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Inheritance

1

Autosomal Recessive HP:0000007

The single reported proband is homozygous for the causal VAX1 allele, which was absent from 96 ethnically matched controls — a biallelic genotype consistent with the autosomal recessive classification of MCOPS11 (OMIM:614402). No heterozygous carrier has been reported with the full phenotype.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:22095910 SUPPORT INDIRECT Human Clinical

"we observed homozygosity for two successive nucleotide substitutions c.453G>A and c.454C>A, predicting p.Arg152Ser, in a proband of Egyptian origin"

A homozygous causal genotype in the single proband, absent from controls, is the basis for recessive inheritance; the abstract states the genotype rather than the inheritance mode itself, hence INDIRECT.

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Discussions and Knowledge Gaps

2

Do humans with biallelic VAX1 loss of function have hypothalamic-pituitary-gonadal (reproductive/endocrine) involvement, as predicted by the mouse Vax1 requirement in GnRH neurons?

KNOWLEDGE GAP vax1-reproductive-axis-human

Attached to

disease#

In mouse, Vax1 is required for GnRH neuron maturation and Gnrh1 expression, and its deletion from GnRH neurons causes hypogonadism and infertility; Vax1 haploinsufficiency causes subfertility and has been proposed as a candidate in polygenic idiopathic hypogonadotropic hypogonadism. The single reported human MCOPS11 proband is a young child, so reproductive-axis involvement in humans has neither been assessed nor excluded. This is a genuine open question rather than an established human phenotype, so it is recorded as a gap rather than as a phenotype.

Show evidence (1 reference)

PMID:27013679 SUPPORT Model Organism

"Vax1 deletion from GnRH neurons leads to complete infertility in males and females"

Establishes the mouse basis for the open question about reproductive-axis involvement in human VAX1 loss of function.

Does human biallelic VAX1 loss produce lobar holoprosencephaly, as the Vax1 null mouse does, or is the human forebrain phenotype restricted to corpus callosum agenesis?

HUMAN MODEL MISMATCH vax1-holoprosencephaly-human-mouse

Attached to

pathophysiology#Disrupted Ventral Forebrain and Optic Stalk Patterning

The Vax1 null mouse shows lobar holoprosencephaly, a severe ventral forebrain malformation, whereas the single human proband is reported with corpus callosum agenesis but not holoprosencephaly. Whether this is a true species difference in VAX1 forebrain requirement or an artefact of n=1 human phenotyping is unresolved and bears on how far the mouse patterning model can be read across to human disease.

Show evidence (1 reference)

PMID:10601036 SUPPORT Model Organism

"Mice carrying a targeted mutation of Vax1 show dysgenesis of the optic nerve, coloboma, defects in the basal telencephalon, and lobar holoprosencephaly."

Reports the mouse holoprosencephaly that is not documented in the human proband.

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Pathophysiology

6

VAX1 Loss of Function

Mechanism confidence: Provisional

A homozygous missense change at an invariant residue of the VAX1 homeodomain (p.Arg152Ser) is the initiating lesion. VAX1 is a homeodomain transcription factor that binds DNA sequence-specifically; the lesion is predicted to reduce its DNA-binding transcription-factor activity. Loss of function is the authors' interpretation, inferred from the human phenotype resembling the Vax1 homozygous null mouse rather than from an assay of this allele.

VAX1 hgnc:12660

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

VAX1 DNA-binding transcription factor activity GO:0000981 ↓ DECREASED

Downstream

Disrupted Ventral Forebrain and Optic Stalk Patterning Loss of VAX1 transcriptional activity disrupts patterning of the ventral forebrain and optic stalk, the domains where Vax1 is normally expressed.

Commissural Axon Guidance Failure VAX1 is required in anterior midline cells to guide commissural axons; its loss removes attractive guidance cues from those cells.

Failure of Craniofacial Fusion Biallelic VAX1 loss is associated with orofacial clefting in the human proband. The intervening craniofacial developmental mechanism is not demonstrated in the cached literature and the link is therefore inferred.

Show evidence (2 references)

PMID:22095910 SUPPORT INDIRECT Human Clinical

"It is likely that the mutation results in a loss of function, as the mutation results in a phenotype similar to the Vax1 homozygous null mouse."

States the loss-of-function interpretation of the causal missense allele.

PMID:27013679 SUPPORT In Vitro

"we found VAX1 to be a direct activator of the GnRH promoter through binding to four ATTA sites in the GnRH enhancer (E1) and proximal promoter (P)"

Demonstrates in cell lines that VAX1 is a sequence-specific DNA-binding transcriptional regulator, grounding the molecular-function annotation.

Disrupted Ventral Forebrain and Optic Stalk Patterning

Mechanism confidence: Provisional

In the Vax1 null mouse, loss of Vax1 causes a proximal expansion of Pax6 and Rx activity in the developing visual system and defects in the basal telencephalon, indicating that Vax1 normally restrains dorsal eye-field programs and specifies ventral forebrain/optic-stalk identity. This is mouse evidence applied to the human disorder by phenocopy.

forebrain development GO:0030900 ⚠ ABNORMAL optic nerve development GO:0021554 ⚠ ABNORMAL

optic stalk UBERON:0003098

Animal models

Vax1 homozygous null mouse (basal forebrain and visual system) Mouse recapitulates The null mouse reproduces the ventral forebrain/visual-system patterning defect, including derepression of Pax6 and Rx.

Downstream

Optic Fissure Closure Failure Disrupted ventral patterning leads to failure of the optic fissure (optic disk) to close, producing coloboma.

Show evidence (2 references)

PMID:10601036 SUPPORT Model Organism

"the absence of Vax1 results in a proximal expansion of the activity of Pax6 and Rx"

Shows that loss of Vax1 derepresses dorsal eye-field transcription factors, the molecular signature of disrupted ventral patterning.

PMID:10601036 SUPPORT Model Organism

"Mice carrying a targeted mutation of Vax1 show dysgenesis of the optic nerve, coloboma, defects in the basal telencephalon, and lobar holoprosencephaly."

Reports the forebrain and visual-system defects of the Vax1 null mouse.

Optic Fissure Closure Failure

Mechanism confidence: Provisional

In the Vax1 null mouse the optic disks fail to close, producing coloboma and loss of the eye-nerve boundary. In the human proband this corresponds to the small, malformed eye (microphthalmia).

optic fissure UBERON:0005412

Animal models

Vax1 homozygous null mouse (basal forebrain and visual system) Mouse recapitulates The null mouse reproduces coloboma (failed optic fissure closure).

Vax1 homozygous null mouse (axon guidance) Mouse recapitulates The null mouse reproduces failure of optic disk closure (coloboma).

Downstream

Microphthalmia Failed optic fissure closure (coloboma) underlies the small, malformed eye in the proband.

Show evidence (1 reference)

PMID:10601035 SUPPORT Model Organism

"the optic disks fail to close, leading to coloboma and loss of the eye-nerve boundary"

Reports the optic fissure/disc closure failure underlying the ocular phenotype.

Retinal Axon Guidance Failure in the Optic Nerve and Chiasm

Mechanism confidence: Provisional

In the Vax1 null mouse, optic nerve glia fail to associate with and appear to repulse ingrowing retinal axons, and retinal axons fail to penetrate the brain in significant numbers and fail to form an optic chiasm. This failure of retinal ganglion cell axon pathfinding corresponds to the small optic nerves (optic nerve hypoplasia) in the human proband.

retinal ganglion cell CL:0000740

retinal ganglion cell axon guidance GO:0031290 ⚠ ABNORMAL

optic chiasm UBERON:0000959

Animal models

Vax1 homozygous null mouse (axon guidance) Mouse recapitulates The null mouse reproduces the failure of retinal axons to form an optic chiasm, the cellular basis for the small optic nerves.

