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Mappings

MONDO

MONDO:0007355 uveal coloboma-cleft lip and palate-intellectual disability

Orphanet ORPHA:1473 lists MONDO:0007355 and OMIM:120433 as exact cross-references, independently confirming the entity identity used for the named-entity-confusion preflight of this entry.

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Inheritance

1

Autosomal Dominant HP:0000006

Autosomal dominant transmission through the index family, documented over three generations in the 1982 report and across four generations on re-evaluation. Expressivity is strikingly variable within that single pedigree, ranging from a minor ocular sign to microphthalmia with clefting, hearing loss and intellectual disability. The causal YAP1 nonsense allele cosegregated with the phenotype (combined LOD 4.2 across the two YAP1 coloboma families reported by Williamson et al.). Incomplete penetrance has been documented for other YAP1 loss-of-function alleles in coloboma families — a later frameshift allele was inherited from an asymptomatic father — so unaffected carriers should be expected.

Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE

Show evidence (4 references)

PMID:7154042 SUPPORT Human Clinical

"This report details a family in whom there is autosomal dominantly inherited uveal colobomata, associated eye defects, and cleft lip and palate occurring in twelve subjects over three generations."

The foundational report establishes autosomal dominant transmission in the pedigree that defines the entity.

PMID:7154042 SUPPORT Human Clinical

"Considerable variability in expression of the gene is apparent"

Supports the VARIABLE expressivity assignment.

PMID:24462371 SUPPORT Human Clinical

"A combined LOD score of 4.2 was obtained for the association between YAP1 loss-of-function mutations and the phenotype in these families."

Quantifies cosegregation of the dominant YAP1 allele with the phenotype.

+ 1 more reference

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Mechanistic Hypotheses

1

Position of the YAP1 nonsense allele relative to the intron-1 alternative transcription start site determines whether the phenotype is isolated coloboma or the full multisystem syndrome

alternative_tss_severity_modulation EMERGING

Evidence balance 1 support

Williamson et al. propose that the intron-1 alternative transcription start site of YAP1 (initiating at Met179) supplies a partially functional protein pool when a nonsense allele falls upstream of it, ameliorating the phenotype to eye-only disease; alleles downstream of both start sites cause NMD of all transcripts and produce the syndromic phenotype of this entity. The hypothesis is attractive because it would explain, from allele position alone, why two families with the same class of YAP1 lesion differ so sharply. It is not established: it rests on predicted rather than measured NMD in the relevant tissues, and a later NMD-escaping frameshift allele was carried by an asymptomatic father, which the model does not readily accommodate. Causal edges belonging to this model opt in via the alternative_tss_severity_modulation hypothesis group.

Pathograph links

Alternative Transcription Start Site Modulation of Phenotype Severity -> YAP1 Haploinsufficiency UNKNOWN Whether a given nonsense allele produces true haploinsufficiency, and hence whether the phenotype is eye-only or syndromic, is proposed to depend on its position relative to the alternative start site.

Show evidence (1 reference)

PMID:24462371 SUPPORT In Vitro

"RT-PCR showed that an alternative transcription start site (TSS) in intron 1 of YAP1 and Yap1 is widely used in human and mouse development, respectively."

Establishes by RT-PCR that the alternative transcript is genuinely used in development. The assay is performed on human and mouse developmental material rather than in living subjects, hence IN_VITRO; the mouse arm is model-organism data reported in the same sentence.

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Discussions and Knowledge Gaps

2

What renal lesion produces the haematuria in YAP1-related syndromic coloboma, and does it carry a risk of progressive kidney disease?

KNOWLEDGE GAP OPEN yap1_haematuria_renal_basis_unknown

Attached to

pathophysiology#Pleiotropic YAP1 Requirement Across Eye, Ear, Palate, and Kidney Primordia

Haematuria is a recurrent feature of YAP1 loss-of-function families and prompted Holt et al. to look specifically for YAP1 expression in the developing kidney, which they found in renal tubules at CS22. But no renal biopsy, imaging, or longitudinal renal-function data have been published for any affected individual, so it is unknown whether the haematuria reflects a glomerular basement membrane defect, a tubular lesion, a structural malformation, or something benign. This matters clinically because it determines whether carriers need renal surveillance, and mechanistically because a glomerular versus tubular origin would point at different YAP1 dependencies.

Proposed experiments

Structured renal phenotyping of genotyped YAP1 carriers

exp_yap1_renal_phenotyping

Perform urinalysis with phase-contrast microscopy for dysmorphic red cells, albumin:creatinine ratio, renal ultrasound, and eGFR in all molecularly confirmed carriers from reported YAP1 families, with longitudinal follow-up in adults. Dysmorphic erythrocytes and albuminuria would indicate a glomerular origin; isolated isomorphic haematuria with normal albumin would favour a tubular or structural cause.

Decision criterion

Presence of dysmorphic erythrocytes and/or albuminuria in a majority of carriers distinguishes a glomerular from a tubular or structural origin.

Compartment-specific conditional Yap1 deletion in mouse kidney

exp_yap1_conditional_kidney_deletion

Delete Yap1 conditionally in nephron progenitors versus differentiated tubular epithelium in mouse and assay for haematuria, glomerular basement-membrane ultrastructure, and tubular integrity, to localise the developmental compartment in which reduced YAP1 dose produces the renal phenotype.

Decision criterion

Haematuria arising only in one compartment-specific deletion localises the YAP1 requirement to that compartment.

Show evidence (1 reference)

PMID:28801591 SUPPORT In Vitro

"we also examined expression in the human embryonic kidney"

The investigators examined kidney expression precisely because the renal phenotype was unexplained, evidencing the gap.

Is uveal coloboma-cleft lip and palate-intellectual disability a distinct nosological entity, or the syndromic tail of a single YAP1-related developmental eye disorder spectrum?

KNOWLEDGE GAP OPEN yap1_single_family_entity_boundary

Attached to

pathophysiology#Alternative Transcription Start Site Modulation of Phenotype Severity

MONDO:0007355 / OMIM:120433 / ORPHA:1473 describe an entity resting on a single pedigree. The same gene, with the same class of lesion, produces isolated non-syndromic coloboma in a second family and in singleton cases. Whether the syndromic label names a real biological subdivision (as the alternative-TSS model would predict) or simply the most severely expressed end of one allelic spectrum cannot be settled without further syndromic families. Until then, curators should be careful not to import generic coloboma or generic clefting literature into this entry, and should not treat the syndrome boundary as mechanistically validated.

Proposed experiments

Allele-position versus extraocular-phenotype audit across YAP1 carriers

exp_yap1_allele_position_genotype_phenotype

Assemble every published and diagnostic-laboratory YAP1 loss-of-function carrier, annotate each allele by position relative to the intron-1 alternative transcription start site, and test whether downstream alleles (those predicted to trigger NMD in both transcript classes) are enriched for extraocular features relative to upstream alleles. Pair this with quantitative allele-specific expression of canonical and alternative YAP1 transcripts in accessible patient tissue.

Decision criterion

Enrichment of extraocular features among alleles downstream of the alternative TSS would support a real syndromic/isolated subdivision; absence of enrichment would favour a single spectrum with stochastic expressivity.

Show evidence (1 reference)

PMID:24462371 SUPPORT Human Clinical

"The phenotypes of the affected families differed in that one included no extraocular features and the other manifested with highly variable multisystem involvement"

The same gene and lesion class yield isolated and syndromic phenotypes, which is exactly the boundary problem.

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Pathophysiology

7

YAP1 Haploinsufficiency

A heterozygous nonsense variant in YAP1 (c.1066G>T, p.Glu356* in the index syndromic family) introduces a premature termination codon in transcripts from both the canonical and the intron-1 alternative transcription start site, so the mutant transcript is expected to be cleared by nonsense-mediated decay and the affected individual is left with roughly half the normal dose of YAP1 protein. YAP1 is not a structural protein of the eye or palate — it is a transcriptional co-activator — so the lesion is a dosage lesion in a developmental transcriptional program rather than loss of a tissue-specific product. The mechanism is loss of function, not gain of function or dominant-negative action. Note that NMD of this specific allele is predicted rather than measured — no patient-tissue transcript assay has been reported for c.1066G>T — which is why the node is PROVISIONAL rather than ESTABLISHED, and why the NMD-escaping YAP1 frameshift reported by Holt et al. is treated as a genuine complication of the model.

YAP1 hgnc:16262

nonsense-mediated decay of the mutant YAP1 transcript GO:0000184 ↑ INCREASED

YAP1 transcriptional co-activator activity GO:0003713 ↓ DECREASED

Downstream

Reduced YAP-TEAD Transcriptional Output in the Hippo Pathway Halving the dose of the Hippo-pathway effector reduces the amount of nuclear YAP1 available to co-activate TEAD-dependent transcription.

Pleiotropic YAP1 Requirement Across Eye, Ear, Palate, and Kidney Primordia The reduced co-activator dose is imposed simultaneously on every developing tissue that expresses YAP1, which is what converts an ocular lesion into a multisystem syndrome. This edge hangs off the dosage lesion itself rather than off the ocular YAP-TEAD node, because the multi-organ requirement is a property of the germline haploinsufficiency, not a consequence of reduced TEAD output in the eye.

Intellectual Disability Intellectual disability is part of the multisystem phenotype attributed to the heterozygous YAP1 loss-of-function allele, but the intervening neurodevelopmental mechanism is unknown. This edge therefore starts at the upstream dosage lesion rather than at the tissue-expression node; it does not assert that embryonic brain expression explains cognition.

Show evidence (2 references)

PMID:24462371 SUPPORT Computational

"The c. 1066G>T mutation in family 132 should result in NMD in transcripts from either TSS."

A prediction, not a measurement — "should result in NMD" is an inference from premature-termination-codon position, so this supports the haploinsufficiency model only partially.

PMID:35318877 SUPPORT Human Clinical

"We report a de novo mutation in YAP1 that likely results in nonsense-mediated decay. Given the association with YAP1 haploinsufficiency and colobomatous microphthalmia, this novel variant provides a molecular diagnosis for the proband."

An independent case argues for haploinsufficiency rather than a dominant-negative effect, but its own NMD claim is hedged ("likely"), so the support is partial.

Reduced YAP-TEAD Transcriptional Output in the Hippo Pathway

YAP1 is a transcriptional co-activator that, with its paralogue TAZ (WWTR1), acts as the major nuclear effector of the Hippo pathway by binding TEAD1-4 to drive transcription; Hippo activation phosphorylates YAP1 and exports it to the cytoplasm, extinguishing this output. Loss of one YAP1 allele lowers the ceiling of YAP-TEAD transcriptional activity available to developing tissues. Zebrafish work shows this activity is not merely permissive but instructive for ocular fate: Yap/Taz-Tead activity is both necessary and sufficient for optic vesicle progenitors to adopt retinal pigment epithelium identity, and both nuclear localisation and Tead binding are required.

retinal pigment epithelial cell CL:0002586

YAP1 hgnc:16262

hippo signaling GO:0035329 ⚠ ABNORMAL

Animal models

Zebrafish yap1 mutant, alone and with wwtr1 (taz) Danio rerio perturbs Genetic removal of yap1, and of yap1 together with wwtr1, lowers Yap/Taz-Tead output in optic vesicle progenitors — the animal counterpart of the reduced co-activator dose imposed by human YAP1 haploinsufficiency.

Downstream

Failure of Optic Fissure Closure Insufficient YAP-TEAD output in optic vesicle/optic cup progenitors compromises RPE specification and the apposition of the optic cup margins that must fuse to close the optic fissure.

Show evidence (3 references)

PMID:28801591 SUPPORT Other

"YAP1 is a transcriptional co-activator, and in combination with TAZ (encoded by WWTR1), is a major effector of the Hippo pathway to regulate organ size, binding TEAD1-4 to promote transcription"

Defines the molecular activity that is reduced by haploinsufficiency. This is a background/review statement in the paper's introduction rather than a result of the study, hence evidence_source OTHER.

PMID:26209646 SUPPORT Model Organism

"We show that Yap/Taz-Tead activity is necessary and sufficient for optic vesicle progenitors to adopt RPE identity in zebrafish."

Establishes in vivo that YAP-TEAD output instructs the ocular cell fate whose failure underlies coloboma.

PMID:26209646 SUPPORT Model Organism

"The mechanism of Yap-dependent RPE cell type determination is reliant on both nuclear localization of Yap and interaction with a Tead co-factor."

Confirms that the relevant activity is specifically YAP-TEAD co-activation.

Failure of Optic Fissure Closure

The uveal coloboma of this syndrome is an optic fissure closure defect. The optic fissure is a transient groove in the ventral optic cup that must fuse between weeks 5 and 7 of human fetal life; failure of that fusion leaves a persistent ventral gap expressed clinically as an inferonasal iris, chorioretinal, and/or optic disc coloboma, and — when tissue deficiency is severe — as microphthalmia. Williamson et al. framed the entire YAP1 phenotype under this heading, describing both the isolated and the syndromic families as optic fissure closure defects.

retinal pigment epithelial cell CL:0002586

closure of optic fissure GO:0061386 ↓ DECREASED

optic fissure UBERON:0005412

Animal models

Zebrafish yap1 mutant, alone and with wwtr1 (taz) Danio rerio recapitulates yap1 mutants develop coloboma — the optic fissure closure defect itself — alongside the RPE deficiency proposed to underlie it.

Downstream

Uveal Coloboma and Colobomatous Microphthalmia The unclosed ventral fissure is the anatomical substrate of the clinical coloboma; associated tissue deficiency produces the small eye.

Show evidence (2 references)

PMID:35318877 SUPPORT Other

"Uveal colobomata are eye defects that result from failure of the optic fissure of the neuroectoderm-derived optic cup to close between weeks 5-7 of fetal life."

States the developmental mechanism and the developmental window for the cardinal ocular feature. This sentence sits under the literal BACKGROUND heading of DeYoung et al.'s abstract — established developmental biology rather than a result of their case report — hence evidence_source OTHER.

PMID:24462371 SUPPORT Human Clinical

"Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."

The authors frame the whole YAP1 phenotype, syndromic included, as an optic fissure closure defect. Note this quote is the paper's title, i.e. the authors' summary claim rather than a result sentence; the mechanistic detail is supplied by the DeYoung evidence item above.

Pleiotropic YAP1 Requirement Across Eye, Ear, Palate, and Kidney Primordia

This is the node that explains why the syndrome is a syndrome, and it carries the shared developmental mechanism the eye and the face have in common. Whole-mount in situ hybridisation in mouse embryos localises Yap1 to the eye, brain, and the fusing facial processes; nonradioactive in situ hybridisation on staged human embryos localises YAP1 to the retina, the otic vesicle (primitive ear), the primordium of the lateral palatine process, the neural tube, and the renal tubules. Optic fissure closure and palatal/facial process fusion are both epithelial fusion events occurring in overlapping embryonic windows, and both depend on the same dosage-sensitive Hippo effector — so a single haploinsufficient allele perturbs both. The correspondence of this expression domain to the clinical phenotype is close to one-to-one: retina to coloboma, otic vesicle to sensorineural hearing loss, lateral palatine process to cleft lip/palate, neural tube to the discussed neural tube defect, and renal tubules to the haematuria.

YAP1 hgnc:16262

optic fissure UBERON:0005412 primordium of the lateral palatine process UBERON:0005871 otic vesicle UBERON:0003051 neural tube UBERON:0001049

Downstream

Impaired Fusion of the Facial Processes and Palatal Shelves Reduced YAP1 dose in the maxillary/lateral palatine process primordium impairs the fusion events that form the primary and secondary palate.

Sensorineural Hearing Loss The otic-vesicle arm of the same pleiotropic requirement. The hearing loss cosegregates with the YAP1 allele in the index family, and Holt et al. read their otic-vesicle expression as consistent with that phenotype; the intervening steps are unresolved, and no cochlear phenotype has been assayed at reduced YAP1 dose in any system.

Hematuria The renal arm of the same pleiotropic requirement. The haematuria cosegregates with the YAP1 allele in the index family, and Holt et al. read their renal expression as consistent with it; the renal lesion itself is uncharacterised — see the open knowledge-gap discussion.

Show evidence (4 references)

PMID:24462371 SUPPORT Model Organism

"whole-mount in situ hybridization in mouse embryos has shown that Yap1 is strongly expressed in the eye, brain, and fusing facial processes"

Provides the shared-mechanism link between the ocular fissure defect and orofacial clefting: the same gene is expressed in the fusing facial processes.

PMID:28801591 SUPPORT In Vitro

"by CS17 the most prominent expression was observed in the retina, diencephalic superventricle, neural tube, and the primordium of the lateral palatine process"

Human embryonic in situ hybridisation places YAP1 in the retina, neural tube, and palatal primordium simultaneously.

PMID:28801591 SUPPORT In Vitro

"YAP1 was also expressed in the otic vesicle (primitive ear)"

Supplies the developmental correlate of the sensorineural hearing loss in the syndrome.

+ 1 more reference

Impaired Fusion of the Facial Processes and Palatal Shelves

Failure of the medial nasal, maxillary, and palatal shelf fusion events yields the cleft lip and cleft palate of the syndrome. Orphanet records the clefting as variably involving lip, palate, and/or uvula, which is the pattern expected of a partially penetrant, dosage-dependent perturbation of a fusion program rather than a complete block. This node is deliberately kept thin: the generic orofacial clefting cascade is not reproduced here, because the YAP1-specific evidence extends only to expression in the fusing processes and the resulting clinical cleft.

roof of mouth development GO:0060021 ⚠ ABNORMAL face morphogenesis (medial nasal and maxillary prominence fusion) GO:0060325 ⚠ ABNORMAL

primordium of the lateral palatine process UBERON:0005871

Downstream

Cleft Lip Failure of medial nasal and maxillary process fusion yields the cleft of the upper lip.

Cleft Palate Failure of palatal shelf fusion yields the cleft palate; Orphanet records the clefting as variably involving lip, palate, and/or uvula.

Show evidence (2 references)

ORPHA:1473 SUPPORT Other

"uveal coloboma (typically bilateral) variably associated with cleft lip, palate and/or uvula"

Orphanet records the variable lip/palate/uvula clefting pattern of the entity.

PMID:9382148 SUPPORT Human Clinical

"autosomal dominant uveal coloboma and microphthalmos associated with cleft lip and palate"

Documents the clefting as a defining feature of the pedigree.

