ATF6-Related Retinopathy

Mendelian MONDO:0100447 Pathograph 12 Show in embeddings browser

ATF6-related retinopathy is an autosomal recessive cone photoreceptor disorder caused by biallelic pathogenic variants in ATF6, encoding activating transcription factor 6, a ubiquitously expressed ER-stress sensor and key regulator of the unfolded protein response (UPR). Unlike the five other achromatopsia genes (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H), which encode components of the cone phototransduction cascade directly, ATF6 acts upstream through cone photoreceptor development: loss of normal ATF6 UPR signaling causes foveal hypoplasia and near-absent cone structure rather than simply disabling an intact phototransduction cascade. Most patients present with the classic achromatopsia phenotype (designated ACHM7 in the achromatopsia gene series), but ATF6 variants have also been reported to cause cone-rod dystrophy and macular involvement -- a yellow macular lesion with reduced fundus autofluorescence has been documented in at least one ATF6-associated patient -- so the clinical spectrum is broader than achromatopsia alone. This entry captures the ATF6-specific gene-disease mechanism and phenotypic spectrum; Achromatopsia.yaml models the ACHM7 subtype within the broader achromatopsia disease umbrella and should be consulted for cross-gene comparison within that phenotype.

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1
Inheritance
4
Pathophys.
10
Phenotypes
12
Pathograph
1
Genes
2
Medical Actions
2
Subtypes
1
References
👪

Inheritance

1
Autosomal recessive HP:0000007
All reported ATF6-related retinopathy families carry biallelic (homozygous or compound heterozygous) pathogenic variants.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:26029869 SUPPORT Human Clinical
"Achromatopsia (ACHM) is an autosomal recessive disorder characterized by color blindness, photophobia, nystagmus and severely reduced visual acuity."
Establishes autosomal recessive inheritance in the founding ATF6 cohort.
PMID:20301591 SUPPORT REVIEW SYNTHESIS Human Clinical
"At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."
States the sibling recurrence risk that follows from autosomal recessive transmission, which is the genetic-counseling consequence of this inheritance mode rather than a restatement of the mode itself.
◆

Subtypes

2
Classic Achromatopsia (ACHM7) MONDO:0014677
The majority ATF6-related phenotype: complete or near-complete cone dysfunction from birth with foveal hypoplasia, corresponding to achromatopsia type 7 (ACHM7) in the achromatopsia gene series.
Show evidence (1 reference)
PMID:26029869 SUPPORT Human Clinical
"Patients had evidence of foveal hypoplasia and disruption of the cone photoreceptor layer."
Founding cohort establishing the classic achromatopsia presentation of ATF6-related disease.
ATF6-Related Cone-Rod Dystrophy MONDO:0015993
A minority phenotype in which cone responses are extinguished but rod responses are also decreased, with some residual color discrimination -- clinically distinct from classic achromatopsia despite the shared genetic cause. No ATF6-specific numbered cone-rod dystrophy entry exists in OMIM/MONDO (ATF6's only disease-specific identifier is achromatopsia 7/ACHM7); this subtype is therefore bound to the generic cone-rod dystrophy disease-series term rather than a gene-specific one.
Show evidence (1 reference)
PMID:28812650 SUPPORT Human Clinical
"Detailed phenotypic examination revealed extinguished cone responses but also decreased rod responses together with the ability to discriminate some colours suggestive rather for cone-rod dystrophy than achromatopsia."
Documents a homozygous ATF6 missense variant producing a cone-rod dystrophy phenotype rather than classic achromatopsia.
⚙