Downstream

Optic nerve hypoplasia Failure of retinal ganglion cell axons to populate the optic nerve corresponds to the small optic nerves reported in the proband.

Show evidence (2 references)

PMID:10601035 SUPPORT Model Organism

"optic nerve glia fail to associate with and appear to repulse ingrowing retinal axons, resulting in a fascicle of axons that are completely segregated from optic nerve astrocytes"

Reports the failure of retinal axon-glia association in the optic nerve.

PMID:10601035 SUPPORT Model Organism

"retinal axons fail to penetrate the brain in significant numbers and fail to form an optic chiasm"

Reports the failure of retinal axons to reach the brain and form the optic chiasm.

Commissural Axon Guidance Failure

Mechanism confidence: Provisional

VAX1 is expressed in anterior midline cells that orchestrate axon trajectories. In the Vax1 null mouse, axons of the corpus callosum and the hippocampal and anterior commissures fail to cross the midline, because the normally Vax1-positive midline cells show markedly diminished expression of attractive guidance cues (the cells survive; the defect is in their guidance function).

anterior midline guidepost cell CL:0000143

axon guidance GO:0007411 ⚠ ABNORMAL

Animal models

Vax1 homozygous null mouse (axon guidance) Mouse recapitulates The null mouse reproduces the commissural axon guidance failure that underlies corpus callosum agenesis.

Downstream

Agenesis of corpus callosum Failure of callosal axons to cross the midline produces agenesis of the corpus callosum, reported in the human proband.

Show evidence (2 references)

PMID:10601035 SUPPORT Model Organism

"axons in multiple commissural tracts of the anterior CNS, including the corpus callosum and the hippocampal and anterior commissures, fail to cross the midline"

Reports the midline commissural axon guidance failure behind callosal agenesis.

PMID:10601035 SUPPORT Model Organism

"These axon guidance defects do not result from the death of normally Vax1(+) midline cells but, instead, correlate with markedly diminished expression of attractive guidance cues in these cells."

Localizes the defect to loss of guidance-cue expression rather than cell death.

Failure of Craniofacial Fusion

Mechanism confidence: Provisional

The human proband has cleft lip/palate. A craniofacial developmental failure is inferred as the proximate cause, but the cached literature does not demonstrate a VAX1-dependent palatal/lip fusion mechanism, so this node links the lesion to the orofacial phenotype rather than asserting a mechanism.

roof of mouth development GO:0060021 ⚠ ABNORMAL

Downstream

Cleft lip Orofacial clefting in the proband includes cleft lip.

Cleft palate Orofacial clefting in the proband includes cleft palate.

Show evidence (1 reference)

PMID:22095910 SUPPORT Human Clinical

"a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate, and corpus callosum agenesis"

Documents the orofacial clefting in the single proband.

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Pathograph

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

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Phenotypes

5

Eye 2

Microphthalmia HP:0000568

Show evidence (1 reference)

PMID:22095910 SUPPORT Human Clinical

"a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate, and corpus callosum agenesis"

Microphthalmia is reported in the proband.

Optic nerve hypoplasia HP:0000609

Show evidence (1 reference)

PMID:22095910 SUPPORT Human Clinical

"a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate, and corpus callosum agenesis"

The small optic nerves reported in the proband correspond to optic nerve hypoplasia.

Head and Neck 2

Cleft lip HP:0410030

Show evidence (1 reference)

PMID:22095910 SUPPORT Human Clinical

"a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate, and corpus callosum agenesis"

Cleft lip is reported in the proband.

Cleft palate HP:0000175

Show evidence (1 reference)

PMID:22095910 SUPPORT Human Clinical

"a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate, and corpus callosum agenesis"

Cleft palate is reported in the proband.

Nervous System 1

Agenesis of corpus callosum HP:0001274

Show evidence (1 reference)

PMID:22095910 SUPPORT Human Clinical

"a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate, and corpus callosum agenesis"

Corpus callosum agenesis is reported in the proband.

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Genetic Associations

1

VAX1 (Biallelic VAX1 variants cause MCOPS11. The reported allele is a homozygous dinucleotide substitution (c.453G>A and c.454C>A) predicting the missense change p.Arg152Ser at an invariant residue of the VAX1 homeodomain. The authors favour loss of function because the human phenotype resembles the Vax1 homozygous null mouse. VAX1 is one of the established genes of the microphthalmia-anophthalmia-coloboma (MAC) spectrum.)

Gene: VAX1 hgnc:12660 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:22095910 SUPPORT Human Clinical

"This is the first description of a phenotype associated with a VAX1 mutation in humans and establishes VAX1 as a new causative gene for A/M."

Establishes VAX1 as the causative gene for this anophthalmia/microphthalmia phenotype.

PMID:24859618 SUPPORT REVIEW SYNTHESIS Other

"This review will focus on MAC phenotypes that are associated with mutation of the genes SOX2, OTX2, PAX6, STRA6, ALDH1A3, RARB, VSX2, RAX, FOXE3, BMP4, BMP7, GDF3, GDF6, ABCB6, ATOH7, C12orf57, TENM3 (ODZ3), and VAX1."

A review places VAX1 among the established genes of the MAC spectrum.

Variants (1)

c.453G>A; c.454C>A (p.Arg152Ser)

Gene: VAX1 hgnc:12660 missense

Homozygous pair of successive nucleotide substitutions within one codon, predicting the missense change p.Arg152Ser. The residue is invariant in the VAX1 homeodomain, the DNA-binding module of the protein, and the allele was absent from 96 Egyptian controls.

Functional effects

LOSS_OF_FUNCTION

A missense change at an invariant homeodomain residue is predicted to impair sequence-specific DNA binding by VAX1. Loss of function is inferred from phenotypic similarity to the Vax1 null mouse; no functional assay of this allele is reported.

Show evidence (2 references)

PMID:22095910 SUPPORT Human Clinical

"This mutation affects an invariant residue in the homeodomain of VAX1 and was absent from 96 Egyptian controls."

Reports the variant location at an invariant homeodomain residue and its absence from controls.

PMID:22095910 SUPPORT INDIRECT Human Clinical

"It is likely that the mutation results in a loss of function, as the mutation results in a phenotype similar to the Vax1 homozygous null mouse."

The loss-of-function interpretation is inferred from phenocopy of the null mouse, not from a direct assay.

💊

Medical Actions

2

Orofacial cleft surgical repair

Action: orofacial cleft repair Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Staged surgical repair of the cleft lip and palate, as for orofacial clefting of any cause. This is symptomatic management of a structural malformation, not a disease-modifying therapy, and no VAX1-specific intervention exists.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Counseling for the affected family, including the 25% recurrence risk that follows from autosomal recessive inheritance once the biallelic VAX1 genotype is known, and the option of carrier and prenatal testing.

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Prevalence

1

Worldwide

Cases In Literature Unknown

No population prevalence estimate exists and none should be inferred. The human entity is defined by a single reported proband (Slavotinek et al. 2012, found among 70 anophthalmia/microphthalmia patients). Prevalence figures for microphthalmia/anophthalmia as a whole must not be substituted for this VAX1-specific entity.

Show evidence (1 reference)

PMID:22095910 SUPPORT Human Clinical

"We sequenced the coding exons of VAX1 and VAX2 in 70 patients with anophthalmia/microphthalmia (A/M)."

The sole VAX1 proband was identified within a cohort of 70 A/M patients; the entity rests on that single case rather than a population estimate.

