"fundus examination showed mild waxy disc pallor with retinal vessel attenuation and mid-peripheral bone-spicules."
Fundus findings of the first c.759del proband.
Optic disc pallor HP:0000543 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Waxy optic disc pallor, annotated with Optic disc pallor (HP:0000543). HP:0000543 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32322264 SUPPORT Human clinical
"fundus examination showed mild waxy disc pallor with retinal vessel attenuation and mid-peripheral bone-spicules."
Waxy disc pallor in the first c.759del proband.
Perifoveal ring of hyperautofluorescence HP:0030629 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Parafoveal ring of hyperautofluorescence, annotated with Perifoveal ring of hyperautofluorescence (HP:0030629). HP:0030629 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34031043 SUPPORT Human clinical
"A parafoveal and peripapillary ring of hyper-autofluorescence was seen initially, and with progression the area of perifoveal hypo-autofluorescence increased to involve the parafoveal area."
The autofluorescence ring and its progression.
PMID:32322264 SUPPORT Human clinical
"There was salient hypo- and hyper-autofluorescence rings present on short-wavelength fundus autofluorescence (FAF) and residual foveal island on SD-OCT (Figure 3)."
The same ring pattern around a residual foveal island in the c.759del proband.
Central thinning of the outer nuclear layer Central thinning of the outer nuclear layer of the retina HP:6000367 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thinning of the foveal outer nuclear layer, annotated with Central thinning of the outer nuclear layer of the retina (HP:6000367). HP:6000367 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34031043 SUPPORT Human clinical
"Mild retinal thinning was identified on OCT imaging with reduction in both foveal total retinal and outer nuclear layer thickness."
Foveal outer nuclear layer thinning in the British family.
Macular edema HP:0040049 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Parafoveal macular edema, annotated with Macular edema (HP:0040049). HP:0040049 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32322264 SUPPORT Human clinical
"Parafoveal macular edema was present in both eyes."
A single-patient observation.
🧬

Genetic Associations

1
RDH12 (Causative heterozygous frameshift variants in the penultimate coding exon that are predicted to escape nonsense-mediated decay and encode a protein with a shared novel C-terminal peptide.)
Gene: RDH12 hgnc:19977 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RDH12 (hgnc:19977). hgnc:19977 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE
Show evidence (2 references)
CGGV:assertion_958d5e41-ea0c-4497-af02-56d6ed3cd341-2023-03-02T170000.000Z SUPPORT Other
"This curation includes three frameshift variants that have been reported in 4 probands in 3 publications (PMIDs: 18779497, 32322264, 34031043)."
ClinGen's summary of the genetic evidence.
CGGV:assertion_958d5e41-ea0c-4497-af02-56d6ed3cd341-2023-03-02T170000.000Z SUPPORT Other
"the difference in inheritance pattern and phenotypic variability between autosomal dominant and autosomal recessive cases led them to be split into separate disease entities"
ClinGen's reason for curating the dominant disease separately from LCA13.
Variants (3)
c.778del p.(Glu260Argfs*18)
The founding dominant allele, segregating in a six-generation American family with 19 affected members; first annotated as 776delG.
Also known as: 776delG c.778delG
Show evidence (1 reference)
PMID:18779497 SUPPORT Human clinical
"A frameshift mutation (776delG) was detected in all affected family members and was not detected in 158 control subjects."
Identification and segregation of the allele.
c.759del p.(Phe254Leufs*24)
Found heterozygous in two unrelated families (an Israeli family of Tunisian paternal descent and an English family); absent from gnomAD.
Show evidence (2 references)
PMID:32322264 SUPPORT Human clinical
"This variant has not been reported on gnomAD."
Population absence of the variant.
PMID:34216980 SUPPORT In vitro / ex vivo
"This variant is predicted to result in premature termination and expression of a truncated protein."
Predicted consequence for the allele carried by the patient iPSC line.
c.763del p.(Val255Serfs*23)
Segregating in a four-generation British family with eight affected carriers, including one carrier identified only by adaptive optics imaging.
Also known as: c.763delG
Show evidence (1 reference)
PMID:34031043 SUPPORT Human clinical
"Eight family members were confirmed as affected by genotyping heterozygous for RDH12 c.763delG."
Segregation of the allele in the British family.
💊

Medical Actions

1
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counseling for a dominant disorder with variable expressivity, in a gene whose other disease is recessive. Each child of an affected parent has a one in two chance of inheriting the variant, and a carrier may have only subclinical signs.
Show evidence (1 reference)
PMID:35994252 SUPPORT Human clinical
"provide new insights for the genetic counseling of patients harboring RDH12 variants"
Genotype-specific counseling for the dominant and recessive RDH12 forms.
🔬

Diagnosis

2
Molecular Genetic Testing
Diagnosis rests on finding one of the penultimate-exon frameshifts in a patient with dominant-pattern rod-cone dystrophy, usually on a retinal gene panel or genome sequencing. Because RDH12 is mainly a recessive gene, a single heterozygous RDH12 variant needs to be interpreted with its position and predicted gain-of-function effect in mind, and with segregation in the family.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:34031043 SUPPORT Human clinical
"It is important to correctly apply the interpretation guidelines with the predicted dominant RDH12-disease association, since we note it is gain of function and not loss of function."
The interpretive caveat for a dominant allele in a mostly recessive gene.
Adaptive Optics Retinal Imaging
Adaptive optics scanning light ophthalmoscopy with short-wavelength autofluorescence detected disease in a minimally symptomatic carrier whose fundus, OCT and ERG were normal, so deep phenotyping can change whether a relative is classed as affected.
Show evidence (1 reference)
PMID:34031043 SUPPORT Human clinical
"One individual with incomplete penetrance, was identified as clinically affected primarily on the basis of AO imaging."
Adaptive optics identified an otherwise unrecognised affected carrier.
📊

Prevalence

1
Worldwide (published families)
Cases/families reported in the literature
No population estimate exists. Four families have been published: one six-generation American family (Fingert 2008), two unrelated families sharing c.759del (Sarkar 2020) and one four-generation British family (Muthiah 2022). A Chinese cohort of 27 families with RDH12 retinopathy found no dominant case.
Show evidence (2 references)
PMID:35994252 SUPPORT Human clinical
"To date, four families of RDH12-associated adRP have been reported."
A 2022 literature count of published dominant families.
PMID:35994252 SUPPORT Human clinical
"However, no heterozygous variants associated with adRP were identified in our cohort."
No dominant case in a 27-family RDH12 cohort, consistent with the rarity of the dominant form.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from RDH12-Related Dominant Retinopathy:

Leber congenital amaurosis 13 MONDO:0012990
Overlapping Features The allelic recessive RDH12 disease, curated as Leber_Congenital_Amaurosis_13. It is caused by biallelic loss-of-function variants and presents in early childhood with severe visual loss and early macular atrophy, whereas the dominant disease is caused by one penultimate-exon frameshift and spares central vision until late.
Distinguishing Features
  • One heterozygous penultimate-exon frameshift with dominant transmission, against two loss-of-function alleles.
  • Late onset with good acuity, against early-onset severe visual impairment.
  • A typical retinitis pigmentosa autofluorescence ring around a residual foveal island, against variegated, petal-shaped macular atrophy.
Show evidence (3 references)
PMID:18779497 SUPPORT Human clinical
"This phenotype is dramatically different from the other disease associated with mutation in this gene, autosomal recessive Leber congenital amaurosis."
The founding report contrasts the two allelic diseases.
PMID:35994252 SUPPORT Human clinical
"Among patients with adRP with accessible clinical data, none had a BCVA <0.6, which was significantly better than that of patients with recessive RDH12-associated retinopathy"
Better acuity in dominant than in recessive RDH12 disease.
PMID:32322264 SUPPORT Human clinical
"This circular pattern is more reminiscent of RP than classic recessive RDH12 retinopathy"
The imaging pattern differs from recessive disease.
📊

Related Datasets

1
Dominant RDH12-retinitis pigmentosa impairs photoreceptor development and cone function in retinal organoids geo:GSE271751
Bulk RNA sequencing of week-44 retinal organoids from an RDH12 c.759del patient iPSC line and an unrelated unaffected control.
human BULK RNA SEQ
PMID:40365019
Accession named in the data availability statement of PMID:40365019; title is GEO's own.
🧫

Experimental Models

1
RDH12 c.759del patient iPSC-derived retinal organoids ORGANOID
Retinal organoids differentiated from the UCLi014-A iPSC line, made from a 32-year-old man heterozygous for c.759del, compared with an unrelated age- and sex-matched control, to week 44. The only disease model of the dominant form; no animal model carries a dominant allele.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Patient-derived human induced pluripotent stem cells (UCLi014-A)
Publication
PMID:40365019
Pathograph links
Photoreceptor Segment Shortening and Loss partially recapitulates fidelity: moderate observes: cellular Patient organoids develop normally and then show fewer photoreceptors with shorter segments late in differentiation, in keeping with the late onset of the human disease.
Limitations: One patient line against one unrelated control, with no isogenic correction, so genetic background is not controlled. Organoids resemble peripheral rather than macular retina, lack RPE, and the electron microscopy counts come from two organoids per line. No increase in cell death was detected, so the organoid does not show how photoreceptors are lost.
Readouts
Photoreceptor number and segment length
Direction: DECREASED
Show evidence (1 reference)
PMID:40365019 SUPPORT In vitro / ex vivo
"however, transmission electron microscopy at week 37 showed that photoreceptors were less abundant and shorter in length."
The structural readout behind the link.
Show evidence (1 reference)
PMID:40365019 SUPPORT In vitro / ex vivo
"Our study is the first to describe an RDH12-AD disease model with pathology at later stages of photoreceptor differentiation, in keeping with the milder disease course seen in humans."
The authors' own statement of what the model reproduces.
Disrupted Vitamin A Pathway and Cone Phototransduction Gene Expression measures fidelity: unknown observes: cellular Bulk RNA sequencing of week-44 organoids, the only source for this node.
Limitations: Transcript levels only; no retinoid or enzyme-activity measurement, no isogenic control, and cone dysfunction is inferred from marker expression.
Show evidence (1 reference)
PMID:40365019 SUPPORT In vitro / ex vivo
"hence, isogenic controls would help validate these results"
The authors note the need for isogenic controls.
{ }

Source YAML

click to show 
name: RDH12-Related Dominant Retinopathy
category: Mendelian
description: >-
  RDH12-related dominant retinopathy is a rare, late-onset and comparatively
  mild rod-cone dystrophy (autosomal dominant retinitis pigmentosa) caused by a
  single heterozygous frameshift in the penultimate coding exon of RDH12. It is
  allelic to, and clinically very different from, the recessive RDH12 disease
  (Leber congenital amaurosis 13 / early-onset severe retinal dystrophy). Four
  families have been published, carrying three single-base deletions within 20
  nucleotides of one another (c.759del, c.763del and c.778del, the last first
  reported as 776delG). Affected people present with night blindness and
  peripheral field loss, mid-peripheral bone-spicule pigmentation, attenuated
  vessels and disc pallor, while central acuity and macular structure are
  relatively preserved; expressivity varies within a family, and one carrier
  was recognised as affected only by adaptive optics imaging.