Pathophysiology

4
ATF6 Unfolded Protein Response Impairment
ATF6 is an ER-membrane-resident transcription factor that normally migrates from the ER to the Golgi under ER stress, where it undergoes regulated intramembrane proteolysis (RIP) to release a cytosolic transcriptional-activator domain that upregulates protein-folding chaperones. Pathogenic ATF6 variants disrupt this UPR arm through three distinct mechanisms rather than a single loss-of-function direction: impaired ER-to-Golgi trafficking with diminished RIP and transcriptional output, aberrant constitutive transcriptional activation independent of ER stress, or complete loss of DNA-binding transcriptional activity.
retinal cone cell CL:0000573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal cone cell (CL:0000573). CL:0000573 is a cell type from the Cell Ontology.
ATF6 hgnc:791 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ATF6 (hgnc:791). hgnc:791 is a gene from the HUGO Gene Nomenclature Committee.
ATF6-mediated unfolded protein response GO:0036500 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated ATF6-mediated unfolded protein response (GO:0036500). GO:0036500 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Impaired Cone Photoreceptor Development Dysregulated ATF6-mediated ER stress response, in either direction, disrupts the normal developmental role of ATF6 in the retina.
Age- and Genotype-Dependent Rod Involvement The same underlying ATF6 UPR impairment that disrupts cone developmental signaling also underlies the age- and genotype-dependent rod-pathway involvement documented in the Atf6-knockout mouse model.
Show evidence (3 references)
PMID:26063662 SUPPORT In Vitro
"a truncated protein that lacks the DNA binding and transmembrane domains"
Documents the truncating founder mutation's effect on ATF6 protein structure.
PMID:26063662 SUPPORT In Vitro
"in heterologous cells ATF6 protein with the p.Glu119Glyfs*8 variant is mainly confined to the nucleus"
Demonstrates aberrant nuclear mislocalization of the truncated ATF6 protein versus cytoplasmic wild-type localization.
PMID:32271167 SUPPORT Human Clinical
"RNAscope revealed that ATF6 and the related ATF6B transcripts were expressed in cones as well as in all retinal layers in normal human retina."
Confirms ATF6 expression in cone photoreceptors and throughout the normal human retina.
Impaired Cone Photoreceptor Development
ATF6-mediated UPR signaling is required for normal cone photoreceptor and foveal development. Its disruption -- rather than a direct block of an otherwise intact phototransduction cascade, as occurs in the other five achromatopsia genes -- produces a severe developmental cone deficit with near-absent foveal cone structure.
retinal cone cell CL:0000573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal cone cell (CL:0000573). CL:0000573 is a cell type from the Cell Ontology.
eye photoreceptor cell development GO:0042462 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased eye photoreceptor cell development (GO:0042462). GO:0042462 is a biological process from the Gene Ontology. ↓ DECREASED
fovea centralis UBERON:0001786 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in fovea centralis (UBERON:0001786). UBERON:0001786 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Foveal Hypoplasia and Near-Absent Cone Structure Impaired cone developmental signaling produces a severely underdeveloped fovea with little to no residual cone structure.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/books/NBK1418/ SUPPORT Human Clinical
"usually have a poorly formed or absent foveal pit"
GeneReviews identifies absent/poorly formed foveal pit as the distinguishing structural feature of ATF6-associated disease.
Foveal Hypoplasia and Near-Absent Cone Structure
The structural endpoint of impaired cone development: foveal hypoplasia with little to no remnant foveal cone mosaic, more severe than the residual (if abnormal) foveal cones seen in the phototransduction-gene forms of achromatopsia such as CNGA3.
retinal cone cell CL:0000573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal cone cell (CL:0000573). CL:0000573 is a cell type from the Cell Ontology.
fovea centralis UBERON:0001786 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in fovea centralis (UBERON:0001786). UBERON:0001786 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Reduced Visual Acuity Near-absent foveal cone structure severely limits central visual acuity.
Color Vision Defect Absence of functioning foveal cone photoreceptors abolishes cone-mediated color discrimination.
Foveal Hypoplasia The structural endpoint node's defining lesion -- near-total absence of the foveal cone mosaic -- is itself the clinical finding of foveal hypoplasia.
Abnormal Cone Electroretinogram Near-absent foveal cone structure abolishes the photopic (cone-driven) ERG signal.
Photophobia Severe cone dysfunction arising from near-absent foveal cone structure produces the characteristic early light sensitivity of ATF6-related disease.
Nystagmus Poor foveal fixation resulting from near-absent foveal cone structure produces the characteristic early pendular nystagmus of ATF6-related disease.
Show evidence (3 references)
PMID:31237654 SUPPORT Human Clinical
"Foveal hypoplasia was observed in all subjects with ATF6 mutations."
Confirms foveal hypoplasia as a consistent (near-universal) structural finding across ATF6-associated cases.
PMID:31237654 SUPPORT Human Clinical
"There was no evidence of remnant foveal cone structure using confocal AOSLO"
Adaptive-optics imaging directly documents the near-total absence of residual foveal cone structure.
PMID:38419580 SUPPORT Human Clinical
"a loss of the foveal pit"
Independent case report corroborating loss of the foveal pit as a structural finding in ATF6-associated disease.
Age- and Genotype-Dependent Rod Involvement
While the human founder cohorts and Atf6-knockout mice show normal rod function at a young age, some genotypes and older individuals show additional rod-pathway involvement beyond the primary cone/foveal deficit, producing a cone-rod dystrophy phenotype in a minority of patients rather than classic stationary achromatopsia.
retinal rod cell CL:0000604 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal rod cell (CL:0000604). CL:0000604 is a cell type from the Cell Ontology.
Downstream
Decreased Rod Response Age- and genotype-dependent rod-pathway involvement manifests clinically as a measurable decrease in rod (dark-adapted) ERG response, distinguishing the cone-rod dystrophy subtype from classic, rod-sparing ATF6-related achromatopsia.
Show evidence (2 references)
PMID:26029869 SUPPORT Model Organism
"Atf6(-/-) mice have normal retinal morphology and function at a young age but develop rod and cone dysfunction with increasing age."
Establishes age-dependent rod involvement in the Atf6-knockout mouse model.
PMID:28812650 SUPPORT Human Clinical
"Detailed phenotypic examination revealed extinguished cone responses but also decreased rod responses together with the ability to discriminate some colours suggestive rather for cone-rod dystrophy than achromatopsia."
Documents combined rod and cone involvement in a human ATF6 cone-rod dystrophy case.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for ATF6-Related Retinopathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

