Blue Cone Monochromacy

Mendelian MONDO:0010563 Pathograph 27 Show in embeddings browser Cone dysfunction syndrome Inherited retinal disease

Blue cone monochromacy (BCM) is an X-linked cone dysfunction disorder caused by pathogenic configurations of the OPN1LW/OPN1MW opsin gene array on Xq28. Long- and middle-wavelength-sensitive cone function is absent or severely impaired, with vision predominantly mediated by S cones and rods. Disease mechanisms include deletions of the upstream locus control region (LCR), deletions of coding sequence, inactivating variants in single or multiple expressed opsin genes, and exon 3 haplotypes that cause aberrant splicing. Typical findings include reduced visual acuity, severe colour discrimination defects, infantile nystagmus, photophobia and myopia. S-cone function does not imply normal blue-yellow colour discrimination. Milder exon 3-associated phenotypes overlap with other opsin-related cone disorders. Foveal hypoplasia and macular structural abnormalities occur; progression varies among individuals and measures. Management supports vision and photophobia, while opsin gene augmentation remains investigational.

Ask OpenScientist

Ask a research question about Blue Cone Monochromacy. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

👪

Inheritance

X-linked recessive HP:0001419

Most affected individuals are hemizygous males, with usually clinically unaffected carrier females. Rare affected females have been reported with markedly skewed X-inactivation in blood and buccal samples; those measurements do not establish retinal X-inactivation. De novo rearrangements occur, so absence of family history does not exclude BCM.

X-linked recessive inheritance

Show evidence (3 references)

PMID:22998501 SUPPORT DIRECT BACKGROUND Human Clinical

"Blue cone monochromatism (BCM) is a rare cone dystrophy with recessive X-linked inheritance and therefore diagnosed in males whereas females are clinically unaffected."

States the inheritance mode and the sex distribution it produces.

PMID:22998501 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We present a female with clinically manifested BCM."

Direct observation of a manifesting female.

PMID:29940872 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The deletion was absent in the X-chromosomes of both the mother and transmitting grandfather."

Segregation supports a de novo event in a sporadic case.

Discussions and Knowledge Gaps

Is blue cone monochromacy a stationary cone dysfunction syndrome or a slowly progressive dystrophy, and how much of the disagreement is explained by genotype rather than by measurement sensitivity?

CONTROVERSY bcm_stationary_versus_progressive

Attached to

pathophysiology#Variable Foveal Cone Loss and Macular Degeneration phenotypes#Progressive Loss of Cone Function

Some families show clinical decline and macular atrophy, while other measurements remain stable over years. Cross-sectional age associations and genotype comparisons do not establish individual longitudinal rates. Quantifying change requires repeated genotype-resolved OCT and functional measures; human treatability cannot be read directly from mouse age or presence of non-waveguiding cells.

Proposed experiments

Longitudinal genotype-stratified AOSLO and microperimetry cohort

bcm_longitudinal_genotype_stratified_aoslo

Follow genetically resolved cohorts with repeated OCT, adaptive-optics imaging where feasible and cone-specific functional testing. Estimate within-person rates and measurement repeatability separately for deletion, coding and splice-associated genotypes.

Show evidence (3 references)

PMID:15094734 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In two families, psychophysical testing demonstrated evidence for progression of disease."

Evidence for the progressive side of the question.

PMID:10982039 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Progressive macular atrophy was observed in affected members of two BCM families while the rest of the families presented with normal fundus."

Shows that progression is a subset finding, which is the other side of the controversy.

PMID:30516820 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Patients with the C203R mutation, however, had decades-longer persistence of foveal photoreceptor outer nuclear layer thickness and a slower rate of development of inner segment/outer segment defects than did patients with large deletion mutations."

The retrospective 34-patient structural comparison supports genotype-associated differences; it does not predict an individual treatment window.

Does genotype at the opsin array predict the clinical phenotype, given that one series found no genotype-phenotype association while later structural work found deletion genotypes progress faster than Cys203Arg?

OPEN QUESTION bcm_genotype_phenotype_correlation

Attached to

pathophysiology#Loss of Function of the OPN1LW/OPN1MW Opsin Gene Array

Clinical severity, residual function and structural progression are different outcomes. The 2018 deletion/Cys203Arg comparison found a structural association, while exon 3 cohorts show milder average acuity and ERG abnormalities. Small cohorts, related patients and incomplete longitudinal data limit patient-specific prediction.

Show evidence (3 references)

PMID:10982039 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"No association was observed between the phenotypes and genotypes in these families."

The negative cross-sectional finding.

PMID:30516820 SUPPORT DIRECT PRIMARY RESULT Human Clinical

The retrospective 34-patient structural comparison supports genotype-associated differences; it does not predict an individual treatment window.

PMID:35400991 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Analysis of the clinical data revealed better best-corrected visual acuity, more severe myopia, and higher 30-Hz cone flicker responses in the patients with exon 3 haplotypes than in those with typical BCM."

The clinical cohort supports a milder average phenotype with important overlap.

Does concomitant GPR143 variation explain the phenotype in the reported opsin-variant family?

OPEN QUESTION bcm_gpr143_blended_phenotype

Attached to

phenotypes#Foveal Hypoplasia

One family had GPR143 splice variation, OPN1MW Cys203Arg and OPN1LW Ser143Pro, which the authors classified as a variant of uncertain significance. The report proposes a combined effect but lacks functional resolution of the individual contributions. Foveal hypoplasia also occurs in BCM cohorts without an established GPR143 diagnosis, so it is not evidence of a general modifier requirement.

Show evidence (3 references)

PMID:34445325 SUPPORT INDIRECT Human Clinical

"To our knowledge, this is the first case of foveal hypoplasia in a BCM patient and of mild clinical affection in a female carrier caused by the concomitant effect of variants in OPN1LW/OPN1MW and GPR143 genes, thus as the result of the simultaneous action of two independent genetic defects."

The authors propose a combined phenotype in one family. This supports discussion of a possible blended diagnosis, not an established general GPR143 modifier effect.

PMID:36186895 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Sixty-two of the total 89 ACHM patients (70%) had foveal hypoplasia, compared with 11 of 33 BCM patients (33%)."

The full-text OCT cohort documents foveal hypoplasia in BCM as well as ACHM.

PMID:34445325 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Indeed, though the novel mutation of the OPN1LW gene identified in this patient has been classified as a VUS, its disease causative role can be sustained by the following findings: the variant was not found in any queried public database; it is in a hemizygous state, inherited by the mother..."

The full text explicitly classifies the OPN1LW variant as uncertain despite the authors’ pathogenicity hypothesis.

⚙

Pathophysiology

Loss of Function of the OPN1LW/OPN1MW Opsin Gene Array

Pathogenic array configurations abolish or markedly reduce functional L- and M-opsin expression. They include LCR-only deletions, larger deletions removing regulatory and coding sequence, coding variants in a single residual or hybrid gene or in multiple expressed genes, and splice-disrupting exon 3 haplotypes. Cys203Arg is recurrent; Arg247Ter, Pro307Leu and functionally tested Met273Lys are additional examples. Array collapse followed by point mutation is one route, not a requirement for all BCM genotypes.

OPN1LW hgnc:9936 OPN1MW hgnc:4206

Genetic context functional_impact_category: LOSS_OF_FUNCTION

G protein-coupled photoreceptor activity GO:0008020 ↓ DECREASED

Downstream

Failure of Locus Control Region-Driven Opsin Expression For LCR-deletion genotypes, removal of the enhancer impairs expression from retained target genes.

Exon 3 Haplotype-Dependent Opsin Missplicing Splice-disrupting exon 3 haplotypes impair opsin transcript processing.

Absent or Non-Functional L and M Cone Photopigment Coding alleles can directly impair photopigment function; Met273Lys is supported by recombinant protein testing.

Show evidence (5 references)

PMID:8213841 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"As observed in an earlier study, the rearrangements involve either deletion of a locus control region adjacent to the gene array or loss of function via homologous recombination and point mutation."

Establishes the two dominant mutational routes that this node represents.

PMID:8213841 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Two other point mutations were identified: (a) Arg247-to-Ter in one subject with a single red-pigment gene and (b) Pro307-to-Leu in one subject with a single 5' red-3' green hybrid gene."

Documents the additional inactivating substitutions named in this node.

PMID:26153062 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In two families, we identified a novel founder mutation that consisted of a complex 3-kb deletion that embraced the cis-regulatory locus control region and insertion of an additional aberrant OPN1MW gene."

Documents the complex rearrangement class that PCR-based testing missed.

+ 2 more references

Failure of Locus Control Region-Driven Opsin Expression

Deletion of the upstream LCR removes an enhancer required for expression of the adjacent L/M opsin genes. LCR-only deletions can silence otherwise retained coding genes, whereas many larger deletions also remove part or all of those genes. Transgenic studies support competition between opsin promoters for LCR interaction. A 358-bp critical interval was inferred by patient deletion mapping, not established as an isolated minimal enhancer by a functional deletion assay.

retinal cone cell CL:0000573

regulation of DNA-templated transcription GO:0006355 ⚠ ABNORMAL

Downstream

Absent or Non-Functional L and M Cone Photopigment With the enhancer gone, neither opsin promoter is transcribed in cones that would otherwise express L or M opsin.

Show evidence (4 references)

PMID:1524826 SUPPORT DIRECT PRIMARY RESULT Model Organism

"a region between 3.1 kb and 3.7 kb 5' of the red pigment gene transcription initiation site is essential for expression"

Transgenic-mouse mapping of the enhancer whose deletion causes the disease.

PMID:1524826 SUPPORT DIRECT BACKGROUND Human Clinical

"Deletion of sequences 5' of the human red and green pigment gene array results in blue cone monochromacy, a disorder in which both red and green cone function are absent."

States the human genotype-phenotype relationship this node encodes.

PMID:11773636 SUPPORT DIRECT PRIMARY RESULT Model Organism

"The results support a model in which the mutually exclusive expression of these genes in their respective cone types is controlled by competition between visual pigment promoters for pairing with the LCR"

Gives the regulatory model — one LCR shared by both promoters — that makes a single deletion sufficient.

+ 1 more reference

Exon 3 Haplotype-Dependent Opsin Missplicing

Specific combinations of common exon 3 variants cause exon skipping. LIAVA minigenes show essentially complete loss of correctly spliced product, while LIVVA and other haplotypes retain variable amounts. Exon 3 skipping changes the reading frame and introduces a premature stop; nonsense-mediated decay is a proposed consequence. Assays using cDNA distinguish splicing from protein effects: LIAVA protein remains functional in mice, whereas LVAVA has additional protein-level defects in an overlapping cone dystrophy spectrum. Clinical severity depends on the other expressed opsin copies and promoter context.

RNA splicing GO:0008380 ⚠ ABNORMAL

Experimental models

Opsin exon 3 minigene splicing assays CELL LINE LIVVA retains approximately 3-5% correctly spliced transcript, whereas LIAVA has no detectable correctly spliced product in these assays.

Downstream

Absent or Non-Functional L and M Cone Photopigment Exon skipping prevents production of normal full-length opsin from the affected copy.

Show evidence (2 references)

PMID:35743313 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Applying minigene assays for all observed exon 3 haplotypes in the patients, we demonstrated that the novel exon 3 haplotype L-I-V-V-A induces a strong but incomplete splicing defect with 3-5% of residual correctly spliced transcripts."

Minigene assays establish incomplete exon 3 splicing for LIVVA.

PMID:28516000 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The only major RT-PCR product detected in the assay using a minigene derived from this subject's OPN1LWLIAVA gene lacked exon 3 and had exon 2 spliced directly to exon 4, introducing a frame shift and a premature translation termination codon seven codons past the exon 2/exon 4 splice junction."

The LIAVA minigene yields exon 3 skipping and a premature termination codon; decay itself was inferred.

Absent or Non-Functional L and M Cone Photopigment

Regulatory loss, coding deletion, splice defects and inactivating coding variants converge on reduced or absent functional L/M photopigment. Cys203Arg can cause misfolding and reduced opsin abundance; in mouse retina its equivalent C198R protein is undetectable or greatly reduced without the aggregates seen in transfected cells. Met273Lys recombinant opsin lacks normal absorption after reconstitution with retinal. The effects of different coding alleles should not be assumed to share a single toxic-aggregation mechanism.

L cone cell CL:0003048 M cone cell CL:0003049

phototransduction GO:0007602 ↓ DECREASED

G protein-coupled photoreceptor activity GO:0008020 ↓ DECREASED

Animal models

Opn1mw C198R knock-in mouse Mouse recapitulates The C198R substitution reduces M-opsin abundance and causes some mislocalization without detectable retinal aggregation.

Opn1mw knockout mouse Mouse recapitulates Cones lacking M-opsin, the null counterpart of the human deletion class.

Opn1mw knockout mouse Mouse rescues AAV5-mediated M-opsin expression restores partial middle-wavelength responses and outer-segment localization.

Opsin-null and C198R/S-opsin-null comparative models Mouse rescues Functional opsin delivery provides comparable rescue in the deletion and missense backgrounds, with diminishing efficacy at older treatment ages.

All-cone opsin-null model Mouse rescues AAV-delivered human L-opsin restores partial cone responses in the triple-knockout retina lacking endogenous M- and S-opsins.

All-cone C198R model Mouse rescues Human L-opsin gene augmentation restores cone responses despite the endogenous C198R mutant allele in an S-opsin-null, Nrl-null background.

Downstream

Cone Outer Segment Disruption Loss of functional cone opsin impairs outer-segment formation and maintenance.

Vision Mediated by Preserved S Cones and Rods When L/M cone function is lost, rod and S-cone pathways dominate the remaining visual responses.

Severe Colour Vision Defect Loss of L/M cone input produces severe colour discrimination deficits, with variable residual yellow-blue sensitivity.

Reduced Visual Acuity Loss of L/M cone-mediated high-acuity vision contributes to reduced acuity.

Severely Reduced Photopic Cone Electroretinogram Markedly impaired L/M cone activity produces diminished photopic responses.

Show evidence (4 references)

PMID:8213841 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"One inactivating mutation, Cys203-to-Arg, was found in 15 probands who carry single genes and in both visual pigment genes in one subject whose array has two genes."

Establishes Cys203Arg as the dominant inactivating substitution.

PMID:30065301 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The analysis of the recombinant proteins of M273K mutants revealed that the opsin with the M273K mutation was significantly detectable in the Western blot and cultured cells (Supplementary Fig. S2) but showed no absorbance at any of the wavelengths tested after reconstitution with 11-cis-retinal..."

Recombinant protein experiments demonstrate loss of pigment absorption for Met273Lys.

PMID:41941983 SUPPORT DIRECT PRIMARY RESULT In Vitro

"In in vitro studies, the mutant M-opsin on either human or murine backgrounds aggregated and was mislocalized in HEK293 cells."

The aggregation result is specific to transfected HEK293 cells.

+ 1 more reference

Cone Outer Segment Disruption

Reduced opsin disrupts outer-segment formation and maintenance. Patients have variable outer-retinal and ellipsoid-zone abnormalities. Mouse opsin-deficiency models have shortened or absent outer segments and reduced localization of phototransduction proteins; early gene augmentation can partially restore these structures. Human adaptive-optics imaging reveals non-waveguiding cells, but their spectral identity, functional competence and capacity for rescue are not established by morphology alone.

retinal cone cell CL:0000573

photoreceptor cell outer segment organization GO:0035845 ⚠ ABNORMAL

fovea centralis UBERON:0001786

Animal models

Opn1mw C198R knock-in mouse Mouse recapitulates Outer-segment loss can coexist with surviving cone cell bodies through six months in the S-opsin-expressing knock-in background.

Downstream

Variable Foveal Cone Loss and Macular Degeneration Outer-segment disruption accompanies later cone loss in the C198R/Opn1sw-null model; long-term human progression is variable.

Show evidence (3 references)

PMID:38060327 SUPPORT DIRECT PRIMARY RESULT Model Organism

"These results indicate that COSs are substantially shortened or missing in Opn1mwC198R Opn1sw–/– retinas."

The opsin-mutant, S-opsin-null model links pigment deficiency to abnormal cone outer segments.

PMID:39408969 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"AOSLO imaging showed reduced total cone density with majority of the population being non-waveguiding."