  RDH12 is an NADPH-dependent retinal reductase of the photoreceptor inner
  segment that clears all-trans-retinal and other aldehydes. Heterozygous
  carriers of recessive loss-of-function alleles are unaffected, so simple
  haploinsufficiency does not explain the dominant disease. All three dominant
  frameshifts are predicted to escape nonsense-mediated decay and to produce a
  truncated protein ending in the same novel C-terminal peptide. Whether that
  protein acts by a toxic gain of function or by dominant-negative interference
  with wild-type RDH12 is not settled; both are recorded here as alternative
  hypotheses, and neither has been tested directly. Patient iPSC-derived
  retinal organoids show fewer, shorter photoreceptors late in differentiation,
  with reduced RDH12 expression and disrupted vitamin A pathway and cone
  phototransduction gene expression.
disease_term:
  preferred_term: RDH12-related dominant retinopathy
  term:
    id: MONDO:0800100
    label: RDH12-related dominant retinopathy
synonyms:
- autosomal dominant RDH12-related retinal dystrophy
- RDH12-related autosomal dominant retinitis pigmentosa
- autosomal dominant RDH12 retinopathy
parents:
- Retinitis Pigmentosa
- Inherited Retinal Dystrophy
creation_date: "2026-11-04T12:00:00Z"
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    A single heterozygous RDH12 frameshift segregates with disease through
    several generations in each published family. Expressivity is highly
    variable within a family: in the four-generation British pedigree one
    carrier with a normal fundus was recognised as affected only by adaptive
    optics imaging and autofluorescence, which the authors read as variable
    expressivity rather than non-penetrance.
  evidence:
  - reference: PMID:18779497
    reference_title: "Association of a novel mutation in the retinol dehydrogenase 12 (RDH12) gene with autosomal dominant retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A frameshift mutation (776delG) was detected in all affected family members and was not detected in 158 control subjects."
    explanation: Cosegregation of the heterozygous frameshift with disease in the founding dominant pedigree.
  - reference: PMID:18779497
    reference_title: "Association of a novel mutation in the retinol dehydrogenase 12 (RDH12) gene with autosomal dominant retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous mutations in RDH12 can cause autosomal dominant RP with a late onset and relatively mild severity."
    explanation: The founding study's conclusion that a heterozygous RDH12 variant causes dominant disease.
  - reference: PMID:34031043
    reference_title: "Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This novel heterozygous variant RDH12 c.763delG is associated with a rod-cone dystrophy with variable expression."
    explanation: Dominant transmission with variable expression in a second, four-generation family.
  - reference: PMID:34031043
    reference_title: "Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings are more in keeping with highly variable expressivity rather than non-penetrance of the disease."
    explanation: The minimally symptomatic carrier is interpreted as variable expressivity.
prevalence:
- population: Worldwide (published families)
  measure_type: CASES_IN_LITERATURE
  notes: >-
    No population estimate exists. Four families have been published: one
    six-generation American family (Fingert 2008), two unrelated families
    sharing c.759del (Sarkar 2020) and one four-generation British family
    (Muthiah 2022). A Chinese cohort of 27 families with RDH12 retinopathy found
    no dominant case.
  evidence:
  - reference: PMID:35994252
    reference_title: "Clinical and Genetic Analysis of RDH12-Associated Retinopathy in 27 Chinese Families: A Hypomorphic Allele Leads to Cone-Rod Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, four families of RDH12-associated adRP have been reported."
    explanation: A 2022 literature count of published dominant families.
  - reference: PMID:35994252
    reference_title: "Clinical and Genetic Analysis of RDH12-Associated Retinopathy in 27 Chinese Families: A Hypomorphic Allele Leads to Cone-Rod Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, no heterozygous variants associated with adRP were identified in our cohort."
    explanation: No dominant case in a 27-family RDH12 cohort, consistent with the rarity of the dominant form.
mechanistic_hypotheses:
- hypothesis_group_id: rdh12_ad_toxic_c_terminal_gain
  hypothesis_label: Toxic gain of function of the aberrant C-terminal peptide
  status: ALTERNATIVE
  description: >-
    The NMD-escaping frameshift protein carries a novel C-terminal peptide that
    is itself toxic to photoreceptors, independently of RDH12 catalytic
    activity. Proposed by the authors of the British family and adopted by the
    ClinGen curation as gain of function; not tested experimentally.
  evidence:
  - reference: PMID:34031043
    reference_title: "Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This rare and specific heterozygous (dominant) variant is predicted to result in a gain of function"
    explanation: The gain-of-function interpretation is a prediction, not a measurement.
  - reference: CGGV:assertion_958d5e41-ea0c-4497-af02-56d6ed3cd341-2023-03-02T170000.000Z
    reference_title: "RDH12 / RDH12-related dominant retinopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism of pathogenicity is reported to be gain-of-function, most likely due to the creation of an alternate reading frame predicted to escape NMD and lead to a truncated protein with altered C-terminus."
    explanation: ClinGen records gain of function as the reported mechanism.
- hypothesis_group_id: rdh12_ad_dominant_negative
  hypothesis_label: Dominant-negative interference with wild-type RDH12
  status: ALTERNATIVE
  description: >-
    The truncated protein retains the cofactor-binding and catalytic regions and
    interferes with the wild-type enzyme, for example by sequestering it if
    RDH12 acts as a dimer, lowering total RDH12 activity below what one normal
    allele provides. Proposed from protein modelling and the organoid data; not
    tested experimentally.
  evidence:
  - reference: PMID:40365019
    reference_title: "Dominant RDH12-retinitis pigmentosa impairs photoreceptor development and implicates cone involvement in retinal organoids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The alternative C-terminus may function as a dominant-negative protein, sequestering WT protein to reduce its activity."
    explanation: Stated as a possibility in the organoid study's discussion.
  - reference: PMID:32322264
    reference_title: "Novel Heterozygous Deletion in Retinol Dehydrogenase 12 (RDH12) Causes Familial Autosomal Dominant Retinitis Pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This C-terminal peptide sequence produced by the dominant variants may be responsible for a protein interaction resulting in gain of function or a dominant negative effect, which may account for the milder phenotype."
    explanation: The authors leave both mechanisms open.
- hypothesis_group_id: rdh12_ad_haploinsufficiency
  hypothesis_label: Haploinsufficiency
  status: DEPRECATED
  description: >-
    Loss of one functional RDH12 allele is not sufficient for disease:
    heterozygous parents of LCA13 patients are unaffected, heterozygous Rdh12
    mice have no retinal phenotype, and other truncating variants that also
    escape NMD but do not create the shared C-terminal peptide have not been
    linked to dominant disease. No causal edge in this entry belongs to this
    hypothesis; it is recorded so that the reason for excluding it is visible.
  evidence:
  - reference: PMID:35994252
    reference_title: "Clinical and Genetic Analysis of RDH12-Associated Retinopathy in 27 Chinese Families: A Hypomorphic Allele Leads to Cone-Rod Dystrophy."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Most individuals with heterozygous RDH12 variants were disease-free, indicating that a single allele was sufficient to maintain the activity of retinol dehydrogenase, except for patients with RDH12-associated adRP."
    explanation: One functional allele suffices outside the dominant families, which argues against haploinsufficiency.
  - reference: PMID:34031043
    reference_title: "Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Importantly, heterozygous carriers of loss of function alleles are entirely asymptomatic, suggesting that a single functional allele is sufficient."
    explanation: Carriers of recessive null alleles are unaffected.
  - reference: PMID:40365019
    reference_title: "Dominant RDH12-retinitis pigmentosa impairs photoreceptor development and implicates cone involvement in retinal organoids."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "The heterozygous Rdh12 mouse model does not exhibit any retinal phenotype"
    explanation: >-
      Heterozygous loss in the mouse gives no retinal phenotype. The organoid
      paper states this as background, citing the original knockout studies.
pathophysiology:
- name: Heterozygous RDH12 Penultimate-Exon Frameshift
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: >-
    The initiating lesion is one of three single-base deletions clustered in the
    penultimate coding exon of RDH12: c.759del p.(Phe254Leufs*24), c.763del
    p.(Val255Serfs*23) and c.778del p.(Glu260Argfs*18). Each was found
    heterozygous and segregating with disease. The frameshifts lie downstream of
    the conserved cofactor-binding (residues 46 to 52) and catalytic (200 to
    204) regions, which are left intact.
  genes:
  - preferred_term: RDH12
    term:
      id: hgnc:19977
      label: RDH12
  molecular_functions:
  - preferred_term: all-trans-retinol dehydrogenase (NADP+) activity
    term:
      id: GO:0052650
      label: all-trans-retinol dehydrogenase (NADP+) activity
    modifier: ABNORMAL
  genetic_context:
    allele_type: frameshift
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: UNKNOWN
    description: >-
      Functional impact is left UNKNOWN on purpose. The sources agree that the
      alleles are not simple loss of function, and disagree on whether they act
      as a toxic gain of function or as dominant negatives (see
      mechanistic_hypotheses).
  evidence:
  - reference: PMID:32322264
    reference_title: "Novel Heterozygous Deletion in Retinol Dehydrogenase 12 (RDH12) Causes Familial Autosomal Dominant Retinitis Pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both heterozygous variants are associated with a late onset RP phenotype, suggesting a possible genotype-phenotype correlation."
    explanation: The c.759del and c.776del (c.778del) frameshifts share a late-onset dominant phenotype.
  - reference: PMID:32322264
    reference_title: "Novel Heterozygous Deletion in Retinol Dehydrogenase 12 (RDH12) Causes Familial Autosomal Dominant Retinitis Pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the two highly conserved catalytic domains: the cofactor binding site at positions 46–52, and the active site at 200–204, possibly accounting for the relatively mild phenotype"
    explanation: The frameshift leaves the conserved cofactor-binding and active sites in place.
  - reference: PMID:35994252
    reference_title: "Clinical and Genetic Analysis of RDH12-Associated Retinopathy in 27 Chinese Families: A Hypomorphic Allele Leads to Cone-Rod Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These three adRP-related variants were located downstream of the domain on the penultimate exon of RDH12"
    explanation: Places all three dominant variants in the penultimate exon.
  downstream:
  - target: NMD-Escaping Transcript Encoding RDH12 With a Novel C-Terminus
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32322264
      reference_title: "Novel Heterozygous Deletion in Retinol Dehydrogenase 12 (RDH12) Causes Familial Autosomal Dominant Retinitis Pigmentosa."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Due to the proximity of the mutation to the final exon–exon junction, this transcript is likely to escape nonsense mediated decay (NMD) and result in the expression of a truncated protein."
      explanation: The position of the premature stop predicts escape from NMD.
- name: NMD-Escaping Transcript Encoding RDH12 With a Novel C-Terminus
  biological_scale: MOLECULAR
  role: central_effector
  mechanism_confidence: PROVISIONAL
  description: >-
    The premature stop codon falls within about 20 nucleotides of the last
    exon-exon junction, so the mutant transcript is predicted to escape
    nonsense-mediated decay. All three dominant frameshifts enter the same
    alternative reading frame and end in an identical novel C-terminal peptide
    (RGRRPACTAPWLRAWSP), replacing roughly 60 wild-type residues. Recessive
    truncations further downstream, such as c.806_810del, also escape NMD but do
    not create this peptide and are not dominant, which is why the peptide
    rather than truncation itself is suspected. In patient-derived organoids the
    mutant mRNA is present while total RDH12 expression is reduced by about 45
    per cent, suggesting partial degradation; the mutant protein itself has not
    been detected separately from the wild-type protein.
  genes:
  - preferred_term: RDH12
    term:
      id: hgnc:19977
      label: RDH12
  molecular_functions:
  - preferred_term: all-trans-retinol dehydrogenase (NADP+) activity
    term:
      id: GO:0052650
      label: all-trans-retinol dehydrogenase (NADP+) activity
    modifier: ABNORMAL
  locations:
  - preferred_term: photoreceptor inner segment layer
    term:
      id: UBERON:0003925
      label: photoreceptor inner segment layer
  evidence:
  - reference: PMID:35994252
    reference_title: "Clinical and Genetic Analysis of RDH12-Associated Retinopathy in 27 Chinese Families: A Hypomorphic Allele Leads to Cone-Rod Dystrophy."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "they all produced an identical terminal peptide (RGRRPACTAPWLRAWSP; see Fig. 2F)"
    explanation: Sequence analysis shows the three dominant variants converge on one terminal peptide.
  - reference: PMID:34031043
    reference_title: "Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we therefore propose that this variant will lead to an aberrant transcript that may survive NMD and lead to a protein product with a mutant 23 amino acid residue C-terminal sequence, replacing 62 residues of the wild-type protein."
    explanation: Predicted NMD escape and C-terminal replacement for c.763del.
  - reference: PMID:35994252
    reference_title: "Clinical and Genetic Analysis of RDH12-Associated Retinopathy in 27 Chinese Families: A Hypomorphic Allele Leads to Cone-Rod Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, these variants have not been causally linked to RDH12-associated adRP."
    explanation: Other NMD-escaping truncations downstream are not dominant, pointing to the shared peptide rather than truncation.
  - reference: PMID:40365019
    reference_title: "Dominant RDH12-retinitis pigmentosa impairs photoreceptor development and implicates cone involvement in retinal organoids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Transcriptomic analysis reveals that RDH12 expression decreased by 45% in RDH12-AD organoids compared to the unaffected control."
    explanation: Reduced but present RDH12 transcript in patient-derived organoids.
  - reference: PMID:40365019
    reference_title: "Dominant RDH12-retinitis pigmentosa impairs photoreceptor development and implicates cone involvement in retinal organoids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RDH12-AD RO exhibited correct localization of RDH12 to the photoreceptor inner segments up to week 44"
    explanation: RDH12 protein still reaches the inner segment in patient organoids.
  downstream:
  - target: Toxic Gain of Function of the Aberrant C-Terminal Peptide
    causal_link_type: DIRECT
    hypothesis_groups:
    - rdh12_ad_toxic_c_terminal_gain
  - target: Dominant-Negative Interference With Wild-Type RDH12
    causal_link_type: DIRECT
    hypothesis_groups:
    - rdh12_ad_dominant_negative
- name: Toxic Gain of Function of the Aberrant C-Terminal Peptide
  biological_scale: MOLECULAR
  role: effector
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Hypothesis: the novel C-terminal peptide confers a toxic property on the
    protein that damages rod photoreceptors, analogous to the toxic C-terminal
    frameshift proposed for dominant RGR chorioretinopathy. On this model,
    silencing the mutant allele would leave patients with the half dose of
    normal RDH12 that unaffected LCA13 carriers have. The toxic activity has not
    been identified or measured.
  evidence:
  - reference: PMID:34031043
    reference_title: "Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all act as dominant alleles, with a toxic effect on the rod photoreceptors"
    explanation: The toxic-allele hypothesis as stated by its authors.
  - reference: PMID:34031043
    reference_title: "Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we believe that this represents the most likely mechanism of disease, although this remains to be molecularly evaluated."
    explanation: The authors state the hypothesis is untested.
  downstream:
  - target: Photoreceptor Segment Shortening and Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - rdh12_ad_toxic_c_terminal_gain
- name: Dominant-Negative Interference With Wild-Type RDH12
  biological_scale: MOLECULAR
  role: effector
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Hypothesis: the truncated protein binds or sequesters wild-type RDH12 and
    lowers total retinal reductase activity in the inner segment below the
    level one normal allele supplies. It rests on the suggestion, from the
    Drosophila photoreceptor ortholog, that RDH12 may act as a dimer; RDH12
    dimerisation and mutant-wild-type interaction have not been shown.