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Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from microphthalmia, syndromic 11:

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Animal Models

2

Vax1 homozygous null mouse (basal forebrain and visual system)

Mice homozygous for a targeted Vax1 mutation show dysgenesis of the optic nerve, coloboma, basal telencephalon defects and lobar holoprosencephaly, with proximal expansion of Pax6 and Rx activity in the visual system. This model established the loss-of-function interpretation of the human allele.

Species

Mouse

Genotype

Vax1 targeted null (homozygous knockout)

Publication

PMID:10601036

Pathograph links

Disrupted Ventral Forebrain and Optic Stalk Patterning recapitulates fidelity: moderate observes: tissue The null mouse reproduces the ventral forebrain/visual-system patterning defect, including derepression of Pax6 and Rx.

Limitations: The mouse also shows lobar holoprosencephaly, which was not reported in the single human proband; whether this reflects a species difference or the limited human phenotyping is unresolved.

Show evidence (1 reference)

PMID:10601036 SUPPORT Model Organism

"the absence of Vax1 results in a proximal expansion of the activity of Pax6 and Rx"

Reports the molecular patterning signature recapitulated by the model.

Optic Fissure Closure Failure recapitulates fidelity: moderate observes: tissue The null mouse reproduces coloboma (failed optic fissure closure).

Limitations: Mouse coloboma is read across to the human microphthalmia by phenocopy; the human eye was not examined histologically in the cached report.

Show evidence (1 reference)

PMID:10601036 SUPPORT Model Organism

"Mice carrying a targeted mutation of Vax1 show dysgenesis of the optic nerve, coloboma, defects in the basal telencephalon, and lobar holoprosencephaly."

Reports the ocular defects recapitulated by the model.

Vax1 homozygous null mouse (axon guidance)

Mice lacking Vax1 show failure of the optic disks to close (coloboma) and failure of axons in the corpus callosum and the hippocampal and anterior commissures to cross the midline, due to diminished expression of attractive guidance cues in anterior midline cells.

Species

Mouse

Genotype

Vax1 targeted null (homozygous knockout)

Publication

PMID:10601035

Pathograph links

Commissural Axon Guidance Failure recapitulates fidelity: moderate observes: cellular The null mouse reproduces the commissural axon guidance failure that underlies corpus callosum agenesis.

Limitations: The mechanism is demonstrated in mouse; the corresponding human defect is inferred from the proband's corpus callosum agenesis by phenocopy.

Show evidence (1 reference)

PMID:10601035 SUPPORT Model Organism

"axons in multiple commissural tracts of the anterior CNS, including the corpus callosum and the hippocampal and anterior commissures, fail to cross the midline"

Reports the commissural axon guidance defect recapitulated by the model.

Optic Fissure Closure Failure recapitulates fidelity: moderate observes: tissue The null mouse reproduces failure of optic disk closure (coloboma).

Limitations: Demonstrated in mouse; read across to the human ocular phenotype by phenocopy.

Show evidence (1 reference)

PMID:10601035 SUPPORT Model Organism

"the optic disks fail to close, leading to coloboma and loss of the eye-nerve boundary"

Reports the optic fissure closure failure recapitulated by the model.

Retinal Axon Guidance Failure in the Optic Nerve and Chiasm recapitulates fidelity: moderate observes: cellular The null mouse reproduces the failure of retinal axons to form an optic chiasm, the cellular basis for the small optic nerves.

Limitations: Demonstrated in mouse; read across to the human optic nerve hypoplasia by phenocopy.

Show evidence (1 reference)

PMID:10601035 SUPPORT Model Organism

"retinal axons fail to penetrate the brain in significant numbers and fail to form an optic chiasm"

Reports the retinal axon pathfinding failure recapitulated by the model.