Uveal Coloboma and Colobomatous Microphthalmia

The clinical ocular endpoint: an inferonasal uveal coloboma that in this entity is typically bilateral and may extend from iris through choroid to the optic disc and macula, with microphthalmia, cataract, and impaired extraocular movement in the fuller expressions. Expression is strikingly variable within the single family, so relatives sharing the allele may range from a minor iris notch to microphthalmia with poor vision — uveal coloboma is nonetheless the most constant feature.

eye UBERON:0000970

Downstream

Uveal Coloboma The clinical uveal coloboma is the direct expression of the unclosed ventral fissure at the level of the uveal tract.

Iris Coloboma Anterior (iris) expression of the same colobomatous defect.

Chorioretinal Coloboma Posterior extension of the same colobomatous defect into choroid and retina.

Optic Disc Coloboma Most posterior extension of the same defect, at the optic disc.

Microphthalmia Where the colobomatous tissue deficiency is severe enough, the globe is also small — colobomatous microphthalmia rather than an isolated cleft.

Show evidence (2 references)

ORPHA:1473 SUPPORT Other

"The spectrum of eye involvement is also variable and includes iris coloboma extending to the choroid, disc, and/or macula, microphthalmia, cataract, and extraocular movement impairment."

Records the ocular spectrum of the entity.

PMID:7154042 SUPPORT Human Clinical

"Considerable variability in expression of the gene is apparent, uveal colobomata being the most constant feature"

Establishes the ocular endpoint as the cardinal, most constant expression of the allele.

Alternative Transcription Start Site Modulation of Phenotype Severity

A candidate explanation for why one YAP1 nonsense family is syndromic and the other is eye-only. YAP1 has an alternative transcription start site in intron 1, widely used in human and mouse development, whose transcripts initiate at codon Met179. The isolated-coloboma allele c.370C>T (p.Arg124*) falls in the 5' UTR of those alternative transcripts and so cannot trigger nonsense-mediated decay in them, leaving a partially rescuing pool of protein; the syndromic allele c.1066G>T (p.Glu356*) lies downstream of both start sites and is predicted to cause NMD of transcripts from either. On this model the syndromic multisystem phenotype of this entity reflects the absence of that alternative-transcript rescue. The model is proposed rather than experimentally demonstrated in patient tissue, and other alleles complicate it — the c.1160delA frameshift escapes NMD altogether yet was inherited from an asymptomatic father.

Position of the YAP1 nonsense allele relative to the intron-1 alternative transcription start site determines whether the phenotype is isolated coloboma or the full multisystem syndrome

YAP1 hgnc:16262

Downstream

YAP1 Haploinsufficiency Whether a given nonsense allele produces true haploinsufficiency, and hence whether the phenotype is eye-only or syndromic, is proposed to depend on its position relative to the alternative start site.

Show evidence (3 references)

PMID:24462371 SUPPORT Computational

"the c.370C>T mutation in family 1305 is within the 5' UTR and cannot result in nonsense-mediated decay"

States that the non-syndromic family's allele lies in the 5' UTR of the alternative transcripts and therefore escapes NMD in them — the positional basis of the proposed rescue. This is a positional inference rather than a transcript measurement, hence COMPUTATIONAL.

PMID:24462371 SUPPORT Other

"Amelioration of the phenotype by the alternative transcripts provides a plausible explanation for the phenotypic differences between the families."

The authors present this explicitly as a plausible explanation, i.e. a hypothesis rather than a demonstrated mechanism. PARTIAL for the same reason this entry marks "should result in NMD" and "likely results in NMD" PARTIAL — the source hedges — and OTHER because the sentence is interpretive discussion rather than a clinical result.

PMID:28801591 SUPPORT Human Clinical

"Thus, the mutation does not lead to either alternate splicing or nonsense mediated decay."

An NMD-escaping YAP1 frameshift inherited from an asymptomatic father shows that NMD status alone does not determine expressivity, so the alternative-TSS model is incomplete.

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Pathograph

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

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Phenotypes

14

Ear 1

Sensorineural Hearing Loss Sensorineural hearing impairment HP:0000407

Show evidence (2 references)

PMID:9382148 SUPPORT Human Clinical

"mid-frequency sensorineural hearing loss"

Documents the audiological phenotype and its frequency profile.

PMID:24462371 SUPPORT Human Clinical

"including hearing loss, intellectual disability, hematuria, and orofacial clefting"

Confirms hearing loss in the YAP1-solved family.

Eye 5

Uveal Coloboma HP:0000589

Onset: CONGENITAL

Show evidence (2 references)

PMID:7154042 SUPPORT Human Clinical

"Considerable variability in expression of the gene is apparent, uveal colobomata being the most constant feature"

Supports the disease-phenotype association and the variable expressivity it sits within. It does not support any frequency band, and none is assigned: "most constant feature" is a comparative claim about coloboma relative to the syndrome's other features, not an absolute rate — coloboma in 9 of 12 subjects (75%) would still be the most constant feature while falling in FREQUENT rather than VERY_FREQUENT.

ORPHA:1473 SUPPORT Other

"characterized by uveal coloboma (typically bilateral) variably associated with cleft lip, palate and/or uvula, hearing impairment, and intellectual disability"

Orphanet builds its definition around uveal coloboma — the entity is "characterized by" it, and every other feature is qualified as "variably associated" — which supports coloboma as the cardinal, diagnostic feature (hence diagnostic: true). It does NOT support a frequency band, and none is assigned. An earlier draft mapped "characterized by" to VERY_FREQUENT as hallmark wording under Pattern C; that was withdrawn on audit, because "characterized by" is the genus-differentia opening of essentially every Orphanet definition rather than one of the frequency terms in the Pattern C table, and because it makes the same comparative contrast (coloboma versus the variably associated features) that made "most constant feature" unusable for a band. No numerator/denominator for the coloboma is published in any cached source, so per docs/frequency-evidence-guidelines.md the frequency is omitted: a missing frequency is honest, a fabricated one is not.

Chorioretinal Coloboma HP:0000567

Onset: CONGENITAL

Show evidence (1 reference)

ORPHA:1473 SUPPORT Other

"iris coloboma extending to the choroid, disc, and/or macula"

Records chorioretinal extension of the colobomatous defect.

Microphthalmia HP:0000568

Onset: CONGENITAL

Show evidence (2 references)

PMID:9382148 SUPPORT Human Clinical

"autosomal dominant uveal coloboma and microphthalmos associated with cleft lip and palate"

Documents microphthalmos in the defining pedigree.

ORPHA:1473 SUPPORT Other

"includes iris coloboma extending to the choroid, disc, and/or macula, microphthalmia, cataract, and extraocular movement impairment"

Orphanet lists microphthalmia within the ocular spectrum.

Cataract HP:0000518

Show evidence (1 reference)

ORPHA:1473 SUPPORT Other

"microphthalmia, cataract, and extraocular movement impairment"

Orphanet lists cataract in the ocular spectrum of the entity.

Impaired Extraocular Movement Abnormality of eye movement HP:0000496

Show evidence (1 reference)

PMID:9382148 SUPPORT Human Clinical

"more recently recognized manifestations include a complete spectrum of eye involvement, impairment of extraocular movement"

Documents impaired extraocular movement in the pedigree.

Genitourinary 1

Hematuria HP:0000790

Show evidence (2 references)

PMID:9382148 SUPPORT Human Clinical

"mid-frequency sensorineural hearing loss, and hematuria"

Documents haematuria in the defining pedigree.

PMID:28801591 SUPPORT Human Clinical

"as haematuria has been reported in some patients with YAP1 mutations"

Indicates haematuria occurs in some YAP1 patients beyond the index family. This is a secondary citation within Holt et al.'s rationale rather than a primary observation of their own, and it says "some" rather than quantifying, hence PARTIAL.

Head and Neck 2

Cleft Lip HP:0410030

Onset: CONGENITAL

Show evidence (2 references)

PMID:7154042 SUPPORT Human Clinical

"autosomal dominantly inherited uveal colobomata, associated eye defects, and cleft lip and palate"

Documents cleft lip in the foundational description of the entity.

PMID:24462371 SUPPORT Human Clinical

"highly variable multisystem involvement, including hearing loss, intellectual disability, hematuria, and orofacial clefting"

Confirms orofacial clefting in the YAP1-solved syndromic family.

Cleft Palate HP:0000175

Onset: CONGENITAL

Show evidence (2 references)

ORPHA:1473 SUPPORT Other

"variably associated with cleft lip, palate and/or uvula"

Records palatal (and uvular) clefting as part of the entity.

PMID:7154042 SUPPORT Human Clinical

"uveal colobomata, associated eye defects, and cleft lip and palate"

Documents cleft palate in the foundational description of the entity.

Nervous System 1

Intellectual Disability HP:0001249

Show evidence (2 references)

PMID:24462371 SUPPORT Human Clinical

"highly variable multisystem involvement, including hearing loss, intellectual disability, hematuria, and orofacial clefting"

Names intellectual disability as a manifestation of the YAP1-solved syndromic family, without a frequency.

PMID:7154042 SUPPORT Human Clinical

"the full syndrome probably includes mental retardation of varying degree"

The foundational report hedges (probably), which is why this item is recorded as PARTIAL despite the feature naming the syndrome.

Other 4

Iris Coloboma HP:0000612

Onset: CONGENITAL

Show evidence (1 reference)

ORPHA:1473 SUPPORT Other

"includes iris coloboma extending to the choroid, disc, and/or macula"

Records iris involvement as the anterior pole of the colobomatous defect.

Optic Disc Coloboma HP:0000588

Onset: CONGENITAL

Show evidence (1 reference)

ORPHA:1473 SUPPORT Other

"extending to the choroid, disc, and/or macula"

Records disc involvement within the colobomatous spectrum.

Specific Learning Disability FREQUENT HP:0001328

Show evidence (1 reference)

PMID:9382148 SUPPORT Human Clinical

"Learning difficulties requiring remedial teaching were present in one third of those affected"

Frequency derivation: one third of affected members (~33%) falls squarely in the HPO FREQUENT band (30-79%). The count is reported for learning difficulties requiring remedial teaching, which is what this phenotype records, so the band and the phenotype term are matched.

Neural Tube Defect HP:0045005

Show evidence (2 references)

PMID:9382148 SUPPORT Human Clinical

"a neural tube defect has occurred in one presumed affected member"

A single observation in a presumed affected member; the authors' own hedging (presumed) is why this is PARTIAL and carries no frequency.

PMID:7154042 SUPPORT Human Clinical

"The possibility of association with neural tube defect is discussed."

The foundational report frames the neural tube defect link as a possibility under discussion, not an established feature.

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Genetic Associations

1

YAP1 (Heterozygous loss-of-function (nonsense and frameshift) variants in YAP1 cause dominantly inherited optic fissure closure defects. The syndromic form corresponding to this entity segregates the nonsense allele c.1066G>T (p.Glu356*), predicted to trigger nonsense-mediated decay in transcripts from both the canonical and the intron-1 alternative transcription start site.)

Gene: YAP1 hgnc:16262 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:24462371 SUPPORT Human Clinical

"Exome sequence analysis of affected individuals from two families with autosomal-dominant inheritance of coloboma identified two different cosegregating heterozygous nonsense mutations"

Identifies the causal YAP1 nonsense alleles in the two coloboma pedigrees.

PMID:24462371 SUPPORT Human Clinical

"The phenotypes of the affected families differed in that one included no extraocular features and the other manifested with highly variable multisystem involvement, including hearing loss, intellectual disability, hematuria, and orofacial clefting."

Assigns the syndromic (extraocular) phenotype — the phenotype of this entity — to one of the two YAP1 families.

PMID:28801591 SUPPORT Other

"In addition to the eye anomalies, affected members of one family also exhibited variable extraocular features including hearing loss, intellectual disability, haematuria and orofacial clefting"

Restates the YAP1 syndromic phenotype attribution. This sentence sits in Holt et al.'s introduction and carries their citations 7 and 8 — it is a secondary citation of Williamson et al., not an observation of their own — so it corroborates the attribution as received knowledge rather than independently, hence PARTIAL and evidence_source OTHER.

🔬

Variants

1

NM_001130145:c.1066G>T (p.Glu356*) Pathogenic

Gene: YAP1 hgnc:16262 nonsense

The cosegregating heterozygous nonsense allele identified in the syndromic family (family 132) that defines this entity. It lies downstream of both the canonical and the intron-1 alternative transcription start sites and is therefore predicted to cause nonsense-mediated decay of transcripts from either, producing true YAP1 haploinsufficiency.

Functional effects

LOSS_OF_FUNCTION

A premature termination codon downstream of both transcription start sites, predicted to clear the mutant transcript by nonsense-mediated decay and so to halve the functional YAP1 dose. Loss of function, not dominant-negative or gain of function: the independent de novo YAP1 frameshift case is argued on haploinsufficiency, and no cached source proposes a dominant-negative mechanism for any YAP1 coloboma allele.

Show evidence (2 references)

PMID:24462371 SUPPORT Human Clinical

"The c. 1066G>T mutation in family 132 should result in NMD in transcripts from either TSS."

Identifies the allele of the syndromic family and its predicted NMD consequence.

PMID:24462371 SUPPORT Human Clinical

"two different cosegregating heterozygous nonsense mutations"

Basis for type: nonsense and for clinical_significance: PATHOGENIC — the allele is a nonsense variant in an established disease gene, cosegregating with the phenotype (the combined LOD of 4.2 is quoted in the inheritance block). Note this is the authors' segregation-based attribution, not a formal ACMG/AMP classification, which no cached source reports.

💊

Medical Actions

1

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Other

The one intervention with disease-specific content in this entity. Counseling must convey a 50% per-conception transmission risk for a heterozygous carrier, but also that neither the presence nor the severity of expression can be predicted from the genotype: expressivity within the single defining pedigree ranges from a minor ocular sign to microphthalmia with clefting, hearing loss and learning difficulty, and YAP1 loss-of-function alleles have been transmitted by clinically unaffected carriers. Cascade testing of at-risk relatives should therefore be paired with ophthalmic examination rather than relied on alone.

Show evidence (2 references)

PMID:7154042 SUPPORT Human Clinical

"Considerable variability in expression of the gene is apparent"

Establishes the variable expressivity that counseling must convey; it is why a genotype-based severity prediction cannot be offered.

PMID:28801591 SUPPORT Human Clinical

"the variant was identified in the heterozygous state in the asymptomatic father"

Documents transmission of a YAP1 loss-of-function allele by a clinically unaffected carrier, the incomplete-penetrance point that counseling and cascade testing must account for.

🔬

Diagnosis

1

Molecular Genetic Testing for YAP1

There is no biochemical marker, imaging finding, or diagnostic criteria guideline specific to this entity, so diagnosis rests on recognising congenital uveal coloboma (particularly bilateral, and particularly with clefting, hearing loss, developmental impairment, or haematuria in a dominant pedigree) and confirming a heterozygous YAP1 loss-of-function variant by exome/genome sequencing or a developmental-eye-disorder panel that includes YAP1. Segregation analysis matters because YAP1 alleles show incomplete penetrance, so an unaffected parent may carry the variant.

molecular genetic testing NCIT:C15709

Show evidence (2 references)

PMID:35318877 SUPPORT Human Clinical

"Whole-genome sequencing of the coding regions and intron-exon boundaries confirmed a mutation in the proband. These genetic findings were verified using the Sanger method of DNA sequencing."

Illustrates the sequencing-based diagnostic route used to establish the molecular diagnosis in a YAP1 coloboma case.

PMID:28801591 SUPPORT Human Clinical

"Parental DNA samples were sequenced for both strands of exon 7, and the variant was identified in the heterozygous state in the asymptomatic father"

Demonstrates why parental segregation testing is required for interpretation: a YAP1 loss-of-function allele may be non-penetrant.

📊

Prevalence

1

Worldwide

Cases In Literature Unknown

No population prevalence estimate exists and none should be inferred. The entity is defined by a single multigenerational pedigree — twelve affected subjects over three generations in the original report, which is also the basis for Orphanet's case count. The broader YAP1 developmental-eye-disorder spectrum is likewise reported only as individual families and singleton cases: YAP1 screening of 258 undiagnosed UK developmental-eye-disorder patients yielded a single novel candidate variant. Prevalence figures for coloboma or the microphthalmia-anophthalmia-coloboma spectrum as a whole must NOT be substituted for this entity.

Show evidence (3 references)

PMID:7154042 SUPPORT Human Clinical

"occurring in twelve subjects over three generations"

Gives the total case count on which the entity rests — twelve affected individuals in one family.

PMID:9382148 SUPPORT Other

"Ocular colobomas and microphthalmos, isolated or as part of a syndrome, are usually sporadic and only rarely found in large families."

Frames the entity as an exceptional familial occurrence rather than a population-characterised disorder. This is Ravine et al.'s opening background sentence about coloboma in general, not a result of their re-evaluation, hence evidence_source OTHER.

PMID:28801591 SUPPORT Human Clinical

"we screened YAP1 for variants in a cohort of 258 undiagnosed UK patients with developmental eye disorders, including anophthalmia, microphthalmia and coloboma"

Indicates the rarity of YAP1 variants among developmental eye disorder patients; only one novel candidate was recovered from 258 screened.

🔀

Differential Diagnoses

7

Conditions with similar clinical presentations that must be differentiated from Uveal Coloboma-Cleft Lip and Palate-Intellectual Disability Syndrome:

CHARGE Syndrome

Overlapping Features CHARGE syndrome (CHD7) is the principal differential because it also pairs coloboma with orofacial clefting, hearing loss, and developmental delay. Features favouring CHARGE are choanal atresia, characteristic external and inner ear anomalies with semicircular canal hypoplasia, cranial nerve dysfunction, and cardiac defects, none of which characterise the YAP1 entity; molecular testing (CHD7 versus YAP1) is definitive. Deliberate note for curators and deep-research tools: coloboma-plus-clefting reports very often concern CHARGE, and CHARGE literature must not be imported into this entry.

Isolated Uveal Coloboma and the Microphthalmia-Anophthalmia-Coloboma Spectrum

Overlapping Features Non-syndromic coloboma — including the isolated YAP1-related coloboma family of Williamson et al. — shares the ocular phenotype but lacks the clefting, hearing loss, intellectual disability, and haematuria. The MAC spectrum is genetically heterogeneous (SOX2, OTX2, BMP4, BMP7, STRA6 among others), and YAP1 accounts for only a small share of it.

Branchio-Oculo-Facial Syndrome

Overlapping Features TFAP2A-related branchio-oculo-facial syndrome also combines ocular anomalies (including coloboma and microphthalmia) with orofacial clefting, but is distinguished by cervical/infra-auricular branchial skin defects, a characteristic facies with a broad nasal bridge, ectopic thymus, and premature greying.

