Microphthalmia with Coloboma

Mendelian MONDO:0000170 Pathograph 5 Show in embeddings browser hereditary disease developmental eye disorder

Microphthalmia with coloboma is a congenital structural eye malformation in which a small eye (microphthalmia) is combined with a colobomatous defect — missing ocular tissue, classically inferonasal, that results from failure of the embryonic optic (choroid) fissure to close. It sits within the microphthalmia–anophthalmia–coloboma (MAC, also called AMC) spectrum and is curated here in its isolated / non-syndromic form, distinct from the syndromic microphthalmia entries (e.g. STRA6-related Matthew-Wood syndrome, CHARGE syndrome). The disorder is genetically heterogeneous: dominant, recessive, and X-linked alleles in eye-development transcription factors and signaling genes (SOX2, OTX2, PAX6, MAB21L2, FOXE3, ALDH1A3, FZD5, and others), copy-number variants, and non-coding regulatory variants all converge on disrupted optic-cup morphogenesis and optic-fissure closure. MAC accounts for roughly 15–20% of severe childhood visual impairment and blindness worldwide.

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3
Inheritance
5
Pathophys.
9
Phenotypes
5
Pathograph
7
Genes
3
Medical Actions
7
Subtypes
2
Trials
1
References
1
Deep Research
👪

Inheritance

3
Autosomal dominant inheritance HP:0000006
Many MAC genes (SOX2, OTX2, PAX6, dominant MAB21L2 and FOXE3 alleles) act dominantly, frequently as de novo variants.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:40038803 SUPPORT Human Clinical
"Chromosomal aberrations and mutations in genes such as PAX6, SOX2, OTX2, and CHD7 are contributors."
Identifies the major dominant MAC transcription-factor genes within the isolated/non-syndromic spectrum.
Autosomal recessive inheritance HP:0000007
Recessive MAC forms include ALDH1A3-related microphthalmia/anophthalmia and the recessive hypomorphic FZD5 allele.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:39503780 SUPPORT Human Clinical
"Whole exome sequencing revealed a homozygous rare missense variant in FZD5."
Documents a recessive (homozygous) MAC/coloboma allele, supporting autosomal recessive inheritance in the spectrum.
X-linked inheritance HP:0001417
X-linked MAC contributors include BCOR and structural variants on the X chromosome identified in MAC cohorts.
X-linked inheritance
Show evidence (1 reference)
PMID:36192130 PARTIAL Human Clinical
"novel variants in six known MAC genes (SOX2, KMT2D, MAB21L2, ALDH1A3, BCOR and FOXE3)"
BCOR (X-linked) is among the solved MAC genes in this cohort, supporting X-linked contributions to the spectrum.
◆

Subtypes

7
SOX2-related microphthalmia/anophthalmia with coloboma
Most common single-gene cause of severe bilateral microphthalmia/anophthalmia in the MAC spectrum, typically de novo dominant SOX2 loss-of-function; explains an estimated 10–15% of cases.
OTX2-related microphthalmia/anophthalmia with coloboma
Dominant OTX2 variants causing microphthalmia/anophthalmia, often with coloboma; estimated to explain 2–5% of cases. OTX2 also binds conserved enhancers upstream of MAB21L2.
PAX6-related microphthalmia with coloboma
PAX6 haploinsufficiency, classically aniridia, can present with microphthalmia and colobomatous defects within the anterior-segment and MAC spectrum.
MAB21L2-related microphthalmia with coloboma
Coding MAB21L2 variants and non-coding regulatory deletions upstream of MAB21L2 cause microphthalmia and coloboma; a worked example of non-coding regulatory pathogenesis in MAC.
FOXE3-related microphthalmia with coloboma
FOXE3 variants cause anterior-segment dysgenesis, microphthalmia, and coloboma; bilateral sensorineural hearing loss reported as a novel association.
ALDH1A3-related microphthalmia/anophthalmia with coloboma
Recessive ALDH1A3 variants disrupt retinaldehyde dehydrogenase / retinoic acid synthesis, causing autosomal recessive microphthalmia/anophthalmia.
FZD5-related coloboma with microcornea
FZD5 (Wnt receptor) variants cause isolated and syndromic ocular coloboma; most are dominant-negative, but a recessive hypomorphic allele causing syndromic coloboma with microcornea is documented.
⚙

Pathophysiology

5
Failure of optic fissure closure
The proximate developmental lesion in colobomatous microphthalmia is failure of the embryonic optic (choroid) fissure to close. During optic-cup morphogenesis the invaginating optic cup forms a transient inferonasal groove (the optic fissure) through which the hyaloid vasculature enters; fusion of its margins completes the eye. When fusion fails, tissue is left "missing" at the inferonasal pole, producing coloboma of the iris, ciliary body, retina/choroid, and/or optic nerve. In humans the fissure normally closes by about the 7th week, so the insult is early-embryonic.
Retinal progenitor cell CL:0002672 Retinal pigment epithelial cell CL:0002586
Closure of optic fissure GO:0061386 ↓ DECREASED Camera-type eye morphogenesis GO:0048593 ⚠ ABNORMAL
Optic fissure UBERON:0005412 Optic cup UBERON:0003072
Downstream
Disrupted optic-cup and globe morphogenesis The developmental disruption causing fissure non-closure also impairs overall optic-cup growth, contributing to a small globe.
Show evidence (1 reference)
PMID:39503780 SUPPORT Human Clinical
"Ocular coloboma (OC) is a congenital disorder caused by the incomplete closure of the embryonic ocular fissure."
Directly states the optic-fissure-closure defect as the mechanism of coloboma, the central pathophysiology of this entry.
Disrupted optic-cup and globe morphogenesis
Disruption of the eye-development gene regulatory network impairs optic vesicle/optic cup specification, growth, and patterning. Reduced or mispatterned neuroepithelial proliferation yields a small globe (microphthalmia), and in severe cases failure of optic-vesicle outgrowth yields anophthalmia. The same developmental disruption that reduces globe size also predisposes to incomplete optic-fissure closure, so microphthalmia and coloboma frequently co-occur.
Retinal progenitor cell CL:0002672 Neural crest cell CL:0011012
Eye development GO:0001654 ⚠ ABNORMAL Eye morphogenesis GO:0048592 ⚠ ABNORMAL
Eye UBERON:0000970
Show evidence (1 reference)
PMID:39455595 SUPPORT Model Organism
"Modelling of the deletion results in transient small lens and coloboma as well as midbrain anomalies in zebrafish, and microphthalmia and coloboma in Xenopus tropicalis."
Animal modelling of a MAB21L2 regulatory lesion recapitulates both microphthalmia and coloboma, supporting shared disruption of eye morphogenesis.
Retinoic acid signaling disruption
Retinoic acid (RA) signaling, generated locally by retinaldehyde dehydrogenases (including ALDH1A3) and acting through retinoic-acid receptors, is required for ventral optic-cup patterning and optic-fissure morphogenesis. Genetic loss of RA synthesis (ALDH1A3) and teratogenic perturbation of the retinoid pathway (e.g. isotretinoin/retinoic-acid embryopathy, maternal vitamin A deficiency) both converge on this pathway, a classic gene–environment phenocopy in MAC.
Retinoic acid receptor signaling pathway GO:0048384 ↓ DECREASED
Downstream
Disrupted optic-cup and globe morphogenesis Loss of retinoic-acid signaling impairs ventral optic-cup patterning and growth, feeding the shared morphogenesis defect.
Show evidence (1 reference)
PMID:39296666 SUPPORT Human Clinical
"medications are specifically known to alter eye morphogenesis during embryonic"
Review evidence that pathway-level (including retinoid) perturbation alters eye morphogenesis, supporting RA signaling as a convergent MAC mechanism (human teratology review).
Wnt/FZD5 signaling disruption
The Wnt receptor FZD5 is expressed throughout eye development; FZD5 variants disrupt Wnt signaling required for optic-fissure closure. Most reported alleles are dominant-negative (the mutant receptor sequesters Wnt ligands), but a recessive hypomorphic missense allele impairing signal transduction causes syndromic coloboma with microcornea, illustrating an alternative Wnt-pathway mechanism in MAC.
Wnt signaling pathway GO:0016055 ↓ DECREASED
Downstream
Failure of optic fissure closure Disrupted Wnt/FZD5 signaling, required during eye development, impairs optic-fissure closure and produces coloboma.
Show evidence (2 references)
PMID:39503780 SUPPORT Human Clinical
"These mutations often result in a dominant-negative effect, where the mutated FZD5 protein disrupts WNT signaling by sequestering WNT ligands."
Establishes Wnt-signaling disruption via FZD5 as a coloboma mechanism in the MAC spectrum.
PMID:39503780 SUPPORT In Vitro
"in vitro TOPFlash assays revealed that the missense variant only caused partial loss-of-function, behaving as a hypomorphic mutation"
In-vitro reporter assay confirms the hypomorphic Wnt-signaling defect of the recessive FZD5 allele.
Non-coding regulatory variant pathogenesis
A substantial fraction of MAC remains undiagnosed because analysis often focuses on coding variants. Conserved non-coding regulatory elements (enhancers) controlling eye-development genes can be deleted or disrupted, abolishing correct spatiotemporal expression. The ~113.5 kb homozygous deletion 19.38 kb upstream of MAB21L2 removes conserved elements, two of which bind OTX2, and causes microphthalmia and coloboma — establishing enhancer loss as a bona fide MAC mechanism.
Eye development GO:0001654 ⚠ ABNORMAL
Downstream
Disrupted optic-cup and globe morphogenesis Enhancer loss abolishes correct spatiotemporal expression of eye-development genes (e.g. MAB21L2), driving the shared optic-cup and globe morphogenesis defect.
Show evidence (2 references)
PMID:39455595 SUPPORT Human Clinical
"The second individual, presenting with microphthalmia, carries an ~ 113.5 kb homozygous deletion 19.38 kb upstream of MAB21L2."
Documents the non-coding regulatory deletion in a human patient.
PMID:39455595 SUPPORT In Vitro
"ChIP-seq data from mouse embryonic stem cells demonstrates that two of these (CE13 and 14) bind Otx2, a protein with an established role in eye development."
Shows the deleted conserved elements are OTX2-bound enhancers, mechanistic link from non-coding deletion to eye-development transcription.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Microphthalmia with Coloboma 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