Direct structural measurement of the residual foveal cone population.

PMID:36301530 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Mean total cone density for Cys203Arg patients was 16,664 ± 11,513 cones/mm2 (n = 10), which is, on average, around 40% of normal."

Quantifies the residual foveal cone population by adaptive-optics imaging.

Variable Foveal Cone Loss and Macular Degeneration

Retinal imaging and some clinical family studies support progressive macular damage in a subset. A 2018 retrospective series compared 21 deletion and 13 Cys203Arg cases and found greater preservation of foveal structure in the latter group. Cross-sectional age associations must be distinguished from longitudinal change. In a 2024 cohort, seven patients had serial OCT over a median 6.5 years with variable structural changes; quantitative outer nuclear layer thickness showed no change, and the two patients with repeated adaptive-optics images had stable mosaics. Progression is neither absent in all BCM nor uniform across patients.

retinal cone cell CL:0000573

fovea centralis UBERON:0001786

Downstream

Progressive Macular Atrophy Progressive macular atrophy was documented in affected members of two families.

Show evidence (4 references)

PMID:30516820 SUPPORT DIRECT PRIMARY RESULT Human Clinical

The retrospective 34-patient structural comparison supports genotype-associated differences; it does not predict an individual treatment window.

PMID:10982039 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Progressive macular atrophy was observed in affected members of two BCM families while the rest of the families presented with normal fundus."

Documents macular atrophy in affected members of two families without establishing a patient-level prevalence.

PMID:39408969 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Quantitatively, ONL thickness showed no changes, but rod sensitivity losses appear to increase in most patients with age (Figure 7). Longitudinal AO images were available for two patients (P6, P7)."

Serial quantitative outer nuclear layer measurements were stable despite changes in some other measures.

+ 1 more reference

Vision Mediated by Preserved S Cones and Rods

S cones and rods provide most residual vision when L/M cone function is lost. Psychophysics shows that rods can mediate detection under conventional daylight testing conditions. S-cone sensitivity is often preserved, but blue-yellow colour discrimination can still be abnormal and varies with the test and illumination. Dark-adapted responses are commonly retained but can be subnormal; normal night vision or a normal S-cone response is not universal.

S cone cell CL:0003050 retinal rod cell CL:0000604

visual perception GO:0007601 ⚠ ABNORMAL

Show evidence (3 references)

PMID:25909963 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"BCM rods continue to signal vision under conditions normally associated with daylight vision."

Direct psychophysical demonstration that rods are carrying photopic vision, which is the claim this node makes.

PMID:25909963 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Short-wavelength (S-) sensitive cone function was normal or near normal in most patients."

Confirms S-cone sparing quantitatively rather than by inference from the genotype.

PMID:36692456 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The patients with BCM we studied with CAD showed different patterns of YB thresholds, with some patients having only moderate threshold elevations and others showing severely elevated thresholds."

All six CAD-tested patients had abnormal yellow-blue thresholds, with variable severity.

Carrier Female Cone Mosaic Disruption

Clinically unaffected female carriers may have altered cone mosaics. Four LCR-deletion carriers examined with adaptive-optics imaging had reduced cone density and irregular organization despite normal colour discrimination. X-inactivation and early loss of opsin-deficient cones are proposed explanations; retinal X-inactivation ratios and actual early cone death were not directly measured. A rare affected female had completely biased X-inactivation in blood and buccal DNA, which cannot establish the retinal pattern.

retinal cone cell CL:0000573

Show evidence (2 references)

PMID:20638402 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"On average, they had cone mosaics with reduced density and disrupted organization compared to normal trichromats."

The imaging result in LCR-deletion carrier females.

PMID:22998501 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The diagnosis was genetically verified with the identification of one single red-green OPN1LW/MW hybrid gene harboring a point mutation c.607C>G, p.Cys203Arg that associates with BCM and in addition a completely biased X-inactivation in DNA isolated from full blood and buccal mucosa."

The female case documents peripheral-tissue X-inactivation and an opsin-array variant. The quoted cDNA designation is reproduced as reported; retinal X-inactivation was not measured.

⬡

Pathograph

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

●

Phenotypes

Severe Colour Vision Defect Ophthalmologic HP:0000551

Show evidence (2 references)

PMID:36692456 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The patients with BCM we studied with CAD showed different patterns of YB thresholds, with some patients having only moderate threshold elevations and others showing severely elevated thresholds."

All six CAD-tested patients had abnormal yellow-blue thresholds, with variable severity.

PMID:15094734 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Affected males were shown to fail the protan and deutan axes, but retained good discrimination on the tritan axis of the MR test, a compelling evidence for residual colour vision in BCM."

The older cohort retained tritan discrimination on the MR test; this test-specific observation does not establish universal normal colour sensitivity.

Reduced Visual Acuity Ophthalmologic HP:0007663

Show evidence (1 reference)

PMID:10982039 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Acuities were reduced in all affected males, and photopic b-wave was reduced by more than 90% in seven families."

Establishes reduced acuity as universal across ten families.

Nystagmus Ophthalmologic HP:0000639

Onset: INFANTILE

Show evidence (1 reference)

PMID:10982039 SUPPORT DIRECT BACKGROUND Human Clinical

"Blue cone monochromacy (BCM) is an X-linked ocular disease characterized by poor visual acuity, nystagmus, and photodysphoria in males with severely reduced color discrimination."

Lists nystagmus among the defining clinical features.

Photophobia Ophthalmologic HP:0000613

Show evidence (1 reference)

PMID:10982039 SUPPORT DIRECT BACKGROUND Human Clinical

"Blue cone monochromacy (BCM) is an X-linked ocular disease characterized by poor visual acuity, nystagmus, and photodysphoria in males with severely reduced color discrimination."

Photodysphoria is the historical term for the light sensitivity recorded here.

Myopia Ophthalmologic HP:0000545

Show evidence (1 reference)

PMID:37001420 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"BCM patients typically suffer from poor visual acuity, severely impaired color discrimination, myopia, and nystagmus."

Lists myopia among the typical features.

Severely Reduced Photopic Cone Electroretinogram Electrophysiologic HP:0000512

Show evidence (2 references)

PMID:10982039 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Acuities were reduced in all affected males, and photopic b-wave was reduced by more than 90% in seven families."

Quantifies the photopic ERG reduction.

PMID:10982039 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In three families, however, the photopic b-wave response showed uncharacteristic relative preservation of 30-80% (of the clinical low-normal value)."

The exception that keeps this phenotype from being curated as invariably absent.

Progressive Macular Atrophy Ophthalmologic HP:0000608

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:10982039 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Progressive macular atrophy was observed in affected members of two BCM families while the rest of the families presented with normal fundus."

Documents macular atrophy in affected members of two families without establishing a patient-level prevalence.

Progressive Loss of Cone Function Ophthalmologic HP:0000529

Course: PROGRESSIVE

Show evidence (2 references)

PMID:15094734 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In two families, psychophysical testing demonstrated evidence for progression of disease."

Demonstrates progression psychophysically in a subset of families.

PMID:19421413 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"A novel mutation was detected in Family 2 that had a single hybrid gene lacking exon 2. This family presented clinical and psychophysical evidence of a slowly progressive phenotype."

Ties a progressive phenotype to a specific genotype, supporting genotype dependence.

Foveal Hypoplasia FREQUENT Ophthalmologic HP:0007750

Show evidence (1 reference)

PMID:36186895 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Sixty-two of the total 89 ACHM patients (70%) had foveal hypoplasia, compared with 11 of 33 BCM patients (33%)."

The full-text OCT cohort documents foveal hypoplasia in BCM as well as ACHM.

🧬

Genetic Associations

OPN1LW/OPN1MW opsin gene array (Genetic Mutation)

Gene: OPN1LW hgnc:9936 gene page relationship_type: CAUSATIVE

X-linked recessive

Show evidence (2 references)

PMID:26153062 SUPPORT DIRECT BACKGROUND Human Clinical

"Blue cone monochromacy (BCM) is an X-linked condition caused by a loss-of-function of both the OPN1LW and OPN1MW opsin genes."

States the two-gene loss-of-function requirement.

PMID:26153062 SUPPORT DIRECT BACKGROUND Human Clinical

"The cone opsin gene cluster is composed of 2-9 paralogs with 99.8% sequence homology and is susceptible to deletions, duplications, and mutations."

Explains the locus architecture that makes recurrent rearrangement the dominant mutational mechanism.

OPN1MW (Genetic Mutation)

Gene: OPN1MW hgnc:4206 gene page relationship_type: CAUSATIVE

X-linked recessive

Show evidence (1 reference)

PMID:10982039 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In one family no mutation was found in the exons of the red gene or the locus control region but showed loss of the complete green gene."

Documents the genotype in which the M gene is the demonstrable lesion.

Locus control region deletion (Genetic Mutation)

Gene: OPN1LW hgnc:9936 gene page relationship_type: CAUSATIVE

X-linked recessive

Show evidence (1 reference)

PMID:35759666 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"However, 90% of SVs encompass the upstream locus control region, an essential enhancer element. Its minimal functional extent based on deletion mapping in patients was refined to 358 bp."

Quantifies how often the enhancer is involved and gives the patient-derived minimal functional extent.

Structural variant landscape of the OPN1LW/OPN1MW cluster (Genetic Mutation)

Gene: OPN1MW hgnc:4206 gene page relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:35759666 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We found that about one-third (n = 73) of the 213 molecularly confirmed BCM families carry an SV, most commonly deletions restricted to the OPN1LW/OPN1MW gene cluster."

Quantifies the share of families with a structural variant.

PMID:35759666 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In total, 42 distinct SVs were identified, including 40 previously unreported SVs, thereby quadrupling the number of precisely mapped SVs underlying BCM. Notably, there was no "region of overlap" among these SVs."

Establishes both the diversity of variants and the absence of a common minimal region.

PMID:35759666 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Using parsimonious assumptions, we reconstructed the composition and copy number of the OPN1LW/OPN1MW gene cluster prior to the mutation event and found evidence that large gene arrays may be predisposed to the occurrence of SVs at this locus."

Links array size to structural-variant susceptibility, supporting the architectural argument.

Cys203Arg recurrent inactivating substitution (Genetic Mutation)

Gene: OPN1LW hgnc:9936 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:8213841 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"This mutation was also found in at least one of the visual pigment genes in 1 subject whose array has multiple genes and in 2 of 321 control subjects, suggesting that preexisting Cys203-to-Arg mutations constitute a reservoir of chromosomes that are predisposed to generate blue-cone-monochromat..."

The allele occurred in affected and control arrays; the authors propose recombination or conversion of pre-existing alleles. This does not exclude population-specific founders.

Splice-disrupting exon 3 haplotypes (Genetic Mutation)

Gene: OPN1LW hgnc:9936 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:35743313 SUPPORT DIRECT PRIMARY RESULT In Vitro

Minigene assays establish incomplete exon 3 splicing for LIVVA.

PMID:35400991 SUPPORT DIRECT PRIMARY RESULT Human Clinical

The clinical cohort supports a milder average phenotype with important overlap.

De novo opsin-array rearrangement (Genetic Mutation)

Gene: OPN1LW hgnc:9936 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:29940872 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The deletion was absent in the X-chromosomes of both the mother and transmitting grandfather."

Segregation supports a de novo event in a sporadic case.

💊

Medical Actions

Tinted Lenses and Low Vision Aids

Action: Supportive Care NCIT:C15747

Tinted lenses and low-vision aids can support photophobia and visual tasks. Refractive correction and individualized educational accommodations also form part of management. These measures do not restore the missing L/M photopigment.

Target Phenotypes: Photophobia HP:0000613

Show evidence (1 reference)

PMID:36932675 SUPPORT DIRECT BACKGROUND Human Clinical

"Current management includes the use of refractive corrective lenses, tinted lenses for disabling photophobia, and educational support."

Background clinical management description, not an intervention trial.

AAV-Mediated L-Opsin Gene Augmentation (investigational)

Action: Gene Therapy NCIT:C15238

Platform: Gene therapy

AAV delivery of functional L- or M-opsin is investigational. Mouse studies restore partial cone ERG responses and outer-segment structure, with age and model background affecting rescue. The 2025 comparison of DKO and C198R/Opn1sw-null mice found no significant genotype difference in therapeutic windows, and weaker responses in older animals. All-cone models also respond after treatment at five months. These studies do not establish a human age cutoff or efficacy. Intravitreal ADVM-062 produced new long-wavelength responses in gerbils and foveal transduction in nonhuman primates; mild ocular inflammation occurred at higher doses. Neither species was a human BCM treatment cohort.

Mechanism Target:

RESTORES Absent or Non-Functional L and M Cone Photopigment — Experimental supplementation supplies functional opsin to surviving cones. Structural rescue and partial electrophysiological rescue have been demonstrated in mouse models; restoration of human vision remains unproven.

Show evidence (1 reference)

PMID:38060327 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Together, these data demonstrate that when treated at 1 or 3 months of age, gene augmentation can provide structural and functional rescue to Opn1mwC198R Opn1sw–/– cones."

Direct experimental rescue in the specified mouse model.

Show evidence (3 references)

PMID:36932675 SUPPORT DIRECT PRIMARY RESULT Model Organism

"A single IVT administration dose of ADVM-062 effectively transduced gerbil cone photoreceptors and produced a de novo response to long-wavelength stimuli."

Preclinical proof that an intravitreally delivered L-opsin vector produces a new long-wavelength response, in an animal whose cone-rich retina naturally lacks L-opsin.

PMID:41286353 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Both DKO and C198R models show comparable therapeutic outcomes, with efficacy consistently decreasing in older mice."

Final peer-reviewed study supersedes the 2025 preprint.

PMID:36932675 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In-life observations were limited to dose-dependent non-adverse slight to mild ocular inflammation characterized by pigment and cells in the vitreous humor."

The primate toxicology study reports inflammation despite its non-adverse classification.

Reading and display adaptations

Action: Supportive Care NCIT:C15747

Individualize magnification, print size, screen brightness and contrast polarity. White text on a black background improved at least one reading parameter in 82% of a 17-person cohort; assess the individual response rather than assuming the same benefit for everyone.

Show evidence (1 reference)

PMID:33344057 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Reverse polarity showed better reading parameters than regular polarity in 82% of the patients."

Seventeen patients were studied; this supports individualized white-on-black reading adaptations, not universal benefit.

Genetic counselling and family testing

Action: Genetic Counseling NCIT:C15240

Counselling uses the resolved familial array configuration to explain X-linked transmission, rare symptomatic females and de novo rearrangements. Carrier analysis should account for complex gene copy number and may require segregation studies.

Show evidence (1 reference)

DOI:10.1038/s41525-022-00334-9 SUPPORT DIRECT Human Clinical

"It is of clinical importance to perform carrier status analysis of the OPN1LW/OPN1MW gene cluster to determine recurrence risk, especially in families with no family history of visual impairment, as shown in four cases in whom the pathogenic allele arose de novo ."

The diagnostic series supports family testing for recurrence-risk counselling.

🔬

Diagnosis

Full-Field Electroretinography

Assess light-adapted and dark-adapted full-field ERG and use S-cone-specific testing where available. Classic BCM has severe L/M dysfunction with retained S-cone and rod responses, but residual photopic responses and subnormal dark-adapted amplitudes occur. Oscillatory potentials from a standard dark-adapted mixed response did not distinguish BCM from achromatopsia in a comparative study. Integrate electrophysiology with molecular testing and clinical findings.

Show evidence (3 references)

PMID:10982039 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Acuities were reduced in all affected males, and photopic b-wave was reduced by more than 90% in seven families."

Quantifies the photopic reduction that anchors the ERG diagnosis.

PMID:38871951 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The comparison between ACHM and BCM didn't show any statistically significant differences in the electrophysiological parameters."

The exploratory mixed-response study does not supply a discriminatory ERG marker.

PMID:25909963 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Short-wavelength (S-) sensitive cone function was normal or near normal in most patients."

Confirms S-cone sparing quantitatively rather than by inference from the genotype.

Colour Vision Testing

Colour testing characterizes residual discrimination but cannot alone establish BCM. D-15 often shows protan/deutan confusion; MR testing may reveal residual tritan discrimination. CAD can distinguish moderate from severe yellow-blue deficits. Brightness cues, rod contribution, illumination and display limits complicate interpretation.