Cat-Eye Syndrome

Overlapping Features Cat-eye syndrome (chromosome 22q11 tetrasomy from a supernumerary bisatellited marker chromosome) presents with iris coloboma, anal atresia, preauricular pits and tags, and cardiac and renal anomalies. It is excluded by karyotype or chromosomal microarray rather than by phenotype alone.

Renal Coloboma (Papillorenal) Syndrome

Overlapping Features PAX2-related renal coloboma syndrome is the highest-yield differential for the specific combination of coloboma with urinary-tract findings, which is exactly the combination this entry curates (coloboma plus haematuria). Distinguishing features are the characteristic optic nerve dysplasia (morning-glory-like disc, excavated with anomalous vessels) rather than a simple inferonasal uveal coloboma, and structural renal hypodysplasia with vesicoureteral reflux and progressive renal insufficiency — as opposed to the isolated, uncharacterised haematuria of the YAP1 entity. Orofacial clefting is not a feature of PAX2 disease. Molecular testing separates them.

Kabuki Syndrome

Overlapping Features KMT2D/KDM6A-related Kabuki syndrome pairs coloboma with intellectual disability, cleft lip/palate, hearing loss, and renal anomalies, so it overlaps this entity on every named element. It is distinguished by the characteristic facies (long palpebral fissures with eversion of the lateral lower lid, arched sparse eyebrows, large prominent ears), persistent fetal fingertip pads, postnatal growth deficiency, hypotonia, and recurrent otitis media, none of which characterise the YAP1 entity.

Baraitser-Winter Cerebrofrontofacial Syndrome

Overlapping Features ACTB/ACTG1-related Baraitser-Winter syndrome also features coloboma with intellectual disability, but is distinguished by ptosis, hypertelorism, a characteristic broad facies, and — critically — cortical malformations such as pachygyria or lissencephaly on brain imaging, which are not a feature of the YAP1 entity.

🐁

Animal Models

1

Zebrafish yap1 mutant, alone and with wwtr1 (taz)

Zebrafish yap1 mutants lack a subset of retinal pigment epithelium and/or develop coloboma, and combined loss of yap and taz abolishes the ability of optic vesicle progenitors to form RPE at all. This is the closest available model of the ocular arm of the syndrome and the source of the instructive (not merely permissive) role of Yap/Taz-Tead in RPE fate. It does not model the clefting, hearing loss, or intellectual disability arms.

Species

Danio rerio

Genotype

yap1 (yap) loss-of-function mutant, alone and combined with wwtr1 (taz)

Publication

PMID:26209646

Pathograph links

Reduced YAP-TEAD Transcriptional Output in the Hippo Pathway perturbs fidelity: moderate Genetic removal of yap1, and of yap1 together with wwtr1, lowers Yap/Taz-Tead output in optic vesicle progenitors — the animal counterpart of the reduced co-activator dose imposed by human YAP1 haploinsufficiency.

Limitations: Homozygous null and double-mutant genotypes model a far deeper loss of output than a human heterozygous nonsense allele, so the model addresses the direction of the lesion rather than its dose.

Readouts

Ability of optic vesicle progenitors to form RPE

Direction: ABOLISHED

Interpretation: The functional consequence of removing that output: complete loss of RPE-forming capacity when both Yap and Taz are absent establishes the requirement as instructive, not merely permissive. Note this measures the capacity the node's output confers, not a direct measurement of transcriptional output in the mutant.

Show evidence (1 reference)

PMID:26209646 SUPPORT Model Organism

"when Yap and Taz are both absent, optic vesicle progenitor cells completely lose their ability to form RPE"

Reports the measured loss of RPE-forming capacity behind this readout.

Show evidence (1 reference)

PMID:26209646 SUPPORT Model Organism

"The mechanism of Yap-dependent RPE cell type determination is reliant on both nuclear localization of Yap and interaction with a Tead co-factor."

Confirms the model reports specifically on YAP-TEAD co-activation, the activity this node describes.

Failure of Optic Fissure Closure recapitulates fidelity: moderate yap1 mutants develop coloboma — the optic fissure closure defect itself — alongside the RPE deficiency proposed to underlie it.

Limitations: The zygosity mismatch bites hardest here, on the stronger claim: the coloboma is scored in homozygous yap1 nulls, whereas the human disorder is caused by a heterozygous nonsense allele, so the model recapitulates the lesion's direction and not its dose. Zebrafish ocular morphogenesis is also not identical to the human weeks-5-to-7 fissure closure window, and the model does not reproduce the clefting, hearing loss, haematuria, or intellectual disability arms of the syndrome.

Readouts

Coloboma incidence in yap1 mutants

Direction: INCREASED

Interpretation: Coloboma arising on loss of yap1 is the model's direct correlate of the human optic fissure closure defect.

Show evidence (1 reference)

PMID:26209646 SUPPORT Model Organism

"yap (yap1) mutants lack a subset of RPE cells and/or exhibit coloboma."

Reports the coloboma scored in the mutants.

Retinal pigment epithelium cell number in yap1 mutants

Direction: DECREASED

Interpretation: The RPE deficiency that accompanies the coloboma, recorded separately because it moves in the opposite direction from coloboma incidence and cannot share a single direction value with it.

Show evidence (1 reference)

PMID:26209646 SUPPORT Model Organism

"yap (yap1) mutants lack a subset of RPE cells and/or exhibit coloboma."

Reports the RPE cell deficiency scored in the mutants.

Show evidence (1 reference)

PMID:26209646 SUPPORT Model Organism

"provides a mechanistic framework for understanding the congenital ocular defects of Sveinsson's chorioretinal atrophy and congenital retinal coloboma"

The authors position the model as a mechanistic framework for congenital retinal coloboma, which is what this node curates.

Show evidence (2 references)

PMID:26209646 SUPPORT Model Organism

"yap (yap1) mutants lack a subset of RPE cells and/or exhibit coloboma."

Establishes the zebrafish yap1 mutant as a model of the coloboma arm of the human phenotype.

PMID:26209646 SUPPORT Model Organism

"Loss of RPE in yap mutants is exacerbated in combination with taz (wwtr1) mutant alleles such that, when Yap and Taz are both absent, optic vesicle progenitor cells completely lose their ability to form RPE."

Demonstrates the dosage-dependent Yap/Taz requirement in ocular development.