{ }

Source YAML

click to show

name: microphthalmia, syndromic 11
creation_date: "2026-10-12T15:45:00Z"
category: Mendelian
description: >-
  An ultra-rare autosomal recessive syndromic microphthalmia/anophthalmia
  (MCOPS11; MONDO:0013734, OMIM:614402) caused by biallelic loss of function of
  VAX1 (ventral anterior homeobox 1), a homeodomain transcription factor
  essential for ventral forebrain, optic stalk and optic nerve development. The
  human entity rests on a single reported proband: Slavotinek et al. (2012)
  sequenced VAX1 and VAX2 in 70 anophthalmia/microphthalmia patients and found,
  in one Egyptian proband, homozygosity for two successive substitutions
  (c.453G>A and c.454C>A, p.Arg152Ser) affecting an invariant homeodomain
  residue, with microphthalmia, small optic nerves, cleft lip/palate and corpus
  callosum agenesis. Loss of function is inferred from the phenotypic similarity
  to the Vax1 homozygous null mouse, in which optic nerve dysgenesis, coloboma,
  basal telencephalon defects and failure of commissural axons (corpus callosum,
  hippocampal and anterior commissures) to cross the midline have been
  demonstrated. The craniofacial (cleft) mechanism in humans is inferred rather
  than demonstrated — the cached mouse abstracts do not report cleft palate — so
  that branch is grounded in the human proband and left mechanistically open.
synonyms:
- MCOPS11
- VAX1 syndromic microphthalmia
- microphthalmia, syndromic type 11
parents:
- hereditary disease
- developmental eye disorder
- syndromic microphthalmia
disease_term:
  preferred_term: microphthalmia, syndromic 11
  term:
    id: MONDO:0013734
    label: microphthalmia, syndromic 11
references:
- reference: PMID:22095910
  title: "VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans."
- reference: PMID:10601035
  title: "The homeodomain protein vax1 is required for axon guidance and major tract formation in the developing forebrain."
- reference: PMID:10601036
  title: "Vax1, a novel homeobox-containing gene, directs development of the basal forebrain and visual system."
- reference: PMID:27013679
  title: "Deletion of Vax1 from Gonadotropin-Releasing Hormone (GnRH) Neurons Abolishes GnRH Expression and Leads to Hypogonadism and Infertility."
- reference: PMID:24859618
  title: "The genetic architecture of microphthalmia, anophthalmia and coloboma."
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    The single reported proband is homozygous for the causal VAX1 allele, which
    was absent from 96 ethnically matched controls — a biallelic genotype
    consistent with the autosomal recessive classification of MCOPS11
    (OMIM:614402). No heterozygous carrier has been reported with the full
    phenotype.
  evidence:
  - reference: PMID:22095910
    reference_title: "VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "we observed homozygosity for two successive nucleotide substitutions c.453G>A and c.454C>A, predicting p.Arg152Ser, in a proband of Egyptian origin"
    explanation: >-
      A homozygous causal genotype in the single proband, absent from controls,
      is the basis for recessive inheritance; the abstract states the genotype
      rather than the inheritance mode itself, hence INDIRECT.
genetic:
- name: VAX1
  gene_term:
    preferred_term: VAX1
    term:
      id: hgnc:12660
      label: VAX1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  association: >-
    Biallelic VAX1 variants cause MCOPS11. The reported allele is a homozygous
    dinucleotide substitution (c.453G>A and c.454C>A) predicting the missense
    change p.Arg152Ser at an invariant residue of the VAX1 homeodomain. The
    authors favour loss of function because the human phenotype resembles the
    Vax1 homozygous null mouse. VAX1 is one of the established genes of the
    microphthalmia-anophthalmia-coloboma (MAC) spectrum.
  notes: >-
    No ClinGen Gene-Disease Validity (CGGV:) record is cached for VAX1 with this
    disease, so no gene_disease_validity assertion is recorded (verified with
    `just list-gene-validity`). The causal relationship rests on the single
    Slavotinek 2012 family plus phenocopy by the Vax1 null mouse. A separate,
    non-causal common-variant association between the 10q25.3 VAX1 region and
    nonsyndromic cleft lip/palate exists in the GWAS literature but is a
    susceptibility signal, not MCOPS11 causation, and is not cited here because
    no primary GWAS source was verified in this curation.
  evidence:
  - reference: PMID:22095910
    reference_title: "VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is the first description of a phenotype associated with a VAX1 mutation in humans and establishes VAX1 as a new causative gene for A/M."
    explanation: Establishes VAX1 as the causative gene for this anophthalmia/microphthalmia phenotype.
  - reference: PMID:24859618
    reference_title: "The genetic architecture of microphthalmia, anophthalmia and coloboma."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "This review will focus on MAC phenotypes that are associated with mutation of the genes SOX2, OTX2, PAX6, STRA6, ALDH1A3, RARB, VSX2, RAX, FOXE3, BMP4, BMP7, GDF3, GDF6, ABCB6, ATOH7, C12orf57, TENM3 (ODZ3), and VAX1."
    explanation: A review places VAX1 among the established genes of the MAC spectrum.
  variants:
  - name: "c.453G>A; c.454C>A (p.Arg152Ser)"
    description: >-
      Homozygous pair of successive nucleotide substitutions within one codon,
      predicting the missense change p.Arg152Ser. The residue is invariant in
      the VAX1 homeodomain, the DNA-binding module of the protein, and the allele
      was absent from 96 Egyptian controls.
    gene:
      preferred_term: VAX1
      term:
        id: hgnc:12660
        label: VAX1
    type: missense
    functional_effects:
    - function: LOSS_OF_FUNCTION
      description: >-
        A missense change at an invariant homeodomain residue is predicted to
        impair sequence-specific DNA binding by VAX1. Loss of function is
        inferred from phenotypic similarity to the Vax1 null mouse; no functional
        assay of this allele is reported.
    evidence:
    - reference: PMID:22095910
      reference_title: "VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This mutation affects an invariant residue in the homeodomain of VAX1 and was absent from 96 Egyptian controls."
      explanation: Reports the variant location at an invariant homeodomain residue and its absence from controls.
    - reference: PMID:22095910
      reference_title: "VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "It is likely that the mutation results in a loss of function, as the mutation results in a phenotype similar to the Vax1 homozygous null mouse."
      explanation: The loss-of-function interpretation is inferred from phenocopy of the null mouse, not from a direct assay.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    No population prevalence estimate exists and none should be inferred. The
    human entity is defined by a single reported proband (Slavotinek et al.
    2012, found among 70 anophthalmia/microphthalmia patients). Prevalence
    figures for microphthalmia/anophthalmia as a whole must not be substituted
    for this VAX1-specific entity.
  evidence:
  - reference: PMID:22095910
    reference_title: "VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We sequenced the coding exons of VAX1 and VAX2 in 70 patients with anophthalmia/microphthalmia (A/M)."
    explanation: >-
      The sole VAX1 proband was identified within a cohort of 70 A/M patients;
      the entity rests on that single case rather than a population estimate.
pathophysiology:
- name: VAX1 Loss of Function
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    A homozygous missense change at an invariant residue of the VAX1 homeodomain
    (p.Arg152Ser) is the initiating lesion. VAX1 is a homeodomain transcription
    factor that binds DNA sequence-specifically; the lesion is predicted to
    reduce its DNA-binding transcription-factor activity. Loss of function is
    the authors' interpretation, inferred from the human phenotype resembling the
    Vax1 homozygous null mouse rather than from an assay of this allele.
  gene:
    preferred_term: VAX1
    term:
      id: hgnc:12660
      label: VAX1
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: VAX1 DNA-binding transcription factor activity
    term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase II-specific
    modifier: DECREASED
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:22095910
    reference_title: "VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is likely that the mutation results in a loss of function, as the mutation results in a phenotype similar to the Vax1 homozygous null mouse."
    explanation: States the loss-of-function interpretation of the causal missense allele.
  - reference: PMID:27013679
    reference_title: "Deletion of Vax1 from Gonadotropin-Releasing Hormone (GnRH) Neurons Abolishes GnRH Expression and Leads to Hypogonadism and Infertility."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we found VAX1 to be a direct activator of the GnRH promoter through binding to four ATTA sites in the GnRH enhancer (E1) and proximal promoter (P)"
    explanation: >-
      Demonstrates in cell lines that VAX1 is a sequence-specific DNA-binding
      transcriptional regulator, grounding the molecular-function annotation.
  downstream:
  - target: Disrupted Ventral Forebrain and Optic Stalk Patterning
    description: >-
      Loss of VAX1 transcriptional activity disrupts patterning of the ventral
      forebrain and optic stalk, the domains where Vax1 is normally expressed.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10601036
      reference_title: "Vax1, a novel homeobox-containing gene, directs development of the basal forebrain and visual system."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "the absence of Vax1 results in a proximal expansion of the activity of Pax6 and Rx"
      explanation: >-
        Shows that loss of Vax1 derepresses the dorsal eye-field transcription
        factors Pax6 and Rx, the molecular signature of disrupted ventral
        patterning.
  - target: Commissural Axon Guidance Failure
    description: >-
      VAX1 is required in anterior midline cells to guide commissural axons;
      its loss removes attractive guidance cues from those cells.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10601035
      reference_title: "The homeodomain protein vax1 is required for axon guidance and major tract formation in the developing forebrain."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Vax1 therefore regulates the guidance properties of a set of anterior midline cells that orchestrate axon trajectories in the developing mammalian forebrain."