Show evidence (4 references)

PMID:15094734 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In addition, we have demonstrated that the Mollon-Reffin (MR) Minimal test is a useful colour-discrimination test to aid in the diagnosis of BCM."

Identifies the colour test with the best discriminating value here.

PMID:15094734 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We have confirmed the reported finding of protan-like D-15 arrangements of patients with BCM."

Documents the D-15 pattern.

PMID:36692456 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"With D-15, there was protan-deutan confusion and no bimodal tendency."

Characterizes the D-15 result pattern specific to this disorder.

+ 1 more reference

Molecular Testing of the Xq28 Opsin Array

Resolve the LCR, copy number, expressed-gene positions, coding variants and exon 3 haplotypes across the OPN1LW/OPN1MW array. Standard short-read sequencing has limited reliability at this highly homologous locus. Targeted long-range amplification and sequence analysis combined with deletion/copy-number testing are useful; a validated approach combines MLPA with long-read sequencing. Custom high-resolution Xq28 microarrays can resolve some rearrangements but should not be equated with routine genome-wide microarrays. Complex arrays and female carrier phasing may require family studies or additional structural analysis.

Genetic Testing NCIT:C15709

The 2022 assay series included 43 diagnostic and seven carrier samples across opsin-related conditions, not 50 BCM patients. Exact assignment can remain unresolved with four or more heterogeneous copies, and female alleles may require segregation to phase. A VUS or an isolated variant without the relevant array context does not establish BCM.

Show evidence (2 references)

DOI:10.1038/s41525-022-00334-9 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"A diagnostic genetic assay was developed for the OPN1LW/OPN1MW gene cluster, consisting of copy number analysis via multiplex ligation-dependent probe amplification and sequence analysis via long-read circular consensus sequencing."

The validated assay combines sequence and dosage analysis; the cohort contained several opsin-related diagnoses.

PMID:26153062 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Pathogenic alterations were revealed in all probands, characterized by sequencing of the breakpoint junctions and quantitative real-time PCR."

Demonstrates the diagnostic yield of the microarray approach.

Retinal imaging and longitudinal assessment

OCT characterizes foveal hypoplasia, outer nuclear layer thickness and ellipsoid-zone disruption. Adaptive-optics imaging is a specialist research measure of residual mosaics; analyzability depends on fixation and image quality. Imaging findings overlap with achromatopsia and cannot independently determine diagnosis, cone identity or treatment eligibility.

Show evidence (2 references)

PMID:36186895 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Sixty-two of the total 89 ACHM patients (70%) had foveal hypoplasia, compared with 11 of 33 BCM patients (33%)."

The full-text OCT cohort documents foveal hypoplasia in BCM as well as ACHM.

PMID:39408969 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"AOSLO imaging showed reduced total cone density with majority of the population being non-waveguiding."

Direct structural measurement of the residual foveal cone population.

📊

Prevalence

Worldwide

Point Prevalence

Approximately 1 in 100,000 is a commonly cited estimate, not a directly measured population prevalence in the cited review. Publications use differing population wording; a male-specific rate is not calculated from this estimate.

Show evidence (1 reference)

PMID:37001420 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"It is estimated that BCM affects approximately 1 in 100,000 people worldwide"

Source of the prevalence estimate.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Blue Cone Monochromacy:

Achromatopsia MONDO:0018852

Overlapping Features Achromatopsia is usually autosomal recessive and involves cone phototransduction or development genes rather than the X-linked L/M opsin array. Complete forms affect all cone classes, but incomplete disease and some GNAT2/PDE6C-associated cases can retain cone or short-wavelength responses. Phenotype, inheritance, appropriate ERG and molecular results must be integrated.

Distinguishing Features

Autosomal recessive inheritance and variants in achromatopsia genes support that diagnosis.
Complete achromatopsia lacks cone-mediated responses, but incomplete forms can overlap BCM.
Foveal hypoplasia was more frequent in achromatopsia than BCM in a comparative OCT cohort; its presence does not exclude BCM.
Neither retained tritan discrimination nor a single OCT feature independently settles the diagnosis.

Show evidence (2 references)

PMID:36186895 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Sixty-two of the total 89 ACHM patients (70%) had foveal hypoplasia, compared with 11 of 33 BCM patients (33%)."

The full-text OCT cohort documents foveal hypoplasia in BCM as well as ACHM.

PMID:36186895 SUPPORT DIRECT BACKGROUND Human Clinical

"Differences between these groups have been found in eye movements using electro-oculography,12 as well as in cone responses using electroretinography (ERG),4,11 although ERG presentation in BCM and both GNAT2- and PDE6C-related ACHM can be similar due to preservation of short-wavelength sensitivity.13,14"

The source describes diagnostic overlap, including retained short-wavelength sensitivity in some achromatopsia genotypes.

X-linked cone dystrophy

Overlapping Features OPN1LW/OPN1MW variants also cause Bornholm eye disease, isolated colour-vision deficiency and progressive cone dysfunction/dystrophy. Splicing haplotypes can produce overlapping mild BCM phenotypes. Array context, residual L/M function, myopia, acuity and longitudinal course determine the clinical interpretation.

Distinguishing Features

Bornholm eye disease often combines high myopia, red-green colour deficiency and residual cone responses.
Progressive cone dystrophy and mild BCM can overlap; a shared opsin variant alone does not resolve the label.

Show evidence (2 references)

PMID:37001420 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"X-linked retinal diseases resulting from mutations in the L- (OPN1LW, OMIM *300822) and M- (OPN1MW, OMIM *300821) opsin gene cluster are associated with a wide range of visual defects, including red/green color vision deficiency, X-linked cone dystrophy/dysfunction, high myopia with abnormal..."

Establishes that the same locus produces a spectrum of distinct diagnoses.

PMID:35400991 SUPPORT DIRECT PRIMARY RESULT Human Clinical

The clinical cohort supports a milder average phenotype with important overlap.

🔬

Clinical Trials

NCT06491615 NOT_APPLICABLE RECRUITING

eyeGENE Stage 3 expands DNA and phenotype repositories for rare inherited ophthalmic diseases, explicitly including blue cone monochromacy and potentially unaffected relatives. This is an observational research resource, not an opsin gene-therapy trial.

Show evidence (1 reference)

clinicaltrials:NCT06491615 SUPPORT DIRECT Other

"Objective: To collect information and DNA samples for the study of eye diseases."

The cached registry describes research sampling, not a treatment intervention.

🧫

Experimental Models

Opsin exon 3 minigene splicing assays CELL_LINE

Minigenes compare exon 3 haplotypes in HEK293 and a cone-like retinoblastoma cell line; the assays show similar relative splice defects in both systems.

Organism

Homo sapiens NCBITaxon:9606

Cell source

HEK293 and WERI-Rb1 retinoblastoma cells

Publication

PMID:35743313

Pathograph links

Exon 3 Haplotype-Dependent Opsin Missplicing recapitulates fidelity: moderate observes: molecular LIVVA retains approximately 3-5% correctly spliced transcript, whereas LIAVA has no detectable correctly spliced product in these assays.

Limitations: Engineered minigenes and tumor-derived cells do not reproduce the complete endogenous opsin array, retinal maturation or clinical course.

Show evidence (1 reference)

PMID:35743313 SUPPORT DIRECT PRIMARY RESULT In Vitro

Minigene assays establish incomplete exon 3 splicing for LIVVA.

Show evidence (1 reference)

PMID:35743313 SUPPORT DIRECT PRIMARY RESULT In Vitro

Minigene assays establish incomplete exon 3 splicing for LIVVA.

🐁

Animal Models

Opn1mw C198R knock-in mouse

Opn1mw C198R knock-in on an S-opsin-expressing background. The substitution is the murine equivalent of human Cys203Arg. It is distinct from the C198R/Opn1sw-null double mutant used in gene-therapy experiments.

Species

Mouse

Genotype

Opn1mw C198R knock-in (murine equivalent of human OPN1MW Cys203Arg)

Publication

PMID:41941983

Pathograph links

Absent or Non-Functional L and M Cone Photopigment recapitulates fidelity: moderate The C198R substitution reduces M-opsin abundance and causes some mislocalization without detectable retinal aggregation.

Limitations: Mouse cones commonly coexpress S-opsin, which can preserve function or structure. The retina lacks a human fovea and L-opsin; transfected-cell aggregation was not reproduced in retina.

Show evidence (1 reference)

PMID:41941983 SUPPORT DIRECT PRIMARY RESULT Model Organism

"The mutation diminished the expression of M-opsin with some apparent mislocalization of the cone opsin without aggregation, which resulted in the loss of cone outer segments in M-cone photoreceptor cells."

The mutant retina has diminished M-opsin expression and some mislocalization; the separate model link records the outer-segment consequence.

Cone Outer Segment Disruption recapitulates fidelity: moderate Outer-segment loss can coexist with surviving cone cell bodies through six months in the S-opsin-expressing knock-in background.

Limitations: Survival through six months in this background does not establish lifelong human cone survival or rule out degeneration in S-opsin-null models.

Show evidence (2 references)

PMID:41941983 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Despite the loss of cone outer segments, cone photoreceptor cells remained viable, even up to 6 months of age in hemizygous and homozygous mutant mice."

The dissociation between outer-segment loss and cone survival.

+ 1 more reference

Opn1mw knockout mouse

M-opsin-null mouse retaining endogenous S-opsin. AAV5-mediated mouse M-opsin supplementation restores partial middle-wavelength ERG responses after treatment at postnatal day 14 or three months.

Species

Mouse

Genotype

Opn1mw -/- (M-opsin knockout, expressing only S-opsin)

Publication

PMID:28751656

Pathograph links

Absent or Non-Functional L and M Cone Photopigment recapitulates fidelity: moderate Cones lacking M-opsin, the null counterpart of the human deletion class.

Limitations: S-opsin coexpression can preserve many murine cones; the model does not reproduce the isolated opsin deficit in human L/M cones or the human fovea.

Show evidence (1 reference)

PMID:28751656 SUPPORT DIRECT PRIMARY RESULT Model Organism

"We generated an M-opsin knockout mouse (Opn1mw -/-) expressing only S-opsin as a model for human BCM."

States the model's design intent.

Absent or Non-Functional L and M Cone Photopigment rescues fidelity: moderate AAV5-mediated M-opsin expression restores partial middle-wavelength responses and outer-segment localization.

Limitations: Rescue in a young mouse retina says nothing about the aged, largely non-waveguiding human foveal cone population that would actually be treated.

Show evidence (1 reference)

PMID:28751656 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Our study demonstrates that cones without M-opsin remain viable and respond to gene augmentation therapy, thereby providing proof-of-concept for cone function restoration in BCM patients."

The proof-of-concept result underpinning the investigational treatment.

Opsin-null and C198R/S-opsin-null comparative models

The 2025 study compares deletion and missense models without endogenous S-opsin compensation. Both show age-dependent declines in rescue; AAV8Y733F performs better than AAV5.

Species

Mouse

Genotype

Opn1mw -/-; Opn1sw -/- versus Opn1mw C198R; Opn1sw -/-

Publication

PMID:41286353

Pathograph links

Absent or Non-Functional L and M Cone Photopigment rescues fidelity: moderate Functional opsin delivery provides comparable rescue in the deletion and missense backgrounds, with diminishing efficacy at older treatment ages.

Limitations: Rod-dominant mouse retinas lack a fovea. Treatment age, capsid, promoter, injection variability and residual structure affect rescue. Candidate Pde6c/Cngb3 promoters were nominated by endogenous transcript persistence; their therapeutic benefit was not tested.

Show evidence (1 reference)

PMID:41286353 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Both DKO and C198R models show comparable therapeutic outcomes, with efficacy consistently decreasing in older mice."

Final peer-reviewed study supersedes the 2025 preprint.

All-cone opsin-null model

Nrl deletion generates a dense all-cone retina. Subretinal human L-opsin delivery at one or five months restores cone ERG and some outer-segment structure, with rescue detectable five months later.

Species

Mouse

Genotype

Opn1mw -/-; Opn1sw -/-; Nrl -/-

Publication

PMID:42157965

Pathograph links

Absent or Non-Functional L and M Cone Photopigment rescues fidelity: moderate AAV-delivered human L-opsin restores partial cone responses in the triple-knockout retina lacking endogenous M- and S-opsins.

Limitations: Nrl-null retinas have developmental rosettes and their own degeneration. Dense murine cones do not recreate human foveal anatomy or visual circuitry. Human durability and benefit are not established.

Show evidence (1 reference)

PMID:42157965 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Rescue effects persisted for at least 5 months post-treatment in both younger and older treated groups."

AAV-mediated rescue in the specified all-cone mouse background.

All-cone C198R model

The C198R missense allele is combined with Opn1sw and Nrl deletion to produce a dense all-cone retina. Human L-opsin delivery at one or five months restores cone ERG responses and some outer-segment structure, with rescue detectable five months later.

Species

Mouse

Genotype

Opn1mw C198R; Opn1sw -/-; Nrl -/-

Publication

PMID:42275379

Pathograph links

Absent or Non-Functional L and M Cone Photopigment rescues fidelity: moderate Human L-opsin gene augmentation restores cone responses despite the endogenous C198R mutant allele in an S-opsin-null, Nrl-null background.

Show evidence (1 reference)

PMID:42275379 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Treatment restored cone function, regenerated outer segment structures, and provided rescue for at least 5 months post-injection in both early- and late-treatment groups."

AAV-mediated rescue in the specified all-cone mouse background.