{ }

Source YAML

click to show

name: Uveal Coloboma-Cleft Lip and Palate-Intellectual Disability Syndrome
creation_date: "2026-08-01T00:00:00Z"
description: >-
  An ultra-rare autosomal dominant multiple congenital anomaly syndrome (COB1;
  MONDO:0007355, OMIM:120433, ORPHA:1473) combining uveal (iris/chorioretinal)
  coloboma with orofacial clefting and variable intellectual disability. The
  entity rests on a single large British pedigree: Kingston, Harper and Jones
  described twelve affected subjects over three generations in 1982, and Ravine
  and colleagues re-evaluated a four-generation Cardiff family in 1997 as a
  dominant coloboma-microphthalmos syndrome that also featured mid-frequency
  sensorineural hearing loss and haematuria. Williamson et al. subsequently
  identified a cosegregating heterozygous nonsense variant in YAP1 (c.1066G>T,
  p.Glu356*) in their syndromic pedigree (family 132), establishing YAP1
  haploinsufficiency as the molecular cause of that phenotype. That this is the
  same pedigree as the 1982 and 1997 reports is inferred from author and
  institutional overlap and is not asserted in any abstract — see the notes
  block. YAP1 encodes the Hippo-pathway transcriptional co-activator
  Yes-associated protein 1, which is expressed in the developing human retina,
  otic vesicle, palatine process primordium, neural tube, and renal tubules — a
  pleiotropic expression domain that maps closely onto the eye, ear, palate,
  neural tube, and kidney features of the syndrome, and that supplies the shared
  developmental logic linking failed optic fissure closure to failed facial
  process fusion. Deliberately scoped: this entry models the YAP1-attributable
  syndromic arm and does NOT reproduce generic coloboma or generic orofacial
  clefting biology.
category: Mendelian
parents:
- hereditary disease
- developmental eye disorder
- multiple congenital anomalies/dysmorphic syndrome-intellectual disability
synonyms:
- COB1
- coloboma, ocular, with or without hearing impairment, cleft lip/palate, and/or intellectual disability
- coloboma-microphthalmos syndrome associated with sensorineural hearing loss, hematuria, and cleft lip/palate
- uveal coloboma-cleft lip/palate-intellectual disability syndrome
- syndromic YAP1-related ocular coloboma
disease_term:
  preferred_term: uveal coloboma-cleft lip and palate-intellectual disability
  term:
    id: MONDO:0007355
    label: uveal coloboma-cleft lip and palate-intellectual disability
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0007355
      label: uveal coloboma-cleft lip and palate-intellectual disability
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:1473
    mapping_justification: >-
      Orphanet ORPHA:1473 lists MONDO:0007355 and OMIM:120433 as exact
      cross-references, independently confirming the entity identity used for
      the named-entity-confusion preflight of this entry.
references:
- reference: PMID:7154042
  title: "An autosomal dominant syndrome of uveal colobomata, cleft lip and palate, and mental retardation."
- reference: PMID:9382148
  title: "Dominant coloboma-microphthalmos syndrome associated with sensorineural hearing loss, hematuria, and cleft lip/palate."
- reference: PMID:24462371
  title: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
- reference: PMID:26209646
  title: "Yap and Taz regulate retinal pigment epithelial cell fate."
- reference: PMID:28801591
  title: "New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders."
- reference: PMID:35318877
  title: "De novo frameshift mutation in YAP1 associated with bilateral uveal coloboma and microphthalmia."
- reference: ORPHA:1473
  title: "Uveal coloboma-cleft lip and palate-intellectual disability"
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  expressivity: VARIABLE
  penetrance: INCOMPLETE
  description: >-
    Autosomal dominant transmission through the index family, documented over
    three generations in the 1982 report and across four generations on
    re-evaluation. Expressivity is strikingly variable within that single
    pedigree, ranging from a minor ocular sign to microphthalmia with clefting,
    hearing loss and intellectual disability. The causal YAP1 nonsense allele
    cosegregated with the phenotype (combined LOD 4.2 across the two YAP1
    coloboma families reported by Williamson et al.). Incomplete penetrance has
    been documented for other YAP1 loss-of-function alleles in coloboma families
    — a later frameshift allele was inherited from an asymptomatic father — so
    unaffected carriers should be expected.
  evidence:
  - reference: PMID:7154042
    reference_title: "An autosomal dominant syndrome of uveal colobomata, cleft lip and palate, and mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report details a family in whom there is autosomal dominantly inherited uveal colobomata, associated eye defects, and cleft lip and palate occurring in twelve subjects over three generations."
    explanation: >-
      The foundational report establishes autosomal dominant transmission in the
      pedigree that defines the entity.
  - reference: PMID:7154042
    reference_title: "An autosomal dominant syndrome of uveal colobomata, cleft lip and palate, and mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Considerable variability in expression of the gene is apparent"
    explanation: Supports the VARIABLE expressivity assignment.
  - reference: PMID:24462371
    reference_title: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A combined LOD score of 4.2 was obtained for the association between YAP1 loss-of-function mutations and the phenotype in these families."
    explanation: Quantifies cosegregation of the dominant YAP1 allele with the phenotype.
  - reference: PMID:28801591
    reference_title: "New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the variant was identified in the heterozygous state in the asymptomatic father"
    explanation: >-
      Documents non-penetrance of a YAP1 loss-of-function allele, supporting the
      incomplete-penetrance caveat.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    No population prevalence estimate exists and none should be inferred. The
    entity is defined by a single multigenerational pedigree — twelve affected
    subjects over three generations in the original report, which is also the
    basis for Orphanet's case count. The broader YAP1 developmental-eye-disorder
    spectrum is likewise reported only as individual families and singleton
    cases: YAP1 screening of 258 undiagnosed UK developmental-eye-disorder
    patients yielded a single novel candidate variant. Prevalence figures for
    coloboma or the microphthalmia-anophthalmia-coloboma spectrum as a whole must
    NOT be substituted for this entity.
  evidence:
  - reference: PMID:7154042
    reference_title: "An autosomal dominant syndrome of uveal colobomata, cleft lip and palate, and mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "occurring in twelve subjects over three generations"
    explanation: >-
      Gives the total case count on which the entity rests — twelve affected
      individuals in one family.
  - reference: PMID:9382148
    reference_title: "Dominant coloboma-microphthalmos syndrome associated with sensorineural hearing loss, hematuria, and cleft lip/palate."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Ocular colobomas and microphthalmos, isolated or as part of a syndrome, are usually sporadic and only rarely found in large families."
    explanation: >-
      Frames the entity as an exceptional familial occurrence rather than a
      population-characterised disorder. This is Ravine et al.'s opening
      background sentence about coloboma in general, not a result of their
      re-evaluation, hence evidence_source OTHER.
  - reference: PMID:28801591
    reference_title: "New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we screened YAP1 for variants in a cohort of 258 undiagnosed UK patients with developmental eye disorders, including anophthalmia, microphthalmia and coloboma"
    explanation: >-
      Indicates the rarity of YAP1 variants among developmental eye disorder
      patients; only one novel candidate was recovered from 258 screened.
genetic:
- name: YAP1
  gene_term:
    preferred_term: YAP1
    term:
      id: hgnc:16262
      label: YAP1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  association: >-
    Heterozygous loss-of-function (nonsense and frameshift) variants in YAP1
    cause dominantly inherited optic fissure closure defects. The syndromic
    form corresponding to this entity segregates the nonsense allele c.1066G>T
    (p.Glu356*), predicted to trigger nonsense-mediated decay in transcripts
    from both the canonical and the intron-1 alternative transcription start
    site.
  notes: >-
    The causal gene IS established for this entity — MONDO:0007355 carries the
    YAP1 gene association (RO:0004003 HGNC:16262), and the defining pedigree is
    the syndromic family (family 132) of Williamson et al. 2014. No second gene
    has been implicated, and no modifier gene, founder allele, epigenetic
    signature, or recurrent rearrangement is known. Genotype-phenotype
    correlation within YAP1 remains incomplete: the isolated-coloboma family
    carried c.370C>T (p.Arg124*), and later reported alleles include a
    non-NMD frameshift (c.1160delA, p.Asn387Thrfs*16) inherited from an
    asymptomatic father and a de novo c.178dupG (p.Asp60GlyfsTer52). Missense
    alleles reported in YAP1 coloboma families should not be assumed pathogenic
    without segregation and ACMG/AMP assessment.
  evidence:
  - reference: PMID:24462371
    reference_title: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequence analysis of affected individuals from two families with autosomal-dominant inheritance of coloboma identified two different cosegregating heterozygous nonsense mutations"
    explanation: Identifies the causal YAP1 nonsense alleles in the two coloboma pedigrees.
  - reference: PMID:24462371
    reference_title: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenotypes of the affected families differed in that one included no extraocular features and the other manifested with highly variable multisystem involvement, including hearing loss, intellectual disability, hematuria, and orofacial clefting."
    explanation: >-
      Assigns the syndromic (extraocular) phenotype — the phenotype of this
      entity — to one of the two YAP1 families.
  - reference: PMID:28801591
    reference_title: "New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In addition to the eye anomalies, affected members of one family also exhibited variable extraocular features including hearing loss, intellectual disability, haematuria and orofacial clefting"
    explanation: >-
      Restates the YAP1 syndromic phenotype attribution. This sentence sits in
      Holt et al.'s introduction and carries their citations 7 and 8 — it is a
      secondary citation of Williamson et al., not an observation of their own —
      so it corroborates the attribution as received knowledge rather than
      independently, hence PARTIAL and evidence_source OTHER.
variants:
- name: "NM_001130145:c.1066G>T (p.Glu356*)"
  description: >-
    The cosegregating heterozygous nonsense allele identified in the syndromic
    family (family 132) that defines this entity. It lies downstream of both the
    canonical and the intron-1 alternative transcription start sites and is
    therefore predicted to cause nonsense-mediated decay of transcripts from
    either, producing true YAP1 haploinsufficiency.
  gene:
    preferred_term: YAP1
    term:
      id: hgnc:16262
      label: YAP1
  type: nonsense
  clinical_significance: PATHOGENIC
  functional_effects:
  - function: LOSS_OF_FUNCTION
    description: >-
      A premature termination codon downstream of both transcription start
      sites, predicted to clear the mutant transcript by nonsense-mediated decay
      and so to halve the functional YAP1 dose. Loss of function, not
      dominant-negative or gain of function: the independent de novo YAP1
      frameshift case is argued on haploinsufficiency, and no cached source
      proposes a dominant-negative mechanism for any YAP1 coloboma allele.
  evidence:
  - reference: PMID:24462371
    reference_title: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The c. 1066G>T mutation in family 132 should result in NMD in transcripts from either TSS."
    explanation: >-
      Identifies the allele of the syndromic family and its predicted NMD
      consequence.
  - reference: PMID:24462371
    reference_title: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two different cosegregating heterozygous nonsense mutations"
    explanation: >-
      Basis for type: nonsense and for clinical_significance: PATHOGENIC — the
      allele is a nonsense variant in an established disease gene, cosegregating
      with the phenotype (the combined LOD of 4.2 is quoted in the inheritance
      block). Note this is the authors' segregation-based attribution, not a
      formal ACMG/AMP classification, which no cached source reports.
pathophysiology:
- name: YAP1 Haploinsufficiency
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    A heterozygous nonsense variant in YAP1 (c.1066G>T, p.Glu356* in the index
    syndromic family) introduces a premature termination codon in transcripts
    from both the canonical and the intron-1 alternative transcription start
    site, so the mutant transcript is expected to be cleared by
    nonsense-mediated decay and the affected individual is left with roughly
    half the normal dose of YAP1 protein. YAP1 is not a structural protein of
    the eye or palate — it is a transcriptional co-activator — so the lesion is
    a dosage lesion in a developmental transcriptional program rather than loss
    of a tissue-specific product. The mechanism is loss of function, not gain of
    function or dominant-negative action. Note that NMD of this specific allele
    is predicted rather than measured — no patient-tissue transcript assay has
    been reported for c.1066G>T — which is why the node is PROVISIONAL rather
    than ESTABLISHED, and why the NMD-escaping YAP1 frameshift reported by Holt
    et al. is treated as a genuine complication of the model.
  gene:
    preferred_term: YAP1
    term:
      id: hgnc:16262
      label: YAP1
  biological_processes:
  - preferred_term: nonsense-mediated decay of the mutant YAP1 transcript
    term:
      id: GO:0000184
      label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
    modifier: INCREASED
  molecular_functions:
  - preferred_term: YAP1 transcriptional co-activator activity
    term:
      id: GO:0003713
      label: transcription coactivator activity
    modifier: DECREASED
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:24462371
    reference_title: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "The c. 1066G>T mutation in family 132 should result in NMD in transcripts from either TSS."
    explanation: >-
      A prediction, not a measurement — "should result in NMD" is an inference
      from premature-termination-codon position, so this supports the
      haploinsufficiency model only partially.
  - reference: PMID:35318877
    reference_title: "De novo frameshift mutation in YAP1 associated with bilateral uveal coloboma and microphthalmia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a de novo mutation in YAP1 that likely results in nonsense-mediated decay. Given the association with YAP1 haploinsufficiency and colobomatous microphthalmia, this novel variant provides a molecular diagnosis for the proband."
    explanation: >-
      An independent case argues for haploinsufficiency rather than a
      dominant-negative effect, but its own NMD claim is hedged ("likely"), so
      the support is partial.
  downstream:
  - target: Reduced YAP-TEAD Transcriptional Output in the Hippo Pathway
    description: >-
      Halving the dose of the Hippo-pathway effector reduces the amount of
      nuclear YAP1 available to co-activate TEAD-dependent transcription.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24462371
      reference_title: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "YAP1 encodes an effector of the HIPPO-pathway-induced growth response"
      explanation: >-
        Places the haploinsufficient product in the Hippo signalling pathway.
        This is a background statement of gene function rather than a clinical
        result of the study, hence evidence_source OTHER — the same treatment
        given to the equivalent Holt et al. statement on the node below.
  - target: Pleiotropic YAP1 Requirement Across Eye, Ear, Palate, and Kidney Primordia
    description: >-
      The reduced co-activator dose is imposed simultaneously on every developing
      tissue that expresses YAP1, which is what converts an ocular lesion into a
      multisystem syndrome. This edge hangs off the dosage lesion itself rather
      than off the ocular YAP-TEAD node, because the multi-organ requirement is a
      property of the germline haploinsufficiency, not a consequence of reduced
      TEAD output in the eye.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28801591
      reference_title: "New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "YAP1 expression was observed in multiple structures at CS15"
      explanation: >-
        A static expression observation. It establishes that the affected
        tissues express YAP1 during the relevant window, but it does not itself
        demonstrate that reduced dose causes the multi-organ phenotype, hence
        PARTIAL.
  - target: Intellectual Disability
    description: >-
      Intellectual disability is part of the multisystem phenotype attributed
      to the heterozygous YAP1 loss-of-function allele, but the intervening
      neurodevelopmental mechanism is unknown. This edge therefore starts at
      the upstream dosage lesion rather than at the tissue-expression node;
      it does not assert that embryonic brain expression explains cognition.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24462371
      reference_title: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "highly variable multisystem involvement, including hearing loss, intellectual disability, hematuria, and orofacial clefting"
      explanation: >-
        Names intellectual disability among the multisystem features of the
        YAP1-solved syndromic family, supporting disease-level attribution to
        the dosage lesion while leaving the causal intermediates unresolved.
    - reference: PMID:28801591
      reference_title: "New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "such correlations must still be approached with caution"
      explanation: >-
        A Discussion caveat rather than an experimental result. Its immediate
        clinical referent is Asperger syndrome in Holt et al.'s Case 1, set
        beside intellectual disability in other YAP1 families and embryonic
        brain expression. It does not independently support this edge; it is
        retained as a PARTIAL qualification on inferring a neurodevelopmental
        mechanism from the expression pattern.
- name: Reduced YAP-TEAD Transcriptional Output in the Hippo Pathway
  role: intermediate
  biological_scale: MOLECULAR
  description: >-
    YAP1 is a transcriptional co-activator that, with its paralogue TAZ
    (WWTR1), acts as the major nuclear effector of the Hippo pathway by binding
    TEAD1-4 to drive transcription; Hippo activation phosphorylates YAP1 and
    exports it to the cytoplasm, extinguishing this output. Loss of one YAP1
    allele lowers the ceiling of YAP-TEAD transcriptional activity available to
    developing tissues. Zebrafish work shows this activity is not merely
    permissive but instructive for ocular fate: Yap/Taz-Tead activity is both
    necessary and sufficient for optic vesicle progenitors to adopt retinal
    pigment epithelium identity, and both nuclear localisation and Tead binding
    are required.
  gene:
    preferred_term: YAP1
    term:
      id: hgnc:16262
      label: YAP1
  biological_processes:
  - preferred_term: hippo signaling
    term:
      id: GO:0035329
      label: hippo signaling
    modifier: ABNORMAL
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:28801591
    reference_title: "New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "YAP1 is a transcriptional co-activator, and in combination with TAZ (encoded by WWTR1), is a major effector of the Hippo pathway to regulate organ size, binding TEAD1-4 to promote transcription"
    explanation: >-
      Defines the molecular activity that is reduced by haploinsufficiency. This
      is a background/review statement in the paper's introduction rather than a
      result of the study, hence evidence_source OTHER.
  - reference: PMID:26209646
    reference_title: "Yap and Taz regulate retinal pigment epithelial cell fate."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We show that Yap/Taz-Tead activity is necessary and sufficient for optic vesicle progenitors to adopt RPE identity in zebrafish."
    explanation: >-
      Establishes in vivo that YAP-TEAD output instructs the ocular cell fate
      whose failure underlies coloboma.
  - reference: PMID:26209646
    reference_title: "Yap and Taz regulate retinal pigment epithelial cell fate."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The mechanism of Yap-dependent RPE cell type determination is reliant on both nuclear localization of Yap and interaction with a Tead co-factor."
    explanation: Confirms that the relevant activity is specifically YAP-TEAD co-activation.
  downstream:
  - target: Failure of Optic Fissure Closure
    description: >-
      Insufficient YAP-TEAD output in optic vesicle/optic cup progenitors
      compromises RPE specification and the apposition of the optic cup margins
      that must fuse to close the optic fissure.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - loss of Yap/Taz-Tead-dependent retinal pigment epithelium specification
    evidence:
    - reference: PMID:26209646
      reference_title: "Yap and Taz regulate retinal pigment epithelial cell fate."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "yap (yap1) mutants lack a subset of RPE cells and/or exhibit coloboma."
      explanation: >-
        Directly links loss of yap1 to RPE deficiency and coloboma in a
        vertebrate model.
- name: Failure of Optic Fissure Closure
  role: intermediate
  biological_scale: TISSUE
  description: >-
    The uveal coloboma of this syndrome is an optic fissure closure defect. The
    optic fissure is a transient groove in the ventral optic cup that must fuse
    between weeks 5 and 7 of human fetal life; failure of that fusion leaves a
    persistent ventral gap expressed clinically as an inferonasal iris,
    chorioretinal, and/or optic disc coloboma, and — when tissue deficiency is
    severe — as microphthalmia. Williamson et al. framed the entire YAP1
    phenotype under this heading, describing both the isolated and the syndromic
    families as optic fissure closure defects.
  locations:
  - preferred_term: optic fissure
    term:
      id: UBERON:0005412
      label: optic fissure
  biological_processes:
  - preferred_term: closure of optic fissure
    term:
      id: GO:0061386
      label: closure of optic fissure
    modifier: DECREASED
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:35318877
    reference_title: "De novo frameshift mutation in YAP1 associated with bilateral uveal coloboma and microphthalmia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Uveal colobomata are eye defects that result from failure of the optic fissure of the neuroectoderm-derived optic cup to close between weeks 5-7 of fetal life."
    explanation: >-
      States the developmental mechanism and the developmental window for the
      cardinal ocular feature. This sentence sits under the literal BACKGROUND
      heading of DeYoung et al.'s abstract — established developmental biology
      rather than a result of their case report — hence evidence_source OTHER.
  - reference: PMID:24462371
    reference_title: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
    explanation: >-
      The authors frame the whole YAP1 phenotype, syndromic included, as an
      optic fissure closure defect. Note this quote is the paper's title, i.e.
      the authors' summary claim rather than a result sentence; the mechanistic
      detail is supplied by the DeYoung evidence item above.
  downstream:
  - target: Uveal Coloboma and Colobomatous Microphthalmia
    description: >-
      The unclosed ventral fissure is the anatomical substrate of the clinical
      coloboma; associated tissue deficiency produces the small eye.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35318877
      reference_title: "De novo frameshift mutation in YAP1 associated with bilateral uveal coloboma and microphthalmia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Given the association with YAP1 haploinsufficiency and colobomatous microphthalmia, this novel variant provides a molecular diagnosis for the proband."
      explanation: Links the YAP1 dosage lesion to colobomatous microphthalmia.
- name: Pleiotropic YAP1 Requirement Across Eye, Ear, Palate, and Kidney Primordia
  role: intermediate
  biological_scale: TISSUE
  description: >-
    This is the node that explains why the syndrome is a syndrome, and it carries
    the shared developmental mechanism the eye and the face have in common.
    Whole-mount in situ hybridisation in mouse embryos localises Yap1 to the eye,
    brain, and the fusing facial processes; nonradioactive in situ hybridisation
    on staged human embryos localises YAP1 to the retina, the otic vesicle
    (primitive ear), the primordium of the lateral palatine process, the neural
    tube, and the renal tubules. Optic fissure closure and palatal/facial process
    fusion are both epithelial fusion events occurring in overlapping embryonic
    windows, and both depend on the same dosage-sensitive Hippo effector — so a
    single haploinsufficient allele perturbs both. The correspondence of this
    expression domain to the clinical phenotype is close to one-to-one: retina to
    coloboma, otic vesicle to sensorineural hearing loss, lateral palatine
    process to cleft lip/palate, neural tube to the discussed neural tube defect,
    and renal tubules to the haematuria.
  gene:
    preferred_term: YAP1
    term:
      id: hgnc:16262
      label: YAP1
  locations:
  - preferred_term: optic fissure
    term:
      id: UBERON:0005412
      label: optic fissure
  - preferred_term: primordium of the lateral palatine process