9
Ear 1
Sensorineural hearing loss Sensorineural hearing impairment HP:0000407
Show evidence (1 reference)
PMID:36192130 SUPPORT Human Clinical
"New phenotypic associations were found for FOXE3 (bilateral sensorineural hearing loss) and MAB21L2 (unilateral microphthalmia)."
Documents the novel FOXE3 hearing-loss association.
Eye 5
Microphthalmia Microphthalmia HP:0000568
Show evidence (1 reference)
PMID:36192130 SUPPORT Human Clinical
"Clinical analysis of 50 MAC patients (15 microphthalmia; 2 anophthalmia; 11 coloboma; and 22 mixed) from 44 unrelated families"
Microphthalmia is a defining and frequent feature of the MAC cohort.
Coloboma Coloboma HP:0000589
Show evidence (1 reference)
PMID:39503780 SUPPORT Human Clinical
"Ocular coloboma (OC) is a congenital disorder caused by the incomplete closure of the embryonic ocular fissure."
Coloboma is a defining feature, mechanistically tied to fissure closure.
Chorioretinal coloboma Chorioretinal coloboma HP:0000567
Show evidence (1 reference)
PMID:20301552 SUPPORT Human Clinical
"Chorioretinal coloboma refers to coloboma of the retina and choroid."
GeneReviews baseline defines chorioretinal coloboma.
Microcornea Microcornea HP:0000482
Show evidence (1 reference)
PMID:39503780 SUPPORT Human Clinical
"we describe a case of syndromic bilateral OC with additional features such as microcornea, bone developmental anomalies, and mild intellectual disability"
Microcornea accompanies coloboma in the FZD5-related presentation.
Visual impairment Visual impairment HP:0000505
Show evidence (1 reference)
PMID:40038803 SUPPORT Human Clinical
"Congenital ocular anomalies significantly contribute to global disability, with 15-20% of infant blindness attributed to these anomalies."
Supports visual impairment / blindness as the major MAC outcome.
Nervous System 1
Developmental delay Global developmental delay HP:0001263
Show evidence (1 reference)
PMID:36192130 SUPPORT Human Clinical
"34% had systemic involvement, most frequently intellectual/developmental delay (8/17)"
Developmental delay is the leading systemic association in MAC patients with extraocular features.
Other 2
Iris coloboma Iris coloboma HP:0000612
Show evidence (1 reference)
PMID:20301552 SUPPORT Human Clinical
"Iris coloboma causes the iris to appear keyhole-shaped."
GeneReviews baseline describes iris coloboma in the MAC spectrum.
Anophthalmia Anophthalmia HP:0000528
Show evidence (1 reference)
PMID:20301552 SUPPORT Human Clinical
"Anophthalmia refers to complete absence of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus)."
GeneReviews baseline defines anophthalmia within the spectrum.
🧬

Genetic Associations

7
SOX2 (Causal dominant variant (often de novo))
Gene: SOX2 hgnc:11195
Show evidence (1 reference)
PMID:40038803 SUPPORT Human Clinical
"Chromosomal aberrations and mutations in genes such as PAX6, SOX2, OTX2, and CHD7 are contributors."
Names SOX2 explicitly as a causal MAC gene; SOX2 is the leading monogenic cause within the spectrum.
OTX2 (Causal dominant variant (often de novo))
Gene: OTX2 hgnc:8522
Show evidence (1 reference)
PMID:40038803 SUPPORT Human Clinical
"Chromosomal aberrations and mutations in genes such as PAX6, SOX2, OTX2, and CHD7 are contributors."
Names OTX2 explicitly among the genes whose mutations contribute to the MAC spectrum.
PAX6 (Causal dominant haploinsufficiency)
Gene: PAX6 hgnc:8620
Show evidence (1 reference)
PMID:40038803 SUPPORT Human Clinical
"Chromosomal aberrations and mutations in genes such as PAX6, SOX2, OTX2, and CHD7 are contributors."
Names PAX6 explicitly among the genes whose mutations contribute to the MAC spectrum.
MAB21L2 (Causal coding and non-coding regulatory variant)
Gene: MAB21L2 hgnc:6758
Show evidence (1 reference)
PMID:39455595 SUPPORT Human Clinical
"We report two families with variants in or near MAB21L2, a gene where genetic variants are known to cause AMC in humans and animal models."
Confirms MAB21L2 as an established MAC gene.
FZD5 (Causal dominant-negative or recessive hypomorphic variant)
Gene: FZD5 hgnc:4043
Show evidence (1 reference)
PMID:39503780 SUPPORT Human Clinical
"Mutations in the Wnt receptor FZD5, which is expressed throughout eye development, have been linked to both isolated and complex forms of coloboma."
Confirms FZD5 as a coloboma gene in isolated and complex forms.
FOXE3 (Causal variant)
Gene: FOXE3 hgnc:3808
Show evidence (1 reference)
PMID:36192130 SUPPORT Human Clinical
"novel variants in six known MAC genes (SOX2, KMT2D, MAB21L2, ALDH1A3, BCOR and FOXE3)"
FOXE3 is among the solved MAC genes in this prospective cohort.
ALDH1A3 (Causal biallelic variant)
Gene: ALDH1A3 hgnc:409
Show evidence (1 reference)
PMID:36192130 SUPPORT Human Clinical
"novel variants in six known MAC genes (SOX2, KMT2D, MAB21L2, ALDH1A3, BCOR and FOXE3)"
ALDH1A3 is among the solved MAC genes; links to the retinoid mechanism.
💊

Medical Actions

3
Genetic counseling
Action: Genetic Counseling NCIT:C15240
Genetic counseling and diagnostic genetic testing (chromosomal microarray, clinical exome or whole-genome sequencing) guide recurrence-risk assessment and family planning in the genetically heterogeneous MAC spectrum.
Show evidence (1 reference)
PMID:40038803 SUPPORT Human Clinical
"This work provides a literature review offering insights for effective management and genetic counseling in a pediatric context."
Genetic counseling is part of recommended MAC management.
Ophthalmic surgical management
Action: surgical procedure MAXO:0000004
Surgical interventions in colobomatous microphthalmia include cataract surgery / lensectomy and vitreoretinal surgery for coloboma-associated retinal detachment, with management individualized by visual potential.
Show evidence (1 reference)
PMID:20301552 SUPPORT Human Clinical
"An oculoplastic surgeon can help determine the most suitable options for surgical intervention after age six months"
GeneReviews describes oculoplastic surgical intervention as part of MAC spectrum management.
Supportive and rehabilitative care
Action: supportive care MAXO:0000950
Multidisciplinary supportive care includes prosthetic/conformer expansion of the orbit for severe microphthalmia/anophthalmia, low-vision aids and vision rehabilitation, and developmental/early-intervention support.
Show evidence (1 reference)
PMID:20301552 SUPPORT Human Clinical
"Prosthetic intervention is appropriate for those with severe microphthalmia and anophthalmia."
GeneReviews baseline supports prosthetic/supportive management.
🌍

Environmental Factors

2
Retinoid pathway teratogens
Prenatal exposures that disrupt retinoid (vitamin A / retinoic acid) biology — including isotretinoin/retinoic-acid embryopathy and maternal vitamin A deficiency — are associated with microphthalmia and coloboma, acting as a phenocopy of genetic retinoid-pathway lesions (e.g. ALDH1A3).
Show evidence (1 reference)
PMID:39296666 SUPPORT Human Clinical
"medications are specifically known to alter eye morphogenesis during embryonic"
Teratology review identifying medications (including retinoids) that alter eye morphogenesis.
Thalidomide and other ocular teratogens
Thalidomide is a classic ocular teratogen, and additional environmental contributors to anophthalmia/microphthalmia include gestational infections, maternal vitamin A deficiency, X-ray exposure, and solvent misuse.
Show evidence (1 reference)
PMID:40491727 SUPPORT Human Clinical
"the contribution of environmental factors such as gestational-acquired infections, maternal vitamin A deficiency (VAD), exposure to X-rays, solvent misuse, and thalidomide exposure."
Review enumerating environmental contributors (infections, vitamin A deficiency, X-rays, solvents, thalidomide) to A/M.
🔬

Clinical Trials

2
NCT01778543 RECRUITING
NEI natural-history and genetics study deep-phenotyping individuals with MAC and unaffected relatives to identify associated genes and build a DNA/cell-line repository.
Target Phenotypes: Coloboma HP:0000589 Microphthalmia HP:0000568
Show evidence (1 reference)
clinicaltrials:NCT01778543 SUPPORT
"Uveal coloboma is part of a spectrum of developmental eye conditions that include anophthalmia and microphthalmia, typically referred to as "MAC""
Trial directly targets the MAC spectrum genetics.
NCT04833361 COMPLETED
NEI pilot study exploring maternal first-trimester exposures as potential environmental causes of uveal coloboma, linking survey data to affected children's clinical data.
Target Phenotypes: Coloboma HP:0000589
Show evidence (1 reference)
clinicaltrials:NCT04833361 SUPPORT
"To explore maternal factors and exposures during the first trimester of pregnancy as potential causes of uveal coloboma"
Trial investigates environmental causes of coloboma in the spectrum.
{ }