{ }

Source YAML

click to show

name: Blue Cone Monochromacy
creation_date: "2026-08-15T00:00:00Z"
category: Mendelian
parents:
- Cone dysfunction syndrome
- Inherited retinal disease
synonyms:
- BCM
- blue cone monochromatism
- S cone monochromacy
- S cone monochromatism
- X-linked incomplete achromatopsia
- X-chromosome-linked achromatopsia
disease_term:
preferred_term: Blue Cone Monochromacy
term:
id: MONDO:0010563
label: blue cone monochromacy
description: >-
Blue cone monochromacy (BCM) is an X-linked cone dysfunction disorder caused by pathogenic configurations
of the OPN1LW/OPN1MW opsin gene array on Xq28. Long- and middle-wavelength-sensitive cone function is absent
or severely impaired, with vision predominantly mediated by S cones and rods. Disease mechanisms include
deletions of the upstream locus control region (LCR), deletions of coding sequence, inactivating variants
in single or multiple expressed opsin genes, and exon 3 haplotypes that cause aberrant splicing. Typical
findings include reduced visual acuity, severe colour discrimination defects, infantile nystagmus, photophobia
and myopia. S-cone function does not imply normal blue-yellow colour discrimination. Milder exon 3-associated
phenotypes overlap with other opsin-related cone disorders. Foveal hypoplasia and macular structural abnormalities
occur; progression varies among individuals and measures. Management supports vision and photophobia, while
opsin gene augmentation remains investigational.
inheritance:
- name: X-linked recessive
inheritance_term:
preferred_term: X-linked recessive inheritance
term:
id: HP:0001419
label: X-linked recessive inheritance
description: >-
Most affected individuals are hemizygous males, with usually clinically unaffected carrier females. Rare
affected females have been reported with markedly skewed X-inactivation in blood and buccal samples; those
measurements do not establish retinal X-inactivation. De novo rearrangements occur, so absence of family
history does not exclude BCM.
evidence:
- reference: PMID:22998501
reference_title: Blue cone monochromatism in a female due to skewed X-inactivation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Blue cone monochromatism (BCM) is a rare cone dystrophy with recessive
X-linked inheritance and therefore diagnosed in males whereas females are
clinically unaffected.
explanation: >-
States the inheritance mode and the sex distribution it produces.
quote_role: BACKGROUND
directness: DIRECT
- reference: PMID:22998501
reference_title: Blue cone monochromatism in a female due to skewed X-inactivation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
We present a female with clinically manifested BCM.
explanation: >-
Direct observation of a manifesting female.
quote_role: PRIMARY_RESULT
- reference: PMID:29940872
reference_title: 'A 73,128 bp de novo deletion encompassing the OPN1LW/OPN1MW gene cluster in sporadic Blue Cone Monochromacy: a case report.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
The deletion was absent in the X-chromosomes of both the mother and transmitting grandfather.
explanation: >-
Segregation supports a de novo event in a sporadic case.
quote_role: PRIMARY_RESULT
prevalence:
- population: Worldwide
measure_type: POINT_PREVALENCE
notes: >-
Approximately 1 in 100,000 is a commonly cited estimate, not a directly measured population prevalence
in the cited review. Publications use differing population wording; a male-specific rate is not calculated
from this estimate.
evidence:
- reference: PMID:37001420
reference_title: Blue cone monochromacy and gene therapy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
It is estimated that BCM affects approximately 1 in 100,000 people worldwide
explanation: >-
Source of the prevalence estimate.
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
pathophysiology:
- name: Loss of Function of the OPN1LW/OPN1MW Opsin Gene Array
biological_scale: MOLECULAR
description: >-
Pathogenic array configurations abolish or markedly reduce functional L- and M-opsin expression. They include
LCR-only deletions, larger deletions removing regulatory and coding sequence, coding variants in a single
residual or hybrid gene or in multiple expressed genes, and splice-disrupting exon 3 haplotypes. Cys203Arg
is recurrent; Arg247Ter, Pro307Leu and functionally tested Met273Lys are additional examples. Array collapse
followed by point mutation is one route, not a requirement for all BCM genotypes.
genes:
- preferred_term: OPN1LW
term:
id: hgnc:9936
label: OPN1LW
- preferred_term: OPN1MW
term:
id: hgnc:4206
label: OPN1MW
genetic_context:
functional_impact_category: LOSS_OF_FUNCTION
downstream:
- target: Failure of Locus Control Region-Driven Opsin Expression
description: >-
For LCR-deletion genotypes, removal of the enhancer impairs expression from retained target genes.
causal_link_type: DIRECT
evidence:
- reference: PMID:1524826
reference_title: >-
A locus control region adjacent to the human red and green visual pigment
genes.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
a region between 3.1 kb and 3.7 kb 5' of the red pigment gene transcription
initiation site is essential for expression
explanation: >-
Transgenic-mouse mapping of the enhancer whose deletion causes the disease.
directness: DIRECT
quote_role: PRIMARY_RESULT
- target: Exon 3 Haplotype-Dependent Opsin Missplicing
description: >-
Splice-disrupting exon 3 haplotypes impair opsin transcript processing.
causal_link_type: DIRECT
evidence:
- reference: PMID:35743313
reference_title: Novel OPN1LW/OPN1MW Exon 3 Haplotype-Associated Splicing Defect in Patients with X-Linked Cone Dysfunction.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
Applying minigene assays for all observed exon 3 haplotypes in the patients, we demonstrated that the
novel exon 3 haplotype L-I-V-V-A induces a strong but incomplete splicing defect with 3-5% of residual
correctly spliced transcripts.
explanation: >-
Minigene assays establish incomplete exon 3 splicing for LIVVA.
quote_role: PRIMARY_RESULT
- target: Absent or Non-Functional L and M Cone Photopigment
description: >-
Coding alleles can directly impair photopigment function; Met273Lys is supported by recombinant protein
testing.
causal_link_type: DIRECT
evidence:
- reference: PMID:30065301
reference_title: 'Genotype determination of the OPN1LW/OPN1MW genes: novel disease-causing mechanisms in Japanese patients with blue cone monochromacy.'
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
The analysis of the recombinant proteins of M273K mutants revealed that the opsin with the M273K mutation
was significantly detectable in the Western blot and cultured cells (Supplementary Fig. S2) but showed
no absorbance at any of the wavelengths tested after reconstitution with 11-cis-retinal (Fig. 3C).
explanation: >-
Recombinant protein experiments demonstrate loss of pigment absorption for Met273Lys.
quote_role: PRIMARY_RESULT
evidence:
- reference: PMID:8213841
reference_title: Genetic heterogeneity among blue-cone monochromats.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
As observed in an earlier study, the rearrangements involve either deletion
of a locus control region adjacent to the gene array or loss of function via
homologous recombination and point mutation.
explanation: >-
Establishes the two dominant mutational routes that this node represents.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:8213841
reference_title: Genetic heterogeneity among blue-cone monochromats.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Two other point mutations were identified: (a) Arg247-to-Ter in one subject
with a single red-pigment gene and (b) Pro307-to-Leu in one subject with a
single 5' red-3' green hybrid gene.
explanation: >-
Documents the additional inactivating substitutions named in this node.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:26153062
reference_title: >-
High-resolution microarray analysis unravels complex Xq28 aberrations in
patients and carriers affected by X-linked blue cone monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In two families, we identified a novel founder mutation that consisted of a
complex 3-kb deletion that embraced the cis-regulatory locus control region
and insertion of an additional aberrant OPN1MW gene.
explanation: >-
Documents the complex rearrangement class that PCR-based testing missed.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: DOI:10.1126/science.2788922
reference_title: >-
Molecular Genetics of Human Blue Cone Monochromacy
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
One class arose from the wild type by a two-step pathway consisting of unequal
homologous recombination and point mutation. The second class arose by
nonhomologous deletion of genomic DNA adjacent to the red and green pigment
gene cluster.
explanation: >-
The original two-class formulation of the mutational routes this node models.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:30065301
reference_title: 'Genotype determination of the OPN1LW/OPN1MW genes: novel disease-causing mechanisms in Japanese patients with blue cone monochromacy.'
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
The analysis of the recombinant proteins of M273K mutants revealed that the opsin with the M273K mutation
was significantly detectable in the Western blot and cultured cells (Supplementary Fig. S2) but showed
no absorbance at any of the wavelengths tested after reconstitution with 11-cis-retinal (Fig. 3C).
explanation: >-
Recombinant protein experiments demonstrate loss of pigment absorption for Met273Lys.
quote_role: PRIMARY_RESULT
molecular_functions:
- preferred_term: G protein-coupled photoreceptor activity
term:
id: GO:0008020
label: G protein-coupled photoreceptor activity
modifier: DECREASED
notes: >-
The molecular-function annotation describes the affected opsin proteins, not enhancer binding. Residual
function varies with genotype and array context; some variants produce a milder cone dysfunction spectrum.
- name: Failure of Locus Control Region-Driven Opsin Expression
biological_scale: MOLECULAR
description: >-
Deletion of the upstream LCR removes an enhancer required for expression of the adjacent L/M opsin genes.
LCR-only deletions can silence otherwise retained coding genes, whereas many larger deletions also remove
part or all of those genes. Transgenic studies support competition between opsin promoters for LCR interaction.
A 358-bp critical interval was inferred by patient deletion mapping, not established as an isolated minimal
enhancer by a functional deletion assay.
biological_processes:
- preferred_term: regulation of DNA-templated transcription
term:
id: GO:0006355
label: regulation of DNA-templated transcription
modifier: ABNORMAL
cell_types:
- preferred_term: retinal cone cell
term:
id: CL:0000573
label: retinal cone cell
downstream:
- target: Absent or Non-Functional L and M Cone Photopigment
causal_link_type: DIRECT
description: >-
With the enhancer gone, neither opsin promoter is transcribed in cones that
would otherwise express L or M opsin.
evidence:
- reference: PMID:1524826
reference_title: >-
A locus control region adjacent to the human red and green visual pigment
genes.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
a region between 3.1 kb and 3.7 kb 5' of the red pigment gene transcription
initiation site is essential for expression
explanation: >-
Transgenic-mouse mapping of the enhancer whose deletion causes the disease.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:1524826
reference_title: >-
A locus control region adjacent to the human red and green visual pigment
genes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Deletion of sequences 5' of the human red and green pigment gene array
results in blue cone monochromacy, a disorder in which both red and green
cone function are absent.
explanation: >-
States the human genotype-phenotype relationship this node encodes.
directness: DIRECT
quote_role: BACKGROUND
- reference: PMID:11773636
reference_title: >-
Role of a locus control region in the mutually exclusive expression of human
red and green cone pigment genes.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The results support a model in which the mutually exclusive expression of
these genes in their respective cone types is controlled by competition
between visual pigment promoters for pairing with the LCR
explanation: >-
Gives the regulatory model — one LCR shared by both promoters — that makes a
single deletion sufficient.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: DOI:10.1126/science.2788922
reference_title: >-
Molecular Genetics of Human Blue Cone Monochromacy
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These deletions define a 579-base pair region that is located 4 kilobases
upstream of the red pigment gene and 43 kilobases upstream of the nearest green
pigment gene; this 579-base pair region is essential for the activity of both
pigment genes.
explanation: >-
The founding observation: patient deletions themselves delimited the essential
shared regulatory element, before it was called a locus control region.
directness: DIRECT
quote_role: PRIMARY_RESULT
notes: >-
The LCR is a cis-regulatory DNA element acting on OPN1LW/OPN1MW; the encoded opsins are photoreceptors,
not transcription factors.
- name: Exon 3 Haplotype-Dependent Opsin Missplicing
description: >-
Specific combinations of common exon 3 variants cause exon skipping. LIAVA minigenes show essentially complete
loss of correctly spliced product, while LIVVA and other haplotypes retain variable amounts. Exon 3 skipping
changes the reading frame and introduces a premature stop; nonsense-mediated decay is a proposed consequence.
Assays using cDNA distinguish splicing from protein effects: LIAVA protein remains functional in mice,
whereas LVAVA has additional protein-level defects in an overlapping cone dystrophy spectrum. Clinical
severity depends on the other expressed opsin copies and promoter context.
biological_scale: MOLECULAR
evidence:
- reference: PMID:35743313
reference_title: Novel OPN1LW/OPN1MW Exon 3 Haplotype-Associated Splicing Defect in Patients with X-Linked Cone Dysfunction.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
Applying minigene assays for all observed exon 3 haplotypes in the patients, we demonstrated that the
novel exon 3 haplotype L-I-V-V-A induces a strong but incomplete splicing defect with 3-5% of residual
correctly spliced transcripts.
explanation: >-
Minigene assays establish incomplete exon 3 splicing for LIVVA.
quote_role: PRIMARY_RESULT
- reference: PMID:28516000
reference_title: Role of a Dual Splicing and Amino Acid Code in Myopia, Cone Dysfunction and Cone Dystrophy Associated with L/M Opsin Interchange Mutations.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
The only major RT-PCR product detected in the assay using a minigene derived from this subject's OPN1LWLIAVA
gene lacked exon 3 and had exon 2 spliced directly to exon 4, introducing a frame shift and a premature
translation termination codon seven codons past the exon 2/exon 4 splice junction.
explanation: >-
The LIAVA minigene yields exon 3 skipping and a premature termination codon; decay itself was inferred.
quote_role: PRIMARY_RESULT
downstream:
- target: Absent or Non-Functional L and M Cone Photopigment
description: >-
Exon skipping prevents production of normal full-length opsin from the affected copy.
causal_link_type: DIRECT
evidence:
- reference: PMID:28516000
reference_title: Role of a Dual Splicing and Amino Acid Code in Myopia, Cone Dysfunction and Cone Dystrophy Associated with L/M Opsin Interchange Mutations.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
The only major RT-PCR product detected in the assay using a minigene derived from this subject's OPN1LWLIAVA
gene lacked exon 3 and had exon 2 spliced directly to exon 4, introducing a frame shift and a premature
translation termination codon seven codons past the exon 2/exon 4 splice junction.
explanation: >-
The LIAVA minigene yields exon 3 skipping and a premature termination codon; decay itself was inferred.
quote_role: PRIMARY_RESULT
biological_processes:
- preferred_term: RNA splicing
term:
id: GO:0008380
label: RNA splicing
modifier: ABNORMAL
- name: Absent or Non-Functional L and M Cone Photopigment
conforms_to: "phototransduction_cascade_dysfunction#Phototransduction Cascade Component Defect"
biological_scale: CELLULAR
description: >-
Regulatory loss, coding deletion, splice defects and inactivating coding variants converge on reduced or
absent functional L/M photopigment. Cys203Arg can cause misfolding and reduced opsin abundance; in mouse
retina its equivalent C198R protein is undetectable or greatly reduced without the aggregates seen in transfected
cells. Met273Lys recombinant opsin lacks normal absorption after reconstitution with retinal. The effects
of different coding alleles should not be assumed to share a single toxic-aggregation mechanism.
cell_types:
- preferred_term: L cone cell
term:
id: CL:0003048
label: L cone cell
- preferred_term: M cone cell
term:
id: CL:0003049
label: M cone cell
molecular_functions:
- preferred_term: G protein-coupled photoreceptor activity
term:
id: GO:0008020
label: G protein-coupled photoreceptor activity
modifier: DECREASED
biological_processes:
- preferred_term: phototransduction
term:
id: GO:0007602
label: phototransduction
modifier: DECREASED
downstream:
- target: Cone Outer Segment Disruption
description: >-
Loss of functional cone opsin impairs outer-segment formation and maintenance.
causal_link_type: DIRECT
evidence:
- reference: PMID:38060327
reference_title: Structural and functional rescue of cones carrying the most common cone opsin C203R missense mutation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
These results indicate that COSs are substantially shortened or missing in Opn1mwC198R Opn1sw–/– retinas.
explanation: >-
The opsin-mutant, S-opsin-null model links pigment deficiency to abnormal cone outer segments.
quote_role: PRIMARY_RESULT
- target: Vision Mediated by Preserved S Cones and Rods
description: >-
When L/M cone function is lost, rod and S-cone pathways dominate the remaining visual responses.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:25909963
reference_title: >-
Blue cone monochromacy: visual function and efficacy outcome measures for
clinical trials.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
BCM rods continue to signal vision under conditions normally associated with
daylight vision.
explanation: >-
Direct psychophysical demonstration that rods are carrying photopic vision,
which is the claim this node makes.
directness: INDIRECT
quote_role: PRIMARY_RESULT
- target: Severe Colour Vision Defect
description: >-
Loss of L/M cone input produces severe colour discrimination deficits, with variable residual yellow-blue
sensitivity.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:36692456
reference_title: 'Color Vision in Blue Cone Monochromacy: Outcome Measures for a Clinical Trial.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