10
Reduced Visual Acuity VERY_FREQUENT Eye HP:0007663 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced visual acuity (HP:0007663). HP:0007663 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/books/NBK1418/ SUPPORT Human Clinical
"Best visual acuity varies with severity of the disease; it is 20/200 or less in complete achromatopsia"
Quantifies severely reduced visual acuity in the complete/classic form.
Color Vision Defect VERY_FREQUENT Eye HP:0000551 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Color vision defect (HP:0000551). HP:0000551 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26063662 SUPPORT Human Clinical
"Achromatopsia (ACHM) is an early-onset retinal dystrophy characterized by photophobia, nystagmus, color blindness and severely reduced visual acuity."
Confirms color blindness as a defining feature of ATF6-related disease.
Photophobia VERY_FREQUENT Eye HP:0000613 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Photophobia (HP:0000613). HP:0000613 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26063662 SUPPORT Human Clinical
"Achromatopsia (ACHM) is an early-onset retinal dystrophy characterized by photophobia, nystagmus, color blindness and severely reduced visual acuity."
Photophobia is documented as a core early-onset feature.
Nystagmus VERY_FREQUENT Eye HP:0012043 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pendular nystagmus (HP:0012043). HP:0012043 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26063662 SUPPORT Human Clinical
"Achromatopsia (ACHM) is an early-onset retinal dystrophy characterized by photophobia, nystagmus, color blindness and severely reduced visual acuity."
Nystagmus is documented as a core early-onset feature.
Foveal Hypoplasia OBLIGATE Eye HP:0008060 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Foveal hypoplasia, annotated with Aplasia/Hypoplasia of the fovea (HP:0008060). HP:0008060 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31237654 SUPPORT Human Clinical
"Foveal hypoplasia was observed in all subjects with ATF6 mutations."
Foveal hypoplasia was observed in every subject in this cohort, supporting an OBLIGATE band.
url:https://www.ncbi.nlm.nih.gov/books/NBK1418/ SUPPORT Human Clinical
"usually have a poorly formed or absent foveal pit"
GeneReviews identifies this as the key distinguishing feature of ATF6-associated achromatopsia.
Abnormal Cone Electroretinogram VERY_FREQUENT Eye HP:0008275 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal cone electroretinogram, annotated with Abnormal light-adapted electroretinogram (HP:0008275). HP:0008275 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/books/NBK1418/ SUPPORT Human Clinical
"The photopic response (including the 30-Hz flicker response) is absent or markedly diminished; the scotopic response is normal or mildly abnormal."
Defines the characteristic abnormal cone-predominant ERG pattern of achromatopsia.
PMID:38419580 SUPPORT Human Clinical
"ERG showed relatively normal rod responses and unrecordable cone responses."
ATF6-specific human case confirming an unrecordable (severely abnormal) cone-driven ERG response, with relatively preserved rod responses in the classic phenotype.
Yellow Macular Lesion Eye HP:0030500 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Yellow/white macular lesion (HP:0030500). HP:0030500 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38419580 SUPPORT Human Clinical
"Small yellow lesion in the macula of both eyes was observed."
Documents a bilateral yellow macular lesion in an ATF6-associated achromatopsia patient.
Abnormal Fundus Autofluorescence Eye HP:0030602 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal fundus autofluorescence imaging (HP:0030602). HP:0030602 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38419580 SUPPORT Human Clinical
"FAF demonstrated hypofluorescence in the macular fovea."
Directly documents abnormal fundus autofluorescence at the macula in an ATF6-associated patient.
Decreased Rod Response Eye HP:0030469 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal dark-adapted electroretinogram (HP:0030469). HP:0030469 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28812650 SUPPORT Human Clinical
"extinguished cone responses but also decreased rod responses"
Directly documents decreased rod ERG responses in the ATF6 cone-rod dystrophy subtype.
PMID:26029869 SUPPORT Model Organism
"Atf6(-/-) mice have normal retinal morphology and function at a young age but develop rod and cone dysfunction with increasing age."
Age-dependent rod dysfunction in the Atf6-knockout mouse model parallels the human cone-rod dystrophy subtype.
Color Vision Defect Eye HP:0000551 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Color vision defect (HP:0000551). HP:0000551 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28812650 SUPPORT Human Clinical
"the ability to discriminate some colours suggestive rather for cone-rod dystrophy than achromatopsia"
Documents residual color discrimination as the clinical feature distinguishing the cone-rod dystrophy subtype from classic achromatopsia.
🧬

Genetic Associations

1
ATF6 (Causative)
Gene: ATF6 hgnc:791 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ATF6 (hgnc:791). hgnc:791 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (5 references)
PMID:28028229 SUPPORT In Vitro
"impaired ER-to-Golgi trafficking and diminished regulated intramembrane proteolysis and transcriptional activity"
Defines the class 1 (trafficking-impaired) mutation mechanism.
PMID:28028229 SUPPORT In Vitro
"the entire ATF6 cytosolic domain with fully intact transcriptional activity and constitutive induction of downstream target genes, even in the absence of ER stress"
Defines the class 2 (constitutively active) mutation mechanism.
PMID:28028229 SUPPORT In Vitro
"complete loss of transcriptional activity because of absent or defective bZIP domains"
Defines the class 3 (transcriptionally null) mutation mechanism.
+ 2 more references
💊

Medical Actions

2
Supportive care and monitoring
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Management is currently entirely supportive: dark or special-filter glasses or red-tinted contact lenses to reduce photophobia, low-vision aids such as high-powered magnifiers and digital/electronic devices, and regular ophthalmologic monitoring.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/books/NBK1418/ SUPPORT Human Clinical
"Dark or special filter glasses or red-tinted contact lenses reduce photophobia and may improve visual acuity."
GeneReviews-recommended supportive management for photophobia in achromatopsia, including ATF6-related cases.
url:https://www.ncbi.nlm.nih.gov/books/NBK1418/ SUPPORT Human Clinical
"Every six to 12 months in children to monitor changes in refraction in order to achieve the best possible corrected visual acuity"
Establishes the recommended ophthalmologic monitoring cadence.
Genetic counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Platform: Behavioral / lifestyle
Genetic counseling is recommended for affected families given the autosomal recessive inheritance pattern.
Show evidence (1 reference)
PMID:26029869 SUPPORT Human Clinical
"Achromatopsia (ACHM) is an autosomal recessive disorder characterized by color blindness, photophobia, nystagmus and severely reduced visual acuity."
Supports genetic counseling given the confirmed autosomal recessive inheritance pattern.
🔬

Diagnosis

3
Molecular genetic testing
A multigene panel including ATF6, CNGA3, CNGB3, GNAT2, PDE6C, and PDE6H, or comprehensive genomic testing, confirms the molecular diagnosis and distinguishes ATF6-related disease from the phototransduction-gene forms of achromatopsia.
molecular genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Identification of biallelic pathogenic ATF6 variants confirms the diagnosis.
Show evidence (1 reference)
PMID:20301591 SUPPORT Human Clinical
"Identification of biallelic pathogenic (or likely pathogenic) variants in ATF6, CNGA3, CNGB3, GNAT2, PDE6C, or PDE6H confirms the clinical diagnosis."
GeneReviews specifies that identifying biallelic pathogenic ATF6 variants confirms the clinical diagnosis of achromatopsia.
Electroretinography
Full-field ERG is the diagnostic cornerstone, and is also used to distinguish the classic achromatopsia (cone-only involvement) from the cone-rod dystrophy (combined cone and rod involvement) ATF6 phenotypes.
electroretinography NCIT:C18020 NCI Thesaurus (NCIT)
Results: Absent or markedly diminished photopic responses confirm cone dysfunction; additional scotopic response reduction indicates the cone-rod dystrophy subtype rather than classic achromatopsia.
Show evidence (1 reference)
PMID:28812650 SUPPORT Human Clinical
"extinguished cone responses but also decreased rod responses"
ERG differentiates the cone-rod dystrophy subtype from classic achromatopsia by showing combined rod/cone loss.
Optical coherence tomography
OCT characterizes the severity of foveal hypoplasia and residual cone structure, which is more severely reduced in ATF6-related disease than in the phototransduction-gene forms of achromatopsia.
optical coherence tomography NCIT:C20828 NCI Thesaurus (NCIT)
Results: Absence of the ellipsoid-zone band within the foveal region or a hyporeflective zone is seen in essentially all ATF6-related cases.
Show evidence (1 reference)
PMID:31237654 SUPPORT Human Clinical
"Absence of the EZ band within the foveal region (grade 3) or appearance of a hyporeflective zone (grade 4) was seen in all subjects"
Quantifies the severe, near-universal OCT abnormality in ATF6-related disease.
📊