      explanation: >-
        Places VAX1 as the regulator of the anterior midline cells that guide
        commissural axon trajectories.
  - target: Failure of Craniofacial Fusion
    description: >-
      Biallelic VAX1 loss is associated with orofacial clefting in the human
      proband. The intervening craniofacial developmental mechanism is not
      demonstrated in the cached literature and the link is therefore inferred.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Disrupted Ventral Forebrain and Optic Stalk Patterning
  role: intermediate
  biological_scale: TISSUE
  description: >-
    In the Vax1 null mouse, loss of Vax1 causes a proximal expansion of Pax6 and
    Rx activity in the developing visual system and defects in the basal
    telencephalon, indicating that Vax1 normally restrains dorsal eye-field
    programs and specifies ventral forebrain/optic-stalk identity. This is mouse
    evidence applied to the human disorder by phenocopy.
  biological_processes:
  - preferred_term: forebrain development
    term:
      id: GO:0030900
      label: forebrain development
    modifier: ABNORMAL
  - preferred_term: optic nerve development
    term:
      id: GO:0021554
      label: optic nerve development
    modifier: ABNORMAL
  locations:
  - preferred_term: optic stalk
    term:
      id: UBERON:0003098
      label: optic stalk
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:10601036
    reference_title: "Vax1, a novel homeobox-containing gene, directs development of the basal forebrain and visual system."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the absence of Vax1 results in a proximal expansion of the activity of Pax6 and Rx"
    explanation: >-
      Shows that loss of Vax1 derepresses dorsal eye-field transcription factors,
      the molecular signature of disrupted ventral patterning.
  - reference: PMID:10601036
    reference_title: "Vax1, a novel homeobox-containing gene, directs development of the basal forebrain and visual system."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice carrying a targeted mutation of Vax1 show dysgenesis of the optic nerve, coloboma, defects in the basal telencephalon, and lobar holoprosencephaly."
    explanation: Reports the forebrain and visual-system defects of the Vax1 null mouse.
  downstream:
  - target: Optic Fissure Closure Failure
    description: >-
      Disrupted ventral patterning leads to failure of the optic fissure (optic
      disk) to close, producing coloboma.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10601036
      reference_title: "Vax1, a novel homeobox-containing gene, directs development of the basal forebrain and visual system."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice carrying a targeted mutation of Vax1 show dysgenesis of the optic nerve, coloboma, defects in the basal telencephalon, and lobar holoprosencephaly."
      explanation: Links Vax1 loss to coloboma (failed optic fissure closure) and optic nerve dysgenesis.
- name: Optic Fissure Closure Failure
  role: intermediate
  biological_scale: TISSUE
  description: >-
    In the Vax1 null mouse the optic disks fail to close, producing coloboma and
    loss of the eye-nerve boundary. In the human proband this corresponds to the
    small, malformed eye (microphthalmia).
  locations:
  - preferred_term: optic fissure
    term:
      id: UBERON:0005412
      label: optic fissure
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:10601035
    reference_title: "The homeodomain protein vax1 is required for axon guidance and major tract formation in the developing forebrain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the optic disks fail to close, leading to coloboma and loss of the eye-nerve boundary"
    explanation: Reports the optic fissure/disc closure failure underlying the ocular phenotype.
  downstream:
  - target: Microphthalmia
    description: >-
      Failed optic fissure closure (coloboma) underlies the small, malformed eye
      in the proband.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Retinal Axon Guidance Failure in the Optic Nerve and Chiasm
  role: intermediate
  biological_scale: CELLULAR
  description: >-
    In the Vax1 null mouse, optic nerve glia fail to associate with and appear to
    repulse ingrowing retinal axons, and retinal axons fail to penetrate the
    brain in significant numbers and fail to form an optic chiasm. This failure
    of retinal ganglion cell axon pathfinding corresponds to the small optic
    nerves (optic nerve hypoplasia) in the human proband.
  biological_processes:
  - preferred_term: retinal ganglion cell axon guidance
    term:
      id: GO:0031290
      label: retinal ganglion cell axon guidance
    modifier: ABNORMAL
  cell_types:
  - preferred_term: retinal ganglion cell
    term:
      id: CL:0000740
      label: retinal ganglion cell
  locations:
  - preferred_term: optic chiasm
    term:
      id: UBERON:0000959
      label: optic chiasma
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:10601035
    reference_title: "The homeodomain protein vax1 is required for axon guidance and major tract formation in the developing forebrain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "optic nerve glia fail to associate with and appear to repulse ingrowing retinal axons, resulting in a fascicle of axons that are completely segregated from optic nerve astrocytes"
    explanation: Reports the failure of retinal axon-glia association in the optic nerve.
  - reference: PMID:10601035
    reference_title: "The homeodomain protein vax1 is required for axon guidance and major tract formation in the developing forebrain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "retinal axons fail to penetrate the brain in significant numbers and fail to form an optic chiasm"
    explanation: Reports the failure of retinal axons to reach the brain and form the optic chiasm.
  downstream:
  - target: Optic nerve hypoplasia
    description: >-
      Failure of retinal ganglion cell axons to populate the optic nerve
      corresponds to the small optic nerves reported in the proband.
    causal_link_type: DIRECT
- name: Commissural Axon Guidance Failure
  role: intermediate
  biological_scale: CELLULAR
  description: >-
    VAX1 is expressed in anterior midline cells that orchestrate axon
    trajectories. In the Vax1 null mouse, axons of the corpus callosum and the
    hippocampal and anterior commissures fail to cross the midline, because the
    normally Vax1-positive midline cells show markedly diminished expression of
    attractive guidance cues (the cells survive; the defect is in their guidance
    function).
  biological_processes:
  - preferred_term: axon guidance
    term:
      id: GO:0007411
      label: axon guidance
    modifier: ABNORMAL
  cell_types:
  - preferred_term: anterior midline guidepost cell
    term:
      id: CL:0000143
      label: guidepost cell
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:10601035
    reference_title: "The homeodomain protein vax1 is required for axon guidance and major tract formation in the developing forebrain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "axons in multiple commissural tracts of the anterior CNS, including the corpus callosum and the hippocampal and anterior commissures, fail to cross the midline"
    explanation: Reports the midline commissural axon guidance failure behind callosal agenesis.
  - reference: PMID:10601035
    reference_title: "The homeodomain protein vax1 is required for axon guidance and major tract formation in the developing forebrain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These axon guidance defects do not result from the death of normally Vax1(+) midline cells but, instead, correlate with markedly diminished expression of attractive guidance cues in these cells."
    explanation: Localizes the defect to loss of guidance-cue expression rather than cell death.
  downstream:
  - target: Agenesis of corpus callosum
    description: >-
      Failure of callosal axons to cross the midline produces agenesis of the
      corpus callosum, reported in the human proband.
    causal_link_type: DIRECT
- name: Failure of Craniofacial Fusion
  role: intermediate
  biological_scale: TISSUE
  description: >-
    The human proband has cleft lip/palate. A craniofacial developmental failure
    is inferred as the proximate cause, but the cached literature does not
    demonstrate a VAX1-dependent palatal/lip fusion mechanism, so this node links
    the lesion to the orofacial phenotype rather than asserting a mechanism.
  biological_processes:
  - preferred_term: roof of mouth development
    term:
      id: GO:0060021
      label: roof of mouth development
    modifier: ABNORMAL
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:22095910
    reference_title: "VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate, and corpus callosum agenesis"
    explanation: Documents the orofacial clefting in the single proband.
  downstream:
  - target: Cleft lip
    description: Orofacial clefting in the proband includes cleft lip.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cleft palate
    description: Orofacial clefting in the proband includes cleft palate.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- name: Microphthalmia
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
  evidence:
  - reference: PMID:22095910
    reference_title: "VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate, and corpus callosum agenesis"
    explanation: Microphthalmia is reported in the proband.
- name: Optic nerve hypoplasia
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Optic nerve hypoplasia
    term:
      id: HP:0000609
      label: Optic nerve hypoplasia
  evidence:
  - reference: PMID:22095910
    reference_title: "VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate, and corpus callosum agenesis"
    explanation: The small optic nerves reported in the proband correspond to optic nerve hypoplasia.
- name: Cleft lip
  category: Craniofacial
  phenotype_term:
    preferred_term: Cleft lip
    term:
      id: HP:0410030
      label: Cleft lip
  evidence:
  - reference: PMID:22095910
    reference_title: "VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate, and corpus callosum agenesis"
    explanation: Cleft lip is reported in the proband.
- name: Cleft palate
  category: Craniofacial
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:22095910
    reference_title: "VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate, and corpus callosum agenesis"