The patients with BCM we studied with CAD showed different patterns of YB thresholds, with some patients
having only moderate threshold elevations and others showing severely elevated thresholds.
explanation: >-
All six CAD-tested patients had abnormal yellow-blue thresholds, with variable severity.
quote_role: PRIMARY_RESULT
- target: Reduced Visual Acuity
description: >-
Loss of L/M cone-mediated high-acuity vision contributes to reduced acuity.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:10982039
reference_title: >-
Spectrum of color gene deletions and phenotype in patients with blue cone
monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Acuities were reduced in all affected males, and photopic b-wave was reduced
by more than 90% in seven families.
explanation: >-
Establishes reduced acuity as universal across ten families.
directness: INDIRECT
quote_role: PRIMARY_RESULT
- target: Severely Reduced Photopic Cone Electroretinogram
description: >-
Markedly impaired L/M cone activity produces diminished photopic responses.
causal_link_type: DIRECT
evidence:
- reference: PMID:10982039
reference_title: >-
Spectrum of color gene deletions and phenotype in patients with blue cone
monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Acuities were reduced in all affected males, and photopic b-wave was reduced
by more than 90% in seven families.
explanation: >-
Quantifies the photopic ERG reduction.
directness: DIRECT
quote_role: PRIMARY_RESULT
evidence:
- reference: PMID:8213841
reference_title: Genetic heterogeneity among blue-cone monochromats.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
One inactivating mutation, Cys203-to-Arg, was found in 15 probands who carry
single genes and in both visual pigment genes in one subject whose array has
two genes.
explanation: >-
Establishes Cys203Arg as the dominant inactivating substitution.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:30065301
reference_title: 'Genotype determination of the OPN1LW/OPN1MW genes: novel disease-causing mechanisms in Japanese patients with blue cone monochromacy.'
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
The analysis of the recombinant proteins of M273K mutants revealed that the opsin with the M273K mutation
was significantly detectable in the Western blot and cultured cells (Supplementary Fig. S2) but showed
no absorbance at any of the wavelengths tested after reconstitution with 11-cis-retinal (Fig. 3C).
explanation: >-
Recombinant protein experiments demonstrate loss of pigment absorption for Met273Lys.
quote_role: PRIMARY_RESULT
- reference: PMID:41941983
reference_title: Molecular and cellular impact of a C203R/C198R M-opsin mutation.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
In in vitro studies, the mutant M-opsin on either human or murine backgrounds aggregated and was mislocalized
in HEK293 cells.
explanation: >-
The aggregation result is specific to transfected HEK293 cells.
quote_role: PRIMARY_RESULT
- reference: PMID:41941983
reference_title: Molecular and cellular impact of a C203R/C198R M-opsin mutation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
The mutation diminished the expression of M-opsin with some apparent mislocalization of the cone opsin
without aggregation, which resulted in the loss of cone outer segments in M-cone photoreceptor cells.
explanation: >-
The knock-in retina differs from the transfected-cell system: reduced opsin and outer segments without
detected aggregates.
quote_role: PRIMARY_RESULT
- name: Cone Outer Segment Disruption
biological_scale: CELLULAR
description: >-
Reduced opsin disrupts outer-segment formation and maintenance. Patients have variable outer-retinal and
ellipsoid-zone abnormalities. Mouse opsin-deficiency models have shortened or absent outer segments and
reduced localization of phototransduction proteins; early gene augmentation can partially restore these
structures. Human adaptive-optics imaging reveals non-waveguiding cells, but their spectral identity, functional
competence and capacity for rescue are not established by morphology alone.
cell_types:
- preferred_term: retinal cone cell
term:
id: CL:0000573
label: retinal cone cell
biological_processes:
- preferred_term: photoreceptor cell outer segment organization
term:
id: GO:0035845
label: photoreceptor cell outer segment organization
modifier: ABNORMAL
locations:
- preferred_term: fovea centralis
term:
id: UBERON:0001786
label: fovea centralis
evidence:
- reference: PMID:38060327
reference_title: Structural and functional rescue of cones carrying the most common cone opsin C203R missense mutation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
These results indicate that COSs are substantially shortened or missing in Opn1mwC198R Opn1sw–/– retinas.
explanation: >-
The opsin-mutant, S-opsin-null model links pigment deficiency to abnormal cone outer segments.
quote_role: PRIMARY_RESULT
- reference: PMID:39408969
reference_title: >-
Evaluation of Retinal Structure and Visual Function in Blue Cone Monochromacy
to Develop Clinical Endpoints for L-opsin Gene Therapy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
AOSLO imaging showed reduced total cone density with majority of the
population being non-waveguiding.
explanation: >-
Direct structural measurement of the residual foveal cone population.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:36301530
reference_title: Foveal Cone Structure in Patients With Blue Cone Monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mean total cone density for Cys203Arg patients was 16,664 ± 11,513 cones/mm2
(n = 10), which is, on average, around 40% of normal.
explanation: >-
Quantifies the residual foveal cone population by adaptive-optics imaging.
directness: DIRECT
quote_role: PRIMARY_RESULT
downstream:
- target: Variable Foveal Cone Loss and Macular Degeneration
description: >-
Outer-segment disruption accompanies later cone loss in the C198R/Opn1sw-null model; long-term human
progression is variable.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:38060327
reference_title: Structural and functional rescue of cones carrying the most common cone opsin C203R missense mutation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: >-
These results indicate that COSs are substantially shortened or missing in Opn1mwC198R Opn1sw–/– retinas.
explanation: >-
The opsin-mutant, S-opsin-null model links pigment deficiency to abnormal cone outer segments.
quote_role: PRIMARY_RESULT
- reference: PMID:38060327
reference_title: Structural and functional rescue of cones carrying the most common cone opsin C203R missense mutation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: >-
However, by 3 months of age, there was a 23% decrease in cone viability (n = 8 mice dorsal, n = 6 ventral;
P < 0.05).
explanation: >-
The same opsin-deficient model develops cone loss; the association supports an indirect link without
identifying the cell-death pathway.
quote_role: PRIMARY_RESULT
- name: Variable Foveal Cone Loss and Macular Degeneration
description: >-
Retinal imaging and some clinical family studies support progressive macular damage in a subset. A 2018
retrospective series compared 21 deletion and 13 Cys203Arg cases and found greater preservation of foveal
structure in the latter group. Cross-sectional age associations must be distinguished from longitudinal
change. In a 2024 cohort, seven patients had serial OCT over a median 6.5 years with variable structural
changes; quantitative outer nuclear layer thickness showed no change, and the two patients with repeated
adaptive-optics images had stable mosaics. Progression is neither absent in all BCM nor uniform across
patients.
biological_scale: TISSUE
evidence:
- reference: PMID:30516820
reference_title: Blue Cone Monochromacy Caused by the C203R Missense Mutation or Large Deletion Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Patients with the C203R mutation, however, had decades-longer persistence of foveal photoreceptor outer
nuclear layer thickness and a slower rate of development of inner segment/outer segment defects than
did patients with large deletion mutations.
explanation: >-
The retrospective 34-patient structural comparison supports genotype-associated differences; it does
not predict an individual treatment window.
quote_role: PRIMARY_RESULT
- reference: PMID:10982039
reference_title: >-
Spectrum of color gene deletions and phenotype in patients with blue cone
monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Progressive macular atrophy was observed in affected members of two BCM
families while the rest of the families presented with normal fundus.
explanation: >-
Documents macular atrophy in affected members of two families without establishing a patient-level prevalence.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:39408969
reference_title: Evaluation of Retinal Structure and Visual Function in Blue Cone Monochromacy to Develop Clinical Endpoints for L-opsin Gene Therapy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: "Quantitatively, ONL thickness showed no changes, but rod sensitivity losses appear to increase in most patients with age (Figure 7). Longitudinal AO images were available for two patients (P6, P7)." # codespell:ignore-line
explanation: >-
Serial quantitative outer nuclear layer measurements were stable despite changes in some other measures.
quote_role: PRIMARY_RESULT
- reference: PMID:39408969
reference_title: Evaluation of Retinal Structure and Visual Function in Blue Cone Monochromacy to Develop Clinical Endpoints for L-opsin Gene Therapy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
AO montages of the photoreceptor mosaic appeared qualitatively stable, though distortions from scanning
and eye motion are present within the montages, thereby precluding cell-by-cell alignments over large
retinal areas.
explanation: >-
Only two patients had repeated adaptive-optics imaging; scan distortion limits precise quantification.
quote_role: PRIMARY_RESULT
downstream:
- target: Progressive Macular Atrophy
description: >-
Progressive macular atrophy was documented in affected members of two families.
causal_link_type: DIRECT
evidence:
- reference: PMID:10982039
reference_title: >-
Spectrum of color gene deletions and phenotype in patients with blue cone
monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Progressive macular atrophy was observed in affected members of two BCM
families while the rest of the families presented with normal fundus.
explanation: >-
Documents macular atrophy in affected members of two families without establishing a patient-level
prevalence.
directness: DIRECT
quote_role: PRIMARY_RESULT
locations:
- preferred_term: fovea centralis
term:
id: UBERON:0001786
label: fovea centralis
cell_types:
- preferred_term: retinal cone cell
term:
id: CL:0000573
label: retinal cone cell
- name: Vision Mediated by Preserved S Cones and Rods
biological_scale: TISSUE
description: >-
S cones and rods provide most residual vision when L/M cone function is lost. Psychophysics shows that
rods can mediate detection under conventional daylight testing conditions. S-cone sensitivity is often
preserved, but blue-yellow colour discrimination can still be abnormal and varies with the test and illumination.
Dark-adapted responses are commonly retained but can be subnormal; normal night vision or a normal S-cone
response is not universal.
cell_types:
- preferred_term: S cone cell
term:
id: CL:0003050
label: S cone cell
- preferred_term: retinal rod cell
term:
id: CL:0000604
label: retinal rod cell
biological_processes:
- preferred_term: visual perception
term:
id: GO:0007601
label: visual perception
modifier: ABNORMAL
evidence:
- reference: PMID:25909963
reference_title: >-
Blue cone monochromacy: visual function and efficacy outcome measures for
clinical trials.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
BCM rods continue to signal vision under conditions normally associated with
daylight vision.
explanation: >-
Direct psychophysical demonstration that rods are carrying photopic vision,
which is the claim this node makes.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:25909963
reference_title: >-
Blue cone monochromacy: visual function and efficacy outcome measures for
clinical trials.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Short-wavelength (S-) sensitive cone function was normal or near normal in most
patients.
explanation: >-
Confirms S-cone sparing quantitatively rather than by inference from the
genotype.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:36692456
reference_title: 'Color Vision in Blue Cone Monochromacy: Outcome Measures for a Clinical Trial.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
The patients with BCM we studied with CAD showed different patterns of YB thresholds, with some patients
having only moderate threshold elevations and others showing severely elevated thresholds.
explanation: >-
All six CAD-tested patients had abnormal yellow-blue thresholds, with variable severity.
quote_role: PRIMARY_RESULT
- name: Carrier Female Cone Mosaic Disruption
biological_scale: TISSUE
description: >-
Clinically unaffected female carriers may have altered cone mosaics. Four LCR-deletion carriers examined
with adaptive-optics imaging had reduced cone density and irregular organization despite normal colour
discrimination. X-inactivation and early loss of opsin-deficient cones are proposed explanations; retinal
X-inactivation ratios and actual early cone death were not directly measured. A rare affected female had
completely biased X-inactivation in blood and buccal DNA, which cannot establish the retinal pattern.
cell_types:
- preferred_term: retinal cone cell
term:
id: CL:0000573
label: retinal cone cell
evidence:
- reference: PMID:20638402
reference_title: >-
Deletion of the X-linked opsin gene array locus control region (LCR) results
in disruption of the cone mosaic.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
On average, they had cone mosaics with reduced density and disrupted
organization compared to normal trichromats.
explanation: >-
The imaging result in LCR-deletion carrier females.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:22998501
reference_title: Blue cone monochromatism in a female due to skewed X-inactivation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The diagnosis was genetically verified with the identification of one single
red-green OPN1LW/MW hybrid gene harboring a point mutation c.607C>G,
p.Cys203Arg that associates with BCM and in addition a completely biased
X-inactivation in DNA isolated from full blood and buccal mucosa.
explanation: >-
The female case documents peripheral-tissue X-inactivation and an opsin-array variant. The quoted cDNA
designation is reproduced as reported; retinal X-inactivation was not measured.
directness: DIRECT
quote_role: PRIMARY_RESULT
phenotypes:
- category: Ophthalmologic
name: Severe Colour Vision Defect
diagnostic: true
description: >-
Severe red-green discrimination loss is typical. Residual yellow-blue discrimination depends on the test
and viewing conditions and can also be severely abnormal. Absence of tritan errors on D-15 does not prove
normal yellow-blue colour vision, since rod/S-cone brightness cues can support sorting.
phenotype_term:
preferred_term: Color vision defect
term:
id: HP:0000551
label: Color vision defect
evidence:
- reference: PMID:36692456
reference_title: 'Color Vision in Blue Cone Monochromacy: Outcome Measures for a Clinical Trial.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
The patients with BCM we studied with CAD showed different patterns of YB thresholds, with some patients
having only moderate threshold elevations and others showing severely elevated thresholds.
explanation: >-
All six CAD-tested patients had abnormal yellow-blue thresholds, with variable severity.
quote_role: PRIMARY_RESULT
- reference: PMID:15094734
reference_title: >-
Blue cone monochromatism: a phenotype and genotype assessment with evidence of
progressive loss of cone function in older individuals.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Affected males were shown to fail the protan and deutan axes, but retained
good discrimination on the tritan axis of the MR test, a compelling evidence
for residual colour vision in BCM.
explanation: >-
The older cohort retained tritan discrimination on the MR test; this test-specific observation does not
establish universal normal colour sensitivity.
directness: DIRECT
quote_role: PRIMARY_RESULT
- category: Ophthalmologic
name: Reduced Visual Acuity
description: >-
Visual acuity is commonly markedly reduced, often around 20/60 to 20/200 in classic cohorts, with a wider
range across variants. Exon 3 haplotype-associated disease can have better acuity and residual cone ERG
responses.
phenotype_term:
preferred_term: Reduced visual acuity
term:
id: HP:0007663
label: Reduced visual acuity
evidence:
- reference: PMID:10982039
reference_title: >-
Spectrum of color gene deletions and phenotype in patients with blue cone
monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Acuities were reduced in all affected males, and photopic b-wave was reduced
by more than 90% in seven families.
explanation: >-
Establishes reduced acuity as universal across ten families.
directness: DIRECT
quote_role: PRIMARY_RESULT
- category: Ophthalmologic
name: Nystagmus
description: >-
Pendular nystagmus, usually evident in infancy and often the presenting sign;
amplitude commonly decreases with age without fully resolving.
phenotype_term:
preferred_term: Nystagmus
term:
id: HP:0000639
label: Nystagmus
onset:
onset_category: INFANTILE
notes: >-
Usually presents in infancy; milder exon 3-associated phenotypes may lack the typical early presentation.
evidence:
- reference: PMID:10982039
reference_title: >-
Spectrum of color gene deletions and phenotype in patients with blue cone
monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Blue cone monochromacy (BCM) is an X-linked ocular disease characterized by
poor visual acuity, nystagmus, and photodysphoria in males with severely
reduced color discrimination.
explanation: >-
Lists nystagmus among the defining clinical features.
directness: DIRECT
quote_role: BACKGROUND
- category: Ophthalmologic
name: Photophobia
description: >-
Light sensitivity and glare intolerance, reported historically as photodysphoria
and often managed with tinted lenses.
phenotype_term:
preferred_term: Photophobia
term:
id: HP:0000613
label: Photophobia
evidence:
- reference: PMID:10982039
reference_title: >-
Spectrum of color gene deletions and phenotype in patients with blue cone
monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Blue cone monochromacy (BCM) is an X-linked ocular disease characterized by
poor visual acuity, nystagmus, and photodysphoria in males with severely
reduced color discrimination.
explanation: >-
Photodysphoria is the historical term for the light sensitivity recorded here.
directness: DIRECT