    term:
      id: UBERON:0005871
      label: palatine process of maxilla
  - preferred_term: otic vesicle
    term:
      id: UBERON:0003051
      label: ear vesicle
  - preferred_term: neural tube
    term:
      id: UBERON:0001049
      label: neural tube
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:24462371
    reference_title: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "whole-mount in situ hybridization in mouse embryos has shown that Yap1 is strongly expressed in the eye, brain, and fusing facial processes"
    explanation: >-
      Provides the shared-mechanism link between the ocular fissure defect and
      orofacial clefting: the same gene is expressed in the fusing facial
      processes.
  - reference: PMID:28801591
    reference_title: "New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "by CS17 the most prominent expression was observed in the retina, diencephalic superventricle, neural tube, and the primordium of the lateral palatine process"
    explanation: >-
      Human embryonic in situ hybridisation places YAP1 in the retina, neural
      tube, and palatal primordium simultaneously.
  - reference: PMID:28801591
    reference_title: "New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "YAP1 was also expressed in the otic vesicle (primitive ear)"
    explanation: >-
      Supplies the developmental correlate of the sensorineural hearing loss in
      the syndrome.
  - reference: PMID:28801591
    reference_title: "New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "was also observed in the renal tubules of the developing kidney at CS22"
    explanation: >-
      Supplies the developmental correlate of the haematuria reported in YAP1
      families; the study explicitly examined kidney for this reason.
  downstream:
  - target: Impaired Fusion of the Facial Processes and Palatal Shelves
    description: >-
      Reduced YAP1 dose in the maxillary/lateral palatine process primordium
      impairs the fusion events that form the primary and secondary palate.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24462371
      reference_title: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Yap1 is strongly expressed in the eye, brain, and fusing facial processes"
      explanation: >-
        Expression in the fusing facial processes is the stated developmental
        rationale for the clefting; the intervening steps between reduced YAP1
        dose and failed shelf fusion are not experimentally resolved, hence
        PARTIAL.
  - target: Sensorineural Hearing Loss
    description: >-
      The otic-vesicle arm of the same pleiotropic requirement. The hearing loss
      cosegregates with the YAP1 allele in the index family, and Holt et al.
      read their otic-vesicle expression as consistent with that phenotype; the
      intervening steps are unresolved, and no cochlear phenotype has been
      assayed at reduced YAP1 dose in any system.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24462371
      reference_title: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "highly variable multisystem involvement, including hearing loss, intellectual disability, hematuria, and orofacial clefting"
      explanation: >-
        Names hearing loss as one of the multisystem features of the
        YAP1-solved syndromic family. This is the paper's phenotype-contrast
        sentence; the words "cosegregating" and "combined LOD score of 4.2"
        belong to the adjacent sentences and are quoted separately in the
        inheritance block, so they are not attributed to this snippet.
    - reference: PMID:28801591
      reference_title: "New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we also identified expression within the developing kidney and otic vesicle, consistent with its relevance to these additional phenotypes"
      explanation: >-
        The authors themselves read the otic-vesicle expression as consistent
        with the deafness phenotype. Expression remains a correlate rather than
        a demonstrated chain, hence PARTIAL.
  - target: Hematuria
    description: >-
      The renal arm of the same pleiotropic requirement. The haematuria
      cosegregates with the YAP1 allele in the index family, and Holt et al.
      read their renal expression as consistent with it; the renal lesion itself
      is uncharacterised — see the open knowledge-gap discussion.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24462371
      reference_title: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "highly variable multisystem involvement, including hearing loss, intellectual disability, hematuria, and orofacial clefting"
      explanation: >-
        Names haematuria as one of the multisystem features of the YAP1-solved
        syndromic family. This is the paper's phenotype-contrast sentence; the
        cosegregation and LOD statements sit in the adjacent sentences and are
        quoted separately in the inheritance block.
    - reference: PMID:28801591
      reference_title: "New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "was also observed in the renal tubules of the developing kidney at CS22"
      explanation: >-
        Supplies the developmental correlate; the study examined kidney
        expression precisely because the renal phenotype was unexplained.
        Expression alone does not establish the causal chain.
- name: Impaired Fusion of the Facial Processes and Palatal Shelves
  role: consequence
  biological_scale: TISSUE
  description: >-
    Failure of the medial nasal, maxillary, and palatal shelf fusion events
    yields the cleft lip and cleft palate of the syndrome. Orphanet records the
    clefting as variably involving lip, palate, and/or uvula, which is the
    pattern expected of a partially penetrant, dosage-dependent perturbation of
    a fusion program rather than a complete block. This node is deliberately
    kept thin: the generic orofacial clefting cascade is not reproduced here,
    because the YAP1-specific evidence extends only to expression in the fusing
    processes and the resulting clinical cleft.
  biological_processes:
  - preferred_term: roof of mouth development
    term:
      id: GO:0060021
      label: roof of mouth development
    modifier: ABNORMAL
  - preferred_term: face morphogenesis (medial nasal and maxillary prominence fusion)
    term:
      id: GO:0060325
      label: face morphogenesis
    modifier: ABNORMAL
  locations:
  - preferred_term: primordium of the lateral palatine process
    term:
      id: UBERON:0005871
      label: palatine process of maxilla
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: ORPHA:1473
    reference_title: "Uveal coloboma-cleft lip and palate-intellectual disability"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "uveal coloboma (typically bilateral) variably associated with cleft lip, palate and/or uvula"
    explanation: >-
      Orphanet records the variable lip/palate/uvula clefting pattern of the
      entity.
  - reference: PMID:9382148
    reference_title: "Dominant coloboma-microphthalmos syndrome associated with sensorineural hearing loss, hematuria, and cleft lip/palate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "autosomal dominant uveal coloboma and microphthalmos associated with cleft lip and palate"
    explanation: Documents the clefting as a defining feature of the pedigree.
  downstream:
  - target: Cleft Lip
    description: >-
      Failure of medial nasal and maxillary process fusion yields the cleft of
      the upper lip.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:7154042
      reference_title: "An autosomal dominant syndrome of uveal colobomata, cleft lip and palate, and mental retardation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "uveal colobomata, associated eye defects, and cleft lip and palate"
      explanation: Documents cleft lip as a feature of the defining pedigree.
  - target: Cleft Palate
    description: >-
      Failure of palatal shelf fusion yields the cleft palate; Orphanet records
      the clefting as variably involving lip, palate, and/or uvula.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:1473
      reference_title: "Uveal coloboma-cleft lip and palate-intellectual disability"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "variably associated with cleft lip, palate and/or uvula"
      explanation: Records palatal and uvular clefting as part of the entity.
- name: Uveal Coloboma and Colobomatous Microphthalmia
  role: consequence
  biological_scale: TISSUE
  description: >-
    The clinical ocular endpoint: an inferonasal uveal coloboma that in this
    entity is typically bilateral and may extend from iris through choroid to
    the optic disc and macula, with microphthalmia, cataract, and impaired
    extraocular movement in the fuller expressions. Expression is strikingly
    variable within the single family, so relatives sharing the allele may range
    from a minor iris notch to microphthalmia with poor vision — uveal coloboma
    is nonetheless the most constant feature.
  locations:
  - preferred_term: eye
    term:
      id: UBERON:0000970
      label: eye
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: ORPHA:1473
    reference_title: "Uveal coloboma-cleft lip and palate-intellectual disability"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The spectrum of eye involvement is also variable and includes iris coloboma extending to the choroid, disc, and/or macula, microphthalmia, cataract, and extraocular movement impairment."
    explanation: Records the ocular spectrum of the entity.
  - reference: PMID:7154042
    reference_title: "An autosomal dominant syndrome of uveal colobomata, cleft lip and palate, and mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Considerable variability in expression of the gene is apparent, uveal colobomata being the most constant feature"
    explanation: >-
      Establishes the ocular endpoint as the cardinal, most constant expression
      of the allele.
  downstream:
  - target: Uveal Coloboma
    description: >-
      The clinical uveal coloboma is the direct expression of the unclosed
      ventral fissure at the level of the uveal tract.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:1473
      reference_title: "Uveal coloboma-cleft lip and palate-intellectual disability"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "characterized by uveal coloboma (typically bilateral)"
      explanation: Records uveal coloboma as the defining clinical feature of the entity.
  - target: Iris Coloboma
    description: >-
      Anterior (iris) expression of the same colobomatous defect.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:1473
      reference_title: "Uveal coloboma-cleft lip and palate-intellectual disability"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "includes iris coloboma extending to the choroid, disc, and/or macula"
      explanation: Records iris involvement as the anterior pole of the defect.
  - target: Chorioretinal Coloboma
    description: >-
      Posterior extension of the same colobomatous defect into choroid and
      retina.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:1473
      reference_title: "Uveal coloboma-cleft lip and palate-intellectual disability"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "iris coloboma extending to the choroid, disc, and/or macula"
      explanation: Records the continuous iris-to-macula extension of the defect.
  - target: Optic Disc Coloboma
    description: >-
      Most posterior extension of the same defect, at the optic disc.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:1473
      reference_title: "Uveal coloboma-cleft lip and palate-intellectual disability"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "extending to the choroid, disc, and/or macula"
      explanation: Records disc involvement within the colobomatous spectrum.
  - target: Microphthalmia
    description: >-
      Where the colobomatous tissue deficiency is severe enough, the globe is
      also small — colobomatous microphthalmia rather than an isolated cleft.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9382148
      reference_title: "Dominant coloboma-microphthalmos syndrome associated with sensorineural hearing loss, hematuria, and cleft lip/palate."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "autosomal dominant uveal coloboma and microphthalmos associated with cleft lip and palate"
      explanation: >-
        Documents coloboma and microphthalmos together in the defining pedigree
        itself, rather than in an out-of-pedigree de novo case.
- name: Alternative Transcription Start Site Modulation of Phenotype Severity
  role: modifier
  biological_scale: MOLECULAR
  description: >-
    A candidate explanation for why one YAP1 nonsense family is syndromic and
    the other is eye-only. YAP1 has an alternative transcription start site in
    intron 1, widely used in human and mouse development, whose transcripts
    initiate at codon Met179. The isolated-coloboma allele c.370C>T (p.Arg124*)
    falls in the 5' UTR of those alternative transcripts and so cannot trigger
    nonsense-mediated decay in them, leaving a partially rescuing pool of
    protein; the syndromic allele c.1066G>T (p.Glu356*) lies downstream of both
    start sites and is predicted to cause NMD of transcripts from either. On
    this model the syndromic multisystem phenotype of this entity reflects the
    absence of that alternative-transcript rescue. The model is proposed rather
    than experimentally demonstrated in patient tissue, and other alleles
    complicate it — the c.1160delA frameshift escapes NMD altogether yet was
    inherited from an asymptomatic father.
  gene:
    preferred_term: YAP1
    term:
      id: hgnc:16262
      label: YAP1
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:24462371
    reference_title: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "the c.370C>T mutation in family 1305 is within the 5' UTR and cannot result in nonsense-mediated decay"
    explanation: >-
      States that the non-syndromic family's allele lies in the 5' UTR of the
      alternative transcripts and therefore escapes NMD in them — the positional
      basis of the proposed rescue. This is a positional inference rather than a
      transcript measurement, hence COMPUTATIONAL.
  - reference: PMID:24462371
    reference_title: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Amelioration of the phenotype by the alternative transcripts provides a plausible explanation for the phenotypic differences between the families."
    explanation: >-
      The authors present this explicitly as a plausible explanation, i.e. a
      hypothesis rather than a demonstrated mechanism. PARTIAL for the same
      reason this entry marks "should result in NMD" and "likely results in
      NMD" PARTIAL — the source hedges — and OTHER because the sentence is
      interpretive discussion rather than a clinical result.
  - reference: PMID:28801591
    reference_title: "New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus, the mutation does not lead to either alternate splicing or nonsense mediated decay."
    explanation: >-
      An NMD-escaping YAP1 frameshift inherited from an asymptomatic father
      shows that NMD status alone does not determine expressivity, so the
      alternative-TSS model is incomplete.
  downstream:
  - target: YAP1 Haploinsufficiency
    description: >-
      Whether a given nonsense allele produces true haploinsufficiency, and
      hence whether the phenotype is eye-only or syndromic, is proposed to
      depend on its position relative to the alternative start site.
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - alternative_tss_severity_modulation
    evidence:
    - reference: PMID:24462371
      reference_title: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "Transcripts from the alternative TSS are predicted to initiate at codon Met179 relative to the canonical transcript"
      explanation: >-
        Defines the alternative transcript that would determine allele
        consequence. The initiation codon is predicted, not experimentally
        mapped, hence COMPUTATIONAL.
mechanistic_hypotheses:
- hypothesis_group_id: alternative_tss_severity_modulation
  hypothesis_label: >-
    Position of the YAP1 nonsense allele relative to the intron-1 alternative
    transcription start site determines whether the phenotype is isolated
    coloboma or the full multisystem syndrome
  status: EMERGING
  description: >-
    Williamson et al. propose that the intron-1 alternative transcription start
    site of YAP1 (initiating at Met179) supplies a partially functional protein
    pool when a nonsense allele falls upstream of it, ameliorating the phenotype
    to eye-only disease; alleles downstream of both start sites cause NMD of all
    transcripts and produce the syndromic phenotype of this entity. The
    hypothesis is attractive because it would explain, from allele position
    alone, why two families with the same class of YAP1 lesion differ so
    sharply. It is not established: it rests on predicted rather than measured
    NMD in the relevant tissues, and a later NMD-escaping frameshift allele was
    carried by an asymptomatic father, which the model does not readily
    accommodate. Causal edges belonging to this model opt in via the
    alternative_tss_severity_modulation hypothesis group.
  evidence:
  - reference: PMID:24462371
    reference_title: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RT-PCR showed that an alternative transcription start site (TSS) in intron 1 of YAP1 and Yap1 is widely used in human and mouse development, respectively."
    explanation: >-
      Establishes by RT-PCR that the alternative transcript is genuinely used in
      development. The assay is performed on human and mouse developmental
      material rather than in living subjects, hence IN_VITRO; the mouse arm is
      model-organism data reported in the same sentence.
phenotypes:
- category: Ocular
  name: Uveal Coloboma
  description: >-
    The cardinal feature: a typically bilateral uveal coloboma arising from
    failure of optic fissure closure, with iris involvement that may extend to
    the choroid, optic disc, and/or macula.
  phenotype_term:
    preferred_term: Uveal coloboma
    term:
      id: HP:0000589
      label: Coloboma
    onset:
      onset_category: CONGENITAL
  diagnostic: true
  evidence:
  - reference: PMID:7154042
    reference_title: "An autosomal dominant syndrome of uveal colobomata, cleft lip and palate, and mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Considerable variability in expression of the gene is apparent, uveal colobomata being the most constant feature"
    explanation: >-
      Supports the disease-phenotype association and the variable expressivity
      it sits within. It does not support any frequency band, and none is
      assigned: "most constant feature" is a comparative claim about coloboma
      relative to the syndrome's other features, not an absolute rate — coloboma
      in 9 of 12 subjects (75%) would still be the most constant feature while
      falling in FREQUENT rather than VERY_FREQUENT.
  - reference: ORPHA:1473
    reference_title: "Uveal coloboma-cleft lip and palate-intellectual disability"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "characterized by uveal coloboma (typically bilateral) variably associated with cleft lip, palate and/or uvula, hearing impairment, and intellectual disability"
    explanation: >-
      Orphanet builds its definition around uveal coloboma — the entity is
      "characterized by" it, and every other feature is qualified as "variably
      associated" — which supports coloboma as the cardinal, diagnostic feature
      (hence diagnostic: true). It does NOT support a frequency band, and none
      is assigned. An earlier draft mapped "characterized by" to VERY_FREQUENT
      as hallmark wording under Pattern C; that was withdrawn on audit, because
      "characterized by" is the genus-differentia opening of essentially every
      Orphanet definition rather than one of the frequency terms in the Pattern
      C table, and because it makes the same comparative contrast (coloboma
      versus the variably associated features) that made "most constant feature"
      unusable for a band. No numerator/denominator for the coloboma is
      published in any cached source, so per
      docs/frequency-evidence-guidelines.md the frequency is omitted: a missing
      frequency is honest, a fabricated one is not.
- category: Ocular
  name: Iris Coloboma
  description: >-
    Iris involvement, the most anterior expression of the uveal coloboma and the
    element named in the entity's own label.
  phenotype_term:
    preferred_term: Iris coloboma
    term:
      id: HP:0000612
      label: Iris coloboma
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: ORPHA:1473
    reference_title: "Uveal coloboma-cleft lip and palate-intellectual disability"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "includes iris coloboma extending to the choroid, disc, and/or macula"
    explanation: Records iris involvement as the anterior pole of the colobomatous defect.
- category: Ocular
  name: Chorioretinal Coloboma
  description: >-
    Posterior extension of the coloboma into the choroid and retina, recorded by
    Orphanet as part of the continuous iris-to-macula defect.
  phenotype_term:
    preferred_term: Chorioretinal coloboma
    term:
      id: HP:0000567
      label: Chorioretinal coloboma
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: ORPHA:1473
    reference_title: "Uveal coloboma-cleft lip and palate-intellectual disability"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "iris coloboma extending to the choroid, disc, and/or macula"
    explanation: Records chorioretinal extension of the colobomatous defect.
- category: Ocular
  name: Optic Disc Coloboma
  description: >-
    Involvement of the optic disc, the most posterior extension of the optic
    fissure closure defect in this entity.
  phenotype_term:
    preferred_term: Optic disc coloboma
    term:
      id: HP:0000588
      label: Optic disc coloboma
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: ORPHA:1473
    reference_title: "Uveal coloboma-cleft lip and palate-intellectual disability"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "extending to the choroid, disc, and/or macula"
    explanation: Records disc involvement within the colobomatous spectrum.
- category: Ocular
  name: Microphthalmia
  description: >-
    Small eye accompanying the colobomatous defect; part of the complete
    spectrum of eye involvement seen across the pedigree and reported repeatedly
    in other YAP1 loss-of-function cases.
  phenotype_term:
    preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:9382148
    reference_title: "Dominant coloboma-microphthalmos syndrome associated with sensorineural hearing loss, hematuria, and cleft lip/palate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "autosomal dominant uveal coloboma and microphthalmos associated with cleft lip and palate"
    explanation: Documents microphthalmos in the defining pedigree.
  - reference: ORPHA:1473
    reference_title: "Uveal coloboma-cleft lip and palate-intellectual disability"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "includes iris coloboma extending to the choroid, disc, and/or macula, microphthalmia, cataract, and extraocular movement impairment"
    explanation: Orphanet lists microphthalmia within the ocular spectrum.
- category: Ocular
  name: Cataract
  description: >-
    Lens opacity reported within the ocular spectrum of the entity.
    Modifier-level detail (age at onset, morphology) is not documented for this
    syndrome.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: ORPHA:1473
    reference_title: "Uveal coloboma-cleft lip and palate-intellectual disability"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "microphthalmia, cataract, and extraocular movement impairment"
    explanation: Orphanet lists cataract in the ocular spectrum of the entity.
- category: Ocular
  name: Impaired Extraocular Movement
  description: >-
    Impairment of extraocular movement, recognised as a manifestation on
    re-evaluation of the pedigree and retained in the Orphanet description.
  phenotype_term:
    preferred_term: Extraocular movement impairment
    term:
      id: HP:0000496
      label: Abnormality of eye movement
  evidence:
  - reference: PMID:9382148
    reference_title: "Dominant coloboma-microphthalmos syndrome associated with sensorineural hearing loss, hematuria, and cleft lip/palate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "more recently recognized manifestations include a complete spectrum of eye involvement, impairment of extraocular movement"
    explanation: Documents impaired extraocular movement in the pedigree.
- category: Craniofacial
  name: Cleft Lip
  description: >-
    Cleft of the upper lip, forming half of the cleft lip and palate element of
    the syndrome name and present alongside the coloboma in the defining family.
  phenotype_term:
    preferred_term: Cleft lip
    term:
      id: HP:0410030
      label: Cleft lip
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:7154042
    reference_title: "An autosomal dominant syndrome of uveal colobomata, cleft lip and palate, and mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "autosomal dominantly inherited uveal colobomata, associated eye defects, and cleft lip and palate"
    explanation: Documents cleft lip in the foundational description of the entity.
  - reference: PMID:24462371
    reference_title: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "highly variable multisystem involvement, including hearing loss, intellectual disability, hematuria, and orofacial clefting"
    explanation: Confirms orofacial clefting in the YAP1-solved syndromic family.
- category: Craniofacial
  name: Cleft Palate
  description: >-
    Cleft of the secondary palate; Orphanet notes the clefting may involve lip,
    palate, and/or uvula, so a submucous or uvular-only cleft is within the
    described spectrum.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: ORPHA:1473
    reference_title: "Uveal coloboma-cleft lip and palate-intellectual disability"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "variably associated with cleft lip, palate and/or uvula"
    explanation: Records palatal (and uvular) clefting as part of the entity.
  - reference: PMID:7154042
    reference_title: "An autosomal dominant syndrome of uveal colobomata, cleft lip and palate, and mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "uveal colobomata, associated eye defects, and cleft lip and palate"