Prevalence

1
International genetically confirmed achromatopsia cohort
Cases In Literature Not yet documented
ATF6 is a rare cause of achromatopsia, identified in ten independent families in the founding cohort study; no independent general-population prevalence estimate for ATF6-related disease specifically has been published.
Show evidence (1 reference)
PMID:26029869 SUPPORT Human Clinical
"we identified ten families carrying six homozygous and two compound-heterozygous mutations in the ATF6 gene"
Total ATF6-related family count identified in the founding cohort study.
{ }

Source YAML

click to show 
name: ATF6-Related Retinopathy
creation_date: "2026-08-03T00:00:00Z"
category: Mendelian
description: >-
  ATF6-related retinopathy is an autosomal recessive cone photoreceptor
  disorder caused by biallelic pathogenic variants in ATF6, encoding
  activating transcription factor 6, a ubiquitously expressed ER-stress
  sensor and key regulator of the unfolded protein response (UPR). Unlike
  the five other achromatopsia genes (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H),
  which encode components of the cone phototransduction cascade directly,
  ATF6 acts upstream through cone photoreceptor development: loss of normal
  ATF6 UPR signaling causes foveal hypoplasia and near-absent cone structure
  rather than simply disabling an intact phototransduction cascade. Most
  patients present with the classic achromatopsia phenotype (designated
  ACHM7 in the achromatopsia gene series), but ATF6 variants have also been
  reported to cause cone-rod dystrophy and macular involvement -- a yellow
  macular lesion with reduced fundus autofluorescence has been documented in
  at least one ATF6-associated patient -- so the clinical spectrum is
  broader than achromatopsia alone. This entry captures
  the ATF6-specific gene-disease mechanism and phenotypic spectrum;
  Achromatopsia.yaml models the ACHM7 subtype within the broader
  achromatopsia disease umbrella and should be consulted for cross-gene
  comparison within that phenotype.
disease_term:
  preferred_term: ATF6-related retinopathy
  term:
    id: MONDO:0100447
    label: ATF6-related retinopathy
has_subtypes:
- name: Classic Achromatopsia
  display_name: Classic Achromatopsia (ACHM7)
  description: >-
    The majority ATF6-related phenotype: complete or near-complete cone
    dysfunction from birth with foveal hypoplasia, corresponding to
    achromatopsia type 7 (ACHM7) in the achromatopsia gene series.
  subtype_term:
    preferred_term: achromatopsia 7
    term:
      id: MONDO:0014677
      label: achromatopsia 7
  evidence:
  - reference: PMID:26029869
    reference_title: "Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had evidence of foveal hypoplasia and disruption of the cone photoreceptor layer."
    explanation: Founding cohort establishing the classic achromatopsia presentation of ATF6-related disease.
- name: Cone-Rod Dystrophy
  display_name: ATF6-Related Cone-Rod Dystrophy
  description: >-
    A minority phenotype in which cone responses are extinguished but rod
    responses are also decreased, with some residual color discrimination --
    clinically distinct from classic achromatopsia despite the shared
    genetic cause. No ATF6-specific numbered cone-rod dystrophy entry exists
    in OMIM/MONDO (ATF6's only disease-specific identifier is achromatopsia
    7/ACHM7); this subtype is therefore bound to the generic cone-rod
    dystrophy disease-series term rather than a gene-specific one.
  subtype_term:
    preferred_term: cone-rod dystrophy
    term:
      id: MONDO:0015993
      label: cone-rod dystrophy
  evidence:
  - reference: PMID:28812650
    reference_title: "Autosomal recessive cone-rod dystrophy can be caused by mutations in the ATF6 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Detailed phenotypic examination revealed extinguished cone responses but also decreased rod responses together with the ability to discriminate some colours suggestive rather for cone-rod dystrophy than achromatopsia."
    explanation: Documents a homozygous ATF6 missense variant producing a cone-rod dystrophy phenotype rather than classic achromatopsia.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    All reported ATF6-related retinopathy families carry biallelic
    (homozygous or compound heterozygous) pathogenic variants.
  evidence:
  - reference: PMID:26029869
    reference_title: "Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Achromatopsia (ACHM) is an autosomal recessive disorder characterized by color blindness, photophobia, nystagmus and severely reduced visual acuity."
    explanation: Establishes autosomal recessive inheritance in the founding ATF6 cohort.
  - reference: PMID:20301591
    reference_title: Achromatopsia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."
    explanation: >-
      States the sibling recurrence risk that follows from autosomal recessive
      transmission, which is the genetic-counseling consequence of this
      inheritance mode rather than a restatement of the mode itself.
genetic:
- name: ATF6
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: ATF6
    term:
      id: hgnc:791
      label: ATF6
  features: >-
    Biallelic loss- or gain-of-function variants in ATF6 (encoding activating
    transcription factor 6) fall into three functional classes: impaired
    ER-to-Golgi trafficking with diminished transcriptional activity (class
    1), constitutively active transcriptional activity even without ER
    stress (class 2), and complete loss of transcriptional activity from a
    defective bZIP DNA-binding domain (class 3). Multiexon deletions have
    also been reported. ATF6 is a rare cause of achromatopsia overall,
    identified in ten independent families in the founding cohort study.
  evidence:
  - reference: PMID:28028229
    reference_title: "Achromatopsia mutations target sequential steps of ATF6 activation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "impaired ER-to-Golgi trafficking and diminished regulated intramembrane proteolysis and transcriptional activity"
    explanation: Defines the class 1 (trafficking-impaired) mutation mechanism.
  - reference: PMID:28028229
    reference_title: "Achromatopsia mutations target sequential steps of ATF6 activation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the entire ATF6 cytosolic domain with fully intact transcriptional activity and constitutive induction of downstream target genes, even in the absence of ER stress"
    explanation: Defines the class 2 (constitutively active) mutation mechanism.
  - reference: PMID:28028229
    reference_title: "Achromatopsia mutations target sequential steps of ATF6 activation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "complete loss of transcriptional activity because of absent or defective bZIP domains"
    explanation: Defines the class 3 (transcriptionally null) mutation mechanism.
  - reference: PMID:32271167