    Normal RDH12 function, which this hypothesis would reduce, is well
    characterised: the purified human enzyme has its highest catalytic
    efficiency for all-trans-retinal, and in rod inner segments it protects
    organelles against aldehyde toxicity from all-trans-retinal leaking out of
    the outer segment and from other aldehydes.
  molecular_functions:
  - preferred_term: all-trans-retinol dehydrogenase (NADP+) activity
    term:
      id: GO:0052650
      label: all-trans-retinol dehydrogenase (NADP+) activity
    modifier: DECREASED
  cell_types:
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  evidence:
  - reference: PMID:35994252
    reference_title: "Clinical and Genetic Analysis of RDH12-Associated Retinopathy in 27 Chinese Families: A Hypomorphic Allele Leads to Cone-Rod Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "produce aberrant proteins carrying toxic peptides (RGRRPACTAPWLRAWSP) at the C-terminal, and interrupt the function of wild-type proteins via dominant-negative effects"
    explanation: Proposed dominant-negative action of the shared peptide, stated as speculation.
  - reference: PMID:40365019
    reference_title: "Dominant RDH12-retinitis pigmentosa impairs photoreceptor development and implicates cone involvement in retinal organoids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RDH12 was suggested to function as a dimer based on the ortholog photoreceptor retinal dehydrogenase in Drosophila melanogaster"
    explanation: The structural premise of the dominant-negative model, itself inferred from an ortholog.
  - reference: PMID:15865448
    reference_title: "Biochemical properties of purified human retinol dehydrogenase 12 (RDH12): catalytic efficiency toward retinoids and C9 aldehydes and effects of cellular retinol-binding protein type I (CRBPI) and cellular retinaldehyde-binding protein (CRALBP) on the oxidation and reduction of retinoids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The enzyme exhibits the highest catalytic efficiency for all-trans-retinal"
    explanation: The normal activity a dominant-negative protein would reduce.
  - reference: PMID:22621924
    reference_title: "Reduction of all-trans-retinal in vertebrate rod photoreceptors requires the combined action of RDH8 and RDH12."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In contrast, RDH12 in inner segments can protect vital cell organelles
      against aldehyde toxicity caused by an intracellular leak of
      all-trans-retinal, as well as other aldehydes originating both inside and
      outside the cell.
    explanation: The protective inner-segment function, measured in mouse rods.
  downstream:
  - target: Disrupted Vitamin A Pathway and Cone Phototransduction Gene Expression
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - rdh12_ad_dominant_negative
- name: Disrupted Vitamin A Pathway and Cone Phototransduction Gene Expression
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: PROVISIONAL
  description: >-
    Mature (week 44) patient-derived organoids show broad transcriptional
    change: 2,446 differentially expressed genes, with disruption of the
    retinol biosynthesis and vitamin A pathways and downregulation of
    cone-specific phototransduction markers, which the authors take as a sign
    that cones are preferentially affected. The data come from one patient line
    against one unrelated control without isogenic correction, and the cause of
    the change (reduced RDH12 activity or something else) is not established;
    it is attached to the dominant-negative branch only because that is the
    branch that predicts reduced RDH12 activity.
  cell_types:
  - preferred_term: retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  biological_processes:
  - preferred_term: retinol metabolic process
    term:
      id: GO:0042572
      label: retinol metabolic process
    modifier: DYSREGULATED
  - preferred_term: cone phototransduction
    term:
      id: GO:0007602
      label: phototransduction
    modifier: DECREASED
  evidence:
  - reference: PMID:40365019
    reference_title: "Dominant RDH12-retinitis pigmentosa impairs photoreceptor development and implicates cone involvement in retinal organoids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Visual cone function, retinol biosynthesis, and the vitamin A pathway were also highly disrupted at week 44."
    explanation: Transcriptomic disruption of the retinoid and cone pathways in patient organoids.
  - reference: PMID:40365019
    reference_title: "Dominant RDH12-retinitis pigmentosa impairs photoreceptor development and implicates cone involvement in retinal organoids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "suggesting cones are preferentially affected in RDH12-AD models"
    explanation: Downregulated cone markers point to cone involvement.
  downstream:
  - target: Photoreceptor Segment Shortening and Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Photoreceptor Segment Shortening and Loss
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: PROVISIONAL
  description: >-
    In patient-derived organoids photoreceptors develop normally to week 18,
    then by weeks 37 to 44 are fewer and have shorter segments, which the
    authors read as loss after differentiation rather than a developmental
    defect; no increase in cell death was detected at the time points sampled,
    so the mode of death is unknown. In patients, adaptive optics imaging shows
    reduced cone density, most marked away from the fovea.
  cell_types:
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  - preferred_term: retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  biological_processes:
  - preferred_term: photoreceptor cell maintenance
    term:
      id: GO:0045494
      label: photoreceptor cell maintenance
    modifier: DECREASED
  evidence:
  - reference: PMID:40365019
    reference_title: "Dominant RDH12-retinitis pigmentosa impairs photoreceptor development and implicates cone involvement in retinal organoids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "however, transmission electron microscopy at week 37 showed that photoreceptors were less abundant and shorter in length."
    explanation: Fewer, shorter photoreceptors in patient-derived organoids.
  - reference: PMID:40365019
    reference_title: "Dominant RDH12-retinitis pigmentosa impairs photoreceptor development and implicates cone involvement in retinal organoids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the percentage of photoreceptors (CRX-positive cells) in RDH12-AD retinal organoids was significantly decreased compared to the unaffected control at week 44"
    explanation: Quantified photoreceptor reduction at week 44.
  - reference: PMID:40365019
    reference_title: "Dominant RDH12-retinitis pigmentosa impairs photoreceptor development and implicates cone involvement in retinal organoids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "immunostaining at various time points failed to detect a significant increase in cell death in RDH12-AD organoids"
    explanation: No detected increase in cell death, so the death mechanism is unresolved.
  - reference: PMID:34031043
    reference_title: "Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cone densities along the temporal meridian were reduced in affected individuals compared with normative values at all temporal eccentricities studied."
    explanation: Cone loss in patients measured by adaptive optics.
  downstream:
  - target: Late-Onset Rod-Cone Degeneration
    causal_link_type: DIRECT
- name: Late-Onset Rod-Cone Degeneration
  biological_scale: TISSUE
  role: outcome
  mechanism_confidence: ESTABLISHED
  description: >-
    The clinical retinal disease: a rod-cone dystrophy that is milder and later
    in onset than recessive RDH12 disease. Rod function is affected first on
    electroretinography, and degeneration starts in the periphery, with bone
    spicules and vessel attenuation, while an island of central photoreceptors
    and good acuity persist. In the founding family the mean age at diagnosis
    was 28.5 years; in the British family the index patient had signs at about
    age 10. The circular autofluorescence ring around a residual foveal island
    resembles typical retinitis pigmentosa rather than the variegated macular
    atrophy of LCA13.
  cell_types:
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  evidence:
  - reference: PMID:34031043
    reference_title: "Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Full-field electroretinography demonstrated a rod-cone pattern of dysfunction and large-field pattern electroretinography identified peripheral macular dysfunction."
    explanation: Rod-cone pattern of dysfunction on ERG.
  - reference: PMID:32322264
    reference_title: "Novel Heterozygous Deletion in Retinol Dehydrogenase 12 (RDH12) Causes Familial Autosomal Dominant Retinitis Pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Affected individuals displayed a milder late onset (average age of diagnosis was 28.5 years) retinitis pigmentosa (RP) phenotype, with intraretinal bone spicule pigmentation and attenuation of retinal arterioles"
    explanation: Sarkar et al. summarise the founding family's late onset and fundus findings.
  - reference: PMID:32322264
    reference_title: "Novel Heterozygous Deletion in Retinol Dehydrogenase 12 (RDH12) Causes Familial Autosomal Dominant Retinitis Pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cases presented here are in stark contrast to this classical representation with relatively intact macular structure and visual acuity."
    explanation: Relative preservation of macula and acuity compared with recessive disease.
  downstream:
  - target: Nyctalopia
  - target: Constriction of peripheral visual field
  - target: Rod-cone dystrophy
  - target: Abnormal electroretinogram
  - target: Spicular pigmentation of the retina
  - target: Attenuation of retinal blood vessels
  - target: Optic disc pallor
  - target: Perifoveal ring of hyperautofluorescence
  - target: Central thinning of the outer nuclear layer
phenotypes:
- name: Nyctalopia
  category: Ophthalmological
  description: Night blindness is the usual presenting symptom.
  phenotype_term:
    preferred_term: Night blindness
    term:
      id: HP:0000662
      label: Nyctalopia
  evidence:
  - reference: PMID:32322264
    reference_title: "Novel Heterozygous Deletion in Retinol Dehydrogenase 12 (RDH12) Causes Familial Autosomal Dominant Retinitis Pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "who presented with nyctalopia and field loss, but preserved central vision."
    explanation: Presenting symptoms of the first c.759del proband.
  - reference: CGGV:assertion_958d5e41-ea0c-4497-af02-56d6ed3cd341-2023-03-02T170000.000Z
    reference_title: "RDH12 / RDH12-related dominant retinopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RDH12-related dominant retinopathy is associated with late onset cases typically diagnosed as retinitis pigmentosa with a milder phenotype, characterized by nyctalopia and visual field loss, but relatively preserved central vision."
    explanation: ClinGen summary of the presentation across the curated probands.
- name: Constriction of peripheral visual field
  category: Ophthalmological
  phenotype_term:
    preferred_term: Constricted visual fields
    term:
      id: HP:0001133
      label: Constriction of peripheral visual field
  evidence:
  - reference: PMID:34031043
    reference_title: "Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Visual acuity ranged from -0.1 to 0.2 logMAR. Affected individuals had constricted visual fields."
    explanation: Constricted fields with good acuity in the British family.
  - reference: PMID:32322264
    reference_title: "Novel Heterozygous Deletion in Retinol Dehydrogenase 12 (RDH12) Causes Familial Autosomal Dominant Retinitis Pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After this he began to notice nyctalopia and progressive visual field loss. He maintains good central and color vision."