quote_role: BACKGROUND
- category: Ophthalmologic
name: Myopia
description: >-
Myopia is common and can be high, particularly in some exon 3 haplotype-associated phenotypes. It is not
universal; occasional emmetropic or hyperopic individuals occur.
phenotype_term:
preferred_term: Myopia
term:
id: HP:0000545
label: Myopia
evidence:
- reference: PMID:37001420
reference_title: Blue cone monochromacy and gene therapy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
BCM patients typically suffer from poor visual acuity, severely impaired color
discrimination, myopia, and nystagmus.
explanation: >-
Lists myopia among the typical features.
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
- category: Electrophysiologic
name: Severely Reduced Photopic Cone Electroretinogram
diagnostic: true
description: >-
L/M-cone-driven photopic and 30-Hz flicker responses are severely reduced or absent in classic disease.
Residual responses occur, especially in milder exon 3-associated disease. S-cone-specific responses and
rod-mediated responses are usually retained and require appropriate stimulus conditions.
phenotype_term:
preferred_term: Abnormal electroretinogram
term:
id: HP:0000512
label: Abnormal electroretinogram
evidence:
- reference: PMID:10982039
reference_title: >-
Spectrum of color gene deletions and phenotype in patients with blue cone
monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Acuities were reduced in all affected males, and photopic b-wave was reduced
by more than 90% in seven families.
explanation: >-
Quantifies the photopic ERG reduction.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:10982039
reference_title: >-
Spectrum of color gene deletions and phenotype in patients with blue cone
monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In three families, however, the photopic b-wave response showed
uncharacteristic relative preservation of 30-80% (of the clinical low-normal
value).
explanation: >-
The exception that keeps this phenotype from being curated as invariably
absent.
directness: DIRECT
quote_role: PRIMARY_RESULT
- category: Ophthalmologic
name: Progressive Macular Atrophy
description: >-
Macular atrophy develops in a subset and is the main late complication beyond
the congenital deficit. It was seen in two of ten families in an early series
while the remainder had a normal fundus, so it is genuinely a subset finding
rather than an inevitable end state.
phenotype_term:
preferred_term: Macular degeneration
term:
id: HP:0000608
label: Macular degeneration
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:10982039
reference_title: >-
Spectrum of color gene deletions and phenotype in patients with blue cone
monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Progressive macular atrophy was observed in affected members of two BCM
families while the rest of the families presented with normal fundus.
explanation: >-
Documents macular atrophy in affected members of two families without establishing a patient-level prevalence.
directness: DIRECT
quote_role: PRIMARY_RESULT
- category: Ophthalmologic
name: Progressive Loss of Cone Function
description: >-
Clinical or psychophysical deterioration has been reported in some families, including an exon 2-deletion
family. This is not a quantified population frequency or evidence that every patient progresses; changes
differ across acuity, colour testing and retinal structure.
phenotype_term:
preferred_term: Progressive visual loss
term:
id: HP:0000529
label: Progressive visual loss
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:15094734
reference_title: >-
Blue cone monochromatism: a phenotype and genotype assessment with evidence of
progressive loss of cone function in older individuals.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In two families, psychophysical testing demonstrated evidence for progression
of disease.
explanation: >-
Demonstrates progression psychophysically in a subset of families.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:19421413
reference_title: >-
Blue cone monochromacy: causative mutations and associated phenotypes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A novel mutation was detected in Family 2 that had a single hybrid gene
lacking exon 2. This family presented clinical and psychophysical evidence of a
slowly progressive phenotype.
explanation: >-
Ties a progressive phenotype to a specific genotype, supporting genotype
dependence.
directness: DIRECT
quote_role: PRIMARY_RESULT
- name: Foveal Hypoplasia
description: >-
Retention of inner retinal layers at the fovea occurred in 11 of 33 BCM patients in one OCT cohort. It
occurs with LCR deletions and Cys203Arg and does not require a second GPR143 diagnosis.
phenotype_term:
preferred_term: Hypoplasia of the fovea
term:
id: HP:0007750
label: Hypoplasia of the fovea
evidence:
- reference: PMID:36186895
reference_title: Comparing Retinal Structure in Patients with Achromatopsia and Blue Cone Monochromacy Using OCT.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Sixty-two of the total 89 ACHM patients (70%) had foveal hypoplasia, compared with 11 of 33 BCM patients
(33%).
explanation: >-
The full-text OCT cohort documents foveal hypoplasia in BCM as well as ACHM.
quote_role: PRIMARY_RESULT
frequency: FREQUENT
category: Ophthalmologic
genetic:
- name: OPN1LW/OPN1MW opsin gene array
association: Genetic Mutation
relationship_type: CAUSATIVE
gene_term:
preferred_term: OPN1LW
term:
id: hgnc:9936
label: OPN1LW
inheritance:
- name: X-linked recessive
notes: >-
OPN1LW and OPN1MW form a highly homologous tandem array at Xq28. BCM requires a configuration causing severe
impairment of both L- and M-cone pathways, not necessarily two separate coding mutations. Regulatory deletion,
recombination, gene conversion, coding loss and missplicing are alternative routes. Interpretation requires
the position and function of expressed copies; a variant in one copy can instead cause an overlapping colour-vision
or cone-dysfunction phenotype.
evidence:
- reference: PMID:26153062
reference_title: >-
High-resolution microarray analysis unravels complex Xq28 aberrations in
patients and carriers affected by X-linked blue cone monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Blue cone monochromacy (BCM) is an X-linked condition caused by a
loss-of-function of both the OPN1LW and OPN1MW opsin genes.
explanation: >-
States the two-gene loss-of-function requirement.
directness: DIRECT
quote_role: BACKGROUND
- reference: PMID:26153062
reference_title: >-
High-resolution microarray analysis unravels complex Xq28 aberrations in
patients and carriers affected by X-linked blue cone monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The cone opsin gene cluster is composed of 2-9 paralogs with 99.8% sequence
homology and is susceptible to deletions, duplications, and mutations.
explanation: >-
Explains the locus architecture that makes recurrent rearrangement the
dominant mutational mechanism.
directness: DIRECT
quote_role: BACKGROUND
- name: OPN1MW
association: Genetic Mutation
relationship_type: CAUSATIVE
gene_term:
preferred_term: OPN1MW
term:
id: hgnc:4206
label: OPN1MW
inheritance:
- name: X-linked recessive
notes: >-
OPN1MW encodes M-opsin within the array. Pathogenic configurations may involve single residual or hybrid
genes or multiple expressed copies. The reported family with a deleted green gene but no identified red-gene
or LCR change remained incompletely explained; it does not demonstrate that isolated OPN1MW loss alone
usually causes BCM.
evidence:
- reference: PMID:10982039
reference_title: >-
Spectrum of color gene deletions and phenotype in patients with blue cone
monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In one family no mutation was found in the exons of the red gene or the locus
control region but showed loss of the complete green gene.
explanation: >-
Documents the genotype in which the M gene is the demonstrable lesion.
directness: DIRECT
quote_role: PRIMARY_RESULT
- name: Locus control region deletion
association: Genetic Mutation
relationship_type: CAUSATIVE
gene_term:
preferred_term: OPN1LW
term:
id: hgnc:9936
label: OPN1LW
inheritance:
- name: X-linked recessive
notes: >-
LCR deletion is a regulatory variant class. Among 42 distinct structural variants in the 2022 study, about
90% involved the LCR; many also deleted coding sequence, while some pathogenic structural variants retained
the LCR. Thus the denominator is distinct structural variants, not all BCM families. Deletion mapping inferred
a 358-bp critical interval; it was not a direct functional assay of that isolated sequence.
evidence:
- reference: PMID:35759666
reference_title: >-
The landscape of submicroscopic structural variants at the OPN1LW/OPN1MW gene
cluster on Xq28 underlying blue cone monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
However, 90% of SVs encompass the upstream locus control region, an essential
enhancer element. Its minimal functional extent based on deletion mapping in
patients was refined to 358 bp.
explanation: >-
Quantifies how often the enhancer is involved and gives the patient-derived
minimal functional extent.
directness: DIRECT
quote_role: PRIMARY_RESULT
- name: Structural variant landscape of the OPN1LW/OPN1MW cluster
association: Genetic Mutation
relationship_type: CAUSATIVE
gene_term:
preferred_term: OPN1MW
term:
id: hgnc:4206
label: OPN1MW
notes: >-
In a molecularly confirmed cohort, 73 of 213 families carried structural variants, comprising 42 distinct
variants with no universal shared deleted interval. Complex rearrangements and founder alleles occur. Predisposition
of larger ancestral arrays was inferred by reconstruction, not directly measured prospectively.
evidence:
- reference: PMID:35759666
reference_title: >-
The landscape of submicroscopic structural variants at the OPN1LW/OPN1MW gene
cluster on Xq28 underlying blue cone monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We found that about one-third (n = 73) of the 213 molecularly confirmed BCM
families carry an SV, most commonly deletions restricted to the OPN1LW/OPN1MW
gene cluster.
explanation: >-
Quantifies the share of families with a structural variant.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:35759666
reference_title: >-
The landscape of submicroscopic structural variants at the OPN1LW/OPN1MW gene
cluster on Xq28 underlying blue cone monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In total, 42 distinct SVs were identified, including 40 previously unreported
SVs, thereby quadrupling the number of precisely mapped SVs underlying BCM.
Notably, there was no "region of overlap" among these SVs.
explanation: >-
Establishes both the diversity of variants and the absence of a common
minimal region.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:35759666
reference_title: >-
The landscape of submicroscopic structural variants at the OPN1LW/OPN1MW gene
cluster on Xq28 underlying blue cone monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Using parsimonious assumptions, we reconstructed the composition and copy
number of the OPN1LW/OPN1MW gene cluster prior to the mutation event and found
evidence that large gene arrays may be predisposed to the occurrence of SVs at
this locus.
explanation: >-
Links array size to structural-variant susceptibility, supporting the
architectural argument.
directness: DIRECT
quote_role: PRIMARY_RESULT
- name: Cys203Arg recurrent inactivating substitution
association: Genetic Mutation
relationship_type: CAUSATIVE
gene_term:
preferred_term: OPN1LW
term:
id: hgnc:9936
label: OPN1LW
notes: >-
Cys203Arg can affect a single residual/hybrid opsin gene or multiple expressed copies. Its detection in
2 of 321 controls in the original study supports dependence on array context and a proposed reservoir for
recombination or conversion. Those observations do not exclude founder effects for particular alleles or
populations.
evidence:
- reference: PMID:8213841
reference_title: Genetic heterogeneity among blue-cone monochromats.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This mutation was also found in at least one of the visual pigment genes in 1
subject whose array has multiple genes and in 2 of 321 control subjects,
suggesting that preexisting Cys203-to-Arg mutations constitute a reservoir of
chromosomes that are predisposed to generate blue-cone-monochromat genotypes
by unequal homologous recombination and/or gene conversion.
explanation: >-
The allele occurred in affected and control arrays; the authors propose recombination or conversion of
pre-existing alleles. This does not exclude population-specific founders.
directness: DIRECT
quote_role: PRIMARY_RESULT
- name: Splice-disrupting exon 3 haplotypes
association: Genetic Mutation
relationship_type: CAUSATIVE
gene_term:
preferred_term: OPN1LW
term:
id: hgnc:9936
label: OPN1LW
notes: >-
LIAVA, LIVVA and related combinations produce variable exon 3 skipping. The phenotype depends on the complete
OPN1LW/OPN1MW array; some configurations cause mild BCM or overlap with Bornholm eye disease and other
cone dysfunction. Single component polymorphisms are not independently equivalent to the pathogenic haplotype.
evidence:
- reference: PMID:35743313
reference_title: Novel OPN1LW/OPN1MW Exon 3 Haplotype-Associated Splicing Defect in Patients with X-Linked Cone Dysfunction.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
Applying minigene assays for all observed exon 3 haplotypes in the patients, we demonstrated that the
novel exon 3 haplotype L-I-V-V-A induces a strong but incomplete splicing defect with 3-5% of residual
correctly spliced transcripts.
explanation: >-
Minigene assays establish incomplete exon 3 splicing for LIVVA.
quote_role: PRIMARY_RESULT
- reference: PMID:35400991
reference_title: Relatively mild blue cone monochromacy phenotype caused by various haplotypes in the L- and M-cone opsin genes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Analysis of the clinical data revealed better best-corrected visual acuity, more severe myopia, and higher
30-Hz cone flicker responses in the patients with exon 3 haplotypes than in those with typical BCM.
explanation: >-
The clinical cohort supports a milder average phenotype with important overlap.
quote_role: PRIMARY_RESULT
- name: De novo opsin-array rearrangement
association: Genetic Mutation
relationship_type: CAUSATIVE
gene_term:
preferred_term: OPN1LW
term:
id: hgnc:9936
label: OPN1LW
notes: >-
A sporadic case carried a 73,128-bp deletion encompassing the LCR, OPN1LW and part of OPN1MW, absent from
maternal and grandfather samples. Breakpoint microhomology supports a proposed Alu-mediated mechanism;
segregation did not directly observe the germline event.
evidence:
- reference: PMID:29940872
reference_title: 'A 73,128 bp de novo deletion encompassing the OPN1LW/OPN1MW gene cluster in sporadic Blue Cone Monochromacy: a case report.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
The deletion was absent in the X-chromosomes of both the mother and transmitting grandfather.
explanation: >-
Segregation supports a de novo event in a sporadic case.
quote_role: PRIMARY_RESULT
diagnosis:
- name: Full-Field Electroretinography
description: >-
Assess light-adapted and dark-adapted full-field ERG and use S-cone-specific testing where available. Classic
BCM has severe L/M dysfunction with retained S-cone and rod responses, but residual photopic responses
and subnormal dark-adapted amplitudes occur. Oscillatory potentials from a standard dark-adapted mixed
response did not distinguish BCM from achromatopsia in a comparative study. Integrate electrophysiology
with molecular testing and clinical findings.
evidence:
- reference: PMID:10982039
reference_title: >-
Spectrum of color gene deletions and phenotype in patients with blue cone
monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Acuities were reduced in all affected males, and photopic b-wave was reduced
by more than 90% in seven families.
explanation: >-
Quantifies the photopic reduction that anchors the ERG diagnosis.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:38871951
reference_title: S-cone contribution to oscillatory potentials in patients with blue cone monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
The comparison between ACHM and BCM didn't show any statistically significant differences in the electrophysiological
parameters.
explanation: >-
The exploratory mixed-response study does not supply a discriminatory ERG marker.
quote_role: PRIMARY_RESULT
- reference: PMID:25909963
reference_title: >-
Blue cone monochromacy: visual function and efficacy outcome measures for
clinical trials.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Short-wavelength (S-) sensitive cone function was normal or near normal in most
patients.
explanation: >-
Confirms S-cone sparing quantitatively rather than by inference from the
genotype.
directness: DIRECT
quote_role: PRIMARY_RESULT
- name: Colour Vision Testing
description: >-
Colour testing characterizes residual discrimination but cannot alone establish BCM. D-15 often shows protan/deutan
confusion; MR testing may reveal residual tritan discrimination. CAD can distinguish moderate from severe
yellow-blue deficits. Brightness cues, rod contribution, illumination and display limits complicate interpretation.
evidence:
- reference: PMID:15094734
reference_title: >-
Blue cone monochromatism: a phenotype and genotype assessment with evidence of
progressive loss of cone function in older individuals.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In addition, we have demonstrated that the Mollon-Reffin (MR) Minimal test is
a useful colour-discrimination test to aid in the diagnosis of BCM.
explanation: >-
Identifies the colour test with the best discriminating value here.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:15094734
reference_title: >-
Blue cone monochromatism: a phenotype and genotype assessment with evidence of
progressive loss of cone function in older individuals.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We have confirmed the reported finding of protan-like D-15 arrangements of
patients with BCM.
explanation: >-
Documents the D-15 pattern.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:36692456
reference_title: >-
Color Vision in Blue Cone Monochromacy: Outcome Measures for a Clinical Trial.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
With D-15, there was protan-deutan confusion and no bimodal tendency.
explanation: >-
Characterizes the D-15 result pattern specific to this disorder.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:36692456
reference_title: 'Color Vision in Blue Cone Monochromacy: Outcome Measures for a Clinical Trial.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
The patients with BCM we studied with CAD showed different patterns of YB thresholds, with some patients
having only moderate threshold elevations and others showing severely elevated thresholds.
explanation: >-
All six CAD-tested patients had abnormal yellow-blue thresholds, with variable severity.
