👪

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 SUPPORT 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

11

SOX2-related microphthalmia/anophthalmia with coloboma

SOX2 hgnc:11195

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

OTX2 hgnc:8522

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 hgnc:8620

PAX6 haploinsufficiency, classically aniridia, can present with microphthalmia and colobomatous defects within the anterior-segment and MAC spectrum.

MAB21L2-related microphthalmia with coloboma

MAB21L2 hgnc:6758

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. Note that the recurrent p.Arg51Cys allele causes a distinct *syndromic* oculo-skeletal disorder with rhizomelic limb shortening and intellectual disability, curated separately as Colobomatous_Microphthalmia-Rhizomelic_Dysplasia_Syndrome and listed in the ISDS skeletal nosology; this entry stays scoped to the isolated MAC presentation and therefore carries no ISDS assignment.

FOXE3-related microphthalmia with coloboma

FOXE3 hgnc:3808

FOXE3 variants cause anterior-segment dysgenesis, microphthalmia, and coloboma; bilateral sensorineural hearing loss reported as a novel association.

ALDH1A3-related microphthalmia/anophthalmia with coloboma

ALDH1A3 hgnc:409

Recessive ALDH1A3 variants disrupt retinaldehyde dehydrogenase / retinoic acid synthesis, causing autosomal recessive microphthalmia/anophthalmia.

Microphthalmia/coloboma 11 — FZD5 (OMIM:620731) MONDO:0958239

FZD5 hgnc:4043

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. This is the MCOPCB11 locus, MONDO:0958239 / OMIM:620731.

Show evidence (2 references)

PMID:39503780 SUPPORT BACKGROUND 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."

Supports the gene assignment for this numbered locus and the isolated / complex split the description records.

PMID:39503780 SUPPORT PRIMARY RESULT In Vitro

"in vitro TOPFlash assays revealed that the missense variant only caused partial loss-of-function, behaving as a hypomorphic mutation"

The functional basis for calling the recessive allele hypomorphic rather than dominant-negative.

Microphthalmia with coloboma 7 — ABCB6 (OMIM:614497) MONDO:0013783

ABCB6 hgnc:47

Autosomal dominant coloboma attributed to ABCB6, an ATP-binding cassette transporter expressed in the retina and retinal pigment epithelium, where it localizes to the endoplasmic reticulum and Golgi. The original report combined positional cloning in one Chinese family with a screen of 116 sporadic cases of microphthalmia with coloboma, isolated coloboma and aniridia. ClinGen's General Inborn Errors of Metabolism expert panel nonetheless classifies ABCB6 for this disease as Limited, so the row is curated with that classification stated. The zebrafish knockdown and rescue experiment behind the loss-of-function reading is cited on the ABCB6 record in the genetic section. The gene's better-attested disease is the pigmentary skin disorder dyschromatosis universalis hereditaria 3 (MONDO:0014169), which ClinGen rates Moderate; nothing about pigmentary skin disease is claimed here.

Show evidence (5 references)

PMID:22226084 SUPPORT PRIMARY RESULT Human Clinical

"Using a positional cloning approach, we identified a mutation in the ATP-binding cassette (ABC) transporter ABCB6 in a Chinese family affected by autosomal-dominant coloboma."

The gene-discovery report and the source of the dominant inheritance stated here.

PMID:22226084 SUPPORT PRIMARY RESULT Human Clinical

"Sequence analysis was performed on the ABCB6 exons from 116 sporadic cases of microphthalmia with coloboma (MAC), isolated coloboma, and aniridia, and an additional mutation (A57T) was identified in three patients with MAC."

The screen this row's description reports, and what extends the association beyond the index family to sporadic microphthalmia-with-coloboma cases - which is why the locus sits in this entry rather than in an isolated-coloboma entry.

PMID:22226084 SUPPORT PRIMARY RESULT In Vitro

"Immunostaining of transiently transfected, Myc-tagged ABCB6 in retinal pigment epithelial (RPE) cells showed that it localized to the endoplasmic reticulum and Golgi apparatus of RPE cells."

Sources the subcellular localization this row's description states.

+ 2 more references

Microphthalmia with coloboma 9 — TENM3 (OMIM:615145) MONDO:0014059

TENM3 hgnc:29944

Autosomal recessive colobomatous microphthalmia reported in a single consanguineous family with third-cousin parents and two affected children, in which exome and autozygome analysis found a null allele of TENM3. HGNC records ODZ3 as the previous symbol, which is the name the discovery report uses. The committed ClinGen gene-validity snapshot carries no assertion for TENM3 under either symbol, and no independent family is cited here, so the assertion rests on that one pedigree.

Show evidence (2 references)

PMID:22766609 SUPPORT PRIMARY RESULT Human Clinical

"Exome and autozygome analysis identified a null mutation in ODZ3, one of four vertebrate orthologs of odz in Drosophila."

The gene-discovery report, using the gene's previous symbol.

PMID:22766609 SUPPORT PRIMARY RESULT Human Clinical

"we enrolled a family that consists of third-cousin parents and two children with isolated colobomatous microphthalmia"

The single pedigree the assertion rests on, and the reason the description states its breadth explicitly.

Microphthalmia with coloboma 10 — RBP4 (OMIM:616428) MONDO:0014635

RBP4 hgnc:9922

Dominant eye malformation caused by RBP4 missense variants, with a mode of inheritance unlike anything else in this entry. RBP4 encodes serum retinol binding protein, which delivers retinol from hepatic stores to the placenta and the fetal eye. The disease alleles bind retinol poorly but bind the cell surface receptor STRA6 more tightly, so the mutant protein occupies STRA6 without delivering its cargo. Because a transmitting mother's circulating mutant protein blocks retinol delivery at the placenta as well as in the fetus, penetrance is incomplete and maternal transmission raises the probability that an allele-carrying fetus is affected — a maternal effect the authors distinguish from imprinting and from oocyte-derived mRNA. The separate recessive RBP4 phenotype, in which serum RBP4 is undetectable and the result is a progressive retinal dystrophy rather than a malformation, is curated as Progressive_Retinal_Dystrophy_Due_To_Retinol_Transport_Defect.

Show evidence (4 references)

PMID:25910211 SUPPORT PRIMARY RESULT Human Clinical

"We identified missense mutations in RBP4, encoding serum retinol binding protein, in three families with eye malformations of differing severity, including bilateral anophthalmia."

The gene-discovery report and the source of the phenotypic range stated here.

PMID:25910211 SUPPORT BACKGROUND Human Clinical

"RBP normally delivers retinol from hepatic stores to peripheral tissues, including the placenta and fetal eye."

The normal function this row's description states, and the reason a transmitting mother's protein can act at the placenta.

PMID:25910211 SUPPORT PRIMARY RESULT Human Clinical

"The mutant phenotypes exhibit dominant inheritance, but incomplete penetrance. Maternal transmission significantly increases the probability of phenotypic expression."

The inheritance pattern this row records, including the maternal effect that separates it from ordinary autosomal dominant transmission.

+ 1 more reference

Microphthalmia/coloboma 13 (IHH enhancer variant hosted in an NHEJ1 intron) MONDO:0975809

IHH hgnc:5956

Autosomal recessive isolated MAC reported in two consanguineous Jewish Iranian pedigrees from the Mashhad region. The homozygous founder allele is a deep intronic single-nucleotide variant in NHEJ1 (NM_024782.2:c.588+18131A>G) that is not predicted to affect NHEJ1 itself: it sits inside "i8", a conserved enhancer of the neighbouring gene IHH. Transgenic mouse reporter assays and chicken ATAC-seq/electroporation show that i8 drives expression in the developing eye and that the patient allele abolishes that eye-specific activity, so the gene whose expression is disturbed is IHH and NHEJ1 is only the element's host. Ocular features range from optic disc coloboma to microphthalmia and anophthalmia and differ between the two eyes of the same patient; no skeletal or cranial abnormality was reported, even though the same enhancer cluster is required for IHH expression in limb and skull.

Show evidence (3 references)

PMID:37580330 SUPPORT Human Clinical

"a spectrum of isolated ocular manifestations, ranging from a milder phenotype of optic nerve coloboma to a severe phenotype of microphthalmia and even anophthalmia"

Defines the subtype's ocular spectrum in the two reported pedigrees.

PMID:37580330 SUPPORT Human Clinical

"None of the affected individuals had skeletal or cranial abnormalities."

Supports classifying this subtype as isolated rather than syndromic MAC, despite the enhancer cluster's known skeletal role.

PMID:37580330 SUPPORT Human Clinical

"an intronic founder variant in NHEJ1, not predicted to affect NHEJ1"

States that the causal allele is not an NHEJ1 functional variant, which is why this subtype is named for the IHH enhancer rather than for NHEJ1.

?

Discussions and Knowledge Gaps

1

Is IHH expression actually reduced in the human developing eye in microphthalmia/coloboma 13, or is the reduction inferred entirely from mouse and chicken assays of the enhancer?

HUMAN MODEL MISMATCH OPEN mcopcb13_ihh_enhancer_human_evidence

Attached to

pathophysiology#IHH i8 enhancer disruption pathophysiology#Reduced IHH signaling to periocular mesenchyme and RPE

Every step from the variant to reduced IHH output rests on non-human systems: a transgenic mouse reporter assay at E11.5, chicken RPE ATAC-seq and electroporation, and mouse genetics for the requirement of Ihh in RPE and scleral mesenchyme. No measurement of IHH transcript or protein in human ocular tissue from an affected individual has been reported, and the variant has been described in two related consanguineous pedigrees from one founder community, with no independent family reported since. The translational question is sharpened rather than settled by the human phenotype: the same enhancer cluster is required for IHH expression in limb and skull, yet the affected individuals have no skeletal or cranial abnormality, so either the element's eye and limb activities are separable sub-modules or the human allele spares the limb-active part. Neither possibility has been tested.

This is recorded as a model-to-human translation question rather than as an absent mechanism. The enhancer's eye activity, the allele's effect on it, and the dependence of periocular mesenchyme and RPE on Ihh are each supported by experiments; what is missing is a human tissue measurement and a second, unrelated family.

⚙

Pathophysiology

7

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

ABCB6 hgnc:47

Closure of optic fissure GO:0061386 ↓ DECREASED Camera-type eye morphogenesis GO:0048593 ⚠ ABNORMAL

Optic fissure UBERON:0005412 Optic cup UBERON:0003072

Animal models

Homozygous 7.8 kb deletion in NHEJ1 intron 4 (Collie eye anomaly allele) Dog Dog partially recapitulates The affected dog shows optic nerve head coloboma with choroidal hypoplasia, so it reproduces the failure-of-optic-fissure-closure outcome after a lesion in the same intronic enhancer cluster. It is partial because the canine disease is confined to the posterior pole and does not include the microphthalmia or anophthalmia seen in MCOPCB13.

Downstream

Coloboma Incomplete apposition and fusion of the optic-fissure margins leaves the persistent ocular cleft that defines coloboma.