Source YAML

click to show 
name: Microphthalmia with Coloboma
creation_date: "2026-06-15T00:00:00Z"
description: >-
  Microphthalmia with coloboma is a congenital structural eye malformation in
  which a small eye (microphthalmia) is combined with a colobomatous defect —
  missing ocular tissue, classically inferonasal, that results from failure of
  the embryonic optic (choroid) fissure to close. It sits within the
  microphthalmia–anophthalmia–coloboma (MAC, also called AMC) spectrum and is
  curated here in its isolated / non-syndromic form, distinct from the
  syndromic microphthalmia entries (e.g. STRA6-related Matthew-Wood syndrome,
  CHARGE syndrome). The disorder is genetically heterogeneous: dominant,
  recessive, and X-linked alleles in eye-development transcription factors and
  signaling genes (SOX2, OTX2, PAX6, MAB21L2, FOXE3, ALDH1A3, FZD5, and others),
  copy-number variants, and non-coding regulatory variants all converge on
  disrupted optic-cup morphogenesis and optic-fissure closure. MAC accounts for
  roughly 15–20% of severe childhood visual impairment and blindness worldwide.
category: Mendelian
parents:
- hereditary disease
- developmental eye disorder
synonyms:
- MAC spectrum
- microphthalmia-anophthalmia-coloboma spectrum
- AMC spectrum
- isolated microphthalmia with coloboma
- colobomatous microphthalmia
disease_term:
  preferred_term: Microphthalmia with coloboma
  term:
    id: MONDO:0000170
    label: microphthalmia, isolated, with coloboma
notes: >-
  Scope: this entry covers the ISOLATED / non-syndromic MAC presentation
  centered on the optic-fissure-closure defect mechanism. Syndromic forms in
  which MAC is one feature of a multisystem disorder (Matthew-Wood/STRA6,
  CHARGE, branchiooculofacial syndrome, etc.) are curated as their own entries
  and are referenced here only as differential diagnoses. The numbered MCOPCB
  (microphthalmia/coloboma) OMIM loci and the gene-defined forms are modeled as
  subtypes. GeneReviews has a retired "Microphthalmia/Anophthalmia/Coloboma
  Spectrum" chapter (PMID:20301552) used as the clinical baseline.
references:
- reference: PMID:20301552
  title: "Microphthalmia/Anophthalmia/Coloboma Spectrum – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
  tags:
  - GeneReviews
has_subtypes:
- name: SOX2-MAC
  display_name: SOX2-related microphthalmia/anophthalmia with coloboma
  description: >-
    Most common single-gene cause of severe bilateral microphthalmia/anophthalmia
    in the MAC spectrum, typically de novo dominant SOX2 loss-of-function;
    explains an estimated 10–15% of cases.
- name: OTX2-MAC
  display_name: OTX2-related microphthalmia/anophthalmia with coloboma
  description: >-
    Dominant OTX2 variants causing microphthalmia/anophthalmia, often with
    coloboma; estimated to explain 2–5% of cases. OTX2 also binds conserved
    enhancers upstream of MAB21L2.
- name: PAX6-MAC
  display_name: PAX6-related microphthalmia with coloboma
  description: >-
    PAX6 haploinsufficiency, classically aniridia, can present with
    microphthalmia and colobomatous defects within the anterior-segment and
    MAC spectrum.
- name: MAB21L2-MAC
  display_name: MAB21L2-related microphthalmia with coloboma
  description: >-
    Coding MAB21L2 variants and non-coding regulatory deletions upstream of
    MAB21L2 cause microphthalmia and coloboma; a worked example of non-coding
    regulatory pathogenesis in MAC.
- name: FOXE3-MAC
  display_name: FOXE3-related microphthalmia with coloboma
  description: >-
    FOXE3 variants cause anterior-segment dysgenesis, microphthalmia, and
    coloboma; bilateral sensorineural hearing loss reported as a novel
    association.
- name: ALDH1A3-MAC
  display_name: ALDH1A3-related microphthalmia/anophthalmia with coloboma
  description: >-
    Recessive ALDH1A3 variants disrupt retinaldehyde dehydrogenase / retinoic
    acid synthesis, causing autosomal recessive microphthalmia/anophthalmia.
- name: FZD5-Coloboma
  display_name: FZD5-related coloboma with microcornea
  description: >-
    FZD5 (Wnt receptor) variants cause isolated and syndromic ocular coloboma;
    most are dominant-negative, but a recessive hypomorphic allele causing
    syndromic coloboma with microcornea is documented.
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    Many MAC genes (SOX2, OTX2, PAX6, dominant MAB21L2 and FOXE3 alleles) act
    dominantly, frequently as de novo variants.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:40038803
    reference_title: "Management of anophthalmia, microphthalmia and coloboma in the newborn, shared care between neonatologist and ophthalmologist: a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chromosomal aberrations and mutations in genes such as PAX6, SOX2, OTX2, and CHD7 are contributors."
    explanation: >-
      Identifies the major dominant MAC transcription-factor genes within the
      isolated/non-syndromic spectrum.
- name: Autosomal recessive inheritance
  description: >-
    Recessive MAC forms include ALDH1A3-related microphthalmia/anophthalmia and
    the recessive hypomorphic FZD5 allele.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:39503780
    reference_title: "Homozygosity for a hypomorphic mutation in frizzled class receptor 5 causes syndromic ocular coloboma with microcornea in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing revealed a homozygous rare missense variant in FZD5."
    explanation: >-
      Documents a recessive (homozygous) MAC/coloboma allele, supporting
      autosomal recessive inheritance in the spectrum.
- name: X-linked inheritance
  description: >-
    X-linked MAC contributors include BCOR and structural variants on the X
    chromosome identified in MAC cohorts.
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
  evidence:
  - reference: PMID:36192130
    reference_title: "Real-world clinical and molecular management of 50 prospective patients with microphthalmia, anophthalmia and/or ocular coloboma."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "novel variants in six known MAC genes (SOX2, KMT2D, MAB21L2, ALDH1A3, BCOR and FOXE3)"
    explanation: >-
      BCOR (X-linked) is among the solved MAC genes in this cohort, supporting
      X-linked contributions to the spectrum.
pathophysiology:
- name: Failure of optic fissure closure
  description: >-
    The proximate developmental lesion in colobomatous microphthalmia is failure
    of the embryonic optic (choroid) fissure to close. During optic-cup
    morphogenesis the invaginating optic cup forms a transient inferonasal
    groove (the optic fissure) through which the hyaloid vasculature enters;
    fusion of its margins completes the eye. When fusion fails, tissue is left
    "missing" at the inferonasal pole, producing coloboma of the iris, ciliary
    body, retina/choroid, and/or optic nerve. In humans the fissure normally
    closes by about the 7th week, so the insult is early-embryonic.
  cell_types:
  - preferred_term: Retinal progenitor cell
    term:
      id: CL:0002672
      label: retinal progenitor cell
  - preferred_term: Retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  biological_processes:
  - preferred_term: Closure of optic fissure
    term:
      id: GO:0061386
      label: closure of optic fissure
    modifier: DECREASED
  - preferred_term: Camera-type eye morphogenesis
    term:
      id: GO:0048593
      label: camera-type eye morphogenesis
    modifier: ABNORMAL
  locations:
  - preferred_term: Optic fissure
    term:
      id: UBERON:0005412
      label: optic fissure
  - preferred_term: Optic cup
    term:
      id: UBERON:0003072
      label: optic cup
  evidence:
  - reference: PMID:39503780
    reference_title: "Homozygosity for a hypomorphic mutation in frizzled class receptor 5 causes syndromic ocular coloboma with microcornea in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ocular coloboma (OC) is a congenital disorder caused by the incomplete closure of the embryonic ocular fissure."
    explanation: >-
      Directly states the optic-fissure-closure defect as the mechanism of
      coloboma, the central pathophysiology of this entry.
  downstream:
  - target: Disrupted optic-cup and globe morphogenesis
    description: >-
      The developmental disruption causing fissure non-closure also impairs
      overall optic-cup growth, contributing to a small globe.
    causal_link_type: DIRECT
- name: Disrupted optic-cup and globe morphogenesis
  description: >-
    Disruption of the eye-development gene regulatory network impairs optic
    vesicle/optic cup specification, growth, and patterning. Reduced or
    mispatterned neuroepithelial proliferation yields a small globe
    (microphthalmia), and in severe cases failure of optic-vesicle outgrowth
    yields anophthalmia. The same developmental disruption that reduces globe
    size also predisposes to incomplete optic-fissure closure, so microphthalmia
    and coloboma frequently co-occur.
  cell_types:
  - preferred_term: Retinal progenitor cell
    term:
      id: CL:0002672
      label: retinal progenitor cell
  - preferred_term: Neural crest cell
    term:
      id: CL:0011012
      label: neural crest cell
  biological_processes:
  - preferred_term: Eye development
    term:
      id: GO:0001654
      label: eye development
    modifier: ABNORMAL
  - preferred_term: Eye morphogenesis
    term:
      id: GO:0048592
      label: eye morphogenesis
    modifier: ABNORMAL
  locations:
  - preferred_term: Eye
    term:
      id: UBERON:0000970
      label: eye
  evidence:
  - reference: PMID:39455595
    reference_title: "Deletion upstream of MAB21L2 highlights the importance of evolutionarily conserved non-coding sequences for eye development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Modelling of the deletion results in transient small lens and coloboma as well as midbrain anomalies in zebrafish, and microphthalmia and coloboma in Xenopus tropicalis."
    explanation: >-
      Animal modelling of a MAB21L2 regulatory lesion recapitulates both
      microphthalmia and coloboma, supporting shared disruption of eye
      morphogenesis.
- name: Retinoic acid signaling disruption
  description: >-
    Retinoic acid (RA) signaling, generated locally by retinaldehyde
    dehydrogenases (including ALDH1A3) and acting through retinoic-acid
    receptors, is required for ventral optic-cup patterning and optic-fissure
    morphogenesis. Genetic loss of RA synthesis (ALDH1A3) and teratogenic
    perturbation of the retinoid pathway (e.g. isotretinoin/retinoic-acid
    embryopathy, maternal vitamin A deficiency) both converge on this pathway,
    a classic gene–environment phenocopy in MAC.