    explanation: Progressive field loss with preserved central vision in the second c.759del proband.
- name: Rod-cone dystrophy
  category: Ophthalmological
  phenotype_term:
    preferred_term: Rod-cone dystrophy (retinitis pigmentosa)
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
  evidence:
  - reference: PMID:18779497
    reference_title: "Association of a novel mutation in the retinol dehydrogenase 12 (RDH12) gene with autosomal dominant retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nineteen family members had a mild form of RP."
    explanation: Mild retinitis pigmentosa in all affected members of the founding family.
  - reference: PMID:34031043
    reference_title: "Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This novel heterozygous variant RDH12 c.763delG is associated with a rod-cone dystrophy with variable expression."
    explanation: Rod-cone dystrophy in the British family.
- name: Abnormal electroretinogram
  category: Ophthalmological
  phenotype_term:
    preferred_term: Rod-cone pattern of ERG dysfunction
    term:
      id: HP:0000512
      label: Abnormal electroretinogram
  evidence:
  - reference: PMID:34031043
    reference_title: "Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Full-field electroretinography demonstrated a rod-cone pattern of dysfunction and large-field pattern electroretinography identified peripheral macular dysfunction."
    explanation: Full-field and pattern ERG abnormalities.
- name: Spicular pigmentation of the retina
  category: Ophthalmological
  description: Mid-peripheral bone-spicule pigmentation.
  phenotype_term:
    preferred_term: Bone-spicule pigmentation
    term:
      id: HP:0007737
      label: Spicular pigmentation of the retina
  evidence:
  - reference: PMID:32322264
    reference_title: "Novel Heterozygous Deletion in Retinol Dehydrogenase 12 (RDH12) Causes Familial Autosomal Dominant Retinitis Pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "fundus examination showed mild waxy disc pallor with retinal vessel attenuation and mid-peripheral bone-spicules."
    explanation: Fundus findings of the first c.759del proband.
- name: Attenuation of retinal blood vessels
  category: Ophthalmological
  phenotype_term:
    preferred_term: Retinal vessel attenuation
    term:
      id: HP:0007843
      label: Attenuation of retinal blood vessels
  evidence:
  - reference: PMID:32322264
    reference_title: "Novel Heterozygous Deletion in Retinol Dehydrogenase 12 (RDH12) Causes Familial Autosomal Dominant Retinitis Pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "fundus examination showed mild waxy disc pallor with retinal vessel attenuation and mid-peripheral bone-spicules."
    explanation: Vessel attenuation in the first c.759del proband; the second proband's fundus was described as similar.
- name: Optic disc pallor
  category: Ophthalmological
  description: Mild waxy pallor of the optic disc.
  phenotype_term:
    preferred_term: Waxy optic disc pallor
    term:
      id: HP:0000543
      label: Optic disc pallor
  evidence:
  - reference: PMID:32322264
    reference_title: "Novel Heterozygous Deletion in Retinol Dehydrogenase 12 (RDH12) Causes Familial Autosomal Dominant Retinitis Pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "fundus examination showed mild waxy disc pallor with retinal vessel attenuation and mid-peripheral bone-spicules."
    explanation: Waxy disc pallor in the first c.759del proband.
- name: Perifoveal ring of hyperautofluorescence
  category: Ophthalmological
  description: >-
    A parafoveal (and peripapillary) ring of hyperautofluorescence that
    constricts with progression as perifoveal hypoautofluorescence spreads
    inward. The HPO term names the perifoveal ring; the sources describe it as
    parafoveal. Peripapillary sparing of the RPE was seen in every affected
    member of the British family.
  phenotype_term:
    preferred_term: Parafoveal ring of hyperautofluorescence
    term:
      id: HP:0030629
      label: Perifoveal ring of hyperautofluorescence
  evidence:
  - reference: PMID:34031043
    reference_title: "Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A parafoveal and peripapillary ring of hyper-autofluorescence was seen initially, and with progression the area of perifoveal hypo-autofluorescence increased to involve the parafoveal area."
    explanation: The autofluorescence ring and its progression.
  - reference: PMID:32322264
    reference_title: "Novel Heterozygous Deletion in Retinol Dehydrogenase 12 (RDH12) Causes Familial Autosomal Dominant Retinitis Pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was salient hypo- and hyper-autofluorescence rings present on short-wavelength fundus autofluorescence (FAF) and residual foveal island on SD-OCT (Figure 3)."
    explanation: The same ring pattern around a residual foveal island in the c.759del proband.
- name: Central thinning of the outer nuclear layer
  category: Ophthalmological
  description: Mild foveal thinning of the total retina and of the outer nuclear layer on OCT.
  phenotype_term:
    preferred_term: Thinning of the foveal outer nuclear layer
    term:
      id: HP:6000367
      label: Central thinning of the outer nuclear layer of the retina
  evidence:
  - reference: PMID:34031043
    reference_title: "Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mild retinal thinning was identified on OCT imaging with reduction in both foveal total retinal and outer nuclear layer thickness."
    explanation: Foveal outer nuclear layer thinning in the British family.
- name: Macular edema
  category: Ophthalmological
  description: Parafoveal macular edema in both eyes of one c.759del proband; not reported in the other families.
  phenotype_term:
    preferred_term: Parafoveal macular edema
    term:
      id: HP:0040049
      label: Macular edema
  evidence:
  - reference: PMID:32322264
    reference_title: "Novel Heterozygous Deletion in Retinol Dehydrogenase 12 (RDH12) Causes Familial Autosomal Dominant Retinitis Pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Parafoveal macular edema was present in both eyes."
    explanation: A single-patient observation.
genetic:
- name: RDH12
  gene_term:
    preferred_term: RDH12
    term:
      id: hgnc:19977
      label: RDH12
  association: >-
    Causative heterozygous frameshift variants in the penultimate coding exon
    that are predicted to escape nonsense-mediated decay and encode a protein
    with a shared novel C-terminal peptide.
  variant_origin: GERMLINE
  notes: >-
    relationship_type is deliberately left unset. The schema defines CAUSATIVE
    as corresponding to ClinGen Definitive or Strong, and ClinGen rates this
    pair Moderate (three variants in four probands); no other
    GeneDiseaseRelationshipEnum value describes a defining gene with moderate
    validity. Two further heterozygous variants reported in single RP patients,
    c.680_684delinsT p.(Ala227Valfs*50) and c.121G>T p.(Val41Leu), lack
    segregation data and are not curated here.
  gene_disease_validity:
  - validity_classification: MODERATE
    classified_by: CLINGEN
    external_id: CGGV:assertion_958d5e41-ea0c-4497-af02-56d6ed3cd341-2023-03-02T170000.000Z
    evidence:
    - reference: CGGV:assertion_958d5e41-ea0c-4497-af02-56d6ed3cd341-2023-03-02T170000.000Z
      reference_title: "RDH12 / RDH12-related dominant retinopathy (Moderate)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "RDH12 | HGNC:19977 | RDH12-related dominant retinopathy | MONDO:0800100 | AD | Moderate"
      explanation: ClinGen gene-disease validity record classifying this pair as Moderate.
  evidence:
  - reference: CGGV:assertion_958d5e41-ea0c-4497-af02-56d6ed3cd341-2023-03-02T170000.000Z
    reference_title: "RDH12 / RDH12-related dominant retinopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This curation includes three frameshift variants that have been reported in 4 probands in 3 publications (PMIDs: 18779497, 32322264, 34031043)."
    explanation: ClinGen's summary of the genetic evidence.
  - reference: CGGV:assertion_958d5e41-ea0c-4497-af02-56d6ed3cd341-2023-03-02T170000.000Z
    reference_title: "RDH12 / RDH12-related dominant retinopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the difference in inheritance pattern and phenotypic variability between autosomal dominant and autosomal recessive cases led them to be split into separate disease entities"
    explanation: ClinGen's reason for curating the dominant disease separately from LCA13.
  variants:
  - name: c.778del p.(Glu260Argfs*18)
    synonyms:
    - 776delG
    - c.778delG
    description: >-
      The founding dominant allele, segregating in a six-generation American
      family with 19 affected members; first annotated as 776delG.
    evidence:
    - reference: PMID:18779497
      reference_title: "Association of a novel mutation in the retinol dehydrogenase 12 (RDH12) gene with autosomal dominant retinitis pigmentosa."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A frameshift mutation (776delG) was detected in all affected family members and was not detected in 158 control subjects."
      explanation: Identification and segregation of the allele.
  - name: c.759del p.(Phe254Leufs*24)
    description: >-
      Found heterozygous in two unrelated families (an Israeli family of
      Tunisian paternal descent and an English family); absent from gnomAD.
    evidence:
    - reference: PMID:32322264
      reference_title: "Novel Heterozygous Deletion in Retinol Dehydrogenase 12 (RDH12) Causes Familial Autosomal Dominant Retinitis Pigmentosa."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This variant has not been reported on gnomAD."
      explanation: Population absence of the variant.
    - reference: PMID:34216980
      reference_title: "Generation of two human iPSC lines from patients with autosomal dominant retinitis pigmentosa (UCLi014-A) and autosomal recessive Leber congenital amaurosis (UCLi015-A), associated with RDH12 variants."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "This variant is predicted to result in premature termination and expression of a truncated protein."
      explanation: Predicted consequence for the allele carried by the patient iPSC line.
  - name: c.763del p.(Val255Serfs*23)
    synonyms:
    - c.763delG
    description: >-
      Segregating in a four-generation British family with eight affected
      carriers, including one carrier identified only by adaptive optics imaging.
    evidence:
    - reference: PMID:34031043
      reference_title: "Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Eight family members were confirmed as affected by genotyping heterozygous for RDH12 c.763delG."
      explanation: Segregation of the allele in the British family.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Diagnosis rests on finding one of the penultimate-exon frameshifts in a
    patient with dominant-pattern rod-cone dystrophy, usually on a retinal gene
    panel or genome sequencing. Because RDH12 is mainly a recessive gene, a
    single heterozygous RDH12 variant needs to be interpreted with its position
    and predicted gain-of-function effect in mind, and with segregation in the
    family.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:34031043
    reference_title: "Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is important to correctly apply the interpretation guidelines with the predicted dominant RDH12-disease association, since we note it is gain of function and not loss of function."
    explanation: The interpretive caveat for a dominant allele in a mostly recessive gene.
- name: Adaptive Optics Retinal Imaging
  description: >-
    Adaptive optics scanning light ophthalmoscopy with short-wavelength