    explanation: Documents cleft palate in the foundational description of the entity.
- category: Neurodevelopmental
  name: Specific Learning Disability
  description: >-
    Learning difficulties requiring remedial teaching, documented in one third of
    affected members of the pedigree on formal re-evaluation. This is the
    quantified neurodevelopmental observation in the literature and is kept
    separate from the intellectual-disability claim below, which the sources
    state only in hedged terms.
  phenotype_term:
    preferred_term: Learning difficulties requiring remedial teaching
    term:
      id: HP:0001328
      label: Specific learning disability
  frequency: FREQUENT
  evidence:
  - reference: PMID:9382148
    reference_title: "Dominant coloboma-microphthalmos syndrome associated with sensorineural hearing loss, hematuria, and cleft lip/palate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Learning difficulties requiring remedial teaching were present in one third of those affected"
    explanation: >-
      Frequency derivation: one third of affected members (~33%) falls squarely
      in the HPO FREQUENT band (30-79%). The count is reported for learning
      difficulties requiring remedial teaching, which is what this phenotype
      records, so the band and the phenotype term are matched.
- category: Neurodevelopmental
  name: Intellectual Disability
  description: >-
    Intellectual disability of variable degree, the feature that gives the
    syndrome the third element of its name. No frequency band is assigned: the
    only quantified neurodevelopmental figure in the literature (one third)
    describes learning difficulties requiring remedial teaching, which is
    curated separately above, and both primary sources state the intellectual
    disability itself only in hedged or unquantified terms.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:24462371
    reference_title: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "highly variable multisystem involvement, including hearing loss, intellectual disability, hematuria, and orofacial clefting"
    explanation: >-
      Names intellectual disability as a manifestation of the YAP1-solved
      syndromic family, without a frequency.
  - reference: PMID:7154042
    reference_title: "An autosomal dominant syndrome of uveal colobomata, cleft lip and palate, and mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the full syndrome probably includes mental retardation of varying degree"
    explanation: >-
      The foundational report hedges (probably), which is why this item is
      recorded as PARTIAL despite the feature naming the syndrome.
- category: Audiologic
  name: Sensorineural Hearing Loss
  description: >-
    Mid-frequency sensorineural hearing loss, recognised on formal audiological
    re-evaluation of the pedigree. YAP1 is expressed in the human embryonic otic
    vesicle, supplying a developmental correlate.
  phenotype_term:
    preferred_term: Mid-frequency sensorineural hearing loss
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:9382148
    reference_title: "Dominant coloboma-microphthalmos syndrome associated with sensorineural hearing loss, hematuria, and cleft lip/palate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mid-frequency sensorineural hearing loss"
    explanation: Documents the audiological phenotype and its frequency profile.
  - reference: PMID:24462371
    reference_title: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including hearing loss, intellectual disability, hematuria, and orofacial clefting"
    explanation: Confirms hearing loss in the YAP1-solved family.
- category: Renal
  name: Hematuria
  description: >-
    Haematuria, recognised as a manifestation on re-evaluation of the pedigree
    and subsequently reported in other individuals with YAP1 variants. Its renal
    basis has not been characterised histologically; YAP1 expression in the renal
    tubules of the CS22 human embryo is the only available developmental
    correlate.
  phenotype_term:
    preferred_term: Hematuria
    term:
      id: HP:0000790
      label: Hematuria
  evidence:
  - reference: PMID:9382148
    reference_title: "Dominant coloboma-microphthalmos syndrome associated with sensorineural hearing loss, hematuria, and cleft lip/palate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mid-frequency sensorineural hearing loss, and hematuria"
    explanation: Documents haematuria in the defining pedigree.
  - reference: PMID:28801591
    reference_title: "New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "as haematuria has been reported in some patients with YAP1 mutations"
    explanation: >-
      Indicates haematuria occurs in some YAP1 patients beyond the index family.
      This is a secondary citation within Holt et al.'s rationale rather than a
      primary observation of their own, and it says "some" rather than
      quantifying, hence PARTIAL.
- category: Neurological
  name: Neural Tube Defect
  description: >-
    An association with neural tube defect was raised in the foundational report
    and a neural tube defect subsequently occurred in one presumed affected
    member of the family. This is a single observation in a presumed — not
    molecularly confirmed — carrier, so it is recorded without a frequency band;
    YAP1 expression in the human embryonic neural tube makes it biologically
    plausible rather than established.
  phenotype_term:
    preferred_term: Neural tube defect
    term:
      id: HP:0045005
      label: Neural tube defect
  evidence:
  - reference: PMID:9382148
    reference_title: "Dominant coloboma-microphthalmos syndrome associated with sensorineural hearing loss, hematuria, and cleft lip/palate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a neural tube defect has occurred in one presumed affected member"
    explanation: >-
      A single observation in a presumed affected member; the authors' own
      hedging (presumed) is why this is PARTIAL and carries no frequency.
  - reference: PMID:7154042
    reference_title: "An autosomal dominant syndrome of uveal colobomata, cleft lip and palate, and mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The possibility of association with neural tube defect is discussed."
    explanation: >-
      The foundational report frames the neural tube defect link as a
      possibility under discussion, not an established feature.
diagnosis:
- name: Molecular Genetic Testing for YAP1
  description: >-
    There is no biochemical marker, imaging finding, or diagnostic criteria
    guideline specific to this entity, so diagnosis rests on recognising
    congenital uveal coloboma (particularly bilateral, and particularly with
    clefting, hearing loss, developmental impairment, or haematuria in a dominant
    pedigree) and confirming a heterozygous YAP1 loss-of-function variant by
    exome/genome sequencing or a developmental-eye-disorder panel that includes
    YAP1. Segregation analysis matters because YAP1 alleles show incomplete
    penetrance, so an unaffected parent may carry the variant.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:35318877
    reference_title: "De novo frameshift mutation in YAP1 associated with bilateral uveal coloboma and microphthalmia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-genome sequencing of the coding regions and intron-exon boundaries confirmed a mutation in the proband. These genetic findings were verified using the Sanger method of DNA sequencing."
    explanation: >-
      Illustrates the sequencing-based diagnostic route used to establish the
      molecular diagnosis in a YAP1 coloboma case.
  - reference: PMID:28801591
    reference_title: "New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Parental DNA samples were sequenced for both strands of exon 7, and the variant was identified in the heterozygous state in the asymptomatic father"
    explanation: >-
      Demonstrates why parental segregation testing is required for
      interpretation: a YAP1 loss-of-function allele may be non-penetrant.
treatments:
- name: Genetic Counseling
  description: >-
    The one intervention with disease-specific content in this entity. Counseling
    must convey a 50% per-conception transmission risk for a heterozygous
    carrier, but also that neither the presence nor the severity of expression
    can be predicted from the genotype: expressivity within the single defining
    pedigree ranges from a minor ocular sign to microphthalmia with clefting,
    hearing loss and learning difficulty, and YAP1 loss-of-function alleles have
    been transmitted by clinically unaffected carriers. Cascade testing of
    at-risk relatives should therefore be paired with ophthalmic examination
    rather than relied on alone.
  therapeutic_modality: OTHER
  notes: >-
    Modality decided on the enum definition rather than on precedent.
    TherapeuticModalityEnum defines BEHAVIORAL as a "non-pharmacologic
    behavioral, physical, dietary, or lifestyle intervention"; genetic
    counseling is none of those four — it is a risk-communication and
    decision-support service — so OTHER ("modality not covered by the above
    categories") is the accurate value. The KB is genuinely split on this:
    measured across kb/disorders/ on 2026-08-11 with this entry already changed,
    578 treatments bind NCIT:C15240 — 57 tagged BEHAVIORAL, 38 OTHER, and 483
    carrying no modality at all. (An earlier draft of this note recorded 58/37,
    which was the split BEFORE this entry was retagged: the note described the
    KB as it was before its own edit. Corrected, and date-stamped, because these
    counts drift with every entry that touches this term.) There is therefore no
    settled convention to defer to, and
    CLAUDE.md lists NCIT:C15240 among the generic action terms that need a
    per-entry look rather than an ID-based rule. Flagged here because a
    KB-wide reconciliation of this term is worth doing on its own.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:7154042
    reference_title: "An autosomal dominant syndrome of uveal colobomata, cleft lip and palate, and mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Considerable variability in expression of the gene is apparent"
    explanation: >-
      Establishes the variable expressivity that counseling must convey; it is
      why a genotype-based severity prediction cannot be offered.
  - reference: PMID:28801591
    reference_title: "New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the variant was identified in the heterozygous state in the asymptomatic father"
    explanation: >-
      Documents transmission of a YAP1 loss-of-function allele by a clinically
      unaffected carrier, the incomplete-penetrance point that counseling and
      cascade testing must account for.
discussions:
- discussion_id: yap1_haematuria_renal_basis_unknown
  prompt: >-
    What renal lesion produces the haematuria in YAP1-related syndromic
    coloboma, and does it carry a risk of progressive kidney disease?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Pleiotropic YAP1 Requirement Across Eye, Ear, Palate, and Kidney Primordia
  rationale: >-
    Haematuria is a recurrent feature of YAP1 loss-of-function families and
    prompted Holt et al. to look specifically for YAP1 expression in the
    developing kidney, which they found in renal tubules at CS22. But no renal
    biopsy, imaging, or longitudinal renal-function data have been published for
    any affected individual, so it is unknown whether the haematuria reflects a
    glomerular basement membrane defect, a tubular lesion, a structural
    malformation, or something benign. This matters clinically because it
    determines whether carriers need renal surveillance, and mechanistically
    because a glomerular versus tubular origin would point at different YAP1
    dependencies.
  proposed_experiments:
  - experiment_id: exp_yap1_renal_phenotyping
    name: Structured renal phenotyping of genotyped YAP1 carriers
    description: >-
      Perform urinalysis with phase-contrast microscopy for dysmorphic red
      cells, albumin:creatinine ratio, renal ultrasound, and eGFR in all
      molecularly confirmed carriers from reported YAP1 families, with
      longitudinal follow-up in adults. Dysmorphic erythrocytes and albuminuria
      would indicate a glomerular origin; isolated isomorphic haematuria with
      normal albumin would favour a tubular or structural cause.
    decision_criterion: >-
      Presence of dysmorphic erythrocytes and/or albuminuria in a majority of
      carriers distinguishes a glomerular from a tubular or structural origin.
  - experiment_id: exp_yap1_conditional_kidney_deletion
    name: Compartment-specific conditional Yap1 deletion in mouse kidney
    description: >-
      Delete Yap1 conditionally in nephron progenitors versus differentiated
      tubular epithelium in mouse and assay for haematuria, glomerular
      basement-membrane ultrastructure, and tubular integrity, to localise the
      developmental compartment in which reduced YAP1 dose produces the renal
      phenotype.
    decision_criterion: >-
      Haematuria arising only in one compartment-specific deletion localises the
      YAP1 requirement to that compartment.
  evidence:
  - reference: PMID:28801591
    reference_title: "New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we also examined expression in the human embryonic kidney"
    explanation: >-
      The investigators examined kidney expression precisely because the renal
      phenotype was unexplained, evidencing the gap.
- discussion_id: yap1_single_family_entity_boundary
  prompt: >-
    Is uveal coloboma-cleft lip and palate-intellectual disability a distinct
    nosological entity, or the syndromic tail of a single YAP1-related
    developmental eye disorder spectrum?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Alternative Transcription Start Site Modulation of Phenotype Severity
  rationale: >-
    MONDO:0007355 / OMIM:120433 / ORPHA:1473 describe an entity resting on a
    single pedigree. The same gene, with the same class of lesion, produces
    isolated non-syndromic coloboma in a second family and in singleton cases.
    Whether the syndromic label names a real biological subdivision (as the
    alternative-TSS model would predict) or simply the most severely expressed
    end of one allelic spectrum cannot be settled without further syndromic
    families. Until then, curators should be careful not to import generic
    coloboma or generic clefting literature into this entry, and should not treat
    the syndrome boundary as mechanistically validated.
  proposed_experiments:
  - experiment_id: exp_yap1_allele_position_genotype_phenotype
    name: Allele-position versus extraocular-phenotype audit across YAP1 carriers
    description: >-
      Assemble every published and diagnostic-laboratory YAP1 loss-of-function
      carrier, annotate each allele by position relative to the intron-1
      alternative transcription start site, and test whether downstream
      alleles (those predicted to trigger NMD in both transcript classes) are
      enriched for extraocular features relative to upstream alleles. Pair this
      with quantitative allele-specific expression of canonical and alternative
      YAP1 transcripts in accessible patient tissue.
    decision_criterion: >-
      Enrichment of extraocular features among alleles downstream of the
      alternative TSS would support a real syndromic/isolated subdivision;
      absence of enrichment would favour a single spectrum with stochastic
      expressivity.
  evidence:
  - reference: PMID:24462371
    reference_title: "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenotypes of the affected families differed in that one included no extraocular features and the other manifested with highly variable multisystem involvement"
    explanation: >-
      The same gene and lesion class yield isolated and syndromic phenotypes,
      which is exactly the boundary problem.
differential_diagnoses:
- name: CHARGE Syndrome
  description: >-
    CHARGE syndrome (CHD7) is the principal differential because it also pairs
    coloboma with orofacial clefting, hearing loss, and developmental delay.
    Features favouring CHARGE are choanal atresia, characteristic external and
    inner ear anomalies with semicircular canal hypoplasia, cranial nerve
    dysfunction, and cardiac defects, none of which characterise the YAP1 entity;
    molecular testing (CHD7 versus YAP1) is definitive. Deliberate note for
    curators and deep-research tools: coloboma-plus-clefting reports very often
    concern CHARGE, and CHARGE literature must not be imported into this entry.
- name: Isolated Uveal Coloboma and the Microphthalmia-Anophthalmia-Coloboma Spectrum
  description: >-
    Non-syndromic coloboma — including the isolated YAP1-related coloboma family
    of Williamson et al. — shares the ocular phenotype but lacks the clefting,
    hearing loss, intellectual disability, and haematuria. The MAC spectrum is
    genetically heterogeneous (SOX2, OTX2, BMP4, BMP7, STRA6 among others), and
    YAP1 accounts for only a small share of it.
- name: Branchio-Oculo-Facial Syndrome
  description: >-
    TFAP2A-related branchio-oculo-facial syndrome also combines ocular anomalies
    (including coloboma and microphthalmia) with orofacial clefting, but is
    distinguished by cervical/infra-auricular branchial skin defects, a
    characteristic facies with a broad nasal bridge, ectopic thymus, and
    premature greying.
- name: Cat-Eye Syndrome
  description: >-
    Cat-eye syndrome (chromosome 22q11 tetrasomy from a supernumerary
    bisatellited marker chromosome) presents with iris coloboma, anal atresia,
    preauricular pits and tags, and cardiac and renal anomalies. It is excluded
    by karyotype or chromosomal microarray rather than by phenotype alone.
- name: Renal Coloboma (Papillorenal) Syndrome
  description: >-
    PAX2-related renal coloboma syndrome is the highest-yield differential for
    the specific combination of coloboma with urinary-tract findings, which is
    exactly the combination this entry curates (coloboma plus haematuria).
    Distinguishing features are the characteristic optic nerve dysplasia
    (morning-glory-like disc, excavated with anomalous vessels) rather than a
    simple inferonasal uveal coloboma, and structural renal hypodysplasia with
    vesicoureteral reflux and progressive renal insufficiency — as opposed to
    the isolated, uncharacterised haematuria of the YAP1 entity. Orofacial
    clefting is not a feature of PAX2 disease. Molecular testing separates them.
- name: Kabuki Syndrome
  description: >-
    KMT2D/KDM6A-related Kabuki syndrome pairs coloboma with intellectual
    disability, cleft lip/palate, hearing loss, and renal anomalies, so it
    overlaps this entity on every named element. It is distinguished by the
    characteristic facies (long palpebral fissures with eversion of the lateral
    lower lid, arched sparse eyebrows, large prominent ears), persistent fetal
    fingertip pads, postnatal growth deficiency, hypotonia, and recurrent otitis
    media, none of which characterise the YAP1 entity.
- name: Baraitser-Winter Cerebrofrontofacial Syndrome
  description: >-
    ACTB/ACTG1-related Baraitser-Winter syndrome also features coloboma with
    intellectual disability, but is distinguished by ptosis, hypertelorism, a
    characteristic broad facies, and — critically — cortical malformations such
    as pachygyria or lissencephaly on brain imaging, which are not a feature of
    the YAP1 entity.
animal_models:
- name: Zebrafish yap1 mutant, alone and with wwtr1 (taz)
  species: Danio rerio
  genotype: yap1 (yap) loss-of-function mutant, alone and combined with wwtr1 (taz)
  publication: PMID:26209646
  description: >-
    Zebrafish yap1 mutants lack a subset of retinal pigment epithelium and/or
    develop coloboma, and combined loss of yap and taz abolishes the ability of
    optic vesicle progenitors to form RPE at all. This is the closest available
    model of the ocular arm of the syndrome and the source of the instructive
    (not merely permissive) role of Yap/Taz-Tead in RPE fate. It does not model
    the clefting, hearing loss, or intellectual disability arms.
  associated_phenotypes:
  - Coloboma
  - Loss of retinal pigment epithelium
  modeled_mechanisms:
  - target: Reduced YAP-TEAD Transcriptional Output in the Hippo Pathway
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Genetic removal of yap1, and of yap1 together with wwtr1, lowers Yap/Taz-Tead
      output in optic vesicle progenitors — the animal counterpart of the reduced
      co-activator dose imposed by human YAP1 haploinsufficiency.
    limitations: >-
      Homozygous null and double-mutant genotypes model a far deeper loss of
      output than a human heterozygous nonsense allele, so the model addresses
      the direction of the lesion rather than its dose.
    readouts:
    - name: Ability of optic vesicle progenitors to form RPE
      target: Reduced YAP-TEAD Transcriptional Output in the Hippo Pathway
      direction: ABOLISHED
      interpretation: >-
        The functional consequence of removing that output: complete loss of
        RPE-forming capacity when both Yap and Taz are absent establishes the
        requirement as instructive, not merely permissive. Note this measures
        the capacity the node's output confers, not a direct measurement of
        transcriptional output in the mutant.
      evidence:
      - reference: PMID:26209646
        reference_title: "Yap and Taz regulate retinal pigment epithelial cell fate."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "when Yap and Taz are both absent, optic vesicle progenitor cells completely lose their ability to form RPE"
        explanation: Reports the measured loss of RPE-forming capacity behind this readout.
    evidence:
    - reference: PMID:26209646
      reference_title: "Yap and Taz regulate retinal pigment epithelial cell fate."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The mechanism of Yap-dependent RPE cell type determination is reliant on both nuclear localization of Yap and interaction with a Tead co-factor."
      explanation: >-
        Confirms the model reports specifically on YAP-TEAD co-activation, the
        activity this node describes.
  - target: Failure of Optic Fissure Closure
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      yap1 mutants develop coloboma — the optic fissure closure defect itself —
      alongside the RPE deficiency proposed to underlie it.
    limitations: >-
      The zygosity mismatch bites hardest here, on the stronger claim: the
      coloboma is scored in homozygous yap1 nulls, whereas the human disorder is
      caused by a heterozygous nonsense allele, so the model recapitulates the
      lesion's direction and not its dose. Zebrafish ocular morphogenesis is
      also not identical to the human weeks-5-to-7 fissure closure window, and
      the model does not reproduce the clefting, hearing loss, haematuria, or
      intellectual disability arms of the syndrome.
    readouts:
    - name: Coloboma incidence in yap1 mutants
      target: Failure of Optic Fissure Closure
      direction: INCREASED
      interpretation: >-
        Coloboma arising on loss of yap1 is the model's direct correlate of the
        human optic fissure closure defect.
      evidence:
      - reference: PMID:26209646
        reference_title: "Yap and Taz regulate retinal pigment epithelial cell fate."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "yap (yap1) mutants lack a subset of RPE cells and/or exhibit coloboma."
        explanation: Reports the coloboma scored in the mutants.
    - name: Retinal pigment epithelium cell number in yap1 mutants
      target: Failure of Optic Fissure Closure
      direction: DECREASED
      interpretation: >-
        The RPE deficiency that accompanies the coloboma, recorded separately
        because it moves in the opposite direction from coloboma incidence and
        cannot share a single direction value with it.
      evidence:
      - reference: PMID:26209646
        reference_title: "Yap and Taz regulate retinal pigment epithelial cell fate."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "yap (yap1) mutants lack a subset of RPE cells and/or exhibit coloboma."
        explanation: Reports the RPE cell deficiency scored in the mutants.
    evidence:
    - reference: PMID:26209646
      reference_title: "Yap and Taz regulate retinal pigment epithelial cell fate."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "provides a mechanistic framework for understanding the congenital ocular defects of Sveinsson's chorioretinal atrophy and congenital retinal coloboma"
      explanation: >-
        The authors position the model as a mechanistic framework for congenital
        retinal coloboma, which is what this node curates.
  evidence:
  - reference: PMID:26209646
    reference_title: "Yap and Taz regulate retinal pigment epithelial cell fate."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "yap (yap1) mutants lack a subset of RPE cells and/or exhibit coloboma."
    explanation: >-
      Establishes the zebrafish yap1 mutant as a model of the coloboma arm of
      the human phenotype.
  - reference: PMID:26209646
    reference_title: "Yap and Taz regulate retinal pigment epithelial cell fate."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Loss of RPE in yap mutants is exacerbated in combination with taz (wwtr1) mutant alleles such that, when Yap and Taz are both absent, optic vesicle progenitor cells completely lose their ability to form RPE."
    explanation: Demonstrates the dosage-dependent Yap/Taz requirement in ocular development.
notes: >-
  Scope and evidence discipline. This entry is deliberately small. The entity is
  defined by one pedigree — twelve affected subjects over three generations in
  Kingston et al. 1982, re-evaluated as a four-generation family by Ravine et al.
  1997 — so there is no cohort, no natural-history study, no treatment literature,
  and no biomarker specific to it. Rather than pad the entry with generic coloboma
  or generic orofacial-clefting biology, the pathophysiology is restricted to what
  can be evidenced for YAP1 specifically: the haploinsufficiency lesion, its
  effect on YAP-TEAD output in the Hippo pathway, the optic fissure closure
  defect, the pleiotropic embryonic expression domain that ties the eye, ear,
  palate, neural tube, and kidney features together, and the proposed
  alternative-TSS severity modifier.