Optic disc coloboma The optic fissure runs up to the optic nerve head, so failure of fusion at its most proximal extent leaves a colobomatous defect of the optic disc. This is the mildest end of the MCOPCB13 spectrum, present even in affected individuals whose globe size is normal.

Show evidence (3 references)

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.

PMID:22226084 SUPPORT PRIMARY RESULT Human Clinical

"Our results demonstrate that ABCB6 mutations cause ocular coloboma."

Places ABCB6, bound on this node, upstream of the fissure-closure failure that this node models.

PMID:22226084 SUPPORT BACKGROUND Human Clinical

"Ocular coloboma is a developmental defect of the eye and is due to abnormal or incomplete closure of the optic fissure."

Independent statement of this node's own mechanism, from the report that assigns ABCB6 to it.

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

SOX2 hgnc:11195 OTX2 hgnc:8522 PAX6 hgnc:8620 MAB21L2 hgnc:6758 FOXE3 hgnc:3808 TENM3 hgnc:29944 ALDH1A3 hgnc:409

Eye development GO:0001654 ⚠ ABNORMAL Eye morphogenesis GO:0048592 ⚠ ABNORMAL Camera-type eye morphogenesis GO:0048593 ⚠ ABNORMAL

Eye UBERON:0000970

Downstream

Failure of optic fissure closure Optic-cup invagination and ventral patterning precede fissure apposition; disturbed cup geometry can therefore compromise the later closure step.

Microphthalmia Partial failure of globe morphogenesis produces a small globe.

Anophthalmia Severe early morphogenesis failure can prevent globe formation.

Show evidence (4 references)

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.

PMID:40038803 SUPPORT Human Clinical

"Chromosomal aberrations and mutations in genes such as PAX6, SOX2, OTX2, and CHD7 are contributors."

Names PAX6, SOX2 and OTX2 - three of the genes bound on this node - as contributors to the spectrum whose developmental lesion this node models.

PMID:36192130 SUPPORT PRIMARY RESULT Human Clinical

"novel variants in six known MAC genes (SOX2, KMT2D, MAB21L2, ALDH1A3, BCOR and FOXE3)"

Names MAB21L2 and FOXE3, also bound here, among the solved genes of a prospective microphthalmia-anophthalmia-coloboma cohort.

+ 1 more reference

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.

RBP4 hgnc:9922

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 (3 references)

PMID:39296666 SUPPORT Human Clinical

"medications are specifically known to alter eye morphogenesis during embryonic development"

Review evidence that pathway-level (including retinoid) perturbation alters eye morphogenesis, supporting RA signaling as a convergent MAC mechanism (human teratology review).

PMID:25910211 SUPPORT BACKGROUND Human Clinical

"RBP normally delivers retinol from hepatic stores to peripheral tissues, including the placenta and fetal eye."

Places RBP4, bound on this node, at the retinol-delivery step that supplies the substrate for local retinoic acid synthesis.

PMID:25910211 SUPPORT PRIMARY RESULT In Vitro

"The disease mutations greatly reduce retinol binding to RBP, yet paradoxically increase the affinity of RBP for its cell surface receptor, STRA6."

The lesion by which RBP4 variants reduce retinol supply to this pathway, which is what binding the gene on this node asserts.

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.

FZD5 hgnc:4043

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.

MAB21L2 hgnc:6758 OTX2 hgnc:8522

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.

IHH i8 enhancer disruption

In microphthalmia/coloboma 13 the initiating lesion is a homozygous deep intronic substitution, NHEJ1 NM_024782.2:c.588+18131A>G, that falls inside a conserved non-coding element of the IHH enhancer cluster named "i8". The element was originally characterised as a limb enhancer; the human variant lies at a position overlapped by a predicted transcription-factor binding motif and by the summit of the chromatin-accessibility peak seen in developing chicken retinal pigment epithelium. Wild-type i8 drives reporter expression in the eye of transgenic mouse embryos at E11.5 and the patient allele does not, so the molecular consequence is loss of eye-specific enhancer output rather than any change to NHEJ1 protein. Because the same cluster remains able to support IHH expression in limb and skull, the expression defect is restricted to a subset of tissues.

IHH hgnc:5956

Downstream

Reduced IHH signaling to periocular mesenchyme and RPE Loss of eye-specific enhancer output lowers IHH expression in the choroid-adjacent cells that supply hedgehog signal to the periocular mesenchyme and retinal pigment epithelium.

Show evidence (3 references)

PMID:37580330 SUPPORT Human Clinical

"The human NHEJ1 intronic variant lies within a known specifically limb-development enhancer of a neighboring gene, Indian hedgehog (Ihh), known to be involved in eye development in mice and chickens"

Places the patient variant inside a characterised IHH enhancer rather than in NHEJ1 regulatory or coding sequence.

PMID:37580330 SUPPORT Model Organism

"the mutated version of this sequence, with the same single-nucleotide variant found in our patients, did not consistently drive eye expression in transgenic mice during embryogenesis at E11.5"

Transgenic reporter result establishing that the patient allele abolishes the element's eye-specific enhancer activity.

PMID:37580330 SUPPORT Model Organism

"a sharp accessibility peak coincided with the conserved i8 enhancer region"

Chicken RPE ATAC-seq shows i8 is an accessible regulatory element during the window in which the optic fissure is still open.

Reduced IHH signaling to periocular mesenchyme and RPE

IHH is made by non-pigmented cells of the developing choroid next to the retinal pigment epithelium and acts on the periocular mesenchyme and the RPE itself, where it is required for normal RPE pigmentation and for the mesenchymal condensation that forms the sclera. Reduced hedgehog input to that compartment disturbs the retina-periocular mesenchyme interaction on which optic fissure closure depends, which is how a regulatory lesion at the IHH locus reaches the same final common pathway as the coding MAC genes.

Retinal pigment epithelial cell CL:0002586

Smoothened signaling pathway GO:0007224 ↓ DECREASED

Retinal pigment epithelium UBERON:0001782

Downstream

Failure of optic fissure closure Deprived of hedgehog input, the periocular mesenchyme cannot support the retina-mesenchyme interaction that completes fissure closure.

Disrupted optic-cup and globe morphogenesis The same signaling loss disturbs RPE differentiation and scleral condensation, feeding the shared globe-morphogenesis defect and the microphthalmia/anophthalmia end of the spectrum.

Show evidence (3 references)

PMID:18582859 SUPPORT Model Organism

"Ihh is required for the normal pigmentation pattern of the RPE and the condensation of mesenchymal cells to form the sclera"

Mouse genetics establishing that the RPE and periocular/scleral mesenchyme depend on Ihh signal, the compartment the enhancer lesion deprives.

PMID:37580330 SUPPORT BACKGROUND Model Organism

"The retina-POM interaction is fundamental to fissure closure"

States the step that connects reduced periocular hedgehog signaling to failure of optic fissure closure. The sentence restates established mouse developmental biology in the citing paper's introduction.

PMID:37580330 SUPPORT BACKGROUND Model Organism

"haploinsufficiency of Ihh leads to the "Creeper" phenotype in chicken, with microphthalmic and colobomatous eyes"

Reduced Ihh dosage alone produces microphthalmia and coloboma in chicken, supporting the direction of this node. Quoted from the citing paper's background rather than from its own experiments.

⬡

Pathograph

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

●

Phenotypes

13

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 11

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 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.

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.

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.

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.

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 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.

Optic disc coloboma HP:0000588

Show evidence (1 reference)

PMID:37580330 SUPPORT Human Clinical

"Optic nerve coloboma OU. Very high myopia OS>OD. Retinal atrophy OU. Nystagmus OU."

Table 1 entry recording bilateral optic nerve coloboma in an affected individual of pedigree 2.

High myopia HP:0011003

Show evidence (1 reference)

PMID:37580330 SUPPORT Human Clinical

"High myopia with myopic chorioretinal degeneration and retinal tears OU."

Table 1 entry recording bilateral high myopia with its chorioretinal consequences.

Nystagmus HP:0000639

Show evidence (1 reference)

PMID:37580330 SUPPORT Human Clinical

"Strabismus (esotropia) OS. Nystagmus OU."

Table 1 entry recording bilateral nystagmus alongside strabismus.

Strabismus HP:0000486

Show evidence (2 references)

PMID:37580330 SUPPORT Human Clinical

"Nuclear cataract OU. Strabismus OS, nystagmus OU."

Table 1 entry for individual VI-7 of pedigree 1, recording left-sided strabismus.

PMID:37580330 SUPPORT Human Clinical

"Strabismus (esotropia) OS. Nystagmus OU."

A second tabulated individual with left esotropia, which is what makes this a recurrent rather than a singleton feature of the subtype.

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.

🧬

Genetic Associations

11

SOX2 (Causal dominant variant (often de novo))

Gene: SOX2 hgnc:11195 gene page

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 gene page

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 gene page

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 gene page

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 gene page

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 gene page

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.

ABCB6 (Causal dominant variant, ClinGen Limited)

Gene: ABCB6 hgnc:47 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:22226084 SUPPORT PRIMARY RESULT Human Clinical

"Our results demonstrate that ABCB6 mutations cause ocular coloboma."

The discovery report's own causal conclusion.

PMID:22226084 SUPPORT PRIMARY RESULT Model Organism

"The knockdown phenotype can be corrected with coinjection of the wild-type, but not mutant, ABCB6 mRNA, suggesting that the phenotypes observed in zebrafish are due to insufficient abcb6 function."

The rescue experiment behind the loss-of-function reading, and the only functional support for the association.

CGGV:assertion_45ec3fba-48fd-4bf4-b865-2c2d7216e8eb-2024-04-26T180000.000Z SUPPORT Other

The ClinGen classification and date quoted in the notes.

TENM3 (Causal recessive null variant in a single consanguineous family)

Gene: TENM3 hgnc:29944 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:22766609 SUPPORT PRIMARY RESULT Human Clinical

"Exome and autozygome analysis identified a null mutation in ODZ3, one of four vertebrate orthologs of odz in Drosophila."

The gene-discovery report, and the source of the ortholog statement in the notes.

PMID:22766609 SUPPORT PRIMARY RESULT Human Clinical

"Our data highlight a role for ODZ3 in the early development of the human eye."

The authors' own conclusion, which is a role claim rather than an established gene-disease assertion.

RBP4 (Causal dominant-negative variant with incomplete penetrance and a maternal effect)

Gene: RBP4 hgnc:9922 gene page relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:25910211 SUPPORT PRIMARY RESULT Human Clinical

"We identified missense mutations in RBP4, encoding serum retinol binding protein, in three families with eye malformations of differing severity, including bilateral anophthalmia."

The gene-discovery report and the range of severity this record covers.

PMID:25910211 SUPPORT PRIMARY RESULT In Vitro

"The disease mutations greatly reduce retinol binding to RBP, yet paradoxically increase the affinity of RBP for its cell surface receptor, STRA6."

The two biochemical changes the dominant-negative mechanism in the notes rests on.

PMID:25910211 SUPPORT PRIMARY RESULT Human Clinical

"These findings establish a previously uncharacterized mode of maternal inheritance, distinct from imprinting and oocyte-derived mRNA, and define a group of hereditary disorders plausibly modulated by dietary vitamin A."