    autofluorescence detected disease in a minimally symptomatic carrier whose
    fundus, OCT and ERG were normal, so deep phenotyping can change whether a
    relative is classed as affected.
  evidence:
  - reference: PMID:34031043
    reference_title: "Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One individual with incomplete penetrance, was identified as clinically affected primarily on the basis of AO imaging."
    explanation: Adaptive optics identified an otherwise unrecognised affected carrier.
treatments:
- name: Genetic Counseling
  description: >-
    Counseling for a dominant disorder with variable expressivity, in a gene
    whose other disease is recessive. Each child of an affected parent has a
    one in two chance of inheriting the variant, and a carrier may have only
    subclinical signs.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:35994252
    reference_title: "Clinical and Genetic Analysis of RDH12-Associated Retinopathy in 27 Chinese Families: A Hypomorphic Allele Leads to Cone-Rod Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "provide new insights for the genetic counseling of patients harboring RDH12 variants"
    explanation: Genotype-specific counseling for the dominant and recessive RDH12 forms.
experimental_models:
- name: RDH12 c.759del patient iPSC-derived retinal organoids
  experimental_model_type: ORGANOID
  description: >-
    Retinal organoids differentiated from the UCLi014-A iPSC line, made from a
    32-year-old man heterozygous for c.759del, compared with an unrelated
    age- and sex-matched control, to week 44. The only disease model of the
    dominant form; no animal model carries a dominant allele.
  cell_source: Patient-derived human induced pluripotent stem cells (UCLi014-A)
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:40365019
  modeled_mechanisms:
  - target: Photoreceptor Segment Shortening and Loss
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Patient organoids develop normally and then show fewer photoreceptors
      with shorter segments late in differentiation, in keeping with the late
      onset of the human disease.
    limitations: >-
      One patient line against one unrelated control, with no isogenic
      correction, so genetic background is not controlled. Organoids resemble
      peripheral rather than macular retina, lack RPE, and the electron
      microscopy counts come from two organoids per line. No increase in cell
      death was detected, so the organoid does not show how photoreceptors are
      lost.
    readouts:
    - name: Photoreceptor number and segment length
      target: Photoreceptor Segment Shortening and Loss
      direction: DECREASED
      evidence:
      - reference: PMID:40365019
        reference_title: "Dominant RDH12-retinitis pigmentosa impairs photoreceptor development and implicates cone involvement in retinal organoids."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "however, transmission electron microscopy at week 37 showed that photoreceptors were less abundant and shorter in length."
        explanation: The structural readout behind the link.
    evidence:
    - reference: PMID:40365019
      reference_title: "Dominant RDH12-retinitis pigmentosa impairs photoreceptor development and implicates cone involvement in retinal organoids."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Our study is the first to describe an RDH12-AD disease model with pathology at later stages of photoreceptor differentiation, in keeping with the milder disease course seen in humans."
      explanation: The authors' own statement of what the model reproduces.
  - target: Disrupted Vitamin A Pathway and Cone Phototransduction Gene Expression
    relationship: MEASURES
    fidelity: UNKNOWN
    model_scale: CELLULAR
    description: >-
      Bulk RNA sequencing of week-44 organoids, the only source for this node.
    limitations: >-
      Transcript levels only; no retinoid or enzyme-activity measurement, no
      isogenic control, and cone dysfunction is inferred from marker expression.
    evidence:
    - reference: PMID:40365019
      reference_title: "Dominant RDH12-retinitis pigmentosa impairs photoreceptor development and implicates cone involvement in retinal organoids."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "hence, isogenic controls would help validate these results"
      explanation: The authors note the need for isogenic controls.
datasets:
- accession: geo:GSE271751
  title: Dominant RDH12-retinitis pigmentosa impairs photoreceptor development and cone function in retinal organoids
  description: >-
    Bulk RNA sequencing of week-44 retinal organoids from an RDH12 c.759del
    patient iPSC line and an unrelated unaffected control.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  publication: PMID:40365019
  notes: Accession named in the data availability statement of PMID:40365019; title is GEO's own.
differential_diagnoses:
- name: Leber congenital amaurosis 13
  disease_term:
    preferred_term: Leber congenital amaurosis 13
    term:
      id: MONDO:0012990
      label: Leber congenital amaurosis 13
  description: >-
    The allelic recessive RDH12 disease, curated as Leber_Congenital_Amaurosis_13.
    It is caused by biallelic loss-of-function variants and presents in early
    childhood with severe visual loss and early macular atrophy, whereas the
    dominant disease is caused by one penultimate-exon frameshift and spares
    central vision until late.
  distinguishing_features:
  - One heterozygous penultimate-exon frameshift with dominant transmission, against two loss-of-function alleles.
  - Late onset with good acuity, against early-onset severe visual impairment.
  - A typical retinitis pigmentosa autofluorescence ring around a residual foveal island, against variegated, petal-shaped macular atrophy.
  evidence:
  - reference: PMID:18779497
    reference_title: "Association of a novel mutation in the retinol dehydrogenase 12 (RDH12) gene with autosomal dominant retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This phenotype is dramatically different from the other disease associated with mutation in this gene, autosomal recessive Leber congenital amaurosis."
    explanation: The founding report contrasts the two allelic diseases.
  - reference: PMID:35994252
    reference_title: "Clinical and Genetic Analysis of RDH12-Associated Retinopathy in 27 Chinese Families: A Hypomorphic Allele Leads to Cone-Rod Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among patients with adRP with accessible clinical data, none had a BCVA <0.6, which was significantly better than that of patients with recessive RDH12-associated retinopathy"
    explanation: Better acuity in dominant than in recessive RDH12 disease.
  - reference: PMID:32322264
    reference_title: "Novel Heterozygous Deletion in Retinol Dehydrogenase 12 (RDH12) Causes Familial Autosomal Dominant Retinitis Pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This circular pattern is more reminiscent of RP than classic recessive RDH12 retinopathy"
    explanation: The imaging pattern differs from recessive disease.
discussions:
- discussion_id: rdh12_ad_gain_vs_dominant_negative
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#NMD-Escaping Transcript Encoding RDH12 With a Novel C-Terminus
  - pathophysiology#Toxic Gain of Function of the Aberrant C-Terminal Peptide
  - pathophysiology#Dominant-Negative Interference With Wild-Type RDH12
  prompt: >-
    Does the shared C-terminal peptide of the dominant RDH12 frameshift protein
    act through a toxic gain of function or by interfering with wild-type RDH12?
  rationale: >-
    Both mechanisms are proposed in the same small literature and neither has
    been tested: the mutant protein has not been detected separately from wild
    type, RDH12 dimerisation is inferred from a Drosophila ortholog, and the
    organoid transcriptome cannot separate the two. The answer decides the
    therapy. Allele-specific silencing of the mutant transcript, proposed by the
    British family's authors, would suffice under a toxic gain of function,
    because one normal allele is enough; under a dominant-negative mechanism
    silencing would also help, but gene supplementation could too.
  evidence:
  - reference: PMID:34031043
    reference_title: "Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "being able to switch off the dominant gain-of-function mutant allele using AON targeting would leave affected patients expressing 50% of normal RDH12 like an unaffected parent of an RDH12 LCA child."
    explanation: The proposed allele-specific antisense strategy and its rationale.
  - reference: PMID:32322264
    reference_title: "Novel Heterozygous Deletion in Retinol Dehydrogenase 12 (RDH12) Causes Familial Autosomal Dominant Retinitis Pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, further functional studies into the differences in disease mechanisms between autosomal recessive and autosomal dominant mutations are required."
    explanation: The authors state that the mechanism needs functional study.
  proposed_experiments:
  - experiment_id: rdh12_ad_isogenic_organoid_coexpression
    experiment_design: TARGETED_PERTURBATION
    name: Isogenic organoids and co-expression assays for the dominant RDH12 allele
    description: >-
      Correct c.759del in the patient iPSC line, and introduce it into a control
      line, then compare photoreceptor number, retinoid reductase activity and
      mutant protein level in the organoids. In parallel, co-express wild-type
      and frameshift RDH12 in cells to test whether the mutant protein binds
      wild-type RDH12 or reduces its activity, and whether the C-terminal
      peptide is toxic when fused to an unrelated protein.
    would_support:
    - pathophysiology#Dominant-Negative Interference With Wild-Type RDH12
    would_refute:
    - pathophysiology#Toxic Gain of Function of the Aberrant C-Terminal Peptide
    supporting_outcome:
    - >-
      The frameshift protein binds wild-type RDH12 and lowers its activity,
      while the peptide alone is not toxic, and correction restores
      photoreceptor number.
    refuting_outcome:
    - >-
      The peptide is toxic on its own and wild-type activity is unchanged by
      co-expression, favouring a gain of function.
references:
- reference: PMID:18779497
  title: "Association of a novel mutation in the retinol dehydrogenase 12 (RDH12) gene with autosomal dominant retinitis pigmentosa."
- reference: PMID:32322264
  title: "Novel Heterozygous Deletion in Retinol Dehydrogenase 12 (RDH12) Causes Familial Autosomal Dominant Retinitis Pigmentosa."
- reference: PMID:34031043
  title: "Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa."
- reference: PMID:40365019
  title: "Dominant RDH12-retinitis pigmentosa impairs photoreceptor development and implicates cone involvement in retinal organoids."
- reference: PMID:35994252
  title: "Clinical and Genetic Analysis of RDH12-Associated Retinopathy in 27 Chinese Families: A Hypomorphic Allele Leads to Cone-Rod Dystrophy."
- reference: PMID:20301590
  title: "Nonsyndromic Retinitis Pigmentosa Overview."
  tags:
  - GeneReviews
notes: >-
  Variant nomenclature differs across reports for the founding allele: Fingert
  et al. 2008 wrote 776delG, and later reports on NM_152443 write c.778del
  p.(Glu260Argfs*18). No GeneReviews chapter is specific to RDH12 dominant
  disease; the Nonsyndromic Retinitis Pigmentosa Overview covers RDH12 among
  many genes, and its cached abstract carries no RDH12-specific phenotype, so
  the phenotype baseline here comes from the four family reports and the
  ClinGen curation. MONDO also has a retinitis pigmentosa 53 class
  (MONDO:0800348) with no gene axiom; MedGen (C3150208) lists RP53 as an entry
  term of OMIM 612712, which MONDO maps to Leber congenital amaurosis 13
  (MONDO:0012990), so RP53 is not mapped to this dominant entry.
📚