  Causal gene status. Contrary to what the sparse clinical literature might
  suggest, the causal gene IS established: YAP1. MONDO:0007355 carries the gene
  association (RO:0004003 HGNC:16262), and Williamson et al. 2014 solved the
  defining pedigree with the cosegregating nonsense allele c.1066G>T (p.Glu356*).
  Family identity across the three reports is inferred, not stated in any
  abstract, and the inference should be treated as strong-but-not-proven. The
  supporting threads are: A.O.M. Wilkie is an author on both Ravine et al. 1997
  and Williamson et al. 2014; A. Clarke of the Institute of Medical Genetics,
  University Hospital of Wales, Cardiff — the institution from which both
  Kingston et al. and Ravine et al. published — is an author on Williamson et al.;
  and Holt et al. 2017 cite Williamson together with a second report for the
  extraocular features of that family. Ravine et al. describe their pedigree as
  "re-evaluated", consistent with the earlier Kingston description. No abstract
  asserts the identity outright, so a curator revisiting this entry should not
  treat the three-report chain as independently confirmed.

  Deliberately omitted, with reasons. (1) Treatments — only genetic counselling
  is curated. No disease-modifying therapy exists, and the rest of management
  (low-vision services, cleft-team care, audiology, developmental support) is
  generic multidisciplinary supportive care for which none of the cached
  references carries a quotable, YAP1-specific statement; adding those entries
  would mean asserting standard-of-care from no source. Genetic counselling is
  the exception because the entry's own inheritance and penetrance evidence
  directly supports what has to be counselled. (1a) Glaucoma (HP:0000501) and
  ptosis (HP:0000508) are named in the fuller ORDO/MONDO definition of this
  entity but appear in neither the current Orphadata cache body for ORPHA:1473
  nor any of the cited abstracts, so there is no quotable snippet for them; they
  are flagged here as the first candidates to add if a citable source is found,
  rather than curated on an uncitable basis. (2) Prevalence rates, incidence, sex ratio, penetrance
  percentages, survival, and phenotype percentages — the deep-research report
  explicitly cautions that these cannot be calculated from single families, and
  coloboma/MAC-spectrum figures must not be substituted. (3) Biochemical markers,
  histopathology, imaging findings, clinical trials, progression and staging —
  none are documented for this entity. (4) Module conformance — no existing
  dismech module covers optic fissure closure failure; the
  pharyngeal_arch_patterning_serial_homology module was considered and rejected
  because YAP1 clefting is not a cranial-neural-crest arch-patterning defect.
  (5) A GeneReviews chapter does not exist for YAP1 or for this syndrome (PubMed
  searches for YAP1 plus GeneReviews and title-level searches returned nothing
  relevant), so the mandatory GeneReviews phenotype baseline is inapplicable.
  (6) Provisional single-case findings from later YAP1 reports (hemifacial
  microsomia, tubular nose, spina bifida occulta, nystagmus, microcornea) are not
  curated as phenotypes of this entity; they belong to individual YAP1 probands
  and the deep-research report itself flags them as provisional extensions.
  (7) Four phenotypes are deliberately left unwired to the pathograph, giving a
  causal-inlink connectivity of 10 of 14 rather than a fuller-looking number
  bought with unsupported edges. The wiring rule applied is a single one: a
  phenotype is wired when a source states it is a feature of the disease caused
  by the YAP1 allele, and not wired when no source does. Cataract and impaired
  extraocular movement are recorded in the ocular spectrum of the entity, but
  neither is an optic fissure closure defect and no source explains either from
  reduced YAP1 dose. Specific learning disability is unwired because it rests on
  Ravine et al.'s "one third of those affected" observation, which this entry
  deliberately keeps separate from the intellectual-disability claim; treating
  the two as one claim is precisely the conflation the phenotype split exists to
  avoid. Neural tube defect is unwired because the sources do not establish the
  claim: Kingston et al. write only that "the possibility of association
  with neural tube defect is discussed", and Ravine et al. that it "has occurred
  in one presumed affected member" — a single event in a relative who was never
  molecularly confirmed. An earlier draft did wire it on YAP1 neural-tube
  expression alone; that edge was removed on audit, because an expression
  correlate is not evidence of causation. (The reasoning given at the time — that
  CausalLinkTypeEnum UNKNOWN, meaning "directness has not yet been determined",
  cannot carry a doubt about whether an edge exists — was itself too strong: the
  alternative-TSS edge in this very entry carries exactly that kind of doubt by
  pairing UNKNOWN with a hypothesis_groups reference to an EMERGING
  mechanistic_hypotheses entry. Deletion was a choice, not the only option; it
  remains the right one here because the sources do not establish the
  association, not merely its directness.)
  (7a) Intellectual disability IS wired, and the earlier draft that excluded it
  was inconsistent. Williamson et al. name hearing loss, intellectual disability,
  haematuria and orofacial clefting in one sentence as the multisystem features
  of the YAP1-solved family; three of those four were wired on that sentence
  while the fourth was excluded on a rationale — Holt et al.'s caution — that
  addresses only the brain-expression route to a mechanism, not the disease-level
  attribution the other three edges rest on. The edge is therefore now curated on
  the same evidential footing as its siblings. The edge is wired directly from
  YAP1 Haploinsufficiency, not from the pleiotropic tissue-expression node, so
  it retains the disease-level attribution while leaving the intervening
  neurodevelopmental mechanism unknown. Holt's "such correlations must still be
  approached with caution" is carried on the edge as a PARTIAL qualifying item
  and no route through brain expression is asserted.
  (8) The seven differential_diagnoses blocks carry no evidence items, and this
  is a recorded gap rather than a completeness claim. Their distinguishing
  features — choanal atresia and semicircular canal hypoplasia in CHARGE, the
  branchial skin defects of branchio-oculo-facial syndrome, the supernumerary
  marker chromosome of cat-eye syndrome, PAX2 renal hypodysplasia with
  vesicoureteral reflux, the Kabuki facies and fetal fingertip pads, the
  Baraitser-Winter cortical malformations, and the genetic heterogeneity of the
  MAC spectrum — are standard clinical knowledge, but none of the seven cached
  references for this entry states any of them, so there is no quotable snippet
  for any of them here. Citing them would mean adding seven new references whose
  only role is to support boundary prose, which is a larger and separately
  reviewable piece of work. Until that is done, no claim is made that the
  differential blocks are evidence-backed.

  Named-entity-confusion preflight. MONDO:0007355 was verified with OAK before any
  content was written: label uveal coloboma-cleft lip and palate-intellectual
  disability, OMIM:120433, Orphanet:1473, gene association HGNC:16262 (YAP1),
  Orphanet definition citing 12 cases from three generations of a single family
  and autosomal dominant transmission. Auditor's note: that case-count sentence
  lives in the MONDO:0007355 definition text (attributed to Orphanet:1473) and is
  NOT present in the Orphadata bulk-snapshot body cached as ORPHA_1473.md. The
  two are different definition texts of different vintages, not a full text and a
  truncation of it — MONDO's runs "is characterized by coloboma of the iris,
  bilateral cleft lip and palate", the cache's "A rare, genetic, multiple
  congenital anomalies/dysmorphic syndrome characterized by uveal coloboma
  (typically bilateral)" — so the case count is not recoverable by quoting more
  of the cached record. It is
  therefore not quotable as an ORPHA:1473 snippet, which is why the prevalence
  record cites PMID:7154042 for the count instead. ORPHA:1473 independently lists OMIM:120433
  and MONDO:0007355 as exact matches, and the Kingston 1982 abstract independently
  confirms the twelve-subjects/three-generations count. This is a high-NEC-risk
  entity because coloboma appears in many named syndromes; CHARGE (CHD7), cat-eye
  syndrome, branchio-oculo-facial syndrome (TFAP2A), COACH/Joubert, and
  Baraitser-Winter were all explicitly excluded, and all but COACH/Joubert are
  recorded under differential_diagnoses so the boundary is auditable. The Edison
  (falcon) deep-research report was read in full and showed no drift onto CHARGE
  or generic coloboma; its own conclusions (YAP1, OMIM 120433, haploinsufficiency,
  single-family basis) match the independently verified identity. The report's
  claim that no MONDO or Orphanet identifier could be verified is a limitation of
  its retrieval, not a contradiction — both were verified here directly against
  OAK and Orphadata.

📚

References & Deep Research

References

7

PMID:7154042

An autosomal dominant syndrome of uveal colobomata, cleft lip and palate, and mental retardation.

No top-level findings curated for this source.

PMID:9382148

Dominant coloboma-microphthalmos syndrome associated with sensorineural hearing loss, hematuria, and cleft lip/palate.

No top-level findings curated for this source.

PMID:24462371

Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects.

No top-level findings curated for this source.

PMID:26209646

Yap and Taz regulate retinal pigment epithelial cell fate.

No top-level findings curated for this source.

PMID:28801591

New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders.

No top-level findings curated for this source.

PMID:35318877

De novo frameshift mutation in YAP1 associated with bilateral uveal coloboma and microphthalmia.

No top-level findings curated for this source.

ORPHA:1473

Uveal coloboma-cleft lip and palate-intellectual disability

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 12 citations 2026-08-01T18:00:44.747169

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: Uveal Coloboma-Cleft Lip and Palate-Intellectual Disability Syndrome
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Uveal Coloboma-Cleft Lip and Palate-Intellectual Disability Syndrome 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:

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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

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Pathogenic Variants:
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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 NCIT (NCI Thesaurus) clinical-intervention 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, NCIT, 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 (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Uveal Coloboma–Cleft Lip/Palate–Intellectual Disability Syndrome

Executive summary

This is an exceptionally rare, congenital Mendelian developmental disorder best regarded as the syndromic end of the YAP1-related ocular-coloboma spectrum, rather than a well-characterized epidemiologic syndrome. It was originally reported as “an autosomal dominant syndrome of uveal colobomata, cleft lip and palate, and mental retardation.” Subsequent molecular studies linked the broader phenotype—including isolated coloboma, syndromic coloboma, hearing impairment, cleft lip/palate, hematuria, and learning or developmental difficulties—to heterozygous YAP1 variants. The principal mechanism is YAP1 loss of function/haploinsufficiency, disrupting Hippo-YAP-regulated ocular morphogenesis and retinal pigment epithelium (RPE) cell-fate specification. Inheritance is autosomal dominant, but penetrance is incomplete and expression highly variable. (deyoung2022denovoframeshift pages 5-6, deyoung2022denovoframeshift pages 6-6)

The available evidence consists chiefly of individual families and case reports, not registries or population cohorts. Consequently, prevalence, incidence, phenotype percentages, penetrance estimates, survival, and treatment-response statistics cannot presently be calculated reliably. No syndrome-specific clinical trial, approved molecular treatment, or 2023–2024 clinical natural-history study was identified.

Domain	Established finding	Ontology suggestions	Evidence strength / limitations
Disease identity / identifiers	Rare Mendelian developmental disorder originally described as an autosomal-dominant syndrome of uveal colobomata, cleft lip/palate, and intellectual disability; current evidence places it within the YAP1-related ocular coloboma spectrum. OMIM phenotype: #120433. Causal gene: YAP1 (HGNC:16262). Do not assign MONDO/Orphanet IDs without external confirmation. (deyoung2022denovoframeshift pages 6-6, deyoung2022denovoframeshift pages 5-6)	OMIM: 120433; Gene: YAP1/HGNC:16262; possible disease label string: YAP1-related ocular coloboma syndrome	Strong gene-disease linkage from multiple human families/cases; disease naming and cross-database mapping remain ambiguous.
Core ocular phenotype	Congenital uveal/ocular coloboma is the defining feature; reported involvement includes iris, retina/choroid, and optic nerve, often bilateral; microphthalmia/microcornea and nystagmus can co-occur. (deyoung2022denovoframeshift pages 1-3, deyoung2022denovoframeshift pages 3-5)	HPO: Coloboma (HP:0000589); Uveal coloboma (HP:0007707); Iris coloboma (HP:0000612); Chorioretinal coloboma (HP:0000539); Optic nerve coloboma (HP:0000588); Microphthalmia (HP:0000568); Microcornea (HP:0000482); Nystagmus (HP:0000639)	Strong for ocular phenotype; exact frequency and laterality distribution unavailable due to very small case numbers.
Craniofacial / neurodevelopmental syndrome features	Syndromic YAP1-associated disease includes cleft lip with or without cleft palate, learning difficulties/developmental delay/intellectual disability, and dysmorphic features; historic reports include a stillbirth with anencephaly and cleft lip/palate. (deyoung2022denovoframeshift pages 5-6, deyoung2022denovoframeshift pages 6-6, jauss2022routinediagnosticsconfirm pages 6-7)	HPO: Cleft upper lip (HP:0000204); Cleft palate (HP:0000175); Intellectual disability (HP:0001249); Global developmental delay (HP:0001263); Learning disability (HP:0001328); Anencephaly (HP:0002323)	Moderate: recurrently cited across later papers, but original 1982 family details were not directly extracted here.
Extra-ocular features	Additional reported syndromic manifestations include sensorineural hearing loss and hematuria; these broaden the phenotype beyond eye and craniofacial findings. (deyoung2022denovoframeshift pages 5-6)	HPO: Sensorineural hearing impairment (HP:0000407); Hematuria (HP:0000790)	Moderate: based mainly on earlier family reports summarized in later publications.
Representative pathogenic / likely pathogenic variants	Reported variants include NM_001130145.3:c.178dupG p.(Asp60GlyfsTer52), a de novo exon-1 frameshift absent from gnomAD; c.284T>C p.(Phe95Ser) in a family with isolated coloboma; and NM_001130145.3:c.1196_1199del reported as likely pathogenic in routine diagnostics. (deyoung2022denovoframeshift pages 3-5, oatts2017novelheterozygousmutation pages 1-6, jauss2022routinediagnosticsconfirm pages 6-7)	Sequence Ontology: frameshift_variant, missense_variant; ACMG/AMP concepts: likely pathogenic, de novo	Strong for existence of these variants; broader allelic series is incompletely captured in available context.
Molecular mechanism	Best-supported mechanism is YAP1 haploinsufficiency / loss of function affecting Hippo-YAP signaling. YAP1 is a transcriptional co-activator regulated by Hippo pathway phosphorylation and TEAD binding; loss disrupts developmental growth-control programs. (deyoung2022denovoframeshift pages 3-5, deyoung2022denovoframeshift pages 5-6)	GO: Hippo signaling (GO:0035329); regulation of cell proliferation (GO:0042127); positive regulation of transcription by RNA polymerase II (GO:0045944)	Strong mechanistic plausibility from human genetics plus animal/in vitro developmental data; direct human tissue functional assays are limited.
Developmental pathophysiology	Evidence supports a role in optic fissure closure / ocular morphogenesis and retinal pigment epithelium (RPE) cell-fate specification; FAT1-Hippo-YAP dysregulation is a plausible upstream pathway. (deyoung2022denovoframeshift pages 5-6, deyoung2022denovoframeshift pages 6-6)	GO: eye morphogenesis (GO:0048592); optic fissure closure; retinal pigment epithelium development (GO:0061299); CL: retinal pigment epithelial cell (CL:0002586)	Moderate-to-strong from model systems; exact causal chain for clefting/intellectual disability remains less well defined than for ocular defects.
Anatomy / tissues affected	Primary structures: uvea/iris, retina-choroid, optic nerve, globe size, and likely embryonic ocular tissues including RPE, periocular mesenchyme, lens vesicle, neural retina during development. (deyoung2022denovoframeshift pages 5-6)	UBERON: eye (UBERON:0000970), iris (UBERON:0001769), retina (UBERON:0000966), optic nerve (UBERON:0001138), lens vesicle, periocular mesenchyme	Moderate: anatomy is well supported for eye; non-ocular tissue localization is less disease-specific.
Inheritance / penetrance	Inheritance is autosomal dominant with incomplete penetrance and variable expressivity; both familial heterozygous and de novo cases are reported. An unaffected mother carrying p.Phe95Ser illustrates reduced penetrance (or possible germline mosaicism). (oatts2017novelheterozygousmutation pages 1-6, deyoung2022denovoframeshift pages 5-6, deyoung2022denovoframeshift pages 3-5)	HPO inheritance terms: Autosomal dominant inheritance (HP:0000006); Incomplete penetrance (HP:0003829); Variable expressivity (HP:0003828)	Strong. Quantitative penetrance estimates are not available.
Temporal course	Ocular anomalies are congenital / early infancy-onset. Visual function may be impaired from infancy and can worsen in some individuals; one reported patient declined from 20/200 to hand movements over 3 years. (deyoung2022denovoframeshift pages 1-3, oatts2017novelheterozygousmutation pages 1-6)	HPO: Congenital onset (HP:0003577); Reduced visual acuity (HP:0007663)	Limited natural-history data; no formal staging studies.
Diagnostics	Most informative test is molecular sequencing (WES/WGS or ocular malformation/developmental disorder panels including YAP1), interpreted with phenotype-driven review and careful read-depth assessment. Ophthalmic evaluation may include fundus photography, OCT, and autofluorescence. (deyoung2022denovoframeshift pages 5-6, oatts2017novelheterozygousmutation pages 6-8, jauss2022routinediagnosticsconfirm pages 6-7)	NCIT: Molecular Genetic Testing; HPO-driven phenotyping; eye imaging terms; possible panel category: coloboma / microphthalmia panel	Strong for sequencing utility; no disease-specific biomarker, lab assay, or diagnostic criteria guideline identified.
Management / real-world care	No disease-modifying therapy is established. Current care is supportive and multidisciplinary: ophthalmology/low-vision care, monitoring for cataract and refractive error, cleft team care if present, developmental assessment/support, audiology, and renal/urinary evaluation when indicated by phenotype. (deyoung2022denovoframeshift pages 5-6, deyoung2022denovoframeshift pages 1-3)	NCIT: Supportive Care, Ophthalmologic Examination, Vision Rehabilitation, Cleft Lip Repair, Speech Therapy, Genetic Counseling	Indirect but clinically standard; syndrome-specific treatment-outcome studies are lacking.
Genetic counseling / prevention	Because AD inheritance with reduced penetrance is documented, genetic counseling, family testing/segregation analysis, and consideration of prenatal or preimplantation testing after familial variant identification are reasonable. (oatts2017novelheterozygousmutation pages 1-6, deyoung2022denovoframeshift pages 5-6, deyoung2022denovoframeshift pages 3-5)	NCIT: Genetic Counseling; HPO inheritance terms above	Strong rationale from inheritance pattern; no formal prevention studies exist.
Model organisms	Zebrafish: yap1 and wwtr1/taz are required for proper RPE fate specification in eye development. Mouse: heterozygous Yap1 alteration causes Müller glia dysfunction and late-onset cone degeneration; broader Yap1 developmental roles support plausibility. (deyoung2022denovoframeshift pages 5-6, deyoung2022denovoframeshift pages 3-5)	NCBI Taxon: Danio rerio, Mus musculus; CL: Müller cell (CL:0002573)	Moderate: models support ocular developmental biology, but no single model fully recapitulating the full human syndromic triad was identified.
Recent developments (2023-2024)	No syndrome-specific 2023-2024 clinical expansion or interventional trial was identified in available searches. Recent work mainly strengthens broader YAP biology and developmental pathway crosstalk rather than this exact syndrome. (deyoung2022denovoframeshift pages 5-6)	GO/Pathway terms above	Important evidence gap; absence of evidence should not be read as disproving future developments.
Explicit evidence gaps	No robust data were found for syndrome prevalence/incidence, sex ratio, standardized prognosis, environmental risk/protective factors, gene-environment interactions, approved targeted therapy, or relevant clinical trials. (deyoung2022denovoframeshift pages 5-6, jauss2022routinediagnosticsconfirm pages 6-7)	Use “not established” rather than assigning ontology IDs	Strong confidence that these are gaps in currently available evidence, not confirmed negatives.

Table: This table summarizes the compact evidence base for uveal coloboma-cleft lip/palate-intellectual disability syndrome as part of the YAP1-related ocular coloboma spectrum. It highlights established findings, ontology suggestions, and important limitations for knowledge-base curation.

1. Disease information

Definition and nomenclature

The defining malformation is congenital uveal coloboma, caused by defective embryonic optic-fissure closure, occurring with cleft lip with or without cleft palate and neurodevelopmental impairment in the classic syndromic presentation. Modern evidence indicates that this historical syndrome overlaps the broader entity YAP1-related developmental eye disorder/ocular coloboma. YAP1 variants can produce either isolated ocular disease or multisystem disease, so the triad should not be treated as obligatory in every molecularly confirmed individual. (deyoung2022denovoframeshift pages 6-6, deyoung2022denovoframeshift pages 5-6)

Identifiers and synonyms

OMIM phenotype: #120433, ocular coloboma with or without hearing impairment, cleft lip/palate, and/or intellectual or learning impairment.
Gene: YAP1; HGNC:16262.
MONDO: no exact MONDO identifier could be verified from the retrieved evidence; it should remain unassigned rather than inferred.
Orphanet: no exact syndrome-specific ORPHA identifier was verified.
ICD-10/ICD-11 and MeSH: no unique syndrome-specific code was identified. Component manifestations are coded separately, such as congenital ocular coloboma, cleft lip/palate, and intellectual developmental disorder.
Synonyms: autosomal dominant syndrome of uveal colobomata, cleft lip and palate, and mental retardation; uveal coloboma–cleft lip/palate–intellectual disability syndrome; syndromic YAP1-related ocular coloboma; YAP1-related developmental eye disorder.