    reference_title: "Multiexon deletion alleles of ATF6 linked to achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a homozygous deletion covering exons 8-14 of the ATF6 gene from 2 siblings from the same family."
    explanation: Documents multiexon deletion alleles as an additional ATF6 mutation mechanism.
  - reference: PMID:38419580
    reference_title: "Novel ATF6 homozygous variant in a Chinese patient with achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing result identified a novel splicing variant"
    explanation: Documents a homozygous ATF6 splice-site variant, broadening the mutational spectrum beyond the three functional classes and multiexon deletions.
pathophysiology:
- name: ATF6 Unfolded Protein Response Impairment
  biological_scale: MOLECULAR
  description: >-
    ATF6 is an ER-membrane-resident transcription factor that normally
    migrates from the ER to the Golgi under ER stress, where it undergoes
    regulated intramembrane proteolysis (RIP) to release a cytosolic
    transcriptional-activator domain that upregulates protein-folding
    chaperones. Pathogenic ATF6 variants disrupt this UPR arm through three
    distinct mechanisms rather than a single loss-of-function direction:
    impaired ER-to-Golgi trafficking with diminished RIP and transcriptional
    output, aberrant constitutive transcriptional activation independent of
    ER stress, or complete loss of DNA-binding transcriptional activity.
  genes:
  - preferred_term: ATF6
    term:
      id: hgnc:791
      label: ATF6
  cell_types:
  - preferred_term: retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  biological_processes:
  - preferred_term: ATF6-mediated unfolded protein response
    term:
      id: GO:0036500
      label: ATF6-mediated unfolded protein response
    modifier: DYSREGULATED
  downstream:
  - target: Impaired Cone Photoreceptor Development
    description: >-
      Dysregulated ATF6-mediated ER stress response, in either direction,
      disrupts the normal developmental role of ATF6 in the retina.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26063662
      reference_title: "Mutation of ATF6 causes autosomal recessive achromatopsia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "response to ER stress as mediated by the ATF6 pathway is essential for color vision in humans"
      explanation: Establishes that intact ATF6-mediated ER stress signaling is required for normal human color vision.
  - target: Age- and Genotype-Dependent Rod Involvement
    description: >-
      The same underlying ATF6 UPR impairment that disrupts cone
      developmental signaling also underlies the age- and genotype-dependent
      rod-pathway involvement documented in the Atf6-knockout mouse model.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26029869
      reference_title: "Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Atf6(-/-) mice have normal retinal morphology and function at a young age but develop rod and cone dysfunction with increasing age."
      explanation: Directly links loss of ATF6 UPR function to the later, age-dependent onset of rod (and cone) dysfunction in the knockout model.
  evidence:
  - reference: PMID:26063662
    reference_title: "Mutation of ATF6 causes autosomal recessive achromatopsia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "a truncated protein that lacks the DNA binding and transmembrane domains"
    explanation: Documents the truncating founder mutation's effect on ATF6 protein structure.
  - reference: PMID:26063662
    reference_title: "Mutation of ATF6 causes autosomal recessive achromatopsia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "in heterologous cells ATF6 protein with the p.Glu119Glyfs*8 variant is mainly confined to the nucleus"
    explanation: Demonstrates aberrant nuclear mislocalization of the truncated ATF6 protein versus cytoplasmic wild-type localization.
  - reference: PMID:32271167
    reference_title: "Multiexon deletion alleles of ATF6 linked to achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RNAscope revealed that ATF6 and the related ATF6B transcripts were expressed in cones as well as in all retinal layers in normal human retina."
    explanation: Confirms ATF6 expression in cone photoreceptors and throughout the normal human retina.
- name: Impaired Cone Photoreceptor Development
  biological_scale: CELLULAR
  description: >-
    ATF6-mediated UPR signaling is required for normal cone photoreceptor
    and foveal development. Its disruption -- rather than a direct block of
    an otherwise intact phototransduction cascade, as occurs in the other
    five achromatopsia genes -- produces a severe developmental cone deficit
    with near-absent foveal cone structure.
  cell_types:
  - preferred_term: retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  locations:
  - preferred_term: fovea centralis
    term:
      id: UBERON:0001786
      label: fovea centralis
  biological_processes:
  - preferred_term: eye photoreceptor cell development
    term:
      id: GO:0042462
      label: eye photoreceptor cell development
    modifier: DECREASED
  downstream:
  - target: Foveal Hypoplasia and Near-Absent Cone Structure
    description: >-
      Impaired cone developmental signaling produces a severely
      underdeveloped fovea with little to no residual cone structure.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31237654
      reference_title: "Characterization of Retinal Structure in ATF6-Associated Achromatopsia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our data demonstrate a near absence of cone structure in subjects harboring ATF6 mutations. This implicates ATF6 as having a major role in cone development"
      explanation: Directly links ATF6 loss of function to a severe cone developmental deficit.
  evidence:
  - reference: "url:https://www.ncbi.nlm.nih.gov/books/NBK1418/"
    reference_title: Achromatopsia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "usually have a poorly formed or absent foveal pit"
    explanation: GeneReviews identifies absent/poorly formed foveal pit as the distinguishing structural feature of ATF6-associated disease.
- name: Foveal Hypoplasia and Near-Absent Cone Structure
  biological_scale: TISSUE
  description: >-
    The structural endpoint of impaired cone development: foveal hypoplasia
    with little to no remnant foveal cone mosaic, more severe than the
    residual (if abnormal) foveal cones seen in the phototransduction-gene
    forms of achromatopsia such as CNGA3.
  cell_types:
  - preferred_term: retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  locations:
  - preferred_term: fovea centralis
    term:
      id: UBERON:0001786
      label: fovea centralis
  evidence:
  - reference: PMID:31237654
    reference_title: "Characterization of Retinal Structure in ATF6-Associated Achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Foveal hypoplasia was observed in all subjects with ATF6 mutations."