    explanation: Cleft palate is reported in the proband.
- name: Agenesis of corpus callosum
  category: Neurologic
  phenotype_term:
    preferred_term: Agenesis of corpus callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
  evidence:
  - reference: PMID:22095910
    reference_title: "VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate, and corpus callosum agenesis"
    explanation: Corpus callosum agenesis is reported in the proband.
animal_models:
- name: Vax1 homozygous null mouse (basal forebrain and visual system)
  species: Mouse
  genotype: Vax1 targeted null (homozygous knockout)
  publication: PMID:10601036
  description: >-
    Mice homozygous for a targeted Vax1 mutation show dysgenesis of the optic
    nerve, coloboma, basal telencephalon defects and lobar holoprosencephaly,
    with proximal expansion of Pax6 and Rx activity in the visual system. This
    model established the loss-of-function interpretation of the human allele.
  modeled_mechanisms:
  - target: Disrupted Ventral Forebrain and Optic Stalk Patterning
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      The null mouse reproduces the ventral forebrain/visual-system patterning
      defect, including derepression of Pax6 and Rx.
    limitations: >-
      The mouse also shows lobar holoprosencephaly, which was not reported in the
      single human proband; whether this reflects a species difference or the
      limited human phenotyping is unresolved.
    evidence:
    - reference: PMID:10601036
      reference_title: "Vax1, a novel homeobox-containing gene, directs development of the basal forebrain and visual system."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "the absence of Vax1 results in a proximal expansion of the activity of Pax6 and Rx"
      explanation: Reports the molecular patterning signature recapitulated by the model.
  - target: Optic Fissure Closure Failure
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: The null mouse reproduces coloboma (failed optic fissure closure).
    limitations: >-
      Mouse coloboma is read across to the human microphthalmia by phenocopy; the
      human eye was not examined histologically in the cached report.
    evidence:
    - reference: PMID:10601036
      reference_title: "Vax1, a novel homeobox-containing gene, directs development of the basal forebrain and visual system."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice carrying a targeted mutation of Vax1 show dysgenesis of the optic nerve, coloboma, defects in the basal telencephalon, and lobar holoprosencephaly."
      explanation: Reports the ocular defects recapitulated by the model.
- name: Vax1 homozygous null mouse (axon guidance)
  species: Mouse
  genotype: Vax1 targeted null (homozygous knockout)
  publication: PMID:10601035
  description: >-
    Mice lacking Vax1 show failure of the optic disks to close (coloboma) and
    failure of axons in the corpus callosum and the hippocampal and anterior
    commissures to cross the midline, due to diminished expression of attractive
    guidance cues in anterior midline cells.
  modeled_mechanisms:
  - target: Commissural Axon Guidance Failure
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The null mouse reproduces the commissural axon guidance failure that
      underlies corpus callosum agenesis.
    limitations: >-
      The mechanism is demonstrated in mouse; the corresponding human defect is
      inferred from the proband's corpus callosum agenesis by phenocopy.
    evidence:
    - reference: PMID:10601035
      reference_title: "The homeodomain protein vax1 is required for axon guidance and major tract formation in the developing forebrain."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "axons in multiple commissural tracts of the anterior CNS, including the corpus callosum and the hippocampal and anterior commissures, fail to cross the midline"
      explanation: Reports the commissural axon guidance defect recapitulated by the model.
  - target: Optic Fissure Closure Failure
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: The null mouse reproduces failure of optic disk closure (coloboma).
    limitations: >-
      Demonstrated in mouse; read across to the human ocular phenotype by
      phenocopy.
    evidence:
    - reference: PMID:10601035
      reference_title: "The homeodomain protein vax1 is required for axon guidance and major tract formation in the developing forebrain."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "the optic disks fail to close, leading to coloboma and loss of the eye-nerve boundary"
      explanation: Reports the optic fissure closure failure recapitulated by the model.
  - target: Retinal Axon Guidance Failure in the Optic Nerve and Chiasm
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The null mouse reproduces the failure of retinal axons to form an optic
      chiasm, the cellular basis for the small optic nerves.
    limitations: >-
      Demonstrated in mouse; read across to the human optic nerve hypoplasia by
      phenocopy.
    evidence:
    - reference: PMID:10601035
      reference_title: "The homeodomain protein vax1 is required for axon guidance and major tract formation in the developing forebrain."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "retinal axons fail to penetrate the brain in significant numbers and fail to form an optic chiasm"
      explanation: Reports the retinal axon pathfinding failure recapitulated by the model.
differential_diagnoses:
- name: SOX2-Related Anophthalmia/Microphthalmia Syndrome
  description: >-
    SOX2 is the most common cause of severe bilateral anophthalmia/microphthalmia,
    typically from de novo heterozygous loss-of-function variants (autosomal
    dominant), whereas MCOPS11 is autosomal recessive. SOX2 syndrome features
    anophthalmia/microphthalmia with brain, oesophageal and genital anomalies;
    the combination with corpus callosum agenesis and orofacial clefting on a
    recessive background favours VAX1.
- name: OTX2-Related Anophthalmia/Microphthalmia Syndrome
  description: >-
    OTX2, like SOX2, is a leading cause of severe bilateral anophthalmia/
    microphthalmia from de novo heterozygous loss-of-function variants and is a
    principal differential. Mode of inheritance (dominant de novo versus the
    recessive VAX1 genotype) and the specific extraocular profile distinguish the
    two; molecular testing is definitive.
treatments:
- name: Orofacial cleft surgical repair
  description: >-
    Staged surgical repair of the cleft lip and palate, as for orofacial
    clefting of any cause. This is symptomatic management of a structural
    malformation, not a disease-modifying therapy, and no VAX1-specific
    intervention exists.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: orofacial cleft repair
    term:
      id: NCIT:C15329
      label: Surgical Procedure
- name: Genetic counseling
  description: >-
    Counseling for the affected family, including the 25% recurrence risk that
    follows from autosomal recessive inheritance once the biallelic VAX1 genotype
    is known, and the option of carrier and prenatal testing.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
discussions:
- discussion_id: vax1-reproductive-axis-human
  kind: KNOWLEDGE_GAP
  attaches_to:
  - disease#
  prompt: >-
    Do humans with biallelic VAX1 loss of function have
    hypothalamic-pituitary-gonadal (reproductive/endocrine) involvement, as
    predicted by the mouse Vax1 requirement in GnRH neurons?
  rationale: >-
    In mouse, Vax1 is required for GnRH neuron maturation and Gnrh1 expression,
    and its deletion from GnRH neurons causes hypogonadism and infertility; Vax1
    haploinsufficiency causes subfertility and has been proposed as a candidate
    in polygenic idiopathic hypogonadotropic hypogonadism. The single reported
    human MCOPS11 proband is a young child, so reproductive-axis involvement in
    humans has neither been assessed nor excluded. This is a genuine open
    question rather than an established human phenotype, so it is recorded as a
    gap rather than as a phenotype.
  evidence:
  - reference: PMID:27013679
    reference_title: "Deletion of Vax1 from Gonadotropin-Releasing Hormone (GnRH) Neurons Abolishes GnRH Expression and Leads to Hypogonadism and Infertility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Vax1 deletion from GnRH neurons leads to complete infertility in males and females"
    explanation: >-
      Establishes the mouse basis for the open question about reproductive-axis
      involvement in human VAX1 loss of function.
- discussion_id: vax1-holoprosencephaly-human-mouse
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - pathophysiology#Disrupted Ventral Forebrain and Optic Stalk Patterning
  prompt: >-
    Does human biallelic VAX1 loss produce lobar holoprosencephaly, as the Vax1
    null mouse does, or is the human forebrain phenotype restricted to corpus
    callosum agenesis?
  rationale: >-
    The Vax1 null mouse shows lobar holoprosencephaly, a severe ventral forebrain
    malformation, whereas the single human proband is reported with corpus
    callosum agenesis but not holoprosencephaly. Whether this is a true species
    difference in VAX1 forebrain requirement or an artefact of n=1 human
    phenotyping is unresolved and bears on how far the mouse patterning model can
    be read across to human disease.
  evidence:
  - reference: PMID:10601036
    reference_title: "Vax1, a novel homeobox-containing gene, directs development of the basal forebrain and visual system."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice carrying a targeted mutation of Vax1 show dysgenesis of the optic nerve, coloboma, defects in the basal telencephalon, and lobar holoprosencephaly."
    explanation: Reports the mouse holoprosencephaly that is not documented in the human proband.
notes: >-
  Single-family entity: the entire human evidence base is one Egyptian proband
  (Slavotinek et al. 2012). Lump/split: curated as a single-gene leaf DISEASE
  with one conserved pathograph; other syndromic-microphthalmia genes (SOX2,
  OTX2) are related as differentials, not grouped. The craniofacial/cleft branch
  is grounded in the human proband only — the cached mouse abstracts
  (Hallonet 1999, Bertuzzi 1999) do not report cleft palate, so the VAX1-to-cleft
  mechanism is left inferred. The hippocampal and pineal findings mentioned in
  aggregator summaries were not quotable from any verified primary source and
  were deliberately omitted. Mouse GnRH/infertility findings are recorded as a
  KNOWLEDGE_GAP about human reproductive-axis involvement rather than as human
  phenotypes.