References & Deep Research

References

6
PMID:18779497
Association of a novel mutation in the retinol dehydrogenase 12 (RDH12) gene with autosomal dominant retinitis pigmentosa.
No top-level findings curated for this source.
PMID:32322264
Novel Heterozygous Deletion in Retinol Dehydrogenase 12 (RDH12) Causes Familial Autosomal Dominant Retinitis Pigmentosa.
No top-level findings curated for this source.
PMID:34031043
Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa.
No top-level findings curated for this source.
PMID:40365019
Dominant RDH12-retinitis pigmentosa impairs photoreceptor development and implicates cone involvement in retinal organoids.
No top-level findings curated for this source.
PMID:35994252
Clinical and Genetic Analysis of RDH12-Associated Retinopathy in 27 Chinese Families: A Hypomorphic Allele Leads to Cone-Rod Dystrophy.
No top-level findings curated for this source.
PMID:20301590
Nonsyndromic Retinitis Pigmentosa Overview.
No top-level findings curated for this source.

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 (1)

Create: RDH12-Related_Dominant_Retinopathy · 2026-11-04T18:51:05Z · View source

New entry for the autosomal dominant RDH12 retinopathy (MONDO:0800100), curated separately from the recessive disease Leber_Congenital_Amaurosis_13 following the ClinGen lumping and splitting decision. Sources: the four published families (Fingert 2008, PMID:18779497; Sarkar 2020, PMID:32322264, two families with c.759del; Muthiah 2022, PMID:34031043), the patient iPSC line (PMID:34216980) and retinal organoid study (PMID:40365019, GEO GSE271751), a 27-family Chinese RDH12 cohort with a literature review of the dominant alleles (PMID:35994252), and the ClinGen Moderate (AD) gene-disease validity record, copied into gene_disease_validity. Normal RDH12 function is cited from PMID:15865448 and PMID:22621924 with the same grading used in the LCA13 entry. The mechanism is recorded as two alternative, untested hypotheses (toxic gain of function of the shared C-terminal peptide, and dominant-negative interference with wild-type RDH12), with haploinsufficiency recorded as deprecated and the reasons given. relationship_type is left unset because CAUSATIVE requires ClinGen Definitive or Strong. MONDO:0800348 (retinitis pigmentosa 53) is deliberately not mapped: MedGen C3150208 lists RP53 as an entry term of OMIM 612712, which MONDO maps to LCA13, so its scope is not this dominant disease. No GeneReviews chapter is specific to this disease; the Nonsyndromic Retinitis Pigmentosa Overview is tagged. The OpenScientist deep-research report (research/RDH12-Related_Dominant_Retinopathy-deep-research-openscientist.md) was read after the entry was drafted. Its reference validation resolved 13/13 references with 1/1 quotes found and none off topic; its term validation flagged needs_review, with four CURIEs named as different terms (for example UBERON:0005396 given as macula lutea, which is carotid artery segment, and HP:0000548 given for reduced cone density), none of which are bound here. just preflight-dr passed (RDH12 mentioned 62 times). The report did not cover the 2020 c.759del families or the 2025 organoid study, and described PMID:32322264 as a recessive deletion, so the entry relies on the primary papers; the report's statement that OMIM 612712 is LCA13 led to dropping a draft RP53 mapping. Checked with just validate, count-verified-snippets (all snippets verified), validate-terms, check-genereviews --online and the offline whole-repo gates.

OpenScientist ▸
1. Disease Information
openscientist-autonomous 2026-11-04T18:51:19.615386

1. Disease Information

Overview. RDH12-related dominant retinopathy is a rare inherited retinal dystrophy (IRD) transmitted in an autosomal dominant fashion and caused by specific heterozygous C-terminal frameshift variants in RDH12. Clinically it is a comparatively mild, late(r)-onset rod–cone dystrophy / retinitis pigmentosa with variable expressivity and incomplete penetrance — in sharp contrast to the severe, blinding, childhood-onset recessive disease caused by biallelic RDH12 loss-of-function. The first dominant family (Fingert et al. 2008, PMID 18779497 [human clinical]) had "a mild form of RP" with "late onset and relatively mild severity … dramatically different from the other disease associated with mutation in this gene, autosomal recessive Leber congenital amaurosis." The most completely characterized dominant pedigree (Muthiah et al. 2022, PMID 34031043 [human clinical]) reclassified the phenotype as a rod–cone dystrophy with variable expression.

Key identifiers. - MONDO: MONDO:0800100 (RDH12-related dominant retinopathy). - Gene OMIM: RDH12 608830. Phenotype OMIM: no distinct dominant phenotype MIM number is currently assigned; the recessive allelic disorder is "Leber congenital amaurosis 13" OMIM #612712. The dominant RP is described in the literature but not given its own MIM phenotype number (consistent with the template note "OMIM: not recorded"). - Orphanet: No dominant-specific ORPHA code; related umbrella entities are retinitis pigmentosa (ORPHA:791) and Leber congenital amaurosis (ORPHA:65). - ICD-11: 9B70 Retinitis pigmentosa / hereditary retinal dystrophy (9B70.0). ICD-10: H35.52 (pigmentary retinal dystrophy). - MeSH: Retinitis Pigmentosa (D012174); Retinal Dystrophies (D058499). - HGNC: 19977. UniProt: Q96NR8.

Synonyms / alternative names. Autosomal dominant RDH12-related retinal dystrophy; autosomal dominant RDH12 retinopathy; RDH12-associated autosomal dominant retinitis pigmentosa; RDH12 rod–cone dystrophy (dominant).

Information source. Disease-level aggregated resources (OMIM, ClinVar, gnomAD, Ensembl) plus individual-patient case series/pedigree studies (Fingert 2008; Muthiah 2022). No EHR-scale datasets exist for this ultra-rare entity.

2. Etiology

Primary cause — genetic. The disease is monogenic/Mendelian, caused by heterozygous pathogenic variants in RDH12. Reported dominant alleles are C-terminal single-nucleotide frameshifts clustering around codons 253–260: - c.776delG (776delG) — original dominant family (Fingert et al. 2008, PMID 18779497) [human clinical]. - c.763delG — four-generation British pedigree (Muthiah et al. 2022, PMID 34031043) [human clinical]. - c.759del, p.(Phe254Leufs*24) — dominant RP patient used to derive iPSC line UCLi014-A (Sarkar et al. 2021, PMID 34216980) [human clinical / in vitro].

Risk factors. - Genetic: The causal heterozygous RDH12 frameshift is the sole established determinant. A positive family history is the dominant risk indicator. No susceptibility loci or validated modifier genes are reported for the dominant form. - Environmental/other: No proven environmental, occupational, infectious, lifestyle, age, or sex risk factors. Light exposure is a biologically plausible modulator (RDH12 detoxifies light-generated retinaldehyde; Rdh12⁻/⁻ mice show light-induced photoreceptor apoptosis — Maeda et al. 2006, PMID 17032653 [model organism]), but no clinical evidence links ambient light to dominant-disease severity.

Protective factors. None established. Genotype itself is protective relative to the recessive disease: within the recessive spectrum, homozygosity for the hypomorphic p.Leu99Ile allele is associated with milder, later disease (Daich Varela et al. 2024, PMID 37714431 [human clinical]).

Gene–environment interactions. Not formally characterized. The inferred interaction is light/oxidative load × RDH12 dysfunction → aldehyde-driven photoreceptor stress (inferred, not demonstrated in dominant patients).

3. Phenotypes

The dominant phenotype is a mild rod–cone dystrophy / retinitis pigmentosa (Muthiah 2022, PMID 34031043; Fingert 2008, PMID 18779497) [human clinical]. Key features, with suggested HPO terms:

Phenotype Type Characteristics (onset / severity / course / frequency) HPO
Rod–cone dystrophy / retinitis pigmentosa clinical sign Adult/late onset; mild–moderate; slowly progressive; defining feature HP:0000510 (Retinitis pigmentosa), HP:0000548 (Cone/cone-rod dystrophy)
Reduced/constricted visual field sign Progressive peripheral constriction; present in affected adults HP:0001133 (Constriction of peripheral visual field), HP:0001123 (Visual field defect)
Relatively preserved central visual acuity sign VA −0.1 to 0.2 logMAR in affected (much better than recessive) HP:0000505 (Visual impairment, mild)
Macular/parafoveal atrophy; perifoveal hypo-autofluorescence with hyper-AF ring sign (imaging) Progressive; parafoveal/peripapillary hyper-AF ring → enlarging perifoveal hypo-AF HP:0007754 (Macular dystrophy), HP:0030506 (Yellow/altered autofluorescence)
Outer retinal / outer nuclear layer thinning (OCT) sign (imaging) Mild foveal total-retinal and ONL thinning HP:0030466 (Abnormal full-field ERG), HP:0011512 (abnormal photoreceptor)
Reduced cone density (adaptive optics) sign (imaging) Reduced along temporal meridian vs normative HP:0000548
Rod–cone ERG dysfunction lab/electrophysiology Rod-cone pattern; peripheral macular dysfunction on pattern ERG HP:0000512 (Abnormal electroretinogram), HP:0007984 (abnormal retinal physiology)
Nyctalopia (night blindness) symptom Typical of rod-predominant dystrophy HP:0000662 (Nyctalopia)

Note: The dominant disease generally lacks the devastating early features of recessive RDH12-LCA (congenital/early childhood blindness, universal macular atrophy from age 2, non-recordable ERG in infancy, dense bone-spicule pigmentation) documented in Fahim et al. 2019 (PMID 30979730) and Daich Varela & Michaelides 2022 (PMID 35491887) [human clinical].