The authors' framing of the maternal effect, which the notes reports as their claim rather than as settled nosology.

IHH (Causal non-coding regulatory variant in an IHH enhancer hosted by an NHEJ1 intron)

Gene: IHH hgnc:5956 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Affected regions (reference genome)

IHH enhancer i8 2q35 enhancer

Within gene: NHEJ1 hgnc:25737

A conserved non-coding element of the IHH enhancer cluster, named i8 when the cluster was characterised in limb development, lying within an intron of NHEJ1 on the reference genome. The relationship recorded here locates the element; it does not assert that NHEJ1 is regulated by it or that NHEJ1 sequence function is disturbed.

Show evidence (3 references)

PMID:37580330 SUPPORT Human Clinical

"a MAC disease-associated 0.5 Mb genomic locus on chromosome 2q35 (maximal LOD score 6.8)"

Linkage result establishing the 2q35 locus that contains the IHH enhancer cluster and NHEJ1.

PMID:37580330 SUPPORT Model Organism

"this variant is within an Ihh enhancer that drives gene expression in the developing eye and that the identified variant affects this eye-specific enhancer activity"

Functional result identifying IHH as the gene whose regulation is disturbed, which is the basis for recording IHH rather than NHEJ1 here.

CGGV:assertion_765b118e-c60a-4696-b401-f63b3349d6d2-2021-05-20T151233.276Z NO_EVIDENCE Other

Cited because it is the assertion readers will find when they look NHEJ1 up, and it is about a different disease. ClinGen's only curated NHEJ1 gene-disease relationship is Cernunnos-XLF deficiency; it says nothing either way about microphthalmia or coloboma, so it neither supports nor refutes this record.

Variants (1)

NHEJ1 NM_024782.2:c.588+18131A>G

Gene: NHEJ1 hgnc:25737 Regulatory target: IHH hgnc:5956 single nucleotide variant mLOE

Genomic context: intron

Homozygous founder substitution reported in two consanguineous Jewish Iranian pedigrees, absent from gnomAD and from 87 ethnically matched controls, and submitted to ClinVar as SCV002769719. The coordinates lie in NHEJ1 intron sequence and the allele is not predicted to alter NHEJ1 splicing or protein. Expression loss is classified mLOE rather than LOE because the affected individuals have no skeletal or cranial phenotype, so IHH expression driven by the rest of the cluster is evidently retained outside the eye.

Functional effects

ENHANCER

Wild-type i8 drives reporter expression in the developing eye of transgenic mouse embryos and the patient allele does not.

Mechanism: Loss of eye-specific enhancer activity; the substituted base sits at a predicted transcription-factor binding motif and at the summit of the chromatin-accessibility peak marking the element in developing retinal pigment epithelium.

Developmental stage: Embryonic eye morphogenesis, before optic fissure closure (mouse E11.5; chicken Hamburger-Hamilton stages 24-26).

Show evidence (3 references)

PMID:37580330 SUPPORT Human Clinical

"NHEJ1 (NM_024782.2): c.588+18131 A > G (NG_007880.1: g.37317 A > G), submitted to ClinVar (SCV002769719), has no reported frequency in gnomAD"

Gives the variant's nomenclature, its ClinVar submission, and its absence from population data.

PMID:37580330 SUPPORT Human Clinical

"RFLP screening of 87 ethnically matched control samples identified no other individuals heterozygous or homozygous for this variant"

Ancestry-matched control screening supporting the allele's rarity in the founder population.

PMID:37580330 SUPPORT Model Organism

"the summit of the observed i8 peak overlaps with the conserved PAX4 binding motif and the orthologous site of the c.588+18131A > G variant"

Locates the substituted base at the accessibility summit and a predicted transcription-factor motif, which is the proposed molecular mechanism.

💊

Medical Actions

3

Genetic counseling

Category: Counseling / Informational 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 Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Surgical interventions in colobomatous microphthalmia include cataract surgery / lensectomy and vitreoretinal surgery for coloboma-associated retinal detachment, with management individualized by visual potential.

Mechanism Target:

Disrupted optic-cup and globe morphogenesis — Addresses the structural consequences of the morphogenetic defect, and in the anophthalmic socket supports orbital growth. It does not act on optic fissure closure, which has already failed in utero.

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 Ontology label: Supportive Care NCIT:C15747

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.

Mechanism Target:

Disrupted optic-cup and globe morphogenesis — Addresses the visual impairment resulting from the malformed globe. Purely supportive.

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 development"

Teratology review identifying medications (including retinoids) that alter eye morphogenesis.

Mechanism Target:

TRIGGERS Retinoic acid signaling disruption — Retinoid drugs act on the very signalling pathway this node names, so the exposure perturbs retinoic acid signalling directly rather than through an intermediate.

Show evidence (1 reference)

PMID:3162101 SUPPORT Human Clinical

"The malformations included microtia/anotia (15 infants), micrognathia (6), cleft palate (3), conotruncal heart defects and aortic-arch abnormalities (8), thymic defects (7), retinal or optic-nerve abnormalities (4), and central nervous system malformations (18)."

Isotretinoin is a retinoic acid analogue, and human pregnancies exposed to it produced a characteristic malformation pattern that includes ocular defects. Because retinoids act as ligands of the retinoic acid receptors, the exposure perturbs the signalling this node names directly rather than through an intermediate.

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.

Mechanism Target:

PREDISPOSES Failure of optic fissure closure — Groups several unrelated environmental contributors, including gestational infection and maternal vitamin A deficiency, whose common feature is raising the chance that fissure closure fails rather than a shared mechanism.

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."

Names gestational infections and maternal vitamin A deficiency among environmental contributors to the malformation, a heterogeneous set of risk factors rather than one mechanism.

🔬

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.

🐁

Animal Models

1

Homozygous 7.8 kb deletion in NHEJ1 intron 4 (Collie eye anomaly allele) Dog Naturally occurring

Collie eye anomaly is a naturally occurring autosomal recessive canine ocular malformation - choroidal hypoplasia with optic nerve head coloboma - that maps to a homozygous 7.8 kb deletion inside an intron of the canine NHEJ1 orthologue. The human MCOPCB13 report placed that canine deletion on the human genome and found it removes a different member of the same IHH enhancer cluster, i9, where the human variant disrupts i8. The dog is therefore a natural experiment in the same enhancer cluster, at a neighbouring element, with a lesion of a different class.

Species

Dog

Genotype

Homozygous 7.8 kb deletion in NHEJ1 intron 4 (Collie eye anomaly allele)

Publication

PMID:17916641

Pathograph links

Failure of optic fissure closure partially recapitulates fidelity: moderate observes: tissue The affected dog shows optic nerve head coloboma with choroidal hypoplasia, so it reproduces the failure-of-optic-fissure-closure outcome after a lesion in the same intronic enhancer cluster. It is partial because the canine disease is confined to the posterior pole and does not include the microphthalmia or anophthalmia seen in MCOPCB13.

Limitations: The canine lesion is a 7.8 kb deletion of i9, not the human single nucleotide substitution in i8, so it does not model the human allele. The canine deletion's own causal status is contested: it is discordant with the phenotype in some breeds and populations, where it behaves as a linked marker rather than the causal variant. IHH has not been shown to be the canine target; the 2007 report describes the deleted sequence as a conserved protein-binding domain without naming a regulated gene.

Divergences from the human mechanism

cause unrepresented qualifying

The element disrupted is i9 in the dog and i8 in the human patients, and the canine lesion is a 7.8 kb deletion rather than a single nucleotide substitution. These are separate enhancers of the same cluster, so the MCOPCB13 allele is not encoded in this model and the dog does not report on the activity of the element that is lesioned in MCOPCB13.

species mismatch qualifying

Optic fissure closure is read out in the canine eye. Dogs have no macula and a tapetal fundus, and the canine phenotype is choroidal hypoplasia with optic nerve head coloboma rather than the microphthalmia and anophthalmia that dominate the human pedigrees, so the severity and distribution of the human malformation are not reproduced.

Show evidence (3 references)

PMID:17916641 SUPPORT Model Organism

"Sequence analysis revealed that all affected dogs share a homozygous deletion of 7.8 kb in the NHEJ1 gene. This intronic deletion spans a highly conserved binding domain to which several developmentally important proteins bind."

Establishes the canine lesion as a deletion of conserved regulatory sequence inside an NHEJ1 intron rather than an NHEJ1 coding lesion.

+ 2 more references

Show evidence (1 reference)

PMID:28702949 REFUTE Model Organism

"Collection of ONH coloboma-affected NSDTR showed lack of concordance of the NHEJ1 intronic deletion with ONH coloboma"

A second breed in which optic nerve head coloboma does not track with the deletion, recorded here so the cross-species argument is not read as stronger than it is.

{ }

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. The MCOPCB13 arm (MONDO:0975809, OMIM 620968) is curated here as the
  IHH-Enhancer-MCOPCB13 subtype rather than as its own disease entry: its MONDO
  parent is this entry's own term, its clinical picture is isolated MAC
  indistinguishable from the rest of the spectrum, and both this file and
  Isolated_Anophthalmia-Microphthalmia_Syndrome already state that the numbered
  MCOPCB loci belong here. The stub for it named NHEJ1 as the causal gene;
  that is a positional artifact of where the variant's coordinates fall, and
  the gene whose expression is disturbed is IHH. NHEJ1's own established
  disease is Cernunnos-XLF deficiency, curated separately as
  Cernunnos-XLF_deficiency, and nothing about DNA double-strand-break repair is
  claimed here.

  MCOPCB SERIES RECONCILIATION (OLS4, 2026-09-25). MONDO:0000170 has twelve
  hierarchical descendants, the numbered MCOPCB loci 1 to 11 and 13; MONDO has
  no MCOPCB12 term. Five carry a causal gene edge and are curated here as
  gene-bound subtype rows: MCOPCB7 (MONDO:0013783, ABCB6), MCOPCB9
  (MONDO:0014059, TENM3), MCOPCB10 (MONDO:0014635, RBP4), MCOPCB11
  (MONDO:0958239, FZD5) and MCOPCB13 (MONDO:0975809, recorded by MONDO against
  NHEJ1 and curated here against IHH for the reason given above). A sixth,
  MCOPCB5 (MONDO:0012709, SHH), is deliberately not duplicated here: it is
  already anchored as a skos:closeMatch on SHH_Holoprosencephaly_Spectrum, whose
  Microform HPE subtype covers microphthalmia with coloboma as the mild end of
  the SHH holoprosencephaly spectrum, and the report OMIM indexes for this locus
  describes iris and uveoretinal colobomas without microphthalmia. The remaining
  six descendants - MCOPCB1 (MONDO:0024549), MCOPCB2 (MONDO:0011589), MCOPCB3
  (MONDO:0012408), MCOPCB4 (MONDO:0009630), MCOPCB6 (MONDO:0013376) and MCOPCB8
  (MONDO:0800324) - carry no causal gene edge in MONDO and are mapped loci
  rather than gene-defined entities, so no row is created for them.