📚

References & Deep Research

References

5

PMID:22095910

VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans.

No top-level findings curated for this source.

PMID:10601035

The homeodomain protein vax1 is required for axon guidance and major tract formation in the developing forebrain.

No top-level findings curated for this source.

PMID:10601036

Vax1, a novel homeobox-containing gene, directs development of the basal forebrain and visual system.

No top-level findings curated for this source.

PMID:27013679

Deletion of Vax1 from Gonadotropin-Releasing Hormone (GnRH) Neurons Abolishes GnRH Expression and Leads to Hypogonadism and Infertility.

No top-level findings curated for this source.

PMID:24859618

The genetic architecture of microphthalmia, anophthalmia and coloboma.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Microphthalmia_Syndromic_11 · 2026-10-12T16:28:38Z · View source

De-novo curation of VAX1-related syndromic microphthalmia (MCOPS11, MONDO:0013734). Deep-research report used as leads only (thin: one human discovery paper + mouse models). Human evidence rests on the single Slavotinek 2012 proband (PMID:22095910); pathophysiology chain grounded in Vax1 null mouse papers (PMID:10601036 Hallonet, PMID:10601035 Bertuzzi) and VAX1 DNA-binding transcription factor activity (PMID:27013679 Hoffmann, IN_VITRO); MAC-gene context from review PMID:24859618. VAX1 verified hgnc:12660. 5 phenotypes (microphthalmia, optic nerve hypoplasia, cleft lip, cleft palate, corpus callosum agenesis), all wired into the pathograph. Mouse GnRH/infertility and holoprosencephaly recorded as discussions (KNOWLEDGE_GAP, HUMAN_MODEL_MISMATCH) rather than human phenotypes. Hippocampal/pineal aggregator-summary findings dropped (no quotable primary source). No ClinGen CGGV record for VAX1, so gene_disease_validity omitted. All gates pass: validate-disorders, count-verified-snippets 26/26, validate-terms, check-gene-activity-grounding, check-snippet-length/grading, entity-refs, causal-targets, enum-values, coarse-phenotypes.

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Research report: microphthalmia, syndromic 11 (MCOPS11)

claude-haiku-5-5, claude-sonnet-5-5 8 citations 2026-10-12T15:59:03.057032

I'll start by loading the search tool and confirming the gene and identifiers.

Research report: microphthalmia, syndromic 11 (MCOPS11)

Evidence base and limits. This report rests on one human discovery paper (Slavotinek et al. 2012), the Vax1 knockout mouse papers (1999), and database summaries. The search tools returned abstracts and aggregator pages, not full texts. PMC returned a bot-verification page, so I could not read the Slavotinek full text.

Not verified: anything beyond the abstract-level facts is marked unverified below. That includes the full patient phenotype, population frequencies, and Orphanet and ClinGen status.
Ontology IDs: I give ontology term names only, without CURIEs. Look each one up before binding it; none was looked up in this session.
Missing search results: the searches found no 2023–2024 VAX1 case reports. Variant-level and recent literature are therefore thin.

1. Disease information

Disease: MCOPS11 is a very rare autosomal recessive syndromic microphthalmia caused by loss of function of the homeobox transcription factor VAX1 (10q25.3). Reported features are microphthalmia with small optic nerves, cleft lip and palate, absent corpus callosum, hippocampal malformations and absent pineal gland. The disease description is from Phenodis and Malacards.
Identifiers:
OMIM 614402 (per LOVD).
MONDO:0013734 (taken from a URL in the search results, concept library).
Disease Ontology DOID:0111804 (DO).
Orphanet, ICD-10/11 and MeSH identifiers were not retrieved.
Synonyms: MCOPS11; VAX1 syndromic microphthalmia; microphthalmia, syndromic 11. LOVD also lists the older "MCOPCB11" abbreviation.
Data level: the information comes from an aggregated, literature-derived resource (OMIM) built on a single published proband. It is not EHR-derived.
Note on the 2012 paper's title: it frames the condition as "microphthalmia, corpus callosum agenesis and orofacial clefting".

2. Etiology

Cause: biallelic VAX1 variants. The Disease Ontology gives the material basis as homozygous or compound heterozygous VAX1 mutation. Only one homozygous missense case has been reported in the literature I could access.
Discovery paper: Slavotinek et al. (Hum Mutat 2012;33:364–368, PMID 22095910, record). The authors sequenced the coding exons of VAX1 and VAX2 in 70 patients with anophthalmia/microphthalmia.
Environmental risk and protective factors: none known. No gene–environment interaction data were found.
Related common-variant signal: a VAX1-region locus (10q25.3) is associated with nonsyndromic cleft lip with or without cleft palate.
Mangold et al. (Nat Genet 2010) reported lead SNP rs7078160, combined P = 1.92 × 10⁻⁸. The PMID was not retrieved.
Beaty et al. 2010 flagged VAX1 as approaching genome-wide significance.
A 2012 resequencing study (384 cases, 384 controls) found no significant excess of functional rare variants in cases (p = 0.17).
Replication in Chinese cohorts is inconsistent. The secondary source is an Open Dentistry Journal paper and the others came from search snippets.
This is a susceptibility signal, not MCOPS11 causation. Do not conflate the two.

3. Phenotypes

Source for the main set: Phenodis/Malacards and the Slavotinek abstract. HPO term names are suggestions only.

Phenotype	Suggested HPO term name	Frequency / notes
Microphthalmia (severe, bilateral in the proband, per Phenodis)	Microphthalmia	Present in the single reported proband
Small optic nerves	Optic nerve hypoplasia	Present in the proband
Cleft lip and palate	Cleft lip; Cleft palate	Present in the proband
Absent corpus callosum	Agenesis of corpus callosum	Present in the proband
Hippocampal malformation	Abnormal hippocampus morphology	From Phenodis/OMIM summary; patient-level source unverified
Absent pineal gland	Absent pineal gland (name to be confirmed)	From Phenodis/OMIM summary; unverified

Onset: congenital (inferred from the structural malformations).
Progression: malformations are static. Course and severity data are not available.
Quality of life: no data.
Frequencies: with one reported proband, no population frequencies can be given.
Mouse-derived additional signals (not human phenotypes):
Hypogonadotropic hypogonadism and subfertility appear in mouse Vax1 loss in GnRH neurons and in heterozygotes. They are not documented in MCOPS11 patients.

4. Genetic and molecular information

Gene: VAX1 (ventral anterior homeobox 1), 10q25.3. It encodes a transcription factor that may function in dorsoventral specification of the forebrain (Phenodis). The HGNC ID was not retrieved. In this knowledge base the form would be lowercase hgnc:<n>, to be looked up.
Reported variant: homozygous c.453G>A and c.454C>A (two adjacent substitutions), predicting p.Arg152Ser.
The proband was of Egyptian origin.
The variant lies at an invariant residue of the homeodomain.
It was absent from 96 Egyptian controls.
The authors favoured loss of function, because the phenotype resembles the Vax1 null mouse.
No VAX2 variants were found in the cohort.
In silico predictions, functional assays and ClinVar classification are unverified.
Other variants: GeneBe lists several VAX1 variants of uncertain significance dated 2023–2024 and one benign call in January 2025. These are submissions without case details and are not evidence for MCOPS11.
Modifier genes and epigenetics: none known.
Chromosomal abnormalities: none specific to this disorder.
Origin: germline.