  biological_processes:
  - preferred_term: Retinoic acid receptor signaling pathway
    term:
      id: GO:0048384
      label: retinoic acid receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:39296666
    reference_title: The first review on prenatal drug exposure and ocular malformation occurrence.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "medications are specifically known to alter eye morphogenesis during embryonic"
    explanation: >-
      Review evidence that pathway-level (including retinoid) perturbation
      alters eye morphogenesis, supporting RA signaling as a convergent MAC
      mechanism (human teratology review).
  downstream:
  - target: Disrupted optic-cup and globe morphogenesis
    description: >-
      Loss of retinoic-acid signaling impairs ventral optic-cup patterning and
      growth, feeding the shared morphogenesis defect.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Wnt/FZD5 signaling disruption
  description: >-
    The Wnt receptor FZD5 is expressed throughout eye development; FZD5 variants
    disrupt Wnt signaling required for optic-fissure closure. Most reported
    alleles are dominant-negative (the mutant receptor sequesters Wnt ligands),
    but a recessive hypomorphic missense allele impairing signal transduction
    causes syndromic coloboma with microcornea, illustrating an alternative
    Wnt-pathway mechanism in MAC.
  biological_processes:
  - preferred_term: Wnt signaling pathway
    term:
      id: GO:0016055
      label: Wnt signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:39503780
    reference_title: "Homozygosity for a hypomorphic mutation in frizzled class receptor 5 causes syndromic ocular coloboma with microcornea in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These mutations often result in a dominant-negative effect, where the mutated FZD5 protein disrupts WNT signaling by sequestering WNT ligands."
    explanation: >-
      Establishes Wnt-signaling disruption via FZD5 as a coloboma mechanism in
      the MAC spectrum.
  - reference: PMID:39503780
    reference_title: "Homozygosity for a hypomorphic mutation in frizzled class receptor 5 causes syndromic ocular coloboma with microcornea in humans."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "in vitro TOPFlash assays revealed that the missense variant only caused partial loss-of-function, behaving as a hypomorphic mutation"
    explanation: >-
      In-vitro reporter assay confirms the hypomorphic Wnt-signaling defect of
      the recessive FZD5 allele.
  downstream:
  - target: Failure of optic fissure closure
    description: >-
      Disrupted Wnt/FZD5 signaling, required during eye development, impairs
      optic-fissure closure and produces coloboma.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Non-coding regulatory variant pathogenesis
  description: >-
    A substantial fraction of MAC remains undiagnosed because analysis often
    focuses on coding variants. Conserved non-coding regulatory elements
    (enhancers) controlling eye-development genes can be deleted or disrupted,
    abolishing correct spatiotemporal expression. The ~113.5 kb homozygous
    deletion 19.38 kb upstream of MAB21L2 removes conserved elements, two of
    which bind OTX2, and causes microphthalmia and coloboma — establishing
    enhancer loss as a bona fide MAC mechanism.
  biological_processes:
  - preferred_term: Eye development
    term:
      id: GO:0001654
      label: eye development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:39455595
    reference_title: "Deletion upstream of MAB21L2 highlights the importance of evolutionarily conserved non-coding sequences for eye development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The second individual, presenting with microphthalmia, carries an ~ 113.5 kb homozygous deletion 19.38 kb upstream of MAB21L2."
    explanation: >-
      Documents the non-coding regulatory deletion in a human patient.
  - reference: PMID:39455595
    reference_title: "Deletion upstream of MAB21L2 highlights the importance of evolutionarily conserved non-coding sequences for eye development."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ChIP-seq data from mouse embryonic stem cells demonstrates that two of these (CE13 and 14) bind Otx2, a protein with an established role in eye development."
    explanation: >-
      Shows the deleted conserved elements are OTX2-bound enhancers, mechanistic
      link from non-coding deletion to eye-development transcription.
  downstream:
  - target: Disrupted optic-cup and globe morphogenesis
    description: >-
      Enhancer loss abolishes correct spatiotemporal expression of
      eye-development genes (e.g. MAB21L2), driving the shared optic-cup and
      globe morphogenesis defect.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
phenotypes:
- category: Ocular
  name: Microphthalmia
  description: >-
    A small eye, defined as a globe with total axial length at least two
    standard deviations below the age-adjusted mean.
  phenotype_term:
    preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
  evidence:
  - reference: PMID:36192130
    reference_title: "Real-world clinical and molecular management of 50 prospective patients with microphthalmia, anophthalmia and/or ocular coloboma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical analysis of 50 MAC patients (15 microphthalmia; 2 anophthalmia; 11 coloboma; and 22 mixed) from 44 unrelated families"
    explanation: Microphthalmia is a defining and frequent feature of the MAC cohort.
- category: Ocular
  name: Coloboma
  description: >-
    Missing ocular tissue resulting from incomplete optic-fissure closure;
    may involve iris, ciliary body, retina/choroid, and/or optic nerve.
  phenotype_term:
    preferred_term: Coloboma
    term:
      id: HP:0000589
      label: Coloboma
  evidence:
  - reference: PMID:39503780
    reference_title: "Homozygosity for a hypomorphic mutation in frizzled class receptor 5 causes syndromic ocular coloboma with microcornea in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ocular coloboma (OC) is a congenital disorder caused by the incomplete closure of the embryonic ocular fissure."
    explanation: Coloboma is a defining feature, mechanistically tied to fissure closure.
- category: Ocular
  name: Iris coloboma
  description: Keyhole-shaped iris defect from failure of fissure closure at the iris.
  phenotype_term:
    preferred_term: Iris coloboma
    term:
      id: HP:0000612
      label: Iris coloboma
  evidence:
  - reference: PMID:20301552
    reference_title: "Microphthalmia/Anophthalmia/Coloboma Spectrum – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Iris coloboma causes the iris to appear keyhole-shaped."
    explanation: GeneReviews baseline describes iris coloboma in the MAC spectrum.
- category: Ocular
  name: Chorioretinal coloboma
  description: Coloboma involving the retina and choroid.
  phenotype_term:
    preferred_term: Chorioretinal coloboma
    term:
      id: HP:0000567
      label: Chorioretinal coloboma
  evidence:
  - reference: PMID:20301552
    reference_title: "Microphthalmia/Anophthalmia/Coloboma Spectrum – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chorioretinal coloboma refers to coloboma of the retina and choroid."
    explanation: GeneReviews baseline defines chorioretinal coloboma.
- category: Ocular
  name: Anophthalmia
  description: >-
    Clinical absence of the globe with preserved ocular adnexa, at the severe
    end of the MAC spectrum.
  phenotype_term:
    preferred_term: Anophthalmia
    term:
      id: HP:0000528
      label: Anophthalmia
  evidence:
  - reference: PMID:20301552
    reference_title: "Microphthalmia/Anophthalmia/Coloboma Spectrum – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Anophthalmia refers to complete absence of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus)."
    explanation: GeneReviews baseline defines anophthalmia within the spectrum.
- category: Ocular
  name: Microcornea
  description: Abnormally small cornea, reported with FZD5-related coloboma.
  phenotype_term:
    preferred_term: Microcornea
    term:
      id: HP:0000482
      label: Microcornea
  evidence:
  - reference: PMID:39503780
    reference_title: "Homozygosity for a hypomorphic mutation in frizzled class receptor 5 causes syndromic ocular coloboma with microcornea in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we describe a case of syndromic bilateral OC with additional features such as microcornea, bone developmental anomalies, and mild intellectual disability"
    explanation: Microcornea accompanies coloboma in the FZD5-related presentation.
- category: Ocular
  name: Visual impairment
  description: >-
    Reduced vision is the principal functional consequence; MAC accounts for
    ~15–20% of severe childhood visual impairment and blindness worldwide.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: PMID:40038803
    reference_title: "Management of anophthalmia, microphthalmia and coloboma in the newborn, shared care between neonatologist and ophthalmologist: a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital ocular anomalies significantly contribute to global disability, with 15-20% of infant blindness attributed to these anomalies."
    explanation: Supports visual impairment / blindness as the major MAC outcome.
- category: Neurologic
  name: Developmental delay
  description: >-
    Intellectual/developmental delay is the most frequent systemic feature in
    MAC patients with extraocular involvement.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:36192130
    reference_title: "Real-world clinical and molecular management of 50 prospective patients with microphthalmia, anophthalmia and/or ocular coloboma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "34% had systemic involvement, most frequently intellectual/developmental delay (8/17)"
    explanation: >-
      Developmental delay is the leading systemic association in MAC patients
      with extraocular features.
- category: Other
  name: Sensorineural hearing loss
  description: >-
    Bilateral sensorineural hearing loss reported as a novel FOXE3-related
    association in a MAC cohort.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:36192130
    reference_title: "Real-world clinical and molecular management of 50 prospective patients with microphthalmia, anophthalmia and/or ocular coloboma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "New phenotypic associations were found for FOXE3 (bilateral sensorineural hearing loss) and MAB21L2 (unilateral microphthalmia)."
    explanation: Documents the novel FOXE3 hearing-loss association.
genetic:
- name: SOX2