  Two of the gene-disease relationships curated here are weak, and are labelled
  rather than presented as settled. ClinGen rates ABCB6 for MCOPCB7 Limited, and
  TENM3 rests on a single consanguineous pedigree with no ClinGen assertion at
  all. Across the eleven genes in this entry the committed ClinGen gene-validity
  snapshot carries assertions for only four - ABCB6, MAB21L2, PAX6 and FOXE3 -
  and apart from ABCB6/MCOPCB7 every one of them is against a different disease
  term: MAB21L2 against colobomatous microphthalmia-rhizomelic dysplasia
  syndrome (Definitive), PAX6 against PAX6-related ocular dysgenesis
  (Definitive), and FOXE3 against anterior segment dysgenesis (Moderate) and
  familial thoracic aortic aneurysm and aortic dissection (Moderate). ClinGen is
  therefore largely silent on the isolated MAC concept this entry models, and
  absence of an assertion here is not evidence against a gene.

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.
  genes:
  - preferred_term: SOX2
    term:
      id: hgnc:11195
      label: SOX2
- 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.
  genes:
  - preferred_term: OTX2
    term:
      id: hgnc:8522
      label: OTX2
- 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.
  genes:
  - preferred_term: PAX6
    term:
      id: hgnc:8620
      label: PAX6
- 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. Note that the recurrent p.Arg51Cys allele
    causes a distinct *syndromic* oculo-skeletal disorder with rhizomelic limb
    shortening and intellectual disability, curated separately as
    Colobomatous_Microphthalmia-Rhizomelic_Dysplasia_Syndrome and listed in the
    ISDS skeletal nosology; this entry stays scoped to the isolated MAC
    presentation and therefore carries no ISDS assignment.
  genes:
  - preferred_term: MAB21L2
    term:
      id: hgnc:6758
      label: MAB21L2
- 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.
  genes:
  - preferred_term: FOXE3
    term:
      id: hgnc:3808
      label: FOXE3
- 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.
  genes:
  - preferred_term: ALDH1A3
    term:
      id: hgnc:409
      label: ALDH1A3
- name: FZD5-Coloboma
  display_name: Microphthalmia/coloboma 11 — FZD5 (OMIM:620731)
  subtype_term:
    preferred_term: microphthalmia/coloboma 11
    term:
      id: MONDO:0958239
      label: microphthalmia/coloboma 11
  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. This is the MCOPCB11
    locus, MONDO:0958239 / OMIM:620731.
  genes:
  - 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
    quote_role: BACKGROUND
    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: >-
      Supports the gene assignment for this numbered locus and the isolated /
      complex split the description records.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: "in vitro TOPFlash assays revealed that the missense variant only caused partial loss-of-function, behaving as a hypomorphic mutation"
    explanation: >-
      The functional basis for calling the recessive allele hypomorphic rather
      than dominant-negative.
- name: MCOPCB7
  display_name: Microphthalmia with coloboma 7 — ABCB6 (OMIM:614497)
  subtype_term:
    preferred_term: microphthalmia, isolated, with coloboma 7
    term:
      id: MONDO:0013783
      label: microphthalmia, isolated, with coloboma 7
  description: >-
    Autosomal dominant coloboma attributed to ABCB6, an ATP-binding cassette
    transporter expressed in the retina and retinal pigment epithelium, where it
    localizes to the endoplasmic reticulum and Golgi. The original report
    combined positional cloning in one Chinese family with a screen of 116
    sporadic cases of microphthalmia with coloboma, isolated coloboma and
    aniridia. ClinGen's General Inborn Errors of Metabolism expert panel
    nonetheless classifies ABCB6 for this disease as Limited, so the row is
    curated with that classification stated. The zebrafish knockdown and rescue
    experiment behind the loss-of-function reading is cited on the ABCB6 record
    in the genetic section. The gene's better-attested disease is the pigmentary
    skin disorder dyschromatosis universalis hereditaria 3 (MONDO:0014169),
    which ClinGen rates Moderate; nothing about pigmentary skin disease is
    claimed here.
  genes:
  - preferred_term: ABCB6
    term:
      id: hgnc:47
      label: ABCB6
  evidence:
  - reference: PMID:22226084
    reference_title: ABCB6 mutations cause ocular coloboma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Using a positional cloning approach, we identified a mutation in the ATP-binding cassette (ABC) transporter ABCB6 in a Chinese family affected by autosomal-dominant coloboma."
    explanation: The gene-discovery report and the source of the dominant inheritance stated here.
  - reference: PMID:22226084
    reference_title: ABCB6 mutations cause ocular coloboma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Sequence analysis was performed on the ABCB6 exons from 116 sporadic cases of microphthalmia with coloboma (MAC), isolated coloboma, and aniridia, and an additional mutation (A57T) was identified in three patients with MAC."
    explanation: >-
      The screen this row's description reports, and what extends the association
      beyond the index family to sporadic microphthalmia-with-coloboma cases -
      which is why the locus sits in this entry rather than in an
      isolated-coloboma entry.
  - reference: PMID:22226084
    reference_title: ABCB6 mutations cause ocular coloboma.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Immunostaining of transiently transfected, Myc-tagged ABCB6 in retinal pigment epithelial (RPE) cells showed that it localized to the endoplasmic reticulum and Golgi apparatus of RPE cells."
    explanation: Sources the subcellular localization this row's description states.
  - reference: PMID:22226084
    reference_title: ABCB6 mutations cause ocular coloboma.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "RT-PCR of ABCB6 mRNA in human cell lines and tissue indicated that ABCB6 is expressed in the retinae and RPE cells."
    explanation: Sources the tissue expression this row's description states.
  - reference: CGGV:assertion_45ec3fba-48fd-4bf4-b865-2c2d7216e8eb-2024-04-26T180000.000Z
    reference_title: "ABCB6 / microphthalmia, isolated, with coloboma 7 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ABCB6 | HGNC:47 | microphthalmia, isolated, with coloboma 7 | MONDO:0013783 | AD | Limited | SOP10 | General Inborn Errors of Metabolism Gene Curation Expert Panel | 2024-04-26T18:00:00.000Z"
    explanation: ClinGen's own classification of this gene-disease relationship, quoted from the committed record.
- name: MCOPCB9
  display_name: Microphthalmia with coloboma 9 — TENM3 (OMIM:615145)
  subtype_term:
    preferred_term: microphthalmia, isolated, with coloboma 9
    term:
      id: MONDO:0014059
      label: microphthalmia, isolated, with coloboma 9
  description: >-
    Autosomal recessive colobomatous microphthalmia reported in a single
    consanguineous family with third-cousin parents and two affected children, in
    which exome and autozygome analysis found a null allele of TENM3. HGNC
    records ODZ3 as the previous symbol, which is the name the discovery report
    uses. The committed ClinGen gene-validity snapshot carries no assertion for
    TENM3 under either symbol, and no independent family is cited here, so the
    assertion rests on that one pedigree.
  genes:
  - preferred_term: TENM3
    term:
      id: hgnc:29944
      label: TENM3
  evidence:
  - reference: PMID:22766609
    reference_title: Homozygous null mutation in ODZ3 causes microphthalmia in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Exome and autozygome analysis identified a null mutation in ODZ3, one of four vertebrate orthologs of odz in Drosophila."
    explanation: The gene-discovery report, using the gene's previous symbol.
  - reference: PMID:22766609
    reference_title: Homozygous null mutation in ODZ3 causes microphthalmia in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "we enrolled a family that consists of third-cousin parents and two children with isolated colobomatous microphthalmia"
    explanation: >-
      The single pedigree the assertion rests on, and the reason the description
      states its breadth explicitly.
- name: MCOPCB10
  display_name: Microphthalmia with coloboma 10 — RBP4 (OMIM:616428)
  subtype_term:
    preferred_term: microphthalmia, isolated, with coloboma 10
    term:
      id: MONDO:0014635
      label: microphthalmia, isolated, with coloboma 10
  description: >-
    Dominant eye malformation caused by RBP4 missense variants, with a mode of
    inheritance unlike anything else in this entry. RBP4 encodes serum retinol
    binding protein, which delivers retinol from hepatic stores to the placenta
    and the fetal eye. The disease alleles bind retinol poorly but bind the cell
    surface receptor STRA6 more tightly, so the mutant protein occupies STRA6
    without delivering its cargo. Because a transmitting mother's circulating
    mutant protein blocks retinol delivery at the placenta as well as in the
    fetus, penetrance is incomplete and maternal transmission raises the
    probability that an allele-carrying fetus is affected — a maternal effect the
    authors distinguish from imprinting and from oocyte-derived mRNA. The
    separate recessive RBP4 phenotype, in which serum RBP4 is undetectable and
    the result is a progressive retinal dystrophy rather than a malformation, is
    curated as Progressive_Retinal_Dystrophy_Due_To_Retinol_Transport_Defect.
  genes:
  - preferred_term: RBP4
    term:
      id: hgnc:9922
      label: RBP4
  evidence:
  - reference: PMID:25910211
    reference_title: "Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "We identified missense mutations in RBP4, encoding serum retinol binding protein, in three families with eye malformations of differing severity, including bilateral anophthalmia."
    explanation: The gene-discovery report and the source of the phenotypic range stated here.
  - reference: PMID:25910211
    reference_title: "Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "RBP normally delivers retinol from hepatic stores to peripheral tissues, including the placenta and fetal eye."
    explanation: >-
      The normal function this row's description states, and the reason a
      transmitting mother's protein can act at the placenta.
  - reference: PMID:25910211
    reference_title: "Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The mutant phenotypes exhibit dominant inheritance, but incomplete penetrance. Maternal transmission significantly increases the probability of phenotypic expression."
    explanation: >-
      The inheritance pattern this row records, including the maternal effect
      that separates it from ordinary autosomal dominant transmission.
  - reference: PMID:25910211
    reference_title: "Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "By occupying STRA6 nonproductively, the dominant-negative proteins disrupt vitamin A delivery from wild-type proteins within the fetus, but also, in the case of maternal transmission, at the placenta."
    explanation: >-
      The biochemical mechanism behind both the dominant-negative action and the
      maternal effect, which is what makes this row's inheritance claim
      mechanistic rather than descriptive.
- name: IHH-Enhancer-MCOPCB13
  display_name: Microphthalmia/coloboma 13 (IHH enhancer variant hosted in an NHEJ1 intron)
  subtype_term:
    preferred_term: Microphthalmia/coloboma 13
    term:
      id: MONDO:0975809
      label: microphthalmia/coloboma 13
  description: >-
    Autosomal recessive isolated MAC reported in two consanguineous Jewish
    Iranian pedigrees from the Mashhad region. The homozygous founder allele is
    a deep intronic single-nucleotide variant in NHEJ1
    (NM_024782.2:c.588+18131A>G) that is not predicted to affect NHEJ1 itself:
    it sits inside "i8", a conserved enhancer of the neighbouring gene IHH.
    Transgenic mouse reporter assays and chicken ATAC-seq/electroporation show
    that i8 drives expression in the developing eye and that the patient allele
    abolishes that eye-specific activity, so the gene whose expression is
    disturbed is IHH and NHEJ1 is only the element's host. Ocular features range
    from optic disc coloboma to microphthalmia and anophthalmia and differ
    between the two eyes of the same patient; no skeletal or cranial abnormality
    was reported, even though the same enhancer cluster is required for IHH
    expression in limb and skull.
  genes:
  - preferred_term: IHH
    term:
      id: hgnc:5956
      label: IHH
  evidence:
  - reference: PMID:37580330
    reference_title: "IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a spectrum of isolated ocular manifestations, ranging from a milder phenotype of optic nerve coloboma to a severe phenotype of microphthalmia and even anophthalmia"
    explanation: >-
      Defines the subtype's ocular spectrum in the two reported pedigrees.
  - reference: PMID:37580330
    reference_title: "IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "None of the affected individuals had skeletal or cranial abnormalities."
    explanation: >-
      Supports classifying this subtype as isolated rather than syndromic MAC,
      despite the enhancer cluster's known skeletal role.
  - reference: PMID:37580330
    reference_title: "IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an intronic founder variant in NHEJ1, not predicted to affect NHEJ1"
    explanation: >-
      States that the causal allele is not an NHEJ1 functional variant, which is
      why this subtype is named for the IHH enhancer rather than for NHEJ1.
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: SUPPORT
    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
  conforms_to: "ocular_morphogenesis_failure#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.
  genes:
  - preferred_term: ABCB6
    term:
      id: hgnc:47
      label: ABCB6
  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.
  - reference: PMID:22226084
    reference_title: ABCB6 mutations cause ocular coloboma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Our results demonstrate that ABCB6 mutations cause ocular coloboma."
    explanation: >-
      Places ABCB6, bound on this node, upstream of the fissure-closure
      failure that this node models.
  - reference: PMID:22226084
    reference_title: ABCB6 mutations cause ocular coloboma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Ocular coloboma is a developmental defect of the eye and is due to abnormal or incomplete closure of the optic fissure."
    explanation: >-
      Independent statement of this node's own mechanism, from the report that
      assigns ABCB6 to it.
  downstream:
  - target: Coloboma
    description: >-
      Incomplete apposition and fusion of the optic-fissure margins leaves the
      persistent ocular cleft that defines coloboma.
    causal_link_type: DIRECT
  - target: Optic disc coloboma
    description: >-
      The optic fissure runs up to the optic nerve head, so failure of fusion at
      its most proximal extent leaves a colobomatous defect of the optic disc.
      This is the mildest end of the MCOPCB13 spectrum, present even in affected
      individuals whose globe size is normal.
    causal_link_type: DIRECT
- name: Disrupted optic-cup and globe morphogenesis
  conforms_to: "ocular_morphogenesis_failure#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.
  genes:
  - preferred_term: SOX2
    term:
      id: hgnc:11195
      label: SOX2
  - preferred_term: OTX2
    term:
      id: hgnc:8522
      label: OTX2
  - preferred_term: PAX6
    term:
      id: hgnc:8620
      label: PAX6
  - preferred_term: MAB21L2
    term:
      id: hgnc:6758
      label: MAB21L2
  - preferred_term: FOXE3
    term:
      id: hgnc:3808
      label: FOXE3
  - preferred_term: TENM3
    term:
      id: hgnc:29944
      label: TENM3
  - preferred_term: ALDH1A3
    term:
      id: hgnc:409
      label: ALDH1A3
  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
  - preferred_term: Camera-type eye morphogenesis
    term:
      id: GO:0048593
      label: camera-type 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.
  - 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, SOX2 and OTX2 - three of the genes bound on this node - as
      contributors to the spectrum whose developmental lesion this node models.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: "novel variants in six known MAC genes (SOX2, KMT2D, MAB21L2, ALDH1A3, BCOR and FOXE3)"
    explanation: >-
      Names MAB21L2 and FOXE3, also bound here, among the solved genes of a
      prospective microphthalmia-anophthalmia-coloboma cohort.
  - reference: PMID:22766609
    reference_title: Homozygous null mutation in ODZ3 causes microphthalmia in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Our data highlight a role for ODZ3 in the early development of the human eye."
    explanation: >-
      Places TENM3, bound here under its current symbol, in early human eye
      development; ODZ3 is the previous symbol HGNC records for that gene.
  downstream:
  - target: Failure of optic fissure closure
    description: >-
      Optic-cup invagination and ventral patterning precede fissure apposition;
      disturbed cup geometry can therefore compromise the later closure step.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Microphthalmia
    description: Partial failure of globe morphogenesis produces a small globe.
    causal_link_type: DIRECT
  - target: Anophthalmia
    description: Severe early morphogenesis failure can prevent globe formation.
    causal_link_type: DIRECT
- name: Retinoic acid signaling disruption
  conforms_to: "ocular_morphogenesis_failure#Eye Field Specification and Optic Vesicle Patterning Perturbation"
  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.
  genes:
  - preferred_term: RBP4
    term:
      id: hgnc:9922
      label: RBP4
  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 development"
    explanation: >-
      Review evidence that pathway-level (including retinoid) perturbation
      alters eye morphogenesis, supporting RA signaling as a convergent MAC
      mechanism (human teratology review).
  - reference: PMID:25910211
    reference_title: "Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "RBP normally delivers retinol from hepatic stores to peripheral tissues, including the placenta and fetal eye."
    explanation: >-
      Places RBP4, bound on this node, at the retinol-delivery step that
      supplies the substrate for local retinoic acid synthesis.
  - reference: PMID:25910211
    reference_title: "Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "The disease mutations greatly reduce retinol binding to RBP, yet paradoxically increase the affinity of RBP for its cell surface receptor, STRA6."
    explanation: >-
      The lesion by which RBP4 variants reduce retinol supply to this pathway,
      which is what binding the gene on this node asserts.
  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
  conforms_to: "ocular_morphogenesis_failure#Eye Field Specification and Optic Vesicle Patterning Perturbation"
  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.
  genes:
  - preferred_term: FZD5
    term:
      id: hgnc:4043
      label: FZD5
  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.
  genes:
  - preferred_term: MAB21L2
    term:
      id: hgnc:6758
      label: MAB21L2
  - preferred_term: OTX2
    term:
      id: hgnc:8522
      label: OTX2
  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
- name: IHH i8 enhancer disruption
  description: >-
    In microphthalmia/coloboma 13 the initiating lesion is a homozygous deep
    intronic substitution, NHEJ1 NM_024782.2:c.588+18131A>G, that falls inside a
    conserved non-coding element of the IHH enhancer cluster named "i8". The
    element was originally characterised as a limb enhancer; the human variant
    lies at a position overlapped by a predicted transcription-factor binding
    motif and by the summit of the chromatin-accessibility peak seen in
    developing chicken retinal pigment epithelium. Wild-type i8 drives reporter
    expression in the eye of transgenic mouse embryos at E11.5 and the patient
    allele does not, so the molecular consequence is loss of eye-specific
    enhancer output rather than any change to NHEJ1 protein. Because the same
    cluster remains able to support IHH expression in limb and skull, the
    expression defect is restricted to a subset of tissues.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: IHH
    term:
      id: hgnc:5956
      label: IHH
  evidence:
  - reference: PMID:37580330
    reference_title: "IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The human NHEJ1 intronic variant lies within a known specifically limb-development enhancer of a neighboring gene, Indian hedgehog (Ihh), known to be involved in eye development in mice and chickens"
    explanation: >-
      Places the patient variant inside a characterised IHH enhancer rather than
      in NHEJ1 regulatory or coding sequence.
  - reference: PMID:37580330
    reference_title: "IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the mutated version of this sequence, with the same single-nucleotide variant found in our patients, did not consistently drive eye expression in transgenic mice during embryogenesis at E11.5"
    explanation: >-
      Transgenic reporter result establishing that the patient allele abolishes
      the element's eye-specific enhancer activity.
  - reference: PMID:37580330
    reference_title: "IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "a sharp accessibility peak coincided with the conserved i8 enhancer region"
    explanation: >-
      Chicken RPE ATAC-seq shows i8 is an accessible regulatory element during
      the window in which the optic fissure is still open.
  downstream:
  - target: Reduced IHH signaling to periocular mesenchyme and RPE
    description: >-
      Loss of eye-specific enhancer output lowers IHH expression in the
      choroid-adjacent cells that supply hedgehog signal to the periocular
      mesenchyme and retinal pigment epithelium.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37580330
      reference_title: "IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Consistent X-gal staining was observed in the developing eye, specifically in the POM, only in the embryos injected with the vector comprising the WT"
      explanation: >-
        The wild-type element's reporter activity is localised to the periocular
        mesenchyme, which is the compartment the mutant allele fails to reach.
- name: Reduced IHH signaling to periocular mesenchyme and RPE
  description: >-
    IHH is made by non-pigmented cells of the developing choroid next to the
    retinal pigment epithelium and acts on the periocular mesenchyme and the RPE
    itself, where it is required for normal RPE pigmentation and for the
    mesenchymal condensation that forms the sclera. Reduced hedgehog input to
    that compartment disturbs the retina-periocular mesenchyme interaction on
    which optic fissure closure depends, which is how a regulatory lesion at the
    IHH locus reaches the same final common pathway as the coding MAC genes.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  biological_processes:
  - preferred_term: Smoothened signaling pathway
    term:
      id: GO:0007224
      label: smoothened signaling pathway
    modifier: DECREASED
  locations:
  - preferred_term: Retinal pigment epithelium
    term:
      id: UBERON:0001782
      label: pigmented layer of retina
  evidence:
  - reference: PMID:18582859
    reference_title: "Indian hedgehog signaling from endothelial cells is required for sclera and retinal pigment epithelium development in the mouse eye."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Ihh is required for the normal pigmentation pattern of the RPE and the condensation of mesenchymal cells to form the sclera"
    explanation: >-
      Mouse genetics establishing that the RPE and periocular/scleral mesenchyme
      depend on Ihh signal, the compartment the enhancer lesion deprives.
  - reference: PMID:37580330
    reference_title: "IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "The retina-POM interaction is fundamental to fissure closure"
    explanation: >-
      States the step that connects reduced periocular hedgehog signaling to
      failure of optic fissure closure. The sentence restates established mouse
      developmental biology in the citing paper's introduction.
  - reference: PMID:37580330
    reference_title: "IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "haploinsufficiency of Ihh leads to the \"Creeper\" phenotype in chicken, with microphthalmic and colobomatous eyes"
    explanation: >-
      Reduced Ihh dosage alone produces microphthalmia and coloboma in chicken,
      supporting the direction of this node. Quoted from the citing paper's
      background rather than from its own experiments.
  downstream:
  - target: Failure of optic fissure closure
    description: >-
      Deprived of hedgehog input, the periocular mesenchyme cannot support the