    explanation: Confirms foveal hypoplasia as a consistent (near-universal) structural finding across ATF6-associated cases.
  - reference: PMID:31237654
    reference_title: "Characterization of Retinal Structure in ATF6-Associated Achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was no evidence of remnant foveal cone structure using confocal AOSLO"
    explanation: Adaptive-optics imaging directly documents the near-total absence of residual foveal cone structure.
  - reference: PMID:38419580
    reference_title: "Novel ATF6 homozygous variant in a Chinese patient with achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a loss of the foveal pit"
    explanation: Independent case report corroborating loss of the foveal pit as a structural finding in ATF6-associated disease.
  downstream:
  - target: Reduced Visual Acuity
    description: Near-absent foveal cone structure severely limits central visual acuity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301591
      reference_title: Achromatopsia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Achromatopsia is characterized by reduced visual acuity, pendular nystagmus"
      explanation: GeneReviews lists reduced visual acuity among the cardinal achromatopsia manifestations of foveal cone loss.
  - target: Color Vision Defect
    description: Absence of functioning foveal cone photoreceptors abolishes cone-mediated color discrimination.
    causal_link_type: DIRECT
    evidence:
    - reference: "url:https://www.ncbi.nlm.nih.gov/books/NBK1418/"
      reference_title: Achromatopsia - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "reduced or complete lack of color discrimination"
      explanation: GeneReviews links loss of cone function to impaired or absent color discrimination.
  - target: Foveal Hypoplasia
    description: >-
      The structural endpoint node's defining lesion -- near-total absence
      of the foveal cone mosaic -- is itself the clinical finding of foveal
      hypoplasia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31237654
      reference_title: "Characterization of Retinal Structure in ATF6-Associated Achromatopsia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Foveal hypoplasia was observed in all subjects with ATF6 mutations."
      explanation: Direct structural-to-clinical mapping from near-absent foveal cone structure to observed foveal hypoplasia.
  - target: Abnormal Cone Electroretinogram
    description: >-
      Near-absent foveal cone structure abolishes the photopic (cone-driven)
      ERG signal.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38419580
      reference_title: "Novel ATF6 homozygous variant in a Chinese patient with achromatopsia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "ERG showed relatively normal rod responses and unrecordable cone responses."
      explanation: Directly ties the structural loss of foveal cone structure to an unrecordable cone-driven ERG response in an ATF6-associated patient.
  - target: Photophobia
    description: >-
      Severe cone dysfunction arising from near-absent foveal cone structure
      produces the characteristic early light sensitivity of ATF6-related
      disease.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301591
      reference_title: Achromatopsia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "increased sensitivity to light (photophobia)"
      explanation: GeneReviews lists photophobia among the cardinal manifestations of cone dysfunction in achromatopsia, including the ATF6-associated form.
  - target: Nystagmus
    description: >-
      Poor foveal fixation resulting from near-absent foveal cone structure
      produces the characteristic early pendular nystagmus of ATF6-related
      disease.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301591
      reference_title: Achromatopsia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Nystagmus develops during the first few weeks after birth followed by increased sensitivity to bright light."
      explanation: GeneReviews documents early-onset nystagmus as a consequence of the same foveal cone deficit.
- name: Age- and Genotype-Dependent Rod Involvement
  biological_scale: TISSUE
  description: >-
    While the human founder cohorts and Atf6-knockout mice show normal rod
    function at a young age, some genotypes and older individuals show
    additional rod-pathway involvement beyond the primary cone/foveal
    deficit, producing a cone-rod dystrophy phenotype in a minority of
    patients rather than classic stationary achromatopsia.
  cell_types:
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  evidence:
  - reference: PMID:26029869
    reference_title: "Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Atf6(-/-) mice have normal retinal morphology and function at a young age but develop rod and cone dysfunction with increasing age."
    explanation: Establishes age-dependent rod involvement in the Atf6-knockout mouse model.
  - reference: PMID:28812650
    reference_title: "Autosomal recessive cone-rod dystrophy can be caused by mutations in the ATF6 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Detailed phenotypic examination revealed extinguished cone responses but also decreased rod responses together with the ability to discriminate some colours suggestive rather for cone-rod dystrophy than achromatopsia."
    explanation: Documents combined rod and cone involvement in a human ATF6 cone-rod dystrophy case.
  downstream:
  - target: Decreased Rod Response
    description: >-
      Age- and genotype-dependent rod-pathway involvement manifests
      clinically as a measurable decrease in rod (dark-adapted) ERG
      response, distinguishing the cone-rod dystrophy subtype from classic,
      rod-sparing ATF6-related achromatopsia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28812650
      reference_title: "Autosomal recessive cone-rod dystrophy can be caused by mutations in the ATF6 gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "extinguished cone responses but also decreased rod responses"
      explanation: Documents the decreased rod ERG response that defines the cone-rod dystrophy subtype.
phenotypes:
- category: Eye
  name: Reduced Visual Acuity
  subtype: Classic Achromatopsia
  description: >-
    Severely reduced visual acuity from birth or early infancy, reflecting
    near-total loss of foveal cone function.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Reduced visual acuity
    term:
      id: HP:0007663
      label: Reduced visual acuity
  evidence:
  - reference: "url:https://www.ncbi.nlm.nih.gov/books/NBK1418/"
    reference_title: Achromatopsia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Best visual acuity varies with severity of the disease; it is 20/200 or less in complete achromatopsia"
    explanation: Quantifies severely reduced visual acuity in the complete/classic form.
- category: Eye
  name: Color Vision Defect
  subtype: Classic Achromatopsia
  description: >-
    Absent or severely impaired color discrimination along all three color