  association: Causal dominant variant (often de novo)
  notes: >-
    SOX2 loss-of-function (often de novo) is the most common single-gene cause
    of severe bilateral microphthalmia/anophthalmia in MAC, estimated at 10–15%
    of cases.
  gene_term:
    preferred_term: SOX2
    term:
      id: hgnc:11195
      label: SOX2
  evidence:
  - reference: PMID:40038803
    reference_title: "Management of anophthalmia, microphthalmia and coloboma in the newborn, shared care between neonatologist and ophthalmologist: a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chromosomal aberrations and mutations in genes such as PAX6, SOX2, OTX2, and CHD7 are contributors."
    explanation: >-
      Names SOX2 explicitly as a causal MAC gene; SOX2 is the leading monogenic
      cause within the spectrum.
- name: OTX2
  association: Causal dominant variant (often de novo)
  notes: >-
    OTX2 loss-of-function variants (often de novo, dominant) cause severe
    bilateral microphthalmia/anophthalmia and are estimated to explain roughly
    2–5% of MAC cases.
  gene_term:
    preferred_term: OTX2
    term:
      id: hgnc:8522
      label: OTX2
  evidence:
  - reference: PMID:40038803
    reference_title: "Management of anophthalmia, microphthalmia and coloboma in the newborn, shared care between neonatologist and ophthalmologist: a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chromosomal aberrations and mutations in genes such as PAX6, SOX2, OTX2, and CHD7 are contributors."
    explanation: >-
      Names OTX2 explicitly among the genes whose mutations contribute to the
      MAC spectrum.
- name: PAX6
  association: Causal dominant haploinsufficiency
  notes: >-
    PAX6 haploinsufficiency is a classic contributor to the MAC spectrum,
    producing colobomatous microphthalmia and a range of anterior-segment and
    ocular malformations.
  gene_term:
    preferred_term: PAX6
    term:
      id: hgnc:8620
      label: PAX6
  evidence:
  - reference: PMID:40038803
    reference_title: "Management of anophthalmia, microphthalmia and coloboma in the newborn, shared care between neonatologist and ophthalmologist: a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chromosomal aberrations and mutations in genes such as PAX6, SOX2, OTX2, and CHD7 are contributors."
    explanation: >-
      Names PAX6 explicitly among the genes whose mutations contribute to the
      MAC spectrum.
- name: MAB21L2
  association: Causal coding and non-coding regulatory variant
  notes: >-
    Coding MAB21L2 variants and non-coding regulatory deletions upstream of
    MAB21L2 cause microphthalmia and coloboma.
  gene_term:
    preferred_term: MAB21L2
    term:
      id: hgnc:6758
      label: MAB21L2
  evidence:
  - reference: PMID:39455595
    reference_title: "Deletion upstream of MAB21L2 highlights the importance of evolutionarily conserved non-coding sequences for eye development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report two families with variants in or near MAB21L2, a gene where genetic variants are known to cause AMC in humans and animal models."
    explanation: Confirms MAB21L2 as an established MAC gene.
- name: FZD5
  association: Causal dominant-negative or recessive hypomorphic variant
  notes: >-
    FZD5 (Wnt receptor) variants cause isolated and syndromic coloboma via
    disrupted Wnt signaling; dominant-negative and recessive hypomorphic alleles
    are documented.
  gene_term:
    preferred_term: FZD5
    term:
      id: hgnc:4043
      label: FZD5
  evidence:
  - reference: PMID:39503780
    reference_title: "Homozygosity for a hypomorphic mutation in frizzled class receptor 5 causes syndromic ocular coloboma with microcornea in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in the Wnt receptor FZD5, which is expressed throughout eye development, have been linked to both isolated and complex forms of coloboma."
    explanation: Confirms FZD5 as a coloboma gene in isolated and complex forms.
- name: FOXE3
  association: Causal variant
  notes: >-
    FOXE3 variants cause anterior-segment dysgenesis, microphthalmia, and
    coloboma; bilateral sensorineural hearing loss is a reported association.
  gene_term:
    preferred_term: FOXE3
    term:
      id: hgnc:3808
      label: FOXE3
  evidence:
  - reference: PMID:36192130
    reference_title: "Real-world clinical and molecular management of 50 prospective patients with microphthalmia, anophthalmia and/or ocular coloboma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "novel variants in six known MAC genes (SOX2, KMT2D, MAB21L2, ALDH1A3, BCOR and FOXE3)"
    explanation: FOXE3 is among the solved MAC genes in this prospective cohort.
- name: ALDH1A3
  association: Causal biallelic variant
  notes: >-
    Recessive ALDH1A3 variants disrupt retinaldehyde dehydrogenase / retinoic
    acid synthesis, causing autosomal recessive microphthalmia/anophthalmia.
  gene_term:
    preferred_term: ALDH1A3
    term:
      id: hgnc:409
      label: ALDH1A3
  evidence:
  - reference: PMID:36192130
    reference_title: "Real-world clinical and molecular management of 50 prospective patients with microphthalmia, anophthalmia and/or ocular coloboma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "novel variants in six known MAC genes (SOX2, KMT2D, MAB21L2, ALDH1A3, BCOR and FOXE3)"
    explanation: ALDH1A3 is among the solved MAC genes; links to the retinoid mechanism.
environmental:
- name: Retinoid pathway teratogens
  description: >-
    Prenatal exposures that disrupt retinoid (vitamin A / retinoic acid) biology
    — including isotretinoin/retinoic-acid embryopathy and maternal vitamin A
    deficiency — are associated with microphthalmia and coloboma, acting as a
    phenocopy of genetic retinoid-pathway lesions (e.g. ALDH1A3).
  evidence:
  - reference: PMID:39296666
    reference_title: The first review on prenatal drug exposure and ocular malformation occurrence.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "medications are specifically known to alter eye morphogenesis during embryonic"
    explanation: >-
      Teratology review identifying medications (including retinoids) that alter
      eye morphogenesis.
- name: Thalidomide and other ocular teratogens
  description: >-
    Thalidomide is a classic ocular teratogen, and additional environmental
    contributors to anophthalmia/microphthalmia include gestational infections,
    maternal vitamin A deficiency, X-ray exposure, and solvent misuse.
  evidence:
  - reference: PMID:40491727
    reference_title: "Genetic and environmental factors contributing to anophthalmia and microphthalmia: Current understanding and future directions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the contribution of environmental factors such as gestational-acquired infections, maternal vitamin A deficiency (VAD), exposure to X-rays, solvent misuse, and thalidomide exposure."
    explanation: >-
      Review enumerating environmental contributors (infections, vitamin A
      deficiency, X-rays, solvents, thalidomide) to A/M.
treatments:
- name: Genetic counseling
  description: >-
    Genetic counseling and diagnostic genetic testing (chromosomal microarray,
    clinical exome or whole-genome sequencing) guide recurrence-risk assessment
    and family planning in the genetically heterogeneous MAC spectrum.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:40038803
    reference_title: "Management of anophthalmia, microphthalmia and coloboma in the newborn, shared care between neonatologist and ophthalmologist: a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This work provides a literature review offering insights for effective management and genetic counseling in a pediatric context."
    explanation: Genetic counseling is part of recommended MAC management.
- name: Ophthalmic surgical management
  description: >-
    Surgical interventions in colobomatous microphthalmia include cataract
    surgery / lensectomy and vitreoretinal surgery for coloboma-associated
    retinal detachment, with management individualized by visual potential.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:20301552
    reference_title: "Microphthalmia/Anophthalmia/Coloboma Spectrum – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An oculoplastic surgeon can help determine the most suitable options for surgical intervention after age six months"
    explanation: >-
      GeneReviews describes oculoplastic surgical intervention as part of MAC
      spectrum management.
- name: Supportive and rehabilitative care
  description: >-
    Multidisciplinary supportive care includes prosthetic/conformer expansion of
    the orbit for severe microphthalmia/anophthalmia, low-vision aids and vision
    rehabilitation, and developmental/early-intervention support.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:20301552
    reference_title: "Microphthalmia/Anophthalmia/Coloboma Spectrum – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prosthetic intervention is appropriate for those with severe microphthalmia and anophthalmia."
    explanation: GeneReviews baseline supports prosthetic/supportive management.
clinical_trials:
- name: NCT01778543
  status: RECRUITING
  description: >-
    NEI natural-history and genetics study deep-phenotyping individuals with
    MAC and unaffected relatives to identify associated genes and build a
    DNA/cell-line repository.
  target_phenotypes:
  - preferred_term: Coloboma
    term:
      id: HP:0000589
      label: Coloboma
  - preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
  evidence:
  - reference: clinicaltrials:NCT01778543
    reference_title: "Pathogenesis and Genetics of Microphthalmia, Anophthalmia and Uveal Coloboma ( MAC)"
    supports: SUPPORT
    snippet: "Uveal coloboma is part of a spectrum of developmental eye conditions that include anophthalmia and microphthalmia, typically referred to as \"MAC\""
    explanation: Trial directly targets the MAC spectrum genetics.
- name: NCT04833361
  status: COMPLETED
  description: >-
    NEI pilot study exploring maternal first-trimester exposures as potential
    environmental causes of uveal coloboma, linking survey data to affected
    children's clinical data.
  target_phenotypes:
  - preferred_term: Coloboma
    term:
      id: HP:0000589
      label: Coloboma
  evidence:
  - reference: clinicaltrials:NCT04833361
    reference_title: Pilot Evaluation of Potential Environmental Causes of Uveal Coloboma
    supports: SUPPORT
    snippet: "To explore maternal factors and exposures during the first trimester of pregnancy as potential causes of uveal coloboma"
    explanation: Trial investigates environmental causes of coloboma in the spectrum.
📚