      retina-mesenchyme interaction that completes fissure closure.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Disrupted optic-cup and globe morphogenesis
    description: >-
      The same signaling loss disturbs RPE differentiation and scleral
      condensation, feeding the shared globe-morphogenesis defect and the
      microphthalmia/anophthalmia end of the spectrum.
    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.
- category: Ocular
  name: Optic disc coloboma
  subtype: IHH-Enhancer-MCOPCB13
  description: >-
    Colobomatous defect of the optic nerve head, frequently bilateral even where
    microphthalmia is asymmetric, and the mildest end of the MCOPCB13 spectrum.
  phenotype_term:
    preferred_term: Optic nerve coloboma
    term:
      id: HP:0000588
      label: Optic disc coloboma
  evidence:
  - reference: PMID:37580330
    reference_title: "IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Optic nerve coloboma OU. Very high myopia OS>OD. Retinal atrophy OU. Nystagmus OU."
    explanation: >-
      Table 1 entry recording bilateral optic nerve coloboma in an affected
      individual of pedigree 2.
- category: Ocular
  name: High myopia
  subtype: IHH-Enhancer-MCOPCB13
  description: >-
    High or very high myopia accompanies the structural malformation in several
    affected individuals, in some with myopic chorioretinal degeneration and
    retinal tears.
  phenotype_term:
    preferred_term: High myopia
    term:
      id: HP:0011003
      label: High myopia
  evidence:
  - reference: PMID:37580330
    reference_title: "IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High myopia with myopic chorioretinal degeneration and retinal tears OU."
    explanation: >-
      Table 1 entry recording bilateral high myopia with its chorioretinal
      consequences.
- category: Ocular
  name: Nystagmus
  subtype: IHH-Enhancer-MCOPCB13
  description: >-
    Nystagmus is recorded in several affected individuals, in keeping with poor
    visual input from early infancy.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:37580330
    reference_title: "IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Strabismus (esotropia) OS. Nystagmus OU."
    explanation: >-
      Table 1 entry recording bilateral nystagmus alongside strabismus.
- category: Ocular
  name: Strabismus
  subtype: IHH-Enhancer-MCOPCB13
  description: >-
    Unilateral strabismus, esotropic where the deviation is specified, is
    recorded in 2 of the 8 affected individuals tabulated in the index report,
    in each case in the eye with the more severe structural malformation.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:37580330
    reference_title: "IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nuclear cataract OU. Strabismus OS, nystagmus OU."
    explanation: >-
      Table 1 entry for individual VI-7 of pedigree 1, recording left-sided
      strabismus.
  - reference: PMID:37580330
    reference_title: "IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Strabismus (esotropia) OS. Nystagmus OU."
    explanation: >-
      A second tabulated individual with left esotropia, which is what makes
      this a recurrent rather than a singleton feature of the subtype.
genetic:
- name: SOX2
  subtype: SOX2-MAC
  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
  subtype: OTX2-MAC
  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
  subtype: PAX6-MAC
  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
  subtype: MAB21L2-MAC
  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
  subtype: FZD5-Coloboma
  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
  subtype: FOXE3-MAC
  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
  subtype: ALDH1A3-MAC
  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.
- name: ABCB6
  association: Causal dominant variant, ClinGen Limited
  subtype: MCOPCB7
  gene_term:
    preferred_term: ABCB6
    term:
      id: hgnc:47
      label: ABCB6
  relationship_type: CAUSATIVE
  notes: >-
    ABCB6 is an ATP-binding cassette transporter expressed in the retina and the
    retinal pigment epithelium. The dominant coloboma association rests on one
    Chinese pedigree found by positional cloning, one further allele in three
    sporadic microphthalmia-with-coloboma cases, and a zebrafish morpholino
    knockdown rescued by wild-type but not mutant mRNA. ClinGen's General Inborn
    Errors of Metabolism expert panel rates the relationship Limited, and that
    rating is recorded here rather than argued with.
  evidence:
  - reference: PMID:22226084
    reference_title: ABCB6 mutations cause ocular coloboma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Our results demonstrate that ABCB6 mutations cause ocular coloboma."
    explanation: The discovery report's own causal conclusion.
  - reference: PMID:22226084
    reference_title: ABCB6 mutations cause ocular coloboma.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "The knockdown phenotype can be corrected with coinjection of the wild-type, but not mutant, ABCB6 mRNA, suggesting that the phenotypes observed in zebrafish are due to insufficient abcb6 function."
    explanation: >-
      The rescue experiment behind the loss-of-function reading, and the only
      functional support for the association.
  - reference: CGGV:assertion_45ec3fba-48fd-4bf4-b865-2c2d7216e8eb-2024-04-26T180000.000Z
    reference_title: "ABCB6 / microphthalmia, isolated, with coloboma 7 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ABCB6 | HGNC:47 | microphthalmia, isolated, with coloboma 7 | MONDO:0013783 | AD | Limited | SOP10 | General Inborn Errors of Metabolism Gene Curation Expert Panel | 2024-04-26T18:00:00.000Z"
    explanation: The ClinGen classification and date quoted in the notes.
- name: TENM3
  association: Causal recessive null variant in a single consanguineous family
  subtype: MCOPCB9
  gene_term:
    preferred_term: TENM3
    term:
      id: hgnc:29944
      label: TENM3
  relationship_type: CAUSATIVE
  notes: >-
    TENM3 encodes a teneurin transmembrane protein, one of four vertebrate
    orthologs of Drosophila odz. HGNC records ODZ3 as a previous symbol, and the
    discovery report uses that name throughout. The association comes from exome
    and autozygome analysis of one family with third-cousin parents and two
    children with isolated colobomatous microphthalmia. The committed ClinGen
    gene-validity snapshot carries no assertion for this gene under either
    symbol.
  evidence:
  - reference: PMID:22766609
    reference_title: Homozygous null mutation in ODZ3 causes microphthalmia in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Exome and autozygome analysis identified a null mutation in ODZ3, one of four vertebrate orthologs of odz in Drosophila."
    explanation: The gene-discovery report, and the source of the ortholog statement in the notes.
  - reference: PMID:22766609
    reference_title: Homozygous null mutation in ODZ3 causes microphthalmia in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Our data highlight a role for ODZ3 in the early development of the human eye."
    explanation: >-
      The authors' own conclusion, which is a role claim rather than an
      established gene-disease assertion.
- name: RBP4
  association: Causal dominant-negative variant with incomplete penetrance and a maternal effect
  subtype: MCOPCB10
  gene_term:
    preferred_term: RBP4
    term:
      id: hgnc:9922
      label: RBP4
  relationship_type: CAUSATIVE
  notes: >-
    RBP4 encodes serum retinol binding protein, which carries retinol from
    hepatic stores to peripheral tissues including the placenta and the fetal
    eye. The malformation alleles bind retinol poorly yet bind the cell-surface
    receptor STRA6 with higher affinity, so they occupy the receptor without
    delivering vitamin A; that is the dominant-negative step. A transmitting
    mother's mutant protein acts at the placenta as well as in the fetus, so
    maternal transmission raises the chance an allele-carrying fetus is affected,
    and the authors present this as a mode of maternal inheritance distinct from
    imprinting and from oocyte-derived mRNA. This is a distinct RBP4 phenotype
    from the recessive one in which serum RBP4 is undetectable and the result is
    a progressive retinal dystrophy, curated as
    Progressive_Retinal_Dystrophy_Due_To_Retinol_Transport_Defect. The committed
    ClinGen gene-validity snapshot carries no assertion for RBP4.
  evidence:
  - reference: PMID:25910211
    reference_title: "Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "We identified missense mutations in RBP4, encoding serum retinol binding protein, in three families with eye malformations of differing severity, including bilateral anophthalmia."
    explanation: The gene-discovery report and the range of severity this record covers.
  - reference: PMID:25910211
    reference_title: "Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "The disease mutations greatly reduce retinol binding to RBP, yet paradoxically increase the affinity of RBP for its cell surface receptor, STRA6."
    explanation: The two biochemical changes the dominant-negative mechanism in the notes rests on.
  - reference: PMID:25910211
    reference_title: "Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "These findings establish a previously uncharacterized mode of maternal inheritance, distinct from imprinting and oocyte-derived mRNA, and define a group of hereditary disorders plausibly modulated by dietary vitamin A."
    explanation: >-
      The authors' framing of the maternal effect, which the notes reports as
      their claim rather than as settled nosology.
- name: IHH
  subtype: IHH-Enhancer-MCOPCB13
  association: Causal non-coding regulatory variant in an IHH enhancer hosted by an NHEJ1 intron
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: IHH
    term:
      id: hgnc:5956
      label: IHH
  notes: >-
    MONDO, OMIM and the curation stub for this concept index MCOPCB13 under
    NHEJ1, because the variant's coordinates fall inside an NHEJ1 intron. That
    is a positional label, not a statement about NHEJ1 function: the primary
    report states the allele is not predicted to affect NHEJ1, and the gene
    whose expression is disturbed is IHH. NHEJ1's own established disease
    association is a different one - ClinGen's gene-disease validity table
    carries exactly one NHEJ1 assertion, Cernunnos-XLF deficiency (MONDO:0012650,
    autosomal recessive, Definitive), and none for microphthalmia or coloboma;
    the same table carries no IHH assertion at all, so neither the host gene nor
    the regulatory target has a ClinGen assertion covering this phenotype.
    NHEJ1 is recorded here as the host gene of the affected region rather than
    as a causal gene binding.
  affected_regions:
  - name: IHH enhancer i8
    regulatory_element_type: ENHANCER
    chromosomal_region: 2q35
    within_gene:
      preferred_term: NHEJ1
      term:
        id: hgnc:25737
        label: NHEJ1
    description: >-
      A conserved non-coding element of the IHH enhancer cluster, named i8 when
      the cluster was characterised in limb development, lying within an intron
      of NHEJ1 on the reference genome. The relationship recorded here locates
      the element; it does not assert that NHEJ1 is regulated by it or that
      NHEJ1 sequence function is disturbed.
  variants:
  - name: NHEJ1 NM_024782.2:c.588+18131A>G
    variant_type: single nucleotide variant
    genomic_contexts:
    - intron
    regulatory_category: mLOE
    gene:
      preferred_term: NHEJ1
      term:
        id: hgnc:25737
        label: NHEJ1
    regulatory_target_gene:
      preferred_term: IHH
      term:
        id: hgnc:5956
        label: IHH
    description: >-
      Homozygous founder substitution reported in two consanguineous Jewish
      Iranian pedigrees, absent from gnomAD and from 87 ethnically matched
      controls, and submitted to ClinVar as SCV002769719. The coordinates lie in
      NHEJ1 intron sequence and the allele is not predicted to alter NHEJ1
      splicing or protein. Expression loss is classified mLOE rather than LOE
      because the affected individuals have no skeletal or cranial phenotype,
      so IHH expression driven by the rest of the cluster is evidently retained
      outside the eye.
    functional_effects:
    - regulatory_element_type: ENHANCER
      regulatory_mechanism: >-
        Loss of eye-specific enhancer activity; the substituted base sits at a
        predicted transcription-factor binding motif and at the summit of the
        chromatin-accessibility peak marking the element in developing retinal