5. Environmental information

No environmental, lifestyle or infectious contributors are documented. Mark these as not applicable or not available.

6. Mechanism / pathophysiology

Causal chain, with inferred steps marked:

A homozygous missense change at an invariant homeodomain residue (p.Arg152Ser) is the initiating lesion.
This is presumed to impair DNA-binding function of the VAX1 homeodomain, which is the authors' loss-of-function interpretation. It is inferred, not demonstrated, because the abstract reports no functional assay.
Loss of VAX1 function disrupts ventral forebrain, optic stalk and optic nerve patterning. In mouse, Vax1 loss expands Pax6 and Rx activity proximally in the optic cup and stalk (Hallonet et al. 1999, PMID 10601036).
Two downstream branches follow:
Eye branch: failed optic fissure and disc closure, optic nerve dysgenesis and coloboma, leading to small eyes and small optic nerves. Mouse data: Bertuzzi et al. 1999 (PMID 10601035) report optic disks that fail to close.
Midline and brain branch: defective axon guidance across midline commissures (corpus callosum, hippocampal and anterior commissures) leading to callosal agenesis, and abnormal basal forebrain development leading to hippocampal and pineal defects. Mouse null data support the commissural defects; the human hippocampal and pineal findings are from summaries only.
A craniofacial branch leads to cleft palate. The mouse null shows cleft palate (Hallonet). The human cleft lip fits with the common-variant association at this locus.
Candidate GO biological processes: forebrain development; optic nerve development; axon guidance; camera-type eye development. Candidate cell types: retinal ganglion cell, optic stalk and nerve glia, neural progenitors. All are to be confirmed against ontologies.
Molecular detail: a later mouse study reports that Vax1 protein is transferred into retinal ganglion cell axons, and that a non-transferring mutant causes slow axon growth, ipsilateral-only projection, reduced visual acuity and abnormal eye-movement responses. This comes from a KAIST research-highlights page and has not been verified against the paper.
Omics, single-cell, spatial and screen data: none found.

7. Anatomical structures affected

Primary: eye (globe, optic nerve), face (lip, palate), brain (corpus callosum, hippocampus, pineal). Suggested UBERON terms: eye, optic nerve, upper lip, palate, corpus callosum, hippocampal formation, pineal body (to be looked up).
Lateralization: the proband's microphthalmia is described as bilateral (Phenodis).
Subcellular: nucleus, as a transcription factor.

8. Temporal development

Onset: congenital and prenatal. The structural defects arise in early forebrain and eye development.
Progression and remission: nothing documented, and nothing is expected for static malformations.
Critical period: embryonic optic stalk and fissure closure, inferred from the mouse work.

9. Inheritance and population

Inheritance: autosomal recessive (OMIM, per Phenodis).
Prevalence and incidence: not available. Only one reported family is known to me.
Consanguinity, founder effect, sex ratio, geography: the single proband was Egyptian. Parental consanguinity is unverified. No other population data exist.
Carrier frequency: not assessed.

10. Diagnostics

Approach: the literature gives no dedicated protocol, so the following is general reasoning, not a sourced guideline.
Include VAX1 on anophthalmia/microphthalmia gene panels and in exome or genome sequencing.
Use brain MRI to look for callosal agenesis, hippocampal and pineal abnormalities, and optic nerve size.
Do detailed ophthalmic and orofacial assessment.
Differential: other syndromic microphthalmias with callosal or midline defects. Examples: SOX2, OTX2, BMP4, STRA6 and VSX2-related disease (named from general knowledge, unverified here).
Screening: none established.

11. Outcome and prognosis

No data. Expected issues, inferred and not documented: visual impairment, feeding and speech problems from clefting, and neurodevelopmental effects of callosal and hippocampal anomalies.

12. Treatment

No disease-specific therapy. Management is supportive and surgical: cleft repair, ophthalmic and low-vision care, developmental support.
No pharmacogenomics, gene therapy or clinical trials were identified.
Suggested NCIT intervention terms, to be looked up: Surgical Procedure, Supportive Care, Rehabilitation, Genetic Counseling.

13. Prevention

Genetic counseling with 25% recurrence risk for carrier parents follows from autosomal recessive inheritance. This is an inference, not a sourced statement.
Prenatal and preimplantation testing are possible once the familial variants are known.
No primary prevention measures are known.

14. Other species

Natural disease: nothing found. I did not search OMIA.
Orthologs exist in mouse; other species were not checked.

15. Model organisms

Mouse Vax1 null (Hallonet et al. 1999, PMID 10601036):
Optic nerve dysgenesis, coloboma, basal telencephalon defects and lobar holoprosencephaly.
Craniofacial malformations including cleft palate, and growth defects.
Evidence type: MODEL_ORGANISM.
Mouse Vax1 null, axon guidance (Bertuzzi et al. 1999, PMID 10601035):
Optic disks fail to close, giving coloboma.
Retinal axons fail to form an optic chiasm.
Axons of the corpus callosum and the hippocampal and anterior commissures fail to cross the midline.
Fidelity to human disease:
The mouse recapitulates the eye, nerve, midline and cleft features. This is why the human variant was interpreted as loss of function.
It also shows holoprosencephaly, which was not reported in the human proband. This is a possible human–model mismatch.
Vax2: homozygous null mice have rare, milder colobomas, and Vax1/Vax2 double mutants have severe, fully penetrant colobomas (secondary, from the Slavotinek-related summary).
Other mouse findings:
Conditional Vax1 deletion in GnRH neurons gave a 99% drop in GnRH expression, with delayed puberty, hypogonadism and infertility.
Heterozygotes showed reduced sperm motility and subfertility.
These come from PMC4804008, PMC5287408 and an unnamed dissertation; I did not read the primary text.
Zebrafish and other models were not searched. ZFIN lists the Slavotinek paper.

Key citations

Slavotinek A et al. Hum Mutat 2012;33:364–368. PMID 22095910, DOI 10.1002/humu.21658. ZFIN record.
Hallonet M et al. Genes Dev 1999;13:3106. PMID 10601036. Abstract.
Bertuzzi S et al. Genes Dev 1999. PMID 10601035.
Mangold E et al. Nat Genet 2010;42:24–26 (VAX1-region cleft lip locus). PMID not retrieved.
Database summaries: Phenodis, Malacards, LOVD, Disease Ontology.

Items to verify before curation

Full text of PMID 22095910: exact phenotype, consanguinity, and source of the hippocampal and pineal findings.
Exact HPO, UBERON, GO, CL and NCIT CURIEs.
ClinVar and ClinGen status for VAX1, and Orphanet and GeneReviews coverage.
Any further VAX1 families reported after 2012.
PMIDs for Mangold 2010 and Beaty 2010.
Whether the mouse holoprosencephaly is a genuine mismatch with the human phenotype.

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	6
Resolved	6
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	6
On topic	3
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	2
Resolved	2
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0

Every term resolved, and every label the report gave matched.

microphthalmia, syndromic 11

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Deep Research

Research report: microphthalmia, syndromic 11 (MCOPS11)

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism / pathophysiology

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species

15. Model organisms

Key citations

Items to verify before curation

Reference Validation

Term Validation