References & Deep Research

References

1
PMID:20301552
Microphthalmia/Anophthalmia/Coloboma Spectrum – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 32 citations 2026-06-15T22:47:56.123733

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Microphthalmia with Coloboma
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Microphthalmia with Coloboma covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Microphthalmia with Coloboma (MAC/AMC Spectrum) — Comprehensive Disease Characteristics Report (Mendelian)

Executive summary

Microphthalmia with coloboma is typically curated as part of the microphthalmia–anophthalmia–coloboma (MAC/AMC) spectrum, a set of congenital structural eye malformations that are genetically heterogeneous and variably syndromic. Recent clinical cohorts (2023) and exome-based studies (2024) highlight: (i) frequent additional ocular findings and extraocular morbidity; (ii) modest molecular diagnostic yields with traditional targeted panels in unselected cohorts; and (iii) improved yields and new gene discoveries using clinical exome sequencing and non-coding/regulatory variant detection. (harding2023realworldclinicaland pages 1-1, kunisetty2024highclinicalexome pages 1-2, ceroni2024deletionupstreamof pages 1-2)

Topic Data Source
Definition: Microphthalmia Small eye; axial length/eye volume <2 SD below age-adjusted mean (kunisetty2024highclinicalexome pages 1-2, harding2023realworldclinicaland pages 1-2)
Definition: Anophthalmia Clinical absence of ocular tissue / no visible globe (kunisetty2024highclinicalexome pages 1-2, harding2023realworldclinicaland pages 1-2)
Definition: Coloboma Missing ocular tissue; typically inferonasal defects reflect incomplete optic fissure closure; may involve iris, ciliary body, retina/choroid/optic nerve and other ocular structures (kunisetty2024highclinicalexome pages 1-2, harding2023realworldclinicaland pages 1-2)
Epidemiology: combined MAC/AMC ~6–30 per 100,000 live births/children per year for the MAC spectrum (ceroni2024deletionupstreamof pages 1-2, holt2023theimpactof pages 1-3)
Epidemiology: microphthalmia 2–17 per 100,000 births (kunisetty2024highclinicalexome pages 1-2, russo2025managementofanophthalmia pages 1-2)
Epidemiology: anophthalmia 0.6–4.2 per 100,000 births (kunisetty2024highclinicalexome pages 1-2, russo2025managementofanophthalmia pages 1-2)
Epidemiology: coloboma 2–14 per 100,000 births; some reviews cite 2–19 per 100,000 live births (kunisetty2024highclinicalexome pages 1-2, russo2025managementofanophthalmia pages 1-2)
Contribution to childhood visual impairment MAC/AMC account for ~15–20%, sometimes stated as up to 20%, of severe childhood visual impairment/blindness (kunisetty2024highclinicalexome pages 1-2, ceroni2024deletionupstreamof pages 1-2, holt2023theimpactof pages 1-3)
Harding et al. 2023 cohort 50 patients / 44 unrelated families; phenotype mix: 15 microphthalmia, 2 anophthalmia, 11 coloboma, 22 mixed (harding2023realworldclinicaland pages 1-1)
Harding et al. 2023: complex ocular features 22/50 (44%) had additional ocular features (harding2023realworldclinicaland pages 1-1)
Harding et al. 2023: systemic involvement 17/50 (34%) had systemic manifestations (harding2023realworldclinicaland pages 1-1)
Harding et al. 2023: developmental delay Most frequent systemic feature; 8/17 (47%) of those with systemic involvement had intellectual/developmental delay (harding2023realworldclinicaland pages 1-1)
Harding et al. 2023: retinal detachment 7/80 affected eyes (9%), all associated with coloboma (harding2023realworldclinicaland pages 7-8)
Harding et al. 2023: overall molecular diagnostic yield Testing in 39 families identified a genetic association in 11/39 (28%); paper also reports an overall molecular diagnostic rate of ~33% in tested cohorts/patients (harding2023realworldclinicaland pages 1-1, harding2023realworldclinicaland pages 10-11, harding2023realworldclinicaland pages 8-9)
Harding et al. 2023: by test modality Family-level solve rates: WGS 4/17 (24%); targeted panel 3/18 (17%); aCGH 3/3 (100%); familial variant testing 1/1 (harding2023realworldclinicaland pages 8-9)
Harding et al. 2023: genes solved Pathogenic variants/CNVs in SOX2, PAX6, KMT2D, EPHA2, MAB21L2, ALDH1A3, BCOR, FOXE3, plus large deletions on chr10, chr11, X (harding2023realworldclinicaland pages 8-9)
Recent discovery: MAB21L2 regulatory deletion 2024; Ceroni et al.; DOI: https://doi.org/10.1038/s41467-024-53553-2; found an ~113.5 kb homozygous deletion 19.38 kb upstream of MAB21L2, removing conserved non-coding elements; zebrafish/Xenopus modeling caused small lens, coloboma, microphthalmia; supports non-coding regulatory variants as MAC causes (ceroni2024deletionupstreamof pages 1-2)
Recent discovery: FZD5 hypomorphic recessive variant 2024; Cortés-González et al.; DOI: https://doi.org/10.1007/s00439-024-02712-y; reported homozygous FZD5 missense variant causing syndromic bilateral ocular coloboma with microcornea; functional assays showed hypomorphic/partial loss-of-function in WNT signaling, expanding FZD5 disease mechanisms beyond dominant-negative alleles (cortesgonzalez2024homozygosityfora pages 1-2)

Table: This table condenses core disease definitions, epidemiology, major 2023 cohort statistics, and two high-impact 2024 genetic discoveries for microphthalmia with coloboma/MAC. It is useful as a quick reference for clinical, genetic, and knowledge-base curation work.

1. Disease information

1.1 Disease overview (current understanding)

Microphthalmia with coloboma refers to a congenital combination of (a) a reduced-size eye and (b) a colobomatous defect, most often involving inferonasal ocular structures due to incomplete embryonic fissure closure. In practice and in the genetics literature it is frequently discussed within the MAC/AMC spectrum (microphthalmia, anophthalmia, and coloboma), because patients often have mixed phenotypes and overlapping etiologies. (kunisetty2024highclinicalexome pages 1-2, harding2023realworldclinicaland pages 1-2)

Definitions (quoted/near-quoted from primary sources): - Microphthalmia: “reduced volume … axial length … less than two standard deviations below the … age-adjusted mean” (kunisetty2024highclinicalexome pages 1-2). - Anophthalmia: “clinical absence of ocular tissue” / “no visible … globe” (kunisetty2024highclinicalexome pages 1-2, harding2023realworldclinicaland pages 1-2). - Coloboma: “tissue is missing from … ocular structures” and typical inferonasal lesions are linked to incomplete fusion of the optic fissure (kunisetty2024highclinicalexome pages 1-2).

1.2 Key identifiers (ontology and clinical coding)

Available from retrieved sources in this run: - Genomics England PanelApp structural eye disorders panel used clinically for gene selection: https://panelapp.genomicsengland.co.uk/panels/509/ (referenced in a 2024 Nature Communications paper discussing AMC diagnostic panels) (ceroni2024deletionupstreamof pages 1-2).

Not retrievable with the current tool evidence: - MONDO ID, OMIM disease entry ID(s), Orphanet ID(s), ICD-10/ICD-11 code(s), and MeSH descriptor IDs were not directly present in the retrieved full-text excerpts and therefore cannot be asserted here without external database lookup beyond the current evidence set.

1.3 Synonyms / alternative names

Commonly used umbrella terms include: - MAC (microphthalmia, anophthalmia, coloboma) (holt2023theimpactof pages 1-3, kunisetty2024highclinicalexome pages 1-2) - AMC/AMC spectrum (anophthalmia, microphthalmia, coloboma) (ceroni2024deletionupstreamof pages 1-2) - “structural developmental eye anomalies” (context of MAC) (harding2023realworldclinicaland pages 1-1)

1.4 Evidence provenance

This report is derived from aggregated disease-level resources (reviews, trials registries) and cohort-based primary literature (e.g., prospective clinical cohorts, sequencing cohorts), not EHR-only summaries. (harding2023realworldclinicaland pages 1-1, kunisetty2024highclinicalexome pages 1-2, NCT01778543 chunk 1)

2. Etiology

2.1 Disease causal factors

MAC/AMC etiology is multifactorial, dominated by genetic causes but with recognized environmental/teratogenic contributors and likely gene–environment interactions. Harding et al. explicitly state: “The aetiology of MAC is complicated by a multitude of genetic and environmental factors.” (harding2023realworldclinicaland pages 9-10)

2.2 Genetic risk factors (causal genes)

Genetic heterogeneity is substantial: - A 2023 prospective MAC cohort identified pathogenic/likely pathogenic variants or CNVs in SOX2, PAX6, KMT2D, EPHA2, MAB21L2, ALDH1A3, BCOR, FOXE3, plus large deletions on chromosomes 10, 11 and X. (harding2023realworldclinicaland pages 8-9) - A 2024 clinical exome sequencing (cES) study in 189 individuals with nonisolated MAC concluded cES is effective and suggested additional low-penetrance MAC expansions in BRCA2, BRIP1, KAT6A, KAT6B, NSF, RAC1, SMARCA4, SMC1A, TUBA1A. (kunisetty2024highclinicalexome pages 1-2)

Abstract quote (cES yield): “We found the efficacy of cES in nonisolated MAC to be between 32.3% (61/189) and 48.1% (91/189).” (kunisetty2024highclinicalexome pages 1-2)

2.3 Environmental risk factors (including drugs) and infectious contributors

A 2024 scoping review emphasized that “prenatal medication exposure is recognized to be involved in fetal malformations” and that “several medications are specifically known to alter eye morphogenesis … leading to congenital eye defects” (dubucs2024thefirstreview pages 1-2). This review and other clinical summaries highlight exposures with reported association to ocular malformations including microphthalmia/coloboma: - Retinoid pathway disruption (vitamin A/retinoic acid dysregulation; isotretinoin/retinoic acid embryopathy) (dubucs2024thefirstreview pages 3-4, dubucs2024thefirstreview pages 11-12) - Thalidomide (classic ocular teratogen; review notes coloboma frequently reported in historical series) (dubucs2024thefirstreview pages 2-3) - Antiepileptics including valproate (coloboma associations in fetal valproate spectrum), carbamazepine, phenytoin/phenobarbital (dubucs2024thefirstreview pages 5-6) - Mycophenolate mofetil, methotrexate, warfarin/coumarins, methimazole (dubucs2024thefirstreview pages 5-6, dubucs2024thefirstreview pages 3-4) - Ionizing radiation/X-rays, solvents (e.g., trichloroethylene/toluene/xylene) and maternal hyperthermia/influenza in some reviews (goyal2025geneticandenvironmental pages 4-5, russo2025managementofanophthalmia pages 5-6) - TORCH and other congenital infections cited as causes of congenital ocular anomalies in general, including rubella/CMV/toxoplasmosis/HSV (dubucs2024thefirstreview pages 2-3)

2.4 Protective factors

Protective factors were not quantified in the retrieved primary evidence for MAC specifically. Mechanistically, maintenance of normal retinoic-acid signaling and avoidance of known teratogens during early gestation are implied prevention strategies (Sections 13–14 in Dubucs et al. emphasize modifiable exposures), but specific protective effect sizes were not available in retrieved excerpts. (dubucs2024thefirstreview pages 1-2)