        pigment epithelium.
      affected_developmental_stage: >-
        Embryonic eye morphogenesis, before optic fissure closure (mouse E11.5;
        chicken Hamburger-Hamilton stages 24-26).
      description: >-
        Wild-type i8 drives reporter expression in the developing eye of
        transgenic mouse embryos and the patient allele does not.
    evidence:
    - reference: PMID:37580330
      reference_title: "IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "NHEJ1 (NM_024782.2): c.588+18131 A > G (NG_007880.1: g.37317 A > G), submitted to ClinVar (SCV002769719), has no reported frequency in gnomAD"
      explanation: >-
        Gives the variant's nomenclature, its ClinVar submission, and its absence
        from population data.
    - reference: PMID:37580330
      reference_title: "IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "RFLP screening of 87 ethnically matched control samples identified no other individuals heterozygous or homozygous for this variant"
      explanation: >-
        Ancestry-matched control screening supporting the allele's rarity in the
        founder population.
    - reference: PMID:37580330
      reference_title: "IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "the summit of the observed i8 peak overlaps with the conserved PAX4 binding motif and the orthologous site of the c.588+18131A > G variant"
      explanation: >-
        Locates the substituted base at the accessibility summit and a predicted
        transcription-factor motif, which is the proposed molecular mechanism.
  evidence:
  - reference: PMID:37580330
    reference_title: "IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a MAC disease-associated 0.5 Mb genomic locus on chromosome 2q35 (maximal LOD score 6.8)"
    explanation: >-
      Linkage result establishing the 2q35 locus that contains the IHH enhancer
      cluster and NHEJ1.
  - reference: PMID:37580330
    reference_title: "IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "this variant is within an Ihh enhancer that drives gene expression in the developing eye and that the identified variant affects this eye-specific enhancer activity"
    explanation: >-
      Functional result identifying IHH as the gene whose regulation is
      disturbed, which is the basis for recording IHH rather than NHEJ1 here.
  - reference: CGGV:assertion_765b118e-c60a-4696-b401-f63b3349d6d2-2021-05-20T151233.276Z
    reference_title: "NHEJ1 / Cernunnos-XLF deficiency (Definitive)"
    supports: NO_EVIDENCE
    evidence_source: OTHER
    snippet: "NHEJ1 | HGNC:25737 | Cernunnos-XLF deficiency | MONDO:0012650 | AR | Definitive"
    explanation: >-
      Cited because it is the assertion readers will find when they look NHEJ1
      up, and it is about a different disease. ClinGen's only curated NHEJ1
      gene-disease relationship is Cernunnos-XLF deficiency; it says nothing
      either way about microphthalmia or coloboma, so it neither supports nor
      refutes this record.
environmental:
- name: Retinoid pathway teratogens
  exposure_term:
    preferred_term: retinoid teratogen exposure
    term:
      id: ECTO:9001346
      label: exposure to retinoid
  influences_mechanisms:
  - target: Retinoic acid signaling disruption
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Retinoid drugs act on the very signalling pathway this node names, so
      the exposure perturbs retinoic acid signalling directly rather than
      through an intermediate.
    evidence:
    - reference: PMID:3162101
      reference_title: "Retinoic acid embryopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The malformations included microtia/anotia (15 infants), micrognathia (6), cleft palate (3), conotruncal heart defects and aortic-arch abnormalities (8), thymic defects (7), retinal or optic-nerve abnormalities (4), and central nervous system malformations (18)."
      explanation: >-
        Isotretinoin is a retinoic acid analogue, and human pregnancies exposed
        to it produced a characteristic malformation pattern that includes
        ocular defects. Because retinoids act as ligands of the retinoic acid
        receptors, the exposure perturbs the signalling this node names
        directly rather than through an intermediate.
  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 development"
    explanation: >-
      Teratology review identifying medications (including retinoids) that alter
      eye morphogenesis.
- name: Thalidomide and other ocular teratogens
  influences_mechanisms:
  - target: Failure of optic fissure closure
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Groups several unrelated environmental contributors, including
      gestational infection and maternal vitamin A deficiency, whose common
      feature is raising the chance that fissure closure fails rather than a
      shared mechanism.
    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: >-
        Names gestational infections and maternal vitamin A deficiency among
        environmental contributors to the malformation, a heterogeneous set of
        risk factors rather than one mechanism.
  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
  action_category: COUNSELING_INFORMATIONAL
  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.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Disrupted optic-cup and globe morphogenesis
    description: >-
      Addresses the structural consequences of the morphogenetic defect, and in
      the anophthalmic socket supports orbital growth. It does not act on optic
      fissure closure, which has already failed in utero.
  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: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Disrupted optic-cup and globe morphogenesis
    description: >-
      Addresses the visual impairment resulting from the malformed globe.
      Purely supportive.
  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.
animal_models:
- species: Dog
  genotype: Homozygous 7.8 kb deletion in NHEJ1 intron 4 (Collie eye anomaly allele)
  category: Naturally occurring
  description: >-
    Collie eye anomaly is a naturally occurring autosomal recessive canine
    ocular malformation - choroidal hypoplasia with optic nerve head coloboma -
    that maps to a homozygous 7.8 kb deletion inside an intron of the canine
    NHEJ1 orthologue. The human MCOPCB13 report placed that canine deletion on
    the human genome and found it removes a different member of the same IHH
    enhancer cluster, i9, where the human variant disrupts i8. The dog is
    therefore a natural experiment in the same enhancer cluster, at a
    neighbouring element, with a lesion of a different class.
  publication: PMID:17916641
  modeled_mechanisms:
  - target: Failure of optic fissure closure
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      The affected dog shows optic nerve head coloboma with choroidal
      hypoplasia, so it reproduces the failure-of-optic-fissure-closure outcome
      after a lesion in the same intronic enhancer cluster. It is partial
      because the canine disease is confined to the posterior pole and does not
      include the microphthalmia or anophthalmia seen in MCOPCB13.
    limitations: >-
      The canine lesion is a 7.8 kb deletion of i9, not the human single
      nucleotide substitution in i8, so it does not model the human allele. The
      canine deletion's own causal status is contested: it is discordant with
      the phenotype in some breeds and populations, where it behaves as a linked
      marker rather than the causal variant. IHH has not been shown to be the
      canine target; the 2007 report describes the deleted sequence as a
      conserved protein-binding domain without naming a regulated gene.
    divergences:
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: >-
        The element disrupted is i9 in the dog and i8 in the human patients,
        and the canine lesion is a 7.8 kb deletion rather than a single
        nucleotide substitution. These are separate enhancers of the same
        cluster, so the MCOPCB13 allele is not encoded in this model and the
        dog does not report on the activity of the element that is lesioned in
        MCOPCB13.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Optic fissure closure is read out in the canine eye. Dogs have no
        macula and a tapetal fundus, and the canine phenotype is choroidal
        hypoplasia with optic nerve head coloboma rather than the microphthalmia
        and anophthalmia that dominate the human pedigrees, so the severity and
        distribution of the human malformation are not reproduced.
    evidence:
    - reference: PMID:17916641
      reference_title: "Breed relationships facilitate fine-mapping studies: a 7.8-kb deletion cosegregates with Collie eye anomaly across multiple dog breeds."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Sequence analysis revealed that all affected dogs share a homozygous deletion of 7.8 kb in the NHEJ1 gene. This intronic deletion spans a highly conserved binding domain to which several developmentally important proteins bind."
      explanation: >-
        Establishes the canine lesion as a deletion of conserved regulatory
        sequence inside an NHEJ1 intron rather than an NHEJ1 coding lesion.
    - reference: PMID:37580330
      reference_title: "IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "it encompasses another experimentally verified enhancer of Ihh (in mice), termed 'i9' by Will et al"
      explanation: >-
        The human report's own mapping of the canine deletion onto the IHH
        enhancer cluster, which is what makes the dog informative here.
    - reference: PMID:26732749
      reference_title: "Discrepancy in compliance between the clinical and genetic diagnosis of choroidal hypoplasia in Danish Rough Collies and Shetland Sheepdogs."
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: "the intronic deletion in NHEJ1 is not the causative mutation but, rather, a marker linked to the locus underlying the trait in some populations"
      explanation: >-
        Argues the canine deletion is a linked marker rather than the causal
        variant in Danish Rough Collies, which limits how far this model can be
        pushed as corroboration.
  evidence:
  - reference: PMID:28702949
    reference_title: "Genetic analysis of optic nerve head coloboma in the Nova Scotia Duck Tolling Retriever identifies discordance with the NHEJ1 intronic deletion (collie eye anomaly mutation)."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "Collection of ONH coloboma-affected NSDTR showed lack of concordance of the NHEJ1 intronic deletion with ONH coloboma"
    explanation: >-
      A second breed in which optic nerve head coloboma does not track with the
      deletion, recorded here so the cross-species argument is not read as
      stronger than it is.
discussions:
- discussion_id: mcopcb13_ihh_enhancer_human_evidence
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Is IHH expression actually reduced in the human developing eye in
    microphthalmia/coloboma 13, or is the reduction inferred entirely from
    mouse and chicken assays of the enhancer?
  attaches_to:
  - pathophysiology#IHH i8 enhancer disruption
  - pathophysiology#Reduced IHH signaling to periocular mesenchyme and RPE
  rationale: >-
    Every step from the variant to reduced IHH output rests on non-human
    systems: a transgenic mouse reporter assay at E11.5, chicken RPE ATAC-seq
    and electroporation, and mouse genetics for the requirement of Ihh in RPE
    and scleral mesenchyme. No measurement of IHH transcript or protein in
    human ocular tissue from an affected individual has been reported, and the
    variant has been described in two related consanguineous pedigrees from one
    founder community, with no independent family reported since. The
    translational question is sharpened rather than settled by the human
    phenotype: the same enhancer cluster is required for IHH expression in limb
    and skull, yet the affected individuals have no skeletal or cranial
    abnormality, so either the element's eye and limb activities are separable
    sub-modules or the human allele spares the limb-active part. Neither
    possibility has been tested.
  notes: >-
    This is recorded as a model-to-human translation question rather than as an
    absent mechanism. The enhancer's eye activity, the allele's effect on it,
    and the dependence of periocular mesenchyme and RPE on Ihh are each
    supported by experiments; what is missing is a human tissue measurement and
    a second, unrelated family.