Quality-of-life impact. Progressive peripheral field loss and night blindness impair mobility and night driving; relatively preserved central acuity means reading/face recognition are often retained longer than in the recessive disease. No disease-specific EQ-5D/SF-36/PROMIS data exist for the dominant form; IRDs broadly reduce vision-related QoL (NEI-VFQ).

4. Genetic / Molecular Information

Causal gene. RDH12 (HGNC:19977; OMIM 608830; Ensembl ENSG00000139988; chr14:67,701,886–67,734,451, GRCh38 [computational, gnomAD]). Encodes a 316-aa NADPH-dependent retinal reductase of the short-chain dehydrogenase/reductase (SDR) superfamily (UniProt Q96NR8; Pfam PF00106/adh_short; InterPro IPR002347).

Pathogenic variants (dominant). Heterozygous frameshift C-terminal variants: c.776delG, c.763delG, c.759del p.(Phe254Leufs24). These lie in the final coding region and are predicted to escape nonsense-mediated decay (NMD), producing a stable, altered truncated protein [computational inference]. - ACMG classification: dominant alleles are rare/private and functionally supported; recessive frameshifts here are classified Pathogenic/Likely pathogenic in ClinVar. - Allele frequency: dominant alleles are essentially absent from population databases (Fingert: not in 158 controls; gnomAD does not list these as recurrent) — consistent with private, family-specific mutations. - Origin: germline, segregating through pedigrees (AD). No somatic involvement. - Functional consequence: predicted gain of function / dominant-negative (Muthiah 2022, PMID 34031043): "predicted to result in a gain of function, that causes disease in a gene typically associated with biallelic (recessive) variants." Supported by gnomAD constraint [computational]: pLI = 7.8×10⁻⁵, LOEUF (oe_lof upper) = 0.889, obs/exp LoF = 0.617 — RDH12 tolerates heterozygous LoF*, so haploinsufficiency is not the mechanism.

Variant landscape (gene-wide, mostly recessive). ClinVar lists 674 variants for RDH12 [computational], dominated by frameshift and missense alleles distributed across the coding sequence (e.g., c.43del p.Leu15Cysfs4; c.146T>C p.Leu49Ser; c.295C>A p.Leu99Ile; c.701G>A p.Arg234His; c.759del p.Phe254Leufs24). The recessive common allele p.Leu99Ile (c.295C>A) was the most frequent variant (52/… alleles) in a South American cohort (Daich Varela et al. 2024, PMID 37714431) [human clinical].

Modifier genes / epigenetics / chromosomal abnormalities. None established for the dominant disease. No DNA-methylation/histone or large structural (CNV/translocation) mechanisms are implicated; a heterozygous RDH12 deletion has been reported in the recessive/compound setting (Sarkar et al. 2020, PMID 32322264).

Suggested ontology terms. Gene product GO: GO:0004745 (NAD(P)+-retinol dehydrogenase / all-trans-retinol dehydrogenase activity), GO:0052650 (all-trans-retinol dehydrogenase (NADP+) activity), GO:0042574 (retinal metabolic process), GO:0007601 (visual perception).

5. Environmental Information

No established environmental, toxic, radiation, occupational, dietary, lifestyle, or infectious causes/triggers. The only biologically relevant exogenous factor is light, which generates the all-trans-retinal substrate that RDH12 detoxifies (inferred modulator; CHEBI:17898 all-trans-retinal). No infectious agents are involved. [No data available for this disease specifically.]

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

  1. A heterozygous C-terminal frameshift in RDH12 (e.g., c.763delG, c.776delG, c.759del) results in an mRNA that escapes nonsense-mediated decay (last-exon rule) (inferred).
  2. This leads to expression of a stable mutant RDH12 protein with an altered/extended C-terminus (the C-terminus contains the amphipathic membrane-association region) (inferred; protein-level data limited).
  3. The mutant protein acts via a predicted gain-of-function / dominant-negative mechanism — it is not simple haploinsufficiency, because gnomAD shows RDH12 tolerates heterozygous LoF (pLI≈0) and recessive-allele carriers are unaffected [computational support]. The mutant is inferred to mislocalize and/or poison normal retinoid handling in the photoreceptor inner segment (inferred).
  4. Reduced effective RDH12 reductase activity results in impaired reduction of all-trans-retinal (atRAL) → all-trans-retinol (atROL) in the inner segment [in vitro: Belyaeva 2005 PMID 15865448; Sarkar 2021 PMID 34445569].
  5. atRAL and reactive lipid-peroxidation aldehydes (e.g., 4-HNE) accumulate, which leads to cytotoxicity and disrupted retinoid homeostasis [in vitro: Lee 2008 PMID 18396173].
  6. Aldehyde accumulation induces oxidative stress and the ER unfolded-protein response (upregulation of sXBP1, CHOP/DDIT3, ATF4) [in vitro: Sarkar 2021 PMID 34445569].
  7. Oxidative + ER stress results in photoreceptor apoptosis, branching to rod-predominant degeneration first (night blindness, peripheral field loss) and cone/macular involvement (central atrophy, reduced cone density) [model organism: zebrafish rdh12; human clinical: Muthiah 2022].
  8. Progressive photoreceptor loss manifests clinically as a slowly progressive rod–cone dystrophy/RP with macular atrophy — milder than the recessive disease because residual wild-type RDH12 and partial function persist (inferred).

Branch (recessive comparison): biallelic LoF → near-complete loss of RDH12 → severe early atRAL/aldehyde toxicity → fulminant childhood macular atrophy and LCA (Fahim 2019, PMID 30979730).

Mechanistic detail by category

  • Molecular pathways / biochemistry: Visual (retinoid) cycle; RDH12 reduces atRAL using NADPH (~2000-fold NADP(H) preference; highest catalytic efficiency for all-trans-retinal kcat/Km ≈ 900 min⁻¹ µM⁻¹) (Belyaeva 2005, PMID 15865448) [in vitro]. KEGG "Retinol metabolism" (hsa00830); Reactome "The canonical retinoid cycle in rods."
  • Cellular processes: apoptosis (GO:0006915), response to oxidative stress (GO:0006979/GO:0034599), ER unfolded-protein response (GO:0030968), autophagy alteration (reduced atg12), photoreceptor outer-segment phagocytosis disruption.
  • Protein dysfunction: loss of enzymatic reductase activity in mutants; for dominant alleles, a gain-of-function/dominant-negative stable product (vs misfolding/degradation seen with some missense recessive alleles).
  • Metabolic changes: accumulation of all-trans-retinal (CHEBI:17898) and toxic aldehydes (4-hydroxynonenal, CHEBI:58266); disturbed retinyl ester/retinoic acid balance (Lee 2008, PMID 18396173).
  • Immune involvement: none primary.
  • Tissue-damage mechanism: oxidative stress + aldehyde toxicity + ER stress → photoreceptor cell death.
  • Molecular profiling: iPSC lines (PMID 34216980) and HEK/ARPE-19 models (PMID 34445569; PMID 41683787) provide expression/functional data; no patient tissue transcriptomics/proteomics/metabolomics for the dominant form.

Cell types (CL): photoreceptor cell (CL:0000210), rod (CL:0000604), cone (CL:0000573); adjacent retinal pigment epithelial cell (CL:0002586). Subcellular (GO CC): photoreceptor inner segment (GO:0001917), endoplasmic reticulum membrane (GO:0005789), smooth ER / membrane-anchored.

7. Anatomical Structures Affected

  • Organ level: Eye (UBERON:0000970); specifically the retina (UBERON:0000966) and macula lutea (UBERON:0005396). Primary disease is confined to the eye; no systemic/secondary organ involvement (non-syndromic).
  • Tissue/cell level: Neural retina — photoreceptor layer; rod and cone photoreceptors (CL:0000604, CL:0000573); secondary RPE changes and inner retinal remodeling. Peripapillary sparing and macular/parafoveal atrophy are characteristic patterns.
  • Subcellular: Photoreceptor inner segment (RDH12 localization; GO:0001917), ER (stress response).
  • Localization & laterality: Bilateral and symmetric (HP:0012832 Bilateral). Regional: parafoveal/perifoveal and peripapillary (macula UBERON:0005396; optic disc region).

8. Temporal Development

  • Onset: Adult/late onset for the dominant disease — "late onset and relatively mild severity" (Fingert 2008, PMID 18779497). Variable; some mutation carriers are detectable only subclinically (e.g., on adaptive optics) reflecting incomplete penetrance (Muthiah 2022, PMID 34031043). Pattern is insidious/chronic. (Contrast recessive: congenital/early-childhood onset, mean 4.1 yr — Fahim 2019, PMID 30979730.)
  • Progression: Slowly progressive over decades; stages = early (ring of hyper-AF, mild field constriction) → intermediate (enlarging perifoveal atrophy, ONL thinning) → advanced (extensive outer-retinal atrophy, significant field loss) with relative central-acuity preservation until late. Lifelong chronic disease; no remission.
  • Critical periods / intervention window: Because photoreceptors persist for decades, there is a wide therapeutic window for the dominant disease (in contrast to the narrow infantile window in recessive disease, where early macular atrophy limits gene-replacement benefit).

9. Inheritance and Population

  • Inheritance: Autosomal dominant (AD) for MONDO:0800100 (Fingert 2008; Muthiah 2022). The gene far more commonly causes autosomal recessive LCA13.
  • Penetrance: Incomplete / age-dependent; penetrance determination is modality-dependent (subclinical carriers detected only by adaptive optics) (Muthiah 2022, PMID 34031043).
  • Expressivity: Variable (Muthiah 2022).
  • Anticipation: None reported (not a repeat-expansion disorder).
  • Germline mosaicism / founder effects / consanguinity: No founder effect or consanguinity role for the dominant alleles (private mutations; AD does not require consanguinity). Consanguinity is relevant only to the recessive disease.
  • Carrier frequency: Not applicable in the AD sense (dominant alleles are private). For recessive disease, heterozygous LoF carriers exist in gnomAD but are unaffected.
  • Epidemiology / prevalence: No reliable prevalence/incidence estimate exists for the dominant form — it is described in only a handful of pedigrees worldwide (ultra-rare). As gene-level context, RDH12 accounts for 3.4%–10.5% of LCA/EOSRD (Fahim 2019, PMID 30979730) — but these are predominantly recessive cases.
  • Demographics: Reported dominant families are of European (British/US) ancestry; too few to infer ethnic predilection, geographic clustering, sex ratio (expected ~1:1 for AD), or age distribution.