    axes in classic ATF6-related achromatopsia.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Color vision defect
    term:
      id: HP:0000551
      label: Color vision defect
  evidence:
  - reference: PMID:26063662
    reference_title: "Mutation of ATF6 causes autosomal recessive achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Achromatopsia (ACHM) is an early-onset retinal dystrophy characterized by photophobia, nystagmus, color blindness and severely reduced visual acuity."
    explanation: Confirms color blindness as a defining feature of ATF6-related disease.
- category: Eye
  name: Photophobia
  description: >-
    Light sensitivity is a characteristic early presenting symptom.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Photophobia
    term:
      id: HP:0000613
      label: Photophobia
  evidence:
  - reference: PMID:26063662
    reference_title: "Mutation of ATF6 causes autosomal recessive achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Achromatopsia (ACHM) is an early-onset retinal dystrophy characterized by photophobia, nystagmus, color blindness and severely reduced visual acuity."
    explanation: Photophobia is documented as a core early-onset feature.
- category: Eye
  name: Nystagmus
  description: >-
    Pendular nystagmus is a characteristic early finding, consistent with
    poor foveal fixation from severe cone dysfunction.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Pendular nystagmus
    term:
      id: HP:0012043
      label: Pendular nystagmus
  evidence:
  - reference: PMID:26063662
    reference_title: "Mutation of ATF6 causes autosomal recessive achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Achromatopsia (ACHM) is an early-onset retinal dystrophy characterized by photophobia, nystagmus, color blindness and severely reduced visual acuity."
    explanation: Nystagmus is documented as a core early-onset feature.
- category: Eye
  name: Foveal Hypoplasia
  description: >-
    Poorly formed or absent foveal pit, more severe and more consistently
    present than in the phototransduction-gene forms of achromatopsia --
    the clinically distinguishing structural feature of ATF6-related
    disease.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Foveal hypoplasia
    term:
      id: HP:0008060
      label: Aplasia/Hypoplasia of the fovea
  evidence:
  - reference: PMID:31237654
    reference_title: "Characterization of Retinal Structure in ATF6-Associated Achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Foveal hypoplasia was observed in all subjects with ATF6 mutations."
    explanation: Foveal hypoplasia was observed in every subject in this cohort, supporting an OBLIGATE band.
  - reference: "url:https://www.ncbi.nlm.nih.gov/books/NBK1418/"
    reference_title: Achromatopsia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "usually have a poorly formed or absent foveal pit"
    explanation: GeneReviews identifies this as the key distinguishing feature of ATF6-associated achromatopsia.
- category: Eye
  name: Abnormal Cone Electroretinogram
  description: >-
    Full-field ERG shows absent or markedly diminished photopic responses
    in classic ATF6-related achromatopsia; the cone-rod dystrophy subtype
    additionally shows decreased scotopic (rod) responses.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal cone electroretinogram
    term:
      id: HP:0008275
      label: Abnormal light-adapted electroretinogram
  evidence:
  - reference: "url:https://www.ncbi.nlm.nih.gov/books/NBK1418/"
    reference_title: Achromatopsia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The photopic response (including the 30-Hz flicker response) is absent or markedly diminished; the scotopic response is normal or mildly abnormal."
    explanation: Defines the characteristic abnormal cone-predominant ERG pattern of achromatopsia.
  - reference: PMID:38419580
    reference_title: "Novel ATF6 homozygous variant in a Chinese patient with achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ERG showed relatively normal rod responses and unrecordable cone responses."
    explanation: ATF6-specific human case confirming an unrecordable (severely abnormal) cone-driven ERG response, with relatively preserved rod responses in the classic phenotype.
- category: Eye
  name: Yellow Macular Lesion
  description: >-
    A small yellow macular lesion has been documented in at least one
    ATF6-associated achromatopsia patient, one of the sources of macular
    involvement in the broader ATF6 phenotypic spectrum.
  phenotype_term:
    preferred_term: Yellow/white macular lesion
    term:
      id: HP:0030500
      label: Yellow/white macular lesion
  evidence:
  - reference: PMID:38419580
    reference_title: "Novel ATF6 homozygous variant in a Chinese patient with achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Small yellow lesion in the macula of both eyes was observed."
    explanation: Documents a bilateral yellow macular lesion in an ATF6-associated achromatopsia patient.
- category: Eye
  name: Abnormal Fundus Autofluorescence
  description: >-
    Fundus autofluorescence (FAF) imaging shows hypofluorescence in the
    macular fovea, corresponding to the macular lesion documented in some
    ATF6-associated patients.
  phenotype_term:
    preferred_term: Abnormal fundus autofluorescence imaging
    term:
      id: HP:0030602
      label: Abnormal fundus autofluorescence imaging
  evidence:
  - reference: PMID:38419580
    reference_title: "Novel ATF6 homozygous variant in a Chinese patient with achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FAF demonstrated hypofluorescence in the macular fovea."
    explanation: Directly documents abnormal fundus autofluorescence at the macula in an ATF6-associated patient.
- category: Eye
  name: Decreased Rod Response
  subtype: Cone-Rod Dystrophy
  description: >-
    Decreased scotopic (rod) ERG responses accompany the extinguished cone
    responses in the cone-rod dystrophy subtype, distinguishing it from the
    rod-sparing classic achromatopsia presentation.
  phenotype_term:
    preferred_term: Abnormal dark-adapted electroretinogram
    term:
      id: HP:0030469
      label: Abnormal dark-adapted electroretinogram
  evidence:
  - reference: PMID:28812650
    reference_title: "Autosomal recessive cone-rod dystrophy can be caused by mutations in the ATF6 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "extinguished cone responses but also decreased rod responses"
    explanation: Directly documents decreased rod ERG responses in the ATF6 cone-rod dystrophy subtype.
  - reference: PMID:26029869
    reference_title: "Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Atf6(-/-) mice have normal retinal morphology and function at a young age but develop rod and cone dysfunction with increasing age."
    explanation: Age-dependent rod dysfunction in the Atf6-knockout mouse model parallels the human cone-rod dystrophy subtype.