📚

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

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)

Add MCOPCB13 (MONDO:0975809) as the IHH-Enhancer-MCOPCB13 subtype · 2026-09-24T17:45:00Z · View source

Curated microphthalmia/coloboma 13 (MONDO:0975809, OMIM 620968) after deciding it is a subtype of this entry rather than a new Disease entry. The stub named NHEJ1 (hgnc:25737) as the causal gene; the primary report (PMID:37580330, Wormser et al. 2023, npj Genomic Medicine, PMC full text) states the homozygous founder allele NM_024782.2:c.588+18131A>G is not predicted to affect NHEJ1 and lies inside 'i8', a conserved enhancer of the neighbouring gene IHH (hgnc:5956, verified against the HGNC REST API and cache/hgnc/terms.csv; the deep-research report offered HGNC:5384 for IHH, which is wrong and was not used). Recorded IHH as the causal gene with NHEJ1 as the host gene of the affected region, using the noncoding-variant-impact pattern: Variant.gene NHEJ1, regulatory_target_gene IHH, variant_type single nucleotide variant, genomic_contexts intron, regulatory_category mLOE, functional_effects regulatory_element_type ENHANCER, and affected_regions 'IHH enhancer i8' with within_gene NHEJ1. Added two pathophysiology nodes joining the existing 'Failure of optic fissure closure' and 'Disrupted optic-cup and globe morphogenesis' nodes, three subtype-scoped phenotypes from Table 1 of PMID:37580330, one animal model (canine Collie eye anomaly, PMID:17916641) carrying REFUTE evidence for its own limitations (PMID:26732749, PMID:28702949), and a HUMAN_MODEL_MISMATCH discussion recording that every step from variant to reduced IHH output rests on mouse and chicken assays with no human tissue measurement and no second unrelated family. Checked ClinGen directly by downloading the live gene-validity CSV on 2026-09-24: NHEJ1 has one assertion (Cernunnos-XLF deficiency, MONDO:0012650, AR, Definitive) and IHH has none, so no ClinGen assertion covers this phenotype; cited the NHEJ1 row as supports NO_EVIDENCE. Deep research: falcon requested, returned HTTP 402 (out of credits), claude_code produced the report under fallback; preflight-dr returned WARN because IHH is mentioned more often than NHEJ1, which is the expected signal for this disease rather than a wrong-disease report. Report reference validation 10/10 resolved, 0 off topic; term validation flagged UBERON:0000384 as non-existent and UBERON:0001789/UBERON:0001786 as mislabelled, none of which were bound. Validated under linkml-reference-validator 0.3.0rc1 in a dedicated venv: just validate (58/58 snippets, 36 titles, 0 issues), count-verified-snippets, validate-terms, check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, list-gene-term-mismatches, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens, check-environmental-evidence, check-coarse-phenotypes, check-case-collisions, pytest tests/test_data.py -k Microphthalmia, and validate-disorders.

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

(harding2023realworldclinicaland pages 1-1): 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.
(kunisetty2024highclinicalexome pages 1-2): Bhavana Kunisetty, Bailey A. Martin-Giacalone, Xiaonan Zhao, Pamela N. Luna, Brian P. Brooks, Robert B. Hufnagel, Chad A. Shaw, Jill A. Rosenfeld, A. J. Agopian, Philip J. Lupo, and Daryl A. Scott. High clinical exome sequencing diagnostic rates and novel phenotypic expansions for nonisolated microphthalmia, anophthalmia, and coloboma. Investigative Opthalmology & Visual Science, 65:25, Mar 2024. URL: https://doi.org/10.1167/iovs.65.3.25, doi:10.1167/iovs.65.3.25. This article has 7 citations.
(ceroni2024deletionupstreamof pages 1-2): Fabiola Ceroni, Munevver B. Cicekdal, Richard Holt, Elena Sorokina, Nicolas Chassaing, Samuel Clokie, Thomas Naert, Lidiya V. Talbot, Sanaa Muheisen, Dorine A. Bax, Yesim Kesim, Emma C. Kivuva, Catherine Vincent-Delorme, Soeren S. Lienkamp, Julie Plaisancié, Elfride De Baere, Patrick Calvas, Kris Vleminckx, Elena V. Semina, and Nicola K. Ragge. Deletion upstream of mab21l2 highlights the importance of evolutionarily conserved non-coding sequences for eye development. Nature Communications, Oct 2024. URL: https://doi.org/10.1038/s41467-024-53553-2, doi:10.1038/s41467-024-53553-2. This article has 7 citations and is from a highest quality peer-reviewed journal.
(harding2023realworldclinicaland pages 1-2): 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.
(holt2023theimpactof pages 1-3): Richard Holt. The impact of genetic testing for microphthalmia, anophthalmia, and coloboma: experiences from a translational approach. Expert Review of Ophthalmology, 18:351-353, Nov 2023. URL: https://doi.org/10.1080/17469899.2023.2281441, doi:10.1080/17469899.2023.2281441. This article has 0 citations.
(russo2025managementofanophthalmia pages 1-2): Monica Russo, Serena Palmeri, Alice Zucconi, Aldo Vagge, and Cesare Arioni. Management of anophthalmia, microphthalmia and coloboma in the newborn, shared care between neonatologist and ophthalmologist: a literature review. Italian Journal of Pediatrics, Mar 2025. URL: https://doi.org/10.1186/s13052-025-01882-3, doi:10.1186/s13052-025-01882-3. This article has 6 citations and is from a peer-reviewed journal.
(harding2023realworldclinicaland pages 7-8): 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.
(harding2023realworldclinicaland pages 10-11): 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.
(harding2023realworldclinicaland pages 8-9): 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.
(cortesgonzalez2024homozygosityfora pages 1-2): Vianney Cortés-González, Miguel Rodriguez-Morales, Paris Ataliotis, Claudine Mayer, Julie Plaisancié, Nicolas Chassaing, Hane Lee, Jean-Michel Rozet, Florencia Cavodeassi, and Lucas Fares Taie. Homozygosity for a hypomorphic mutation in frizzled class receptor 5 causes syndromic ocular coloboma with microcornea in humans. Human Genetics, 143:1509-1521, Nov 2024. URL: https://doi.org/10.1007/s00439-024-02712-y, doi:10.1007/s00439-024-02712-y. This article has 4 citations and is from a peer-reviewed journal.
(NCT01778543 chunk 1): Pathogenesis and Genetics of Microphthalmia, Anophthalmia and Uveal Coloboma (MAC). National Eye Institute (NEI). 2013. ClinicalTrials.gov Identifier: NCT01778543
(harding2023realworldclinicaland pages 9-10): 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.
(dubucs2024thefirstreview pages 1-2): Charlotte Dubucs, Julie Plaisancié, Monique Courtade-Saidi, and Christine Damase-Michel. The first review on prenatal drug exposure and ocular malformation occurrence. Frontiers in Pediatrics, Sep 2024. URL: https://doi.org/10.3389/fped.2024.1379875, doi:10.3389/fped.2024.1379875. This article has 6 citations.
(dubucs2024thefirstreview pages 3-4): Charlotte Dubucs, Julie Plaisancié, Monique Courtade-Saidi, and Christine Damase-Michel. The first review on prenatal drug exposure and ocular malformation occurrence. Frontiers in Pediatrics, Sep 2024. URL: https://doi.org/10.3389/fped.2024.1379875, doi:10.3389/fped.2024.1379875. This article has 6 citations.
(dubucs2024thefirstreview pages 11-12): Charlotte Dubucs, Julie Plaisancié, Monique Courtade-Saidi, and Christine Damase-Michel. The first review on prenatal drug exposure and ocular malformation occurrence. Frontiers in Pediatrics, Sep 2024. URL: https://doi.org/10.3389/fped.2024.1379875, doi:10.3389/fped.2024.1379875. This article has 6 citations.
(dubucs2024thefirstreview pages 2-3): Charlotte Dubucs, Julie Plaisancié, Monique Courtade-Saidi, and Christine Damase-Michel. The first review on prenatal drug exposure and ocular malformation occurrence. Frontiers in Pediatrics, Sep 2024. URL: https://doi.org/10.3389/fped.2024.1379875, doi:10.3389/fped.2024.1379875. This article has 6 citations.
(dubucs2024thefirstreview pages 5-6): Charlotte Dubucs, Julie Plaisancié, Monique Courtade-Saidi, and Christine Damase-Michel. The first review on prenatal drug exposure and ocular malformation occurrence. Frontiers in Pediatrics, Sep 2024. URL: https://doi.org/10.3389/fped.2024.1379875, doi:10.3389/fped.2024.1379875. This article has 6 citations.
(goyal2025geneticandenvironmental pages 4-5): Shiwali Goyal, Shailja Tibrewal, Ria Ratna, and Vanita Vanita. Genetic and environmental factors contributing to anophthalmia and microphthalmia: current understanding and future directions. World Journal of Clinical Pediatrics, Jun 2025. URL: https://doi.org/10.5409/wjcp.v14.i2.101982, doi:10.5409/wjcp.v14.i2.101982. This article has 10 citations.
(russo2025managementofanophthalmia pages 5-6): Monica Russo, Serena Palmeri, Alice Zucconi, Aldo Vagge, and Cesare Arioni. Management of anophthalmia, microphthalmia and coloboma in the newborn, shared care between neonatologist and ophthalmologist: a literature review. Italian Journal of Pediatrics, Mar 2025. URL: https://doi.org/10.1186/s13052-025-01882-3, doi:10.1186/s13052-025-01882-3. This article has 6 citations and is from a peer-reviewed journal.
(harding2023realworldclinicaland pages 5-7): 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.
(NCT06293560 chunk 1): Melissa Anne Richard. Microphthalmia, Anophthalmia, and Coloboma Genetic Epidemiology in Children. Baylor College of Medicine. 2022. ClinicalTrials.gov Identifier: NCT06293560
(NCT04833361 chunk 1): Potential Environmental Causes of Uveal Coloboma. National Eye Institute (NEI). 2023. ClinicalTrials.gov Identifier: NCT04833361
(NCT06408701 chunk 1): Modeling Ocular Developmental Diseases From 3D Cultures of Optic Vesicle Organoids Derived From hiPSCs of Patients With Ocular Malformations. University Hospital, Toulouse. 2024. ClinicalTrials.gov Identifier: NCT06408701
(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.
(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.

Artifacts

Edison artifact artifact-00

Ask OpenScientist

OpenScientist Report

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Clinical Trials

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

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

Executive summary

1. Disease information

1.1 Disease overview (current understanding)

1.2 Key identifiers (ontology and clinical coding)

1.3 Synonyms / alternative names

1.4 Evidence provenance

2. Etiology

2.1 Disease causal factors

2.2 Genetic risk factors (causal genes)

2.3 Environmental risk factors (including drugs) and infectious contributors

2.4 Protective factors

2.5 Gene–environment interactions

3. Phenotypes (with HPO suggestions)

3.1 Core ocular phenotypes (congenital)

3.2 Additional ocular features and complications (frequency where available)

3.3 Extraocular/systemic phenotypes (frequency where available)

3.4 Age of onset, severity, progression

3.5 Quality of life impact

4. Genetic / molecular information

4.1 Causal genes (illustrative, not exhaustive)

4.2 Pathogenic variant classes and functional consequences

4.3 Inheritance patterns, penetrance/expressivity

4.4 Diagnostic yield statistics (recent)

5. Mechanism / pathophysiology

5.1 Causal chain (high-level)

5.2 Key pathways and mechanisms (with evidence)

5.3 Suggested ontology terms

6. Anatomical structures affected

7. Temporal development

8. Inheritance and population

8.1 Epidemiology (statistics)

8.2 Population genetics notes

9. Diagnostics

9.1 Clinical and imaging evaluation

9.2 Genetic testing strategy (real-world implementation)

9.3 Differential diagnosis (examples)

9.4 Screening / prenatal diagnosis

10. Outcomes / prognosis

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

11.1 Ophthalmic interventions and supportive care

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

12. Prevention