2.5 Gene–environment interactions

The 2024 prenatal drug exposure review highlights genetic “phenocopies”: distinct insults (genetic or environmental/drug) that converge on shared pathways (e.g., retinoid biology) can produce similar ocular malformations. This supports a gene–environment interaction framework at the pathway level. (dubucs2024thefirstreview pages 11-12)

3. Phenotypes (with HPO suggestions)

3.1 Core ocular phenotypes (congenital)

  • Microphthalmia (HP:0000568)
  • Coloboma (general; HP:0000589), with possible subtypes:
  • Iris coloboma (HP:0000612)
  • Chorioretinal coloboma (HP:0001137)
  • Optic disc coloboma (HP:0000588)
  • Anophthalmia (HP:0000528) in severe spectrum cases

3.2 Additional ocular features and complications (frequency where available)

From a prospective 50-patient cohort (Moorfields Eye Hospital ocular genetics service; referrals 2017–2020): - “Complex” additional ocular features: 22/50 (44%) (harding2023realworldclinicaland pages 1-1) - Retinal detachment (RD): 7/80 affected eyes (9%), all associated with coloboma (harding2023realworldclinicaland pages 7-8) - Cataract occurred and lensectomy was performed in multiple patients in the cohort (with complications including secondary glaucoma reported after lensectomy in some eyes) (harding2023realworldclinicaland pages 7-8)

Suggested HPO terms: - Cataract (HP:0000518) - Retinal detachment (HP:0000541) - Glaucoma (HP:0000501) - Aphakia (HP:0000458)

3.3 Extraocular/systemic phenotypes (frequency where available)

In the same prospective cohort: - Systemic manifestations: 17/50 (34%) (harding2023realworldclinicaland pages 1-1) - Most frequent systemic feature: intellectual/developmental delay in 8/17 (47%) of those with systemic involvement (harding2023realworldclinicaland pages 1-1)

Suggested HPO terms: - Global developmental delay (HP:0001263) - Intellectual disability (HP:0001249) - Sensorineural hearing impairment (HP:0000407) (noted as a novel association for FOXE3 in the cohort) (harding2023realworldclinicaland pages 1-1)

3.4 Age of onset, severity, progression

  • Onset: congenital/embryonic. Eye morphogenesis occurs early: the 2024 review notes “the eye develops very early with all its structures in place before the 8th week of gestation.” (dubucs2024thefirstreview pages 2-3)
  • Course/progression: structural anomalies are typically stable, but complications (e.g., cataract, retinal detachment) can evolve and require monitoring/intervention. (harding2023realworldclinicaland pages 7-8)

3.5 Quality of life impact

Direct QoL statistics specific to microphthalmia with coloboma were not present in retrieved excerpts. However, MAC/AMC are consistently framed as contributing substantially to childhood severe visual impairment and blindness (15–20% / up to 20%), implying major functional and psychosocial impact. (kunisetty2024highclinicalexome pages 1-2, ceroni2024deletionupstreamof pages 1-2)

4. Genetic / molecular information

4.1 Causal genes (illustrative, not exhaustive)

High-confidence and/or cohort-supported genes in retrieved evidence include: - Transcription factor and developmental regulators: SOX2, OTX2, PAX6, FOXE3 (ceroni2024deletionupstreamof pages 1-2, harding2023realworldclinicaland pages 8-9) - Retinoid biology: ALDH1A3, STRA6 (harding2023realworldclinicaland pages 8-9, kunisetty2024highclinicalexome pages 1-2) - Other ocular developmental genes/regulators: MAB21L2, FZD5, BCOR, KMT2D, EPHA2 (harding2023realworldclinicaland pages 8-9, ceroni2024deletionupstreamof pages 1-2, cortesgonzalez2024homozygosityfora pages 1-2)

Gene contribution estimates reported in a 2024 Nature Communications paper: SOX2 and OTX2 are described as “the most common causes … explaining 10–15% and 2–5% of cases, respectively.” (ceroni2024deletionupstreamof pages 1-2)

4.2 Pathogenic variant classes and functional consequences

Observed variant classes in retrieved primary literature include: - Frameshift/nonsense/LoF (e.g., SOX2 c.867del; KMT2D c.6354del; MAB21L2 nonsense; BCOR frameshift; FOXE3 frameshift) (harding2023realworldclinicaland pages 8-9) - Missense (e.g., ALDH1A3 c.104T>C p.Phe35Ser reported as VUS in a compatible phenotype; MAB21L2 missense in 2024 report) (harding2023realworldclinicaland pages 8-9, ceroni2024deletionupstreamof pages 1-2) - Copy-number variants / structural variants including large deletions (chromosomes 10/11/X in the cohort; upstream MAB21L2 deletion) (harding2023realworldclinicaland pages 8-9, ceroni2024deletionupstreamof pages 1-2) - Non-coding regulatory deletions: ~113.5 kb homozygous deletion upstream of MAB21L2 deleting conserved regulatory elements bound by OTX2 (ceroni2024deletionupstreamof pages 1-2)

4.3 Inheritance patterns, penetrance/expressivity

Within the MAC spectrum, inheritance is variable (autosomal dominant, autosomal recessive, X-linked; often de novo in practice). In the 2024 FZD5 report, prior FZD5 coloboma mechanisms often involved dominant-negative effects, but the authors report a recessive/homozygous hypomorphic allele in a syndromic case, expanding inheritance/mechanism diversity. (cortesgonzalez2024homozygosityfora pages 1-2)

4.4 Diagnostic yield statistics (recent)

Prospective “real-world” cohort (Harding et al., British Journal of Ophthalmology; published Oct 2023; DOI URL https://doi.org/10.1136/bjo-2022-321991): - Genetic testing used in 39 families: WGS 17/39, targeted panel 18/39, aCGH 3/39, familial variant testing 1/39 (harding2023realworldclinicaland pages 7-8) - “Genetic association” identified in 11/39 (28%) families (harding2023realworldclinicaland pages 8-9) - Solve rates by test modality: WGS 4/17 (24%), targeted panel 3/18 (17%), aCGH 3/3 (100%) (harding2023realworldclinicaland pages 8-9)

Clinical exome sequencing (Kunisetty et al., IOVS; published Mar 19, 2024; DOI URL https://doi.org/10.1167/iovs.65.3.25): - Diagnostic efficacy 32.3%–48.1% in nonisolated MAC (kunisetty2024highclinicalexome pages 1-2) - Key conclusion (quote): cES “may identify putatively damaging variants that would be missed if only a clinically available ophthalmologic gene panel was obtained.” (kunisetty2024highclinicalexome pages 1-2)

5. Mechanism / pathophysiology

5.1 Causal chain (high-level)

1) Upstream trigger: germline coding variants, structural variants (CNVs), or non-coding regulatory variants in eye-development genes; or teratogenic/infectious exposures in early gestation (weeks ~3–8 are emphasized for vulnerability). (ceroni2024deletionupstreamof pages 1-2, dubucs2024thefirstreview pages 2-3) 2) Developmental disruption: altered gene regulatory networks and signaling (retinoic acid signaling, transcription factor networks; WNT signaling via FZD5), causing impaired optic vesicle/optic cup morphogenesis and optic fissure closure. (cortesgonzalez2024homozygosityfora pages 1-2, ceroni2024deletionupstreamof pages 1-2) 3) Anatomical malformations: microphthalmia (reduced axial length), coloboma (missing tissue), sometimes anophthalmia. (kunisetty2024highclinicalexome pages 1-2) 4) Downstream outcomes: visual impairment, cataract, retinal detachment, secondary glaucoma, and syndromic features depending on gene/system involvement. (harding2023realworldclinicaland pages 7-8, harding2023realworldclinicaland pages 1-1)

5.2 Key pathways and mechanisms (with evidence)

A. Non-coding regulatory mechanisms (2024 advance) - Ceroni et al. report a ~113.5 kb homozygous deletion upstream of MAB21L2; conservation analysis identified 15 conserved elements and ChIP-seq showed two bind Otx2; functional perturbation in zebrafish and Xenopus produced small lens, coloboma, microphthalmia**. This supports enhancer loss / dysregulated developmental transcription as a disease mechanism. (ceroni2024deletionupstreamof pages 1-2)

B. WNT signaling via FZD5 (2024 advance) - Cortés-González et al. describe FZD5 mutations as disrupting WNT signaling (dominant-negative alleles may sequester WNT ligands), and report a homozygous hypomorphic FZD5 missense** variant causing syndromic coloboma with microcornea, supported by zebrafish and TOPFlash functional assays. (cortesgonzalez2024homozygosityfora pages 1-2)

**C. Transcription factor networks and developmental regulators - Cohort data show frequent involvement of developmental regulators and transcription factors (SOX2, PAX6, FOXE3) and chromatin/gene expression regulators (KMT2D, BCOR) in solved cases, consistent with early developmental disruption as the proximate mechanism. (harding2023realworldclinicaland pages 9-10, harding2023realworldclinicaland pages 8-9)

5.3 Suggested ontology terms

GO Biological Process (suggestions): - eye development (GO:0001654) - camera-type eye morphogenesis (GO:0048592) - optic cup morphogenesis (GO:0003409) - retina development (GO:0060041) - Wnt signaling pathway (GO:0016055)

Cell types (CL suggestions): - neuroepithelial cell / retinal progenitor cell (broadly consistent with early optic cup neuroepithelium; exact CL IDs not asserted from retrieved text)

Anatomy (UBERON suggestions): - eye (UBERON:0000970) - retina (UBERON:0000966) - optic nerve (UBERON:0001130) - lens (UBERON:0000969)

6. Anatomical structures affected

Primary affected structures include the globe and internal ocular tissues (iris, retina/choroid, optic nerve) consistent with the coloboma definition (“tissue is missing from … eyelid, cornea, iris, lens, … retina, choroid, and/or optic nerve”). (kunisetty2024highclinicalexome pages 1-2)