The foundational report is Kingston, Harper, and Jones, Journal of Medical Genetics, December 1982, DOI: https://doi.org/10.1136/jmg.19.6.444. The retrieved system did not provide a verified PMID, so none is guessed here. Later literature explicitly cites this report as an autosomal-dominant uveal-coloboma/clefting/intellectual-disability syndrome. (deyoung2022denovoframeshift pages 6-6)

Evidence granularity: the evidence is primarily human family-level or individual-patient clinical data, subsequently aggregated in OMIM and later case reports. It is not based on EHR-scale analyses.

2. Etiology

Causal factor

The best-supported cause is a germline heterozygous loss-of-function variant in YAP1. Nonsense and frameshift alleles support haploinsufficiency; familial missense variants have also been reported. Both inherited and de novo variants occur. A 2022 case carried de novo NM_001130145.3:c.178dupG, p.(Asp60GlyfsTer52), predicted to undergo nonsense-mediated decay and remove amino acids 61–504. (deyoung2022denovoframeshift pages 3-5, deyoung2022denovoframeshift pages 1-3)

Risk factors

Genetic: a pathogenic/likely pathogenic heterozygous YAP1 allele is the established risk factor. A positive family history raises risk, but an unaffected carrier may transmit disease because penetrance is incomplete.
Modifiers: alternative YAP1 transcriptional start sites and variable expression from the normal allele have been proposed to explain variable expression. These remain hypotheses rather than validated clinical modifiers. (oatts2017novelheterozygousmutation pages 1-6, deyoung2022denovoframeshift pages 3-5)
Environmental, infectious, lifestyle, occupational, sex, or age-related risks: none is established for this specific syndrome.
Gene–environment interaction: no syndrome-specific evidence was found.

Environmental associations reported for anophthalmia/microphthalmia broadly must not be assigned to YAP1-related disease without direct evidence.

Protective factors

No protective allele, diet, medication, behavior, or exposure has been demonstrated. Reduced penetrance in carriers is not equivalent to an identified protective factor.

3. Phenotypes

Because published denominators are very small and ascertainment differs among reports, frequencies should be recorded as unknown/variable, not converted into percentages.

Ocular manifestations

Uveal/ocular coloboma: congenital, often bilateral, involving iris, choroid/retina, and/or optic nerve; severity ranges from structurally evident disease with preserved acuity to major visual impairment. Suggested HPO: Coloboma HP:0000589; Uveal coloboma HP:0007707; Iris coloboma HP:0000612; Chorioretinal coloboma HP:0000539; Optic nerve coloboma HP:0000588.
Microphthalmia and microcornea: congenital and variably present. HPO: Microphthalmia HP:0000568; Microcornea HP:0000482.
Nystagmus, reduced visual acuity, astigmatism, cataract: secondary or associated ocular findings. In one molecularly confirmed one-year-old, visual acuity was 20/200, with nystagmus, bilateral microcornea, right microphthalmia, and an inferior cortical cataract. (deyoung2022denovoframeshift pages 1-3, deyoung2022denovoframeshift pages 3-5)

One 2017 family illustrates extreme variability: a 20-year-old had bilateral iris/retinal colobomas and acuity declining from 20/200 to hand movements over three years, whereas his 12-year-old half-brother had bilateral retinal/optic-disc colobomas with normal acuity. Their clinically unaffected mother carried the same p.Phe95Ser variant. (oatts2017novelheterozygousmutation pages 1-6)

Craniofacial and neurodevelopmental manifestations

Cleft lip with or without cleft palate: congenital and surgically relevant; frequency unknown. HPO: Cleft upper lip HP:0000204; Cleft palate HP:0000175.
Developmental delay, learning difficulty, or intellectual disability: recognized syndromic manifestations, with variable severity. HPO: Global developmental delay HP:0001263; Learning disability HP:0001328; Intellectual disability HP:0001249. A 2022 diagnostic report broadened the phenotype by associating a likely pathogenic YAP1 deletion with developmental delay and additional syndromic features. (deyoung2022denovoframeshift pages 5-6, jauss2022routinediagnosticsconfirm pages 6-7)
Anencephaly: reported in a stillbirth from an earlier family, together with cleft lip/palate; this is a rare observation, not an established routine feature. HPO: Anencephaly HP:0002323. (deyoung2022denovoframeshift pages 5-6)

Other manifestations

Sensorineural hearing impairment and hematuria have been reported in syndromic families. Suggested HPO terms are Sensorineural hearing impairment HP:0000407 and Hematuria HP:0000790. Possible hemifacial microsomia, tubular nose, and spina bifida occulta were noted in one 2022 proband but should be regarded as provisional extensions rather than core findings. (deyoung2022denovoframeshift pages 5-6, deyoung2022denovoframeshift pages 1-3)

Quality-of-life effects

No EQ-5D, SF-36, PROMIS, or disease-specific quality-of-life study was found. Expected burdens include visual disability, educational and adaptive-function limitations, hearing-related communication difficulties, and feeding, speech, dental, and psychosocial burdens associated with clefting. These are clinical inferences from the manifestations, not syndrome-specific quantitative outcomes.

4. Genetic and molecular information

Gene and protein

YAP1 encodes Yes-associated protein 1, a transcriptional co-activator and central Hippo-pathway effector. YAP1 lacks intrinsic DNA-binding activity and acts through transcription factors including TEAD proteins. When growth-suppressive Hippo signaling is inactive, nuclear YAP1/TAZ promotes pro-growth and anti-apoptotic transcription. (deyoung2022denovoframeshift pages 3-5)

Representative variants

NM_001130145.3:c.178dupG, p.(Asp60GlyfsTer52): de novo heterozygous exon-1 frameshift; absent from gnomAD; predicted nonsense-mediated decay; classified likely pathogenic using PS2 and PM2 evidence in the 2022 report. (deyoung2022denovoframeshift pages 3-5)
c.284T>C, p.(Phe95Ser): heterozygous missense variant in a family with isolated ocular coloboma. It was absent from contemporary variant databases and affects a residue conserved across nine species. In-silico predictions were discordant—SIFT 0.04, damaging; PolyPhen-2 0.085, tolerated—so its interpretation relies importantly on segregation and phenotype data. (oatts2017novelheterozygousmutation pages 1-6)
NM_001130145.3:c.1196_1199del: paternal, likely pathogenic four-base deletion reported in a neurodevelopmental diagnostic cohort. (jauss2022routinediagnosticsconfirm pages 6-7)

The variants are germline, not somatic cancer variants. The established mechanism is loss of function/haploinsufficiency, not gain of function or dominant negative action. No validated modifier gene, syndrome-specific epigenetic signature, recurrent chromosomal rearrangement, founder allele, or disease-relevant methylation biomarker was identified.

5. Environmental information

No toxin, radiation exposure, pollution source, maternal infection, nutritional deficiency, smoking, alcohol exposure, exercise pattern, or infectious organism has been causally linked to this exact YAP1 syndrome. Environmental factors associated with ocular malformations generally are differential etiologic considerations, but they do not replace molecular diagnosis and should not be annotated as syndrome causes.

6. Mechanism and pathophysiology

Proposed causal chain

Upstream germline YAP1 loss-of-function variant → reduced functional YAP1 dosage → abnormal Hippo-YAP/TEAD transcriptional output during embryogenesis → altered proliferation, survival, migration, and cell-fate specification in developing ocular tissues → defective optic-fissure closure and uveal coloboma. Microphthalmia and microcornea plausibly reflect broader disturbance of ocular growth. Zebrafish evidence particularly implicates failure of proper RPE specification. (deyoung2022denovoframeshift pages 5-6, deyoung2022denovoframeshift pages 3-5)

YAP1 is expressed during optic-fissure closure in presumptive RPE, periocular mesenchyme, lens vesicle, and scattered neural-retinal cells. Zebrafish yap1 and wwtr1/taz are required for RPE fate; FAT1 knockdown, affecting an upstream Hippo regulator implicated in coloboma, causes nuclear YAP1 accumulation in vitro. These observations position Hippo regulation upstream, and abnormal developmental transcription and tissue morphogenesis downstream. (deyoung2022denovoframeshift pages 5-6)

The mechanistic bridge from YAP1 deficiency to clefting and intellectual disability is less directly resolved than the ocular mechanism. It likely reflects the broader requirement for YAP1-regulated growth and lineage decisions in craniofacial and neural development, but direct syndrome-specific single-cell, spatial-transcriptomic, proteomic, metabolomic, or human organoid evidence was not identified.

Suggested GO terms: Hippo signaling GO:0035329; regulation of cell proliferation GO:0042127; positive regulation of transcription by RNA polymerase II GO:0045944; eye morphogenesis GO:0048592; retinal pigment epithelium development GO:0061299; regulation of apoptotic process GO:0042981.

Suggested cell types: retinal pigment epithelial cell CL:0002586; Müller glial cell CL:0002573; neural retinal cell; periocular mesenchymal cell; lens epithelial cell. Exact CL identifiers should be ontology-validated before ingestion where not listed.

There is no established metabolic, immune, inflammatory, fibrotic, or biochemical-enzyme defect in this syndrome.

7. Anatomical structures affected

The primary organ is the eye, particularly the uvea/iris, retina and choroid, optic disc/nerve, and globe. Suggested UBERON terms include eye UBERON:0000970, retina UBERON:0000966, iris UBERON:0001769, and optic nerve UBERON:0001138. Developmentally relevant tissues include RPE, periocular mesenchyme, lens vesicle, and neural retina. (deyoung2022denovoframeshift pages 1-3, deyoung2022denovoframeshift pages 5-6)

Secondary systems can include the lip and palate, central nervous system/neurodevelopment, auditory system, and urinary tract/kidneys. Coloboma may be unilateral or bilateral and can be anatomically asymmetric; bilateral disease is prominent in several molecularly documented cases. (deyoung2022denovoframeshift pages 1-3, oatts2017novelheterozygousmutation pages 1-6)

At the subcellular level, the relevant localization is principally cytoplasmic versus nuclear YAP1, controlled by Hippo-dependent phosphorylation and nuclear translocation. Suggested GO cellular-component annotations include nucleus and cytoplasm; these are gene-level rather than disease-specific annotations. (deyoung2022denovoframeshift pages 3-5)

8. Temporal development

The structural defects arise prenatally and are present at birth. There are no recognized acute, relapsing-remitting, or remitting stages. Clefting and coloboma are structurally stable congenital malformations, but their consequences are lifelong. Visual function may remain stable or deteriorate because of retinal complications, cataract, refractive error, or other secondary ocular disease; the 2017 report documents substantial decline in one individual over three years. (oatts2017novelheterozygousmutation pages 1-6, oatts2017novelheterozygousmutation pages 6-8)

Critical intervention periods are infancy and childhood: prompt ophthalmic characterization and visual habilitation, cleft feeding/surgical pathways, hearing assessment, and early developmental intervention may reduce secondary disability. No disease-specific longitudinal staging framework exists.

9. Inheritance and population

Inheritance is autosomal dominant. Both multigenerational familial transmission and de novo occurrence are documented. Penetrance is incomplete, and expression varies from an unaffected carrier or isolated ocular coloboma to multisystem disease. The unaffected mother carrying p.Phe95Ser is direct evidence of reduced penetrance, although germline mosaicism was also discussed. (oatts2017novelheterozygousmutation pages 1-6, deyoung2022denovoframeshift pages 5-6)

No numeric penetrance, prevalence, incidence, carrier frequency, sex ratio, age distribution, founder effect, ethnic enrichment, geographic clustering, anticipation, or consanguinity effect is established. The disorder is so rare that general coloboma prevalence must not be substituted for syndrome prevalence. Germline mosaicism is possible in principle but has not been quantified.

For a heterozygous affected individual, the formal transmission probability is 50% per conception, but the probability and severity of clinical expression in a carrier cannot be predicted accurately because of reduced penetrance and variable expressivity.

10. Diagnostics

Clinical evaluation

Diagnosis begins with recognition of congenital ocular coloboma, particularly when accompanied by microphthalmia, clefting, developmental impairment, hearing loss, hematuria, or a dominant family history. Detailed ophthalmic evaluation should define iris, chorioretinal, and optic-nerve involvement and assess acuity, refraction, cataract, nystagmus, and retinal complications. Fundus photography, fundus autofluorescence, and optical coherence tomography have been used in reported families. (oatts2017novelheterozygousmutation pages 6-8)

Audiology, developmental/neuropsychological assessment, cleft-team evaluation, and urinalysis/renal assessment are phenotype-directed. Brain imaging is not a universal diagnostic requirement but is appropriate for neurologic abnormalities or major developmental impairment.

Genetic testing strategy

Trio exome or genome sequencing is appropriate for syndromic coloboma, especially in sporadic cases.
A microphthalmia–anophthalmia–coloboma or developmental-eye-disorder panel should include YAP1 and major differential genes.
Single-gene YAP1 sequencing with deletion/duplication analysis is reasonable where the phenotype or family segregation is compelling.
Review exon-level read depth because inadequate coverage can lead to missed calls; the 2022 authors specifically cautioned that unbiased exome analysis alone can be misleading. (deyoung2022denovoframeshift pages 5-6)
Chromosomal microarray is useful for syndromic congenital anomalies but does not exclude a sequence-level YAP1 variant. Karyotype/FISH should be reserved for suspected large rearrangements.

RNA sequencing may help resolve a suspected splice variant, but no validated transcriptomic diagnostic signature exists. Mitochondrial, repeat-expansion, liquid-biopsy, proteomic, and metabolomic tests are not indicated routinely.

Differential diagnosis

Important alternatives include CHARGE syndrome (CHD7), branchio-oculo-facial syndrome (TFAP2A), renal-coloboma syndrome (PAX2), Cat-eye syndrome, Kabuki syndrome, and other MAC-spectrum disorders involving SOX2, OTX2, PAX6, MAB21L2, SALL2, or FAT1. Distinction relies on the complete phenotype and molecular testing. No universally accepted syndrome-specific clinical criteria exist.

11. Outcome and prognosis

No five- or ten-year survival estimates, mortality rate, or life-expectancy data exist. The syndrome is not known to be intrinsically degenerative or lethal in its usual presentation, although severe congenital anomalies can affect individual prognosis. A stillbirth with anencephaly in one historical family demonstrates that rare severe outcomes may occur but does not establish a general mortality risk. (deyoung2022denovoframeshift pages 5-6)

Principal long-term morbidity is visual impairment, potentially compounded by hearing loss, intellectual/developmental disability, and cleft-related speech, feeding, dental, and psychosocial effects. Prognosis depends more on anatomical coloboma extent, retinal/optic-nerve involvement, associated anomalies, and developmental severity than on a validated molecular biomarker. No syndrome-specific prognostic model or quality-of-life instrument has been studied.

12. Treatment

There is no approved pharmacologic, gene, cell, RNA, targeted, or immunologic therapy that corrects YAP1 haploinsufficiency or restores embryonic optic-fissure closure. No relevant syndrome-specific ClinicalTrials.gov study was identified.

Management is individualized and supportive:

pediatric and lifelong ophthalmology; refractive correction, amblyopia treatment where feasible, cataract management, retinal surveillance, and low-vision services;
cleft feeding support, staged cleft-lip/palate repair, dentistry/orthodontics, and speech therapy;
early developmental, educational, occupational, physical, and behavioral supports;
audiologic monitoring and hearing devices when indicated;
renal/urinary investigation when hematuria is present;
genetic counseling and family testing.

Suggested NCIt concepts include Genetic Counseling, Molecular Genetic Testing, Supportive Care, Ophthalmologic Examination, Vision Rehabilitation, Cleft Lip Repair, Cleft Palate Repair, Speech Therapy, Occupational Therapy, and Hearing Aid. There are no syndrome-specific response-rate or adverse-event data.

13. Prevention

Primary prevention through lifestyle, vaccination, diet, or medication is not available because this is a germline developmental disorder. Secondary and tertiary prevention are nevertheless important:

identify the disorder early and initiate visual, hearing, developmental, and cleft interventions;
perform cascade testing after a familial variant is found;
offer prenatal diagnosis or preimplantation genetic testing when the familial pathogenic variant is known;
counsel families about the 50% transmission probability and unpredictable clinical expression.

Routine population or newborn molecular screening is not recommended. Prenatal ultrasound may detect clefting, microphthalmia, or major CNS malformations, but a normal scan cannot exclude coloboma or later neurodevelopmental impairment.

14. Other species and natural disease

No naturally occurring veterinary syndrome confidently homologous to the complete human triad was identified. Accordingly, no affected breed, VBO term, zoonotic potential, transmission risk, or cross-species natural-disease epidemiology can be assigned. YAP1 and Hippo signaling are evolutionarily conserved, making experimental comparative biology highly informative, but this does not establish spontaneous disease in another species.

15. Model organisms

Zebrafish

Genetic studies show that yap1 and wwtr1/taz are required for proper RPE cell-fate specification. These models support the causal chain from abnormal Hippo-YAP signaling to defective ocular differentiation and coloboma-like developmental abnormalities. Their strengths are accessible embryology, live imaging, and genetic manipulation; limitations include anatomical differences from human craniofacial and cortical development and incomplete recapitulation of the full human syndrome. (deyoung2022denovoframeshift pages 5-6)

A 2024 zebrafish reporter study—Astone et al., published September 2024, DOI: https://doi.org/10.3390/ijms251810005—showed broad developmental crosstalk between Wnt/β-catenin and Yap/Taz activity using pharmacologic and genetic perturbations. This is a recent mechanistic development relevant to YAP biology, but it is not direct evidence about patients with this syndrome.

Mouse

YAP1 is expressed in developing RPE, periocular mesenchyme, lens vesicle, and neural retina. Heterozygous Yap1 alteration has been associated with Müller-glial dysfunction and late-onset cone degeneration, supporting roles in retinal differentiation and maintenance. Mouse models are valuable for mammalian retinal cell biology but do not yet provide a validated full model of the ocular-cleft-neurodevelopmental triad. (deyoung2022denovoframeshift pages