- category: Eye
  name: Color Vision Defect
  subtype: Cone-Rod Dystrophy
  description: >-
    Unlike the complete or near-complete color blindness of classic
    ATF6-related achromatopsia, the cone-rod dystrophy subtype retains some
    residual color discrimination.
  severity: MILD
  phenotype_term:
    preferred_term: Color vision defect
    term:
      id: HP:0000551
      label: Color vision defect
  evidence:
  - reference: PMID:28812650
    reference_title: "Autosomal recessive cone-rod dystrophy can be caused by mutations in the ATF6 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the ability to discriminate some colours suggestive rather for cone-rod dystrophy than achromatopsia"
    explanation: Documents residual color discrimination as the clinical feature distinguishing the cone-rod dystrophy subtype from classic achromatopsia.
diagnosis:
- name: Molecular genetic testing
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    A multigene panel including ATF6, CNGA3, CNGB3, GNAT2, PDE6C, and PDE6H,
    or comprehensive genomic testing, confirms the molecular diagnosis and
    distinguishes ATF6-related disease from the phototransduction-gene forms
    of achromatopsia.
  results: >-
    Identification of biallelic pathogenic ATF6 variants confirms the
    diagnosis.
  evidence:
  - reference: PMID:20301591
    reference_title: Achromatopsia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of biallelic pathogenic (or likely pathogenic) variants in ATF6, CNGA3, CNGB3, GNAT2, PDE6C, or PDE6H confirms the clinical diagnosis."
    explanation: GeneReviews specifies that identifying biallelic pathogenic ATF6 variants confirms the clinical diagnosis of achromatopsia.
- name: Electroretinography
  diagnosis_term:
    preferred_term: electroretinography
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    Full-field ERG is the diagnostic cornerstone, and is also used to
    distinguish the classic achromatopsia (cone-only involvement) from the
    cone-rod dystrophy (combined cone and rod involvement) ATF6 phenotypes.
  results: >-
    Absent or markedly diminished photopic responses confirm cone
    dysfunction; additional scotopic response reduction indicates the
    cone-rod dystrophy subtype rather than classic achromatopsia.
  evidence:
  - reference: PMID:28812650
    reference_title: "Autosomal recessive cone-rod dystrophy can be caused by mutations in the ATF6 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "extinguished cone responses but also decreased rod responses"
    explanation: ERG differentiates the cone-rod dystrophy subtype from classic achromatopsia by showing combined rod/cone loss.
- name: Optical coherence tomography
  diagnosis_term:
    preferred_term: optical coherence tomography
    term:
      id: NCIT:C20828
      label: Optical Coherence Tomography
  description: >-
    OCT characterizes the severity of foveal hypoplasia and residual cone
    structure, which is more severely reduced in ATF6-related disease than
    in the phototransduction-gene forms of achromatopsia.
  results: >-
    Absence of the ellipsoid-zone band within the foveal region or a
    hyporeflective zone is seen in essentially all ATF6-related cases.
  evidence:
  - reference: PMID:31237654
    reference_title: "Characterization of Retinal Structure in ATF6-Associated Achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Absence of the EZ band within the foveal region (grade 3) or appearance of a hyporeflective zone (grade 4) was seen in all subjects"
    explanation: Quantifies the severe, near-universal OCT abnormality in ATF6-related disease.
treatments:
- name: Supportive care and monitoring
  description: >-
    Management is currently entirely supportive: dark or special-filter
    glasses or red-tinted contact lenses to reduce photophobia, low-vision
    aids such as high-powered magnifiers and digital/electronic devices, and
    regular ophthalmologic monitoring.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: "url:https://www.ncbi.nlm.nih.gov/books/NBK1418/"
    reference_title: Achromatopsia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dark or special filter glasses or red-tinted contact lenses reduce photophobia and may improve visual acuity."
    explanation: GeneReviews-recommended supportive management for photophobia in achromatopsia, including ATF6-related cases.
  - reference: "url:https://www.ncbi.nlm.nih.gov/books/NBK1418/"
    reference_title: Achromatopsia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Every six to 12 months in children to monitor changes in refraction in order to achieve the best possible corrected visual acuity"
    explanation: Establishes the recommended ophthalmologic monitoring cadence.
- name: Genetic counseling
  description: >-
    Genetic counseling is recommended for affected families given the
    autosomal recessive inheritance pattern.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:26029869
    reference_title: "Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Achromatopsia (ACHM) is an autosomal recessive disorder characterized by color blindness, photophobia, nystagmus and severely reduced visual acuity."
    explanation: Supports genetic counseling given the confirmed autosomal recessive inheritance pattern.
notes: >-
  Unlike CNGA3- and CNGB3-related achromatopsia, which have completed and
  active AAV gene-augmentation clinical trials, no ATF6-specific gene
  therapy trial exists as of the most recent review, and ATF6-related
  disease's near-total loss of foveal cone structure (rather than the
  persistent-but-abnormal cones seen in some CNGA3 cases) may make patients
  poorer candidates for cone-targeted gene replacement even if a trial were
  developed. This entry (MONDO:0100447) models the ATF6 gene-disease
  mechanism and its full phenotypic spectrum (classic achromatopsia plus
  the cone-rod dystrophy presentation and documented macular involvement);
  the ACHM7 subtype specifically is also modeled within Achromatopsia.yaml for
  cross-gene comparison against the five phototransduction-cascade
  achromatopsia genes.
prevalence:
- population: International genetically confirmed achromatopsia cohort
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    ATF6 is a rare cause of achromatopsia, identified in ten independent
    families in the founding cohort study; no independent general-population
    prevalence estimate for ATF6-related disease specifically has been
    published.
  evidence:
  - reference: PMID:26029869
    reference_title: "Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified ten families carrying six homozygous and two compound-heterozygous mutations in the ATF6 gene"
    explanation: Total ATF6-related family count identified in the founding cohort study.
references:
- reference: PMID:20301591
  title: Achromatopsia.
  tags:
  - GeneReviews
📚

References & Deep Research

References

1
PMID:20301591
Achromatopsia.
No top-level findings curated for this source.