Complication-relevant structures include lens (cataract/aphakia after surgery) and retina (retinal detachment in coloboma-associated eyes). (harding2023realworldclinicaland pages 7-8)

7. Temporal development

  • Critical window: early embryogenesis; ocular structures established before week 8, and optic fissure closure occurs by week 7 (as summarized in the 2024 prenatal exposure review). (dubucs2024thefirstreview pages 2-3)
  • Clinical course: congenital malformation with later complications (RD, cataract) and variable need for surgical rehabilitation and developmental supports. (harding2023realworldclinicaland pages 7-8, harding2023realworldclinicaland pages 9-10)

8. Inheritance and population

8.1 Epidemiology (statistics)

Across recent sources, reported birth prevalence ranges are: - Microphthalmia: 2–17 per 100,000 births (kunisetty2024highclinicalexome pages 1-2) - Anophthalmia: 0.6–4.2 per 100,000 births (kunisetty2024highclinicalexome pages 1-2) - Coloboma: 2–14 per 100,000 births (kunisetty2024highclinicalexome pages 1-2) - Combined MAC/AMC spectrum: approximately 6–30 per 100,000 (ceroni2024deletionupstreamof pages 1-2, holt2023theimpactof pages 1-3)

Contribution to visual impairment: - MAC account for “approximately 15% to 20% of severe visual impairment and blindness in children worldwide.” (kunisetty2024highclinicalexome pages 1-2) - Multiple sources state MAC/AMC can account for “up to 20% of childhood visual impairment.” (ceroni2024deletionupstreamof pages 1-2, holt2023theimpactof pages 1-3)

8.2 Population genetics notes

Founder variants, carrier frequencies, and variant geographic clustering were not extractable from the retrieved evidence set.

9. Diagnostics

9.1 Clinical and imaging evaluation

A 2023 “real-world” cohort recommends a multidisciplinary approach with “full phenotyping (with ophthalmic and systemic examination including parents, appropriate imaging and paediatric review for children)” and measurement of axial length by “ultrasound B-scan or orbital MRI.” (harding2023realworldclinicaland pages 9-10)

9.2 Genetic testing strategy (real-world implementation)

Evidence from 2023–2024 supports using a tiered strategy: - Chromosomal microarray (aCGH/CMA) to capture CNVs (high solve rate in the 2023 cohort’s small aCGH-tested subset, and recognition of large deletions in solved cases). (harding2023realworldclinicaland pages 8-9) - Clinical exome sequencing for nonisolated/syndromic MAC because many diagnoses may be missed by restricted ophthalmic panels; 2024 cES cohort emphasizes under-coverage of panel content. (kunisetty2024highclinicalexome pages 1-2) - Whole genome sequencing when available to detect a broader spectrum including structural/non-coding variants (and practical use in the 2023 cohort). (harding2023realworldclinicaland pages 8-9)

9.3 Differential diagnosis (examples)

Not comprehensively extractable from the retrieved excerpts, but syndromic entities repeatedly implicated include STRA6-related syndromic microphthalmia (Matthew–Wood syndrome) and other multisystem disorders where MAC is part of the phenotype. (kunisetty2024highclinicalexome pages 1-2)

9.4 Screening / prenatal diagnosis

The early timing of eye development implies that prevention/screening must target early pregnancy exposures, and prenatal genetic testing is feasible when familial pathogenic variants are known, but specific guideline statements were not present in retrieved excerpts. (dubucs2024thefirstreview pages 2-3)

10. Outcomes / prognosis

Quantitative survival/mortality is not applicable for most isolated MAC. Functional outcomes are driven by visual impairment severity and complications: - Retinal detachment occurred in 9% of affected eyes in a prospective cohort, with variable management and some eyes becoming phthisical when untreated/unsuitable for surgery. (harding2023realworldclinicaland pages 7-8) - Systemic/neurodevelopmental involvement is common (34% in the cohort), influencing long-term developmental outcomes and service needs. (harding2023realworldclinicaland pages 1-1)

11. Treatment (current applications and real-world implementation)

11.1 Ophthalmic interventions and supportive care

In the 2023 cohort, real-world care included: - Cataract management: lensectomy performed in several individuals; secondary glaucoma occurred in some eyes post-lensectomy. (harding2023realworldclinicaland pages 7-8) - Retinal detachment: vitreoretinal surgery attempted selectively based on visual potential; others managed conservatively due to extent or poor prognosis, with some eyes progressing to painless phthisis. (harding2023realworldclinicaland pages 5-7, harding2023realworldclinicaland pages 7-8) - Emphasis on multidisciplinary care and visual/aesthetic rehabilitation is stated as part of the recommended pathway. (harding2023realworldclinicaland pages 9-10)

MAXO suggestions (treatment actions): - Cataract extraction / lensectomy (MAXO term suggestion: cataract extraction) - Vitreoretinal surgery (MAXO suggestion: retinal detachment repair) - Genetic counseling (MAXO suggestion: genetic counseling) - Vision rehabilitation (MAXO suggestion: vision rehabilitation therapy)

11.2 Clinical trials / ongoing studies (real-world research implementations)

Key ClinicalTrials.gov studies directly relevant to MAC/AMC include: - NCT01778543 (NEI; recruiting; start 2013-01-08; enrollment 600): “Pathogenesis and Genetics of Microphthalmia, Anophthalmia and Uveal Coloboma (MAC)” — deep phenotyping + repository of DNA/cell lines to define ocular/systemic associations and risk factors. (NCT01778543 chunk 1) - NCT06293560 (Baylor; recruiting; start 2022-09-25; target enrollment 3,000): “Microphthalmia, Anophthalmia, and Coloboma Genetic Epidemiology in Children (MAGIC)” — staged phenotyping and genetic variant characterization, with optional deep phenotyping at NIH. (NCT06293560 chunk 1) - NCT04833361 (NEI; completed; enrollment 76): “Potential Environmental Causes of Uveal Coloboma” — maternal first-trimester exposures (e.g., hypothyroidism, alcohol) via phone survey + linkage to child clinical data to generate hypotheses. (NCT04833361 chunk 1) - NCT06408701 (Toulouse; recruiting; start 2024-11-05; target enrollment 20): “Modeling Ocular Developmental Diseases From 3D Cultures of Optic Vesicle Organoids …” — patient-derived hiPSC organoids for mechanistic studies and preclinical testing. (NCT06408701 chunk 1)

12. Prevention

The 2024 prenatal drug exposure review emphasizes modifiable exposures and calls for “high epidemiological vigilance,” noting that “medication exposures are potentially modifiable risk factors,” which creates prevention opportunities (avoid known teratogens; optimize pregnancy medication safety). (dubucs2024thefirstreview pages 1-2)

Practical prevention themes supported by recent reviews include: - Avoidance of known ocular teratogens during the early gestational window (e.g., isotretinoin/retinoic acid; thalidomide; certain antiepileptics; mycophenolate) (dubucs2024thefirstreview pages 3-4) - Management of maternal conditions and review of medications in pregnancy, given early eye development timing. (dubucs2024thefirstreview pages 2-3)

13. Other species / natural disease

Natural disease in non-human species was not captured in the retrieved evidence set.

14. Model organisms (key evidence)

  • Zebrafish and Xenopus tropicalis were used to model non-coding regulatory deletion upstream of MAB21L2, recapitulating microphthalmia and coloboma phenotypes and supporting enhancer-level pathogenic mechanisms. (ceroni2024deletionupstreamof pages 1-2)
  • Zebrafish + in vitro TOPFlash assays were used to characterize a recessive hypomorphic FZD5 allele affecting WNT signaling, linking pathway function to syndromic coloboma phenotypes. (cortesgonzalez2024homozygosityfora pages 1-2)

Visual evidence (figures/tables)

Harding et al. figure panels summarizing cohort demographics/ocular-systemic features and genetic testing yield by methodology were retrieved for visual support. (harding2023realworldclinicaland media 1f6eb4a9, harding2023realworldclinicaland media b580f419)

Expert opinion and analysis (authoritative interpretations)

  • A translational perspective emphasizes that MAC genetic testing has major clinical impact but requires “careful and thorough phenotyping” and that diagnostic yield is higher in severely affected bilateral cases than unilateral/mild cases. (holt2023theimpactof pages 1-3)
  • Recent high-impact primary research argues that a substantial fraction of severe AMC remains undiagnosed because many analyses focus on coding SNVs/CNVs and miss intronic/regulatory variants, reinforcing the need for genome-scale and regulatory-aware diagnostics. (ceroni2024deletionupstreamof pages 1-2)

Notes on citation format

Where available, the report provides DOI URLs and publication months/years (e.g., Oct 2023; Mar 2024; Oct/Nov 2024). PubMed IDs (PMIDs) were not present in the retrieved excerpts; therefore, PMID-specific citations could not be verified within the current evidence set.

References

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  22. (NCT04833361 chunk 1): Potential Environmental Causes of Uveal Coloboma. National Eye Institute (NEI). 2023. ClinicalTrials.gov Identifier: NCT04833361

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  24. (harding2023realworldclinicaland media 1f6eb4a9): Philippa Harding, Sri Gore, Samantha Malka, Jayashree Rajkumar, Ngozi Oluonye, and Mariya Moosajee. Real-world clinical and molecular management of 50 prospective patients with microphthalmia, anophthalmia and/or ocular coloboma. The British Journal of Ophthalmology, 107:1925-1935, Oct 2023. URL: https://doi.org/10.1136/bjo-2022-321991, doi:10.1136/bjo-2022-321991. This article has 26 citations.

  25. (harding2023realworldclinicaland media b580f419): Philippa Harding, Sri Gore, Samantha Malka, Jayashree Rajkumar, Ngozi Oluonye, and Mariya Moosajee. Real-world clinical and molecular management of 50 prospective patients with microphthalmia, anophthalmia and/or ocular coloboma. The British Journal of Ophthalmology, 107:1925-1935, Oct 2023. URL: https://doi.org/10.1136/bjo-2022-321991, doi:10.1136/bjo-2022-321991. This article has 26 citations.

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