quote_role: PRIMARY_RESULT
- name: Molecular Testing of the Xq28 Opsin Array
diagnosis_term:
preferred_term: Genetic Testing
term:
id: NCIT:C15709
label: Genetic Testing
description: >-
Resolve the LCR, copy number, expressed-gene positions, coding variants and exon 3 haplotypes across the
OPN1LW/OPN1MW array. Standard short-read sequencing has limited reliability at this highly homologous locus.
Targeted long-range amplification and sequence analysis combined with deletion/copy-number testing are
useful; a validated approach combines MLPA with long-read sequencing. Custom high-resolution Xq28 microarrays
can resolve some rearrangements but should not be equated with routine genome-wide microarrays. Complex
arrays and female carrier phasing may require family studies or additional structural analysis.
evidence:
- reference: DOI:10.1038/s41525-022-00334-9
reference_title: Diagnostic analysis of the highly complex OPN1LW/OPN1MW gene cluster using long-read sequencing and MLPA
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
A diagnostic genetic assay was developed for the OPN1LW/OPN1MW gene cluster, consisting of copy number
analysis via multiplex ligation-dependent probe amplification and sequence analysis via long-read circular
consensus sequencing.
explanation: >-
The validated assay combines sequence and dosage analysis; the cohort contained several opsin-related
diagnoses.
quote_role: PRIMARY_RESULT
- reference: PMID:26153062
reference_title: >-
High-resolution microarray analysis unravels complex Xq28 aberrations in
patients and carriers affected by X-linked blue cone monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Pathogenic alterations were revealed in all probands, characterized by
sequencing of the breakpoint junctions and quantitative real-time PCR.
explanation: >-
Demonstrates the diagnostic yield of the microarray approach.
directness: DIRECT
quote_role: PRIMARY_RESULT
notes: >-
The 2022 assay series included 43 diagnostic and seven carrier samples across opsin-related conditions,
not 50 BCM patients. Exact assignment can remain unresolved with four or more heterogeneous copies, and
female alleles may require segregation to phase. A VUS or an isolated variant without the relevant array
context does not establish BCM.
- name: Retinal imaging and longitudinal assessment
description: >-
OCT characterizes foveal hypoplasia, outer nuclear layer thickness and ellipsoid-zone disruption. Adaptive-optics
imaging is a specialist research measure of residual mosaics; analyzability depends on fixation and image
quality. Imaging findings overlap with achromatopsia and cannot independently determine diagnosis, cone
identity or treatment eligibility.
evidence:
- reference: PMID:36186895
reference_title: Comparing Retinal Structure in Patients with Achromatopsia and Blue Cone Monochromacy Using OCT.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Sixty-two of the total 89 ACHM patients (70%) had foveal hypoplasia, compared with 11 of 33 BCM patients
(33%).
explanation: >-
The full-text OCT cohort documents foveal hypoplasia in BCM as well as ACHM.
quote_role: PRIMARY_RESULT
- reference: PMID:39408969
reference_title: >-
Evaluation of Retinal Structure and Visual Function in Blue Cone Monochromacy
to Develop Clinical Endpoints for L-opsin Gene Therapy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
AOSLO imaging showed reduced total cone density with majority of the
population being non-waveguiding.
explanation: >-
Direct structural measurement of the residual foveal cone population.
directness: DIRECT
quote_role: PRIMARY_RESULT
differential_diagnoses:
- name: Achromatopsia
description: >-
Achromatopsia is usually autosomal recessive and involves cone phototransduction or development genes rather
than the X-linked L/M opsin array. Complete forms affect all cone classes, but incomplete disease and some
GNAT2/PDE6C-associated cases can retain cone or short-wavelength responses. Phenotype, inheritance, appropriate
ERG and molecular results must be integrated.
disease_term:
preferred_term: achromatopsia
term:
id: MONDO:0018852
label: achromatopsia
distinguishing_features:
- Autosomal recessive inheritance and variants in achromatopsia genes support that diagnosis.
- Complete achromatopsia lacks cone-mediated responses, but incomplete forms can overlap BCM.
- Foveal hypoplasia was more frequent in achromatopsia than BCM in a comparative OCT cohort; its presence does not exclude BCM.
- Neither retained tritan discrimination nor a single OCT feature independently settles the diagnosis.
evidence:
- reference: PMID:36186895
reference_title: Comparing Retinal Structure in Patients with Achromatopsia and Blue Cone Monochromacy Using OCT.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Sixty-two of the total 89 ACHM patients (70%) had foveal hypoplasia, compared with 11 of 33 BCM patients
(33%).
explanation: >-
The full-text OCT cohort documents foveal hypoplasia in BCM as well as ACHM.
quote_role: PRIMARY_RESULT
- reference: PMID:36186895
reference_title: Comparing Retinal Structure in Patients with Achromatopsia and Blue Cone Monochromacy Using OCT.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Differences between these groups have been found in eye movements using electro-oculography,12 as well
as in cone responses using electroretinography (ERG),4,11 although ERG presentation in BCM and both GNAT2-
and PDE6C-related ACHM can be similar due to preservation of short-wavelength sensitivity.13,14
explanation: >-
The source describes diagnostic overlap, including retained short-wavelength sensitivity in some achromatopsia
genotypes.
quote_role: BACKGROUND
- name: X-linked cone dystrophy
description: >-
OPN1LW/OPN1MW variants also cause Bornholm eye disease, isolated colour-vision deficiency and progressive
cone dysfunction/dystrophy. Splicing haplotypes can produce overlapping mild BCM phenotypes. Array context,
residual L/M function, myopia, acuity and longitudinal course determine the clinical interpretation.
distinguishing_features:
- Bornholm eye disease often combines high myopia, red-green colour deficiency and residual cone responses.
- Progressive cone dystrophy and mild BCM can overlap; a shared opsin variant alone does not resolve the label.
evidence:
- reference: PMID:37001420
reference_title: Blue cone monochromacy and gene therapy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
X-linked retinal diseases resulting from mutations in the L- (OPN1LW, OMIM
*300822) and M- (OPN1MW, OMIM *300821) opsin gene cluster are associated with
a wide range of visual defects, including red/green color vision deficiency,
X-linked cone dystrophy/dysfunction, high myopia with abnormal cone function,
and blue cone monochromacy (BCM)
explanation: >-
Establishes that the same locus produces a spectrum of distinct diagnoses.
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
- reference: PMID:35400991
reference_title: Relatively mild blue cone monochromacy phenotype caused by various haplotypes in the L- and M-cone opsin genes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Analysis of the clinical data revealed better best-corrected visual acuity, more severe myopia, and higher
30-Hz cone flicker responses in the patients with exon 3 haplotypes than in those with typical BCM.
explanation: >-
The clinical cohort supports a milder average phenotype with important overlap.
quote_role: PRIMARY_RESULT
treatments:
- name: Tinted Lenses and Low Vision Aids
description: >-
Tinted lenses and low-vision aids can support photophobia and visual tasks. Refractive correction and individualized
educational accommodations also form part of management. These measures do not restore the missing L/M
photopigment.
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
target_phenotypes:
- preferred_term: Photophobia
term:
id: HP:0000613
label: Photophobia
evidence:
- reference: PMID:36932675
reference_title: Preclinical evaluation of ADVM-062, a novel intravitreal gene therapy vector for the treatment of blue cone monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Current management includes the use of refractive corrective lenses, tinted lenses for disabling photophobia,
and educational support.
explanation: >-
Background clinical management description, not an intervention trial.
quote_role: BACKGROUND
- name: AAV-Mediated L-Opsin Gene Augmentation (investigational)
description: >-
AAV delivery of functional L- or M-opsin is investigational. Mouse studies restore partial cone ERG responses
and outer-segment structure, with age and model background affecting rescue. The 2025 comparison of DKO
and C198R/Opn1sw-null mice found no significant genotype difference in therapeutic windows, and weaker
responses in older animals. All-cone models also respond after treatment at five months. These studies
do not establish a human age cutoff or efficacy. Intravitreal ADVM-062 produced new long-wavelength responses
in gerbils and foveal transduction in nonhuman primates; mild ocular inflammation occurred at higher doses.
Neither species was a human BCM treatment cohort.
therapeutic_modality: GENE_THERAPY
treatment_term:
preferred_term: Gene Therapy
term:
id: NCIT:C15238
label: Gene Therapy
target_mechanisms:
- target: Absent or Non-Functional L and M Cone Photopigment
treatment_effect: RESTORES
description: >-
Experimental supplementation supplies functional opsin to surviving cones. Structural rescue and partial
electrophysiological rescue have been demonstrated in mouse models; restoration of human vision remains
unproven.
evidence:
- reference: PMID:38060327
reference_title: Structural and functional rescue of cones carrying the most common cone opsin C203R missense mutation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
Together, these data demonstrate that when treated at 1 or 3 months of age, gene augmentation can provide
structural and functional rescue to Opn1mwC198R Opn1sw–/– cones.
explanation: >-
Direct experimental rescue in the specified mouse model.
quote_role: PRIMARY_RESULT
evidence:
- reference: PMID:36932675
reference_title: >-
Preclinical evaluation of ADVM-062, a novel intravitreal gene therapy vector
for the treatment of blue cone monochromacy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
A single IVT administration dose of ADVM-062 effectively transduced gerbil
cone photoreceptors and produced a de novo response to long-wavelength
stimuli.
explanation: >-
Preclinical proof that an intravitreally delivered L-opsin vector produces a
new long-wavelength response, in an animal whose cone-rich retina naturally
lacks L-opsin.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:41286353
reference_title: Molecular mechanisms limiting the AAV gene therapy treatment window in mouse models of blue cone monochromacy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
Both DKO and C198R models show comparable therapeutic outcomes, with efficacy consistently decreasing
in older mice.
explanation: >-
Final peer-reviewed study supersedes the 2025 preprint.
quote_role: PRIMARY_RESULT
- reference: PMID:36932675
reference_title: Preclinical evaluation of ADVM-062, a novel intravitreal gene therapy vector for the treatment of blue cone monochromacy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
In-life observations were limited to dose-dependent non-adverse slight to mild ocular inflammation characterized
by pigment and cells in the vitreous humor.
explanation: >-
The primate toxicology study reports inflammation despite its non-adverse classification.
quote_role: PRIMARY_RESULT
- name: Reading and display adaptations
description: >-
Individualize magnification, print size, screen brightness and contrast polarity. White text on a black
background improved at least one reading parameter in 82% of a 17-person cohort; assess the individual
response rather than assuming the same benefit for everyone.
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:33344057
reference_title: 'Reading Performance in Blue Cone Monochromacy: Defining an Outcome Measure for a Clinical Trial.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Reverse polarity showed better reading parameters than regular polarity in 82% of the patients.
explanation: >-
Seventeen patients were studied; this supports individualized white-on-black reading adaptations, not
universal benefit.
quote_role: PRIMARY_RESULT
- name: Genetic counselling and family testing
description: >-
Counselling uses the resolved familial array configuration to explain X-linked transmission, rare symptomatic
females and de novo rearrangements. Carrier analysis should account for complex gene copy number and may
require segregation studies.
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: DOI:10.1038/s41525-022-00334-9
reference_title: Diagnostic analysis of the highly complex OPN1LW/OPN1MW gene cluster using long-read sequencing and MLPA
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
It is of clinical importance to perform carrier status analysis of the OPN1LW/OPN1MW gene cluster to
determine recurrence risk, especially in families with no family history of visual impairment, as shown
in four cases in whom the pathogenic allele arose de novo .
explanation: >-
The diagnostic series supports family testing for recurrence-risk counselling.
animal_models:
- name: Opn1mw C198R knock-in mouse
species: Mouse
genotype: Opn1mw C198R knock-in (murine equivalent of human OPN1MW Cys203Arg)
publication: PMID:41941983
description: >-
Opn1mw C198R knock-in on an S-opsin-expressing background. The substitution is the murine equivalent of
human Cys203Arg. It is distinct from the C198R/Opn1sw-null double mutant used in gene-therapy experiments.
modeled_mechanisms:
- target: Absent or Non-Functional L and M Cone Photopigment
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
The C198R substitution reduces M-opsin abundance and causes some mislocalization without detectable retinal
aggregation.
limitations: >-
Mouse cones commonly coexpress S-opsin, which can preserve function or structure. The retina lacks a
human fovea and L-opsin; transfected-cell aggregation was not reproduced in retina.
evidence:
- reference: PMID:41941983
reference_title: Molecular and cellular impact of a C203R/C198R M-opsin mutation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The mutation diminished the expression of M-opsin with some apparent
mislocalization of the cone opsin without aggregation, which resulted in the
loss of cone outer segments in M-cone photoreceptor cells.
explanation: >-
The mutant retina has diminished M-opsin expression and some mislocalization; the separate model link
records the outer-segment consequence.
directness: DIRECT
quote_role: PRIMARY_RESULT
- target: Cone Outer Segment Disruption
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
Outer-segment loss can coexist with surviving cone cell bodies through six months in the S-opsin-expressing
knock-in background.
limitations: >-
Survival through six months in this background does not establish lifelong human cone survival or rule
out degeneration in S-opsin-null models.
evidence:
- reference: PMID:41941983
reference_title: Molecular and cellular impact of a C203R/C198R M-opsin mutation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Despite the loss of cone outer segments, cone photoreceptor cells remained
viable, even up to 6 months of age in hemizygous and homozygous mutant mice.
explanation: >-
The dissociation between outer-segment loss and cone survival.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:41941983
reference_title: Molecular and cellular impact of a C203R/C198R M-opsin mutation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Thus, in contrast to rhodopsin mutants, the M-opsin mutant does not appear to
form toxic aggregates that cause cone photoreceptor cell death.
explanation: >-
States the negative mechanistic conclusion that distinguishes this from the
rhodopsin misfolding diseases.
directness: DIRECT
quote_role: PRIMARY_RESULT
- name: Opn1mw knockout mouse
species: Mouse
genotype: Opn1mw -/- (M-opsin knockout, expressing only S-opsin)
publication: PMID:28751656
description: >-
M-opsin-null mouse retaining endogenous S-opsin. AAV5-mediated mouse M-opsin supplementation restores partial
middle-wavelength ERG responses after treatment at postnatal day 14 or three months.
modeled_mechanisms:
- target: Absent or Non-Functional L and M Cone Photopigment
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
Cones lacking M-opsin, the null counterpart of the human deletion class.
limitations: >-
S-opsin coexpression can preserve many murine cones; the model does not reproduce the isolated opsin
deficit in human L/M cones or the human fovea.
evidence:
- reference: PMID:28751656
reference_title: >-
Gene-based Therapy in a Mouse Model of Blue Cone Monochromacy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We generated an M-opsin knockout mouse (Opn1mw -/-) expressing only S-opsin
as a model for human BCM.
explanation: >-
States the model's design intent.
directness: DIRECT
quote_role: PRIMARY_RESULT
- target: Absent or Non-Functional L and M Cone Photopigment
relationship: RESCUES
fidelity: MODERATE
description: >-
AAV5-mediated M-opsin expression restores partial middle-wavelength responses and outer-segment localization.
limitations: >-
Rescue in a young mouse retina says nothing about the aged, largely
non-waveguiding human foveal cone population that would actually be treated.
evidence:
- reference: PMID:28751656
reference_title: >-
Gene-based Therapy in a Mouse Model of Blue Cone Monochromacy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Our study demonstrates that cones without M-opsin remain viable and respond
to gene augmentation therapy, thereby providing proof-of-concept for cone
function restoration in BCM patients.
explanation: >-
The proof-of-concept result underpinning the investigational treatment.
directness: DIRECT
quote_role: PRIMARY_RESULT
- name: Opsin-null and C198R/S-opsin-null comparative models
species: Mouse
genotype: Opn1mw -/-; Opn1sw -/- versus Opn1mw C198R; Opn1sw -/-
publication: PMID:41286353
description: >-
The 2025 study compares deletion and missense models without endogenous S-opsin compensation. Both show
age-dependent declines in rescue; AAV8Y733F performs better than AAV5.
modeled_mechanisms:
- target: Absent or Non-Functional L and M Cone Photopigment
relationship: RESCUES
fidelity: MODERATE
description: >-
Functional opsin delivery provides comparable rescue in the deletion and missense backgrounds, with diminishing
efficacy at older treatment ages.
limitations: >-
Rod-dominant mouse retinas lack a fovea. Treatment age, capsid, promoter, injection variability and residual
structure affect rescue. Candidate Pde6c/Cngb3 promoters were nominated by endogenous transcript persistence;
their therapeutic benefit was not tested.
evidence:
- reference: PMID:41286353
reference_title: Molecular mechanisms limiting the AAV gene therapy treatment window in mouse models of blue cone monochromacy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
Both DKO and C198R models show comparable therapeutic outcomes, with efficacy consistently decreasing
in older mice.
explanation: >-
Final peer-reviewed study supersedes the 2025 preprint.
quote_role: PRIMARY_RESULT
- name: All-cone opsin-null model
species: Mouse
genotype: Opn1mw -/-; Opn1sw -/-; Nrl -/-
publication: PMID:42157965
description: >-
Nrl deletion generates a dense all-cone retina. Subretinal human L-opsin delivery at one or five months
restores cone ERG and some outer-segment structure, with rescue detectable five months later.
modeled_mechanisms:
- target: Absent or Non-Functional L and M Cone Photopigment
relationship: RESCUES
fidelity: MODERATE
description: >-
AAV-delivered human L-opsin restores partial cone responses in the triple-knockout retina lacking endogenous
M- and S-opsins.
limitations: >-
Nrl-null retinas have developmental rosettes and their own degeneration. Dense murine cones do not recreate
human foveal anatomy or visual circuitry. Human durability and benefit are not established.
evidence:
- reference: PMID:42157965
reference_title: Gene therapy rescues cone function in opn1mw (-/-) /opn1sw (-/-) /Nrl (-/-) mice, an all-cone model of blue cone monochromacy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
Rescue effects persisted for at least 5 months post-treatment in both younger and older treated groups.
explanation: >-
AAV-mediated rescue in the specified all-cone mouse background.
quote_role: PRIMARY_RESULT
- name: All-cone C198R model
species: Mouse
genotype: Opn1mw C198R; Opn1sw -/-; Nrl -/-
publication: PMID:42275379
description: >-
The C198R missense allele is combined with Opn1sw and Nrl deletion to produce a dense all-cone retina.
Human L-opsin delivery at one or five months restores cone ERG responses and some outer-segment structure,
with rescue detectable five months later.
modeled_mechanisms:
- target: Absent or Non-Functional L and M Cone Photopigment
relationship: RESCUES
fidelity: MODERATE
description: >-
Human L-opsin gene augmentation restores cone responses despite the endogenous C198R mutant allele in
an S-opsin-null, Nrl-null background.
limitations: >-
Nrl-null retinas have developmental rosettes and their own degeneration. Dense murine cones do not recreate
human foveal anatomy or visual circuitry. Human durability and benefit are not established.
evidence:
- reference: PMID:42275379
reference_title: Gene therapy rescues cone function in an all-cone retina mouse model with the most common cone opsin C203R missense mutation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
Treatment restored cone function, regenerated outer segment structures, and provided rescue for at
least 5 months post-injection in both early- and late-treatment groups.
explanation: >-
AAV-mediated rescue in the specified all-cone mouse background.
quote_role: PRIMARY_RESULT
discussions:
- discussion_id: bcm_stationary_versus_progressive
kind: CONTROVERSY
prompt: >-
Is blue cone monochromacy a stationary cone dysfunction syndrome or a slowly
progressive dystrophy, and how much of the disagreement is explained by genotype
rather than by measurement sensitivity?
attaches_to:
- pathophysiology#Variable Foveal Cone Loss and Macular Degeneration
- phenotypes#Progressive Loss of Cone Function
rationale: >-
Some families show clinical decline and macular atrophy, while other measurements remain stable over years.
Cross-sectional age associations and genotype comparisons do not establish individual longitudinal rates.
Quantifying change requires repeated genotype-resolved OCT and functional measures; human treatability
cannot be read directly from mouse age or presence of non-waveguiding cells.
proposed_experiments:
- experiment_id: bcm_longitudinal_genotype_stratified_aoslo
name: Longitudinal genotype-stratified AOSLO and microperimetry cohort
description: >-
Follow genetically resolved cohorts with repeated OCT, adaptive-optics imaging where feasible and cone-specific
functional testing. Estimate within-person rates and measurement repeatability separately for deletion,
coding and splice-associated genotypes.
evidence:
- reference: PMID:15094734
reference_title: >-
Blue cone monochromatism: a phenotype and genotype assessment with evidence of
progressive loss of cone function in older individuals.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In two families, psychophysical testing demonstrated evidence for progression
of disease.
explanation: >-
Evidence for the progressive side of the question.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:10982039
reference_title: >-
Spectrum of color gene deletions and phenotype in patients with blue cone
monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Progressive macular atrophy was observed in affected members of two BCM
families while the rest of the families presented with normal fundus.
explanation: >-
Shows that progression is a subset finding, which is the other side of the
controversy.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:30516820
reference_title: Blue Cone Monochromacy Caused by the C203R Missense Mutation or Large Deletion Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Patients with the C203R mutation, however, had decades-longer persistence of foveal photoreceptor outer
nuclear layer thickness and a slower rate of development of inner segment/outer segment defects than
did patients with large deletion mutations.
explanation: >-
The retrospective 34-patient structural comparison supports genotype-associated differences; it does
not predict an individual treatment window.
quote_role: PRIMARY_RESULT
- discussion_id: bcm_genotype_phenotype_correlation
kind: OPEN_QUESTION
prompt: >-
Does genotype at the opsin array predict the clinical phenotype, given that one
series found no genotype-phenotype association while later structural work found
deletion genotypes progress faster than Cys203Arg?
attaches_to:
- pathophysiology#Loss of Function of the OPN1LW/OPN1MW Opsin Gene Array
rationale: >-
Clinical severity, residual function and structural progression are different outcomes. The 2018 deletion/Cys203Arg
comparison found a structural association, while exon 3 cohorts show milder average acuity and ERG abnormalities.
Small cohorts, related patients and incomplete longitudinal data limit patient-specific prediction.
evidence:
- reference: PMID:10982039
reference_title: >-
Spectrum of color gene deletions and phenotype in patients with blue cone
monochromacy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
No association was observed between the phenotypes and genotypes in these
families.
explanation: >-
The negative cross-sectional finding.
directness: DIRECT
quote_role: PRIMARY_RESULT
- reference: PMID:30516820
reference_title: Blue Cone Monochromacy Caused by the C203R Missense Mutation or Large Deletion Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Patients with the C203R mutation, however, had decades-longer persistence of foveal photoreceptor outer
nuclear layer thickness and a slower rate of development of inner segment/outer segment defects than
did patients with large deletion mutations.
explanation: >-
The retrospective 34-patient structural comparison supports genotype-associated differences; it does
not predict an individual treatment window.
quote_role: PRIMARY_RESULT
- reference: PMID:35400991
reference_title: Relatively mild blue cone monochromacy phenotype caused by various haplotypes in the L- and M-cone opsin genes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Analysis of the clinical data revealed better best-corrected visual acuity, more severe myopia, and higher
30-Hz cone flicker responses in the patients with exon 3 haplotypes than in those with typical BCM.
explanation: >-
The clinical cohort supports a milder average phenotype with important overlap.
quote_role: PRIMARY_RESULT
- discussion_id: bcm_gpr143_blended_phenotype
kind: OPEN_QUESTION
prompt: Does concomitant GPR143 variation explain the phenotype in the reported opsin-variant family?
attaches_to:
- phenotypes#Foveal Hypoplasia
rationale: >-
One family had GPR143 splice variation, OPN1MW Cys203Arg and OPN1LW Ser143Pro, which the authors classified
as a variant of uncertain significance. The report proposes a combined effect but lacks functional resolution
of the individual contributions. Foveal hypoplasia also occurs in BCM cohorts without an established GPR143
diagnosis, so it is not evidence of a general modifier requirement.
evidence:
- reference: PMID:34445325
reference_title: >-
Blue Cone Monochromatism with Foveal Hypoplasia Caused by the Concomitant
Effect of Variants in OPN1LW/OPN1MW and GPR143 Genes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
To our knowledge, this is the first case of foveal hypoplasia in a BCM patient
and of mild clinical affection in a female carrier caused by the concomitant
effect of variants in OPN1LW/OPN1MW and GPR143 genes, thus as the result of the
simultaneous action of two independent genetic defects.
explanation: >-
The authors propose a combined phenotype in one family. This supports discussion of a possible blended
diagnosis, not an established general GPR143 modifier effect.
directness: INDIRECT
- reference: PMID:36186895
reference_title: Comparing Retinal Structure in Patients with Achromatopsia and Blue Cone Monochromacy Using OCT.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Sixty-two of the total 89 ACHM patients (70%) had foveal hypoplasia, compared with 11 of 33 BCM patients
(33%).
explanation: >-
The full-text OCT cohort documents foveal hypoplasia in BCM as well as ACHM.
quote_role: PRIMARY_RESULT
- reference: PMID:34445325
reference_title: Blue Cone Monochromatism with Foveal Hypoplasia Caused by the Concomitant Effect of Variants in OPN1LW/OPN1MW and GPR143 Genes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Indeed, though the novel mutation of the OPN1LW gene identified in this patient has been classified as
a VUS, its disease causative role can be sustained by the following findings: the variant was not found
in any queried public database; it is in a hemizygous state, inherited by the mother showing mild clinical
sign of the disease and determining a full phenotype only in the proband in line with the X-linked transmission
of the disease; it affects a highly conserved amino acid of the protein across species (Figure 7); and
the presence of the common missense mutation c.607T > C (p.Cys203Arg) in the OPN1MW gene.
explanation: >-
The full text explicitly classifies the OPN1LW variant as uncertain despite the authors’ pathogenicity
hypothesis.
quote_role: PRIMARY_RESULT
notes: >-
BCM overlaps clinically with achromatopsia and other opsin-related cone disorders but has a distinct X-linked
opsin-array basis. Molecular interpretation must account for regulatory sequence, copy number, gene position
and haplotypes. Residual S-cone function, foveal morphology and non-waveguiding cells each provide different
information and are not interchangeable measures of normal colour vision or therapeutic potential.
references:
- reference: DOI:10.1038/s41525-022-00334-9
title: Diagnostic analysis of the highly complex OPN1LW/OPN1MW gene cluster using long-read sequencing and MLPA
- reference: DOI:10.1126/science.2788922
title: Molecular Genetics of Human Blue Cone Monochromacy
- reference: PMID:10982039
title: Spectrum of color gene deletions and phenotype in patients with blue cone monochromacy.
- reference: PMID:11773636
title: Role of a locus control region in the mutually exclusive expression of human red and green cone pigment genes.
- reference: PMID:15094734
title: 'Blue cone monochromatism: a phenotype and genotype assessment with evidence of progressive loss of cone function in older individuals.'
- reference: PMID:1524826
title: A locus control region adjacent to the human red and green visual pigment genes.
- reference: PMID:19421413
title: 'Blue cone monochromacy: causative mutations and associated phenotypes.'
- reference: PMID:20638402
title: Deletion of the X-linked opsin gene array locus control region (LCR) results in disruption of the cone mosaic.
- reference: PMID:22998501
title: Blue cone monochromatism in a female due to skewed X-inactivation.
- reference: PMID:25909963
title: 'Blue cone monochromacy: visual function and efficacy outcome measures for clinical trials.'
- reference: PMID:26153062
title: High-resolution microarray analysis unravels complex Xq28 aberrations in patients and carriers affected by X-linked blue cone monochromacy.
- reference: PMID:28516000
title: Role of a Dual Splicing and Amino Acid Code in Myopia, Cone Dysfunction and Cone Dystrophy Associated with L/M Opsin Interchange Mutations.
- reference: PMID:28751656
title: Gene-based Therapy in a Mouse Model of Blue Cone Monochromacy.
- reference: PMID:29940872
title: 'A 73,128 bp de novo deletion encompassing the OPN1LW/OPN1MW gene cluster in sporadic Blue Cone Monochromacy: a case report.'
- reference: PMID:30065301
title: 'Genotype determination of the OPN1LW/OPN1MW genes: novel disease-causing mechanisms in Japanese patients with blue cone monochromacy.'
- reference: PMID:30516820
title: Blue Cone Monochromacy Caused by the C203R Missense Mutation or Large Deletion Mutations.
- reference: PMID:33344057
title: 'Reading Performance in Blue Cone Monochromacy: Defining an Outcome Measure for a Clinical Trial.'
- reference: PMID:34445325
title: Blue Cone Monochromatism with Foveal Hypoplasia Caused by the Concomitant Effect of Variants in OPN1LW/OPN1MW and GPR143 Genes.
- reference: PMID:35400991
title: Relatively mild blue cone monochromacy phenotype caused by various haplotypes in the L- and M-cone opsin genes.
- reference: PMID:35743313
title: Novel OPN1LW/OPN1MW Exon 3 Haplotype-Associated Splicing Defect in Patients with X-Linked Cone Dysfunction.
- reference: PMID:35759666
title: The landscape of submicroscopic structural variants at the OPN1LW/OPN1MW gene cluster on Xq28 underlying blue cone monochromacy.
- reference: PMID:36186895
title: Comparing Retinal Structure in Patients with Achromatopsia and Blue Cone Monochromacy Using OCT.
- reference: PMID:36301530
title: Foveal Cone Structure in Patients With Blue Cone Monochromacy.
- reference: PMID:36692456
title: 'Color Vision in Blue Cone Monochromacy: Outcome Measures for a Clinical Trial.'
- reference: PMID:36932675
title: Preclinical evaluation of ADVM-062, a novel intravitreal gene therapy vector for the treatment of blue cone monochromacy.
- reference: PMID:37001420
title: Blue cone monochromacy and gene therapy.
- reference: PMID:38060327
title: Structural and functional rescue of cones carrying the most common cone opsin C203R missense mutation.
- reference: PMID:38871951
title: S-cone contribution to oscillatory potentials in patients with blue cone monochromacy.
- reference: PMID:39408969
title: Evaluation of Retinal Structure and Visual Function in Blue Cone Monochromacy to Develop Clinical Endpoints for L-opsin Gene Therapy.
- reference: PMID:41286353
title: Molecular mechanisms limiting the AAV gene therapy treatment window in mouse models of blue cone monochromacy.
- reference: PMID:41941983
title: Molecular and cellular impact of a C203R/C198R M-opsin mutation.
- reference: PMID:42157965
title: Gene therapy rescues cone function in opn1mw (-/-) /opn1sw (-/-) /Nrl (-/-) mice, an all-cone model of blue cone monochromacy.
- reference: PMID:42275379
title: Gene therapy rescues cone function in an all-cone retina mouse model with the most common cone opsin C203R missense mutation.
- reference: PMID:8213841
title: Genetic heterogeneity among blue-cone monochromats.
- reference: clinicaltrials:NCT06491615
title: National Ophthalmic Genotyping and Phenotyping Network, Stage 3 - Expansion of DNA and Data Repositories for Rare Inherited Ophthalmic Diseases
experimental_models:
- name: Opsin exon 3 minigene splicing assays
experimental_model_type: CELL_LINE
organism:
preferred_term: Homo sapiens
term:
id: NCBITaxon:9606
label: Homo sapiens
cell_source: HEK293 and WERI-Rb1 retinoblastoma cells
publication: PMID:35743313
description: >-
Minigenes compare exon 3 haplotypes in HEK293 and a cone-like retinoblastoma cell line; the assays show
similar relative splice defects in both systems.
modeled_mechanisms:
- target: Exon 3 Haplotype-Dependent Opsin Missplicing
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: MOLECULAR
description: >-
LIVVA retains approximately 3-5% correctly spliced transcript, whereas LIAVA has no detectable correctly
spliced product in these assays.
limitations: >-
Engineered minigenes and tumor-derived cells do not reproduce the complete endogenous opsin array, retinal
maturation or clinical course.
evidence:
- reference: PMID:35743313
reference_title: Novel OPN1LW/OPN1MW Exon 3 Haplotype-Associated Splicing Defect in Patients with X-Linked Cone Dysfunction.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
Applying minigene assays for all observed exon 3 haplotypes in the patients, we demonstrated that the
novel exon 3 haplotype L-I-V-V-A induces a strong but incomplete splicing defect with 3-5% of residual
correctly spliced transcripts.
explanation: >-
Minigene assays establish incomplete exon 3 splicing for LIVVA.
quote_role: PRIMARY_RESULT
evidence:
- reference: PMID:35743313
reference_title: Novel OPN1LW/OPN1MW Exon 3 Haplotype-Associated Splicing Defect in Patients with X-Linked Cone Dysfunction.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
Applying minigene assays for all observed exon 3 haplotypes in the patients, we demonstrated that the
novel exon 3 haplotype L-I-V-V-A induces a strong but incomplete splicing defect with 3-5% of residual
correctly spliced transcripts.
explanation: >-
Minigene assays establish incomplete exon 3 splicing for LIVVA.
quote_role: PRIMARY_RESULT
clinical_trials:
- name: NCT06491615
phase: NOT_APPLICABLE
status: RECRUITING
description: >-
eyeGENE Stage 3 expands DNA and phenotype repositories for rare inherited ophthalmic diseases, explicitly
including blue cone monochromacy and potentially unaffected relatives. This is an observational research
resource, not an opsin gene-therapy trial.
notes: >-
Registry checked 2026-10-01; last update posted 2026-06-09. Estimated enrollment is 1,000 across all included
conditions, not 1,000 BCM participants.
evidence:
- reference: clinicaltrials:NCT06491615
reference_title: National Ophthalmic Genotyping and Phenotyping Network, Stage 3 - Expansion of DNA and Data Repositories for Rare Inherited Ophthalmic Diseases
supports: SUPPORT
evidence_source: OTHER
directness: DIRECT
snippet: >-
Objective: To collect information and DNA samples for the study of eye diseases.
explanation: >-
The cached registry describes research sampling, not a treatment intervention.

📚

References & Deep Research

References

DOI:10.1038/s41525-022-00334-9

Diagnostic analysis of the highly complex OPN1LW/OPN1MW gene cluster using long-read sequencing and MLPA