10. Diagnostics

  • Clinical/imaging tests (core):
  • Fundus autofluorescence (FAF): parafoveal/peripapillary hyper-AF ring, perifoveal hypo-AF (Muthiah 2022).
  • Spectral-domain OCT: foveal total-retinal and ONL thinning; outer-retinal disruption.
  • Adaptive optics scanning light ophthalmoscopy: reduced cone density (sensitive for subclinical carriers).
  • Full-field & pattern ERG: rod–cone pattern of dysfunction; peripheral macular dysfunction.
  • Visual fields (perimetry): peripheral constriction.
  • Fundus photography: variable pigmentary changes/macular atrophy.
  • Laboratory/biomarkers: No blood/urine biomarker or enzyme assay; diagnosis is clinical + genetic. (Research biomarker: all-trans-retinal/aldehyde handling, not clinical.)
  • Genetic testing (definitive): Single-gene / IRD gene-panel next-generation sequencing, whole-exome (WES) and whole-genome sequencing (WGS) identify the heterozygous RDH12 frameshift; segregation analysis across the pedigree confirms dominant transmission (Muthiah 2022 used NGS incl. WGS). Chromosomal microarray/karyotype/FISH/mtDNA/repeat-expansion testing are not indicated (point-level frameshift mechanism). RNA studies can confirm NMD escape (research).
  • Clinical criteria / differential diagnosis: No disease-specific criteria. Differentials: other dominant RP genes (RHO, PRPH2, RP1, PRPF31, NR2E3), cone–rod dystrophy genes (GUCA1A, CRX), and — critically — recessive RDH12-LCA/EOSRD (distinguished by congenital/severe early onset, universal early macular atrophy, non-recordable infantile ERG, biallelic variants). Genotyping + segregation resolves these.
  • Screening: Cascade genetic testing of at-risk relatives in known pedigrees (with adaptive-optics/FAF to detect subclinical carriers). No population newborn/carrier screening (ultra-rare, AD, private alleles).

11. Outcome / Prognosis

  • Survival/mortality: Not life-limiting; normal life expectancy. No disease-specific mortality (eye-restricted disorder).
  • Morbidity/function: Chronic visual disability — progressive peripheral field loss and nyctalopia with relatively preserved central acuity; prognosis is markedly better than the recessive disease, which causes childhood legal blindness. Within recessive RDH12, p.Leu99Ile homozygotes reach legal blindness at an older age (Daich Varela 2024, PMID 37714431) [human clinical].
  • Disease course/complications: Slowly progressive outer-retinal atrophy; possible late cystoid macular changes/cataract (general RP complications). No spontaneous recovery.
  • Prognostic factors: Specific variant, age, extent of macular atrophy on OCT/FAF, cone density on AO, residual field/ERG amplitude. No validated molecular prognostic biomarker.
  • QoL measures: No dominant-form-specific instruments reported; NEI-VFQ-25 applicable clinically.

12. Treatment

No approved disease-specific therapy exists for RDH12 retinopathy (Daich Varela & Michaelides 2022, PMID 35491887: "There is currently no treatment available for RDH12-retinopathy") [human clinical review].

  • Supportive/rehabilitative (standard of care): low-vision aids, orientation & mobility training, occupational therapy, refraction/glare control (tinted lenses), management of cataract/cystoid macular edema, genetic counseling. NCIT: C15277 (Rehabilitation Therapy), C15296 (Supportive Care).
  • Pharmacotherapy / mechanism-based (experimental, in vitro): Aldehyde/retinaldehyde scavengers — pregabalin attenuated atRAL-induced ER stress in mutant RDH12 cells (Sarkar 2021, PMID 34445569) [in vitro]; conceptually related scavengers (e.g., primary-amine trap drugs). Antioxidants/ER-stress modulators are candidate strategies. No clinical trials for the dominant form. NCIT: C47484 (Pregabalin); C275 (Antioxidant).
  • Gene therapy: AAV-mediated RDH12 gene augmentation is in preclinical development (patents held by Ali and Thompson groups per Fahim 2019, PMID 30979730; in-vitro rAAV-RDH12 functional studies, Pavlova et al. 2026, PMID 41683787) [in vitro / preclinical]. Caveat: gene augmentation (adding wild-type) treats loss-of-function recessive disease but may be insufficient for a dominant gain-of-function allele, which may instead require allele-specific knockdown/editing (ASO, siRNA, CRISPR). NCIT: C15431 (Gene Therapy); C117202 (AAV Vector).
  • Cell therapy / other advanced modalities: iPSC-derived retinal models exist for drug screening (PMID 34216980) but no clinical cell therapy. Not applicable: immunotherapy, targeted small molecules, surgery (beyond cataract).
  • Pharmacogenomics: Not applicable.

13. Prevention

  • Primary prevention: Not possible for a germline Mendelian disorder. Genetic counseling for affected AD families (50% transmission risk) with options for prenatal diagnosis and preimplantation genetic testing (PGT-M). NCIT: C15265 (Genetic Counseling).
  • Secondary prevention: Cascade genetic testing and ophthalmic surveillance (FAF/OCT/AO) of at-risk relatives for early detection; monitor for treatable complications (cataract, CME).
  • Tertiary prevention: Low-vision rehabilitation; avoidance of excessive light exposure is biologically rational (RDH12 clears light-generated aldehydes) though unproven clinically.
  • Immunization / public-health / behavioral / prophylaxis: Not applicable.

14. Other Species / Natural Disease

  • Taxonomy / orthologs: RDH12 is conserved in vertebrates — human (NCBI Gene 145226; Homo sapiens NCBI:txid9606), mouse Rdh12 (NCBI Gene 77974; Mus musculus NCBI:txid10090), zebrafish rdh12 (Danio rerio NCBI:txid7955). Orthology: Alliance of Genome Resources / HomoloGene.
  • Natural disease in other species: No well-established naturally occurring RDH12 retinopathy is cataloged in companion animals (no prominent OMIA entry); disease knowledge is from engineered models rather than spontaneous animal disease.
  • Comparative biology: The retinoid (visual) cycle and RDH12's atRAL-reductase role are evolutionarily conserved; however, mice do not recapitulate human severity (redundancy with other RDHs, lower retinoid flux), a key cross-species difference.
  • Transmission: Not applicable (non-infectious, non-zoonotic).

15. Model Organisms

  • Mouse (mammalian): Rdh12-knockout mice (MGI) — mild phenotype that fails to recapitulate human disease: slowed atRAL reduction and delayed dark adaptation, accelerated 11-cis-retinal production, and increased susceptibility to light-induced photoreceptor apoptosis (Maeda et al. 2006, PMID 17032653); grossly normal retinal histology at 10 months with normal ERG and retinoid levels (Kurth et al. 2007, PMID 17130236) [model organism]. Limitation: no spontaneous severe degeneration → poor efficacy model; useful for light-damage and retinoid-flux studies.
  • Zebrafish: CRISPR-Cas9 rdh12 mutant (rdh12^u533, c.17_23del; p.(Val6AlafsTer5)) shows disrupted outer-segment phagocytosis, rhodopsin mislocalization, reduced atg12/sod2 — early rod-predominant degeneration (Sarkar et al. 2021, PMID 34445569) [model organism]. Better captures degeneration/oxidative-ER-stress phenotype.
  • Cellular / in vitro: HEK-293 and ARPE-19 lines expressing WT vs mutant RDH12 for atRAL-toxicity, oxidative/ER-stress, and rAAV-RDH12 functional assays (PMID 34445569; PMID 41683787); purified-enzyme kinetics (PMID 15865448).
  • iPSC / organoids: Patient-derived iPSC line UCLi014-A from a dominant-RP patient (heterozygous c.759del p.(Phe254Leufs24)) and UCLi015-A from a recessive-LCA patient (Sarkar et al. 2021, PMID 34216980) — enabling retinal-organoid disease modeling, mechanism comparison, and drug screening [in vitro]. This dominant-patient iPSC line is the most directly relevant model for MONDO:0800100.*
  • Model databases: MGI (mouse), ZFIN (zebrafish), Cellosaurus (iPSC lines), Alliance of Genome Resources.

Summary of Evidence Types & Key Citations

  • Human clinical: PMID 18779497 (Fingert 2008, first dominant family, 776delG); PMID 34031043 (Muthiah 2022, c.763delG, deep phenotyping, GoF prediction); PMID 34216980 (dominant-patient iPSC, c.759del); PMID 30979730 (recessive natural history; RDH12 = 3.4–10.5% of LCA/EOSRD); PMID 37714431 (South American cohort, p.Leu99Ile); PMID 35491887 (review, no treatment).
  • In vitro: PMID 15865448 (enzyme kinetics); PMID 18396173 (4-HNE/aldehyde toxicity); PMID 34445569 (oxidative/ER stress, pregabalin rescue + zebrafish); PMID 41683787 (rAAV-RDH12).
  • Model organism: PMID 17032653 (light-induced apoptosis KO mouse); PMID 17130236 (KO mouse normal histology).
  • Computational / population genetics: gnomAD constraint (pLI≈0, LOEUF 0.89) — RDH12 tolerant of heterozygous LoF, arguing against haploinsufficiency.

Limitations

  • The dominant entity is ultra-rare (a few pedigrees); phenotype, penetrance, natural history, and epidemiology are based on small samples.
  • The gain-of-function/dominant-negative mechanism is predicted/inferred, not experimentally proven at the protein level for the dominant alleles.
  • Most mechanistic/therapeutic data derive from recessive, cell, or animal contexts and are extrapolated to the dominant disease.
  • No prevalence/incidence, QoL, or clinical-trial outcome data specific to the dominant form.

Future Directions

  • Protein-level studies (localization, stability, dominant-negative testing) of c.763delG/c.776delG/c.759del, ideally in patient iPSC-derived retinal organoids (UCLi014-A).
  • Allele-specific silencing/editing strategies appropriate to a dominant GoF allele, and testing aldehyde scavengers/antioxidants.
  • Natural-history registries and standardized imaging/functional outcome measures for the dominant phenotype.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.5.1.

Outcome Count
References checked 13
Resolved 13
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 1
Quoted claims not found in source 0
References weighed for topical relevance 13
On topic 10
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 36
Resolved 33
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 3
Terms whose name was checked 11
Terms named correctly 4
Terms named as a different term 4
Terms whose name is worth a second look 3

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:0800100 (5 mentions) - the report calls it "RDH12-related dominant retinopathy", "Fingert 2008; Muthiah 2022"; MONDO calls it RDH12-related dominant retinopathy
  • HP:0000548 (2 mentions) - the report calls it "Reduced along temporal meridian vs normative"; HP calls it Cone/cone-rod dystrophy
  • UBERON:0000970 (1 mention) - the report calls it "Organ level: Eye"; UBERON calls it eye**
  • UBERON:0005396 (2 mentions) - the report calls it "macula lutea"; UBERON calls it carotid artery segment

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:

  • HP:0000505 (1 mention) - the report calls it "Visual impairment, mild"; HP calls it Visual impairment
  • CHEBI:17898 (2 mentions) - the report calls it "Metabolic changes: accumulation of all-trans-retinal"; CHEBI calls it all-trans-retinal**
  • GO:0006915 (1 mention) - the report calls it "Cellular processes: apoptosis"; GO calls it apoptotic process**, and lists "activation of apoptosis" among its other names

Terms named inconsistently

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

  • MONDO:0800100 - called "RDH12-related dominant retinopathy", "Fingert 2008; Muthiah 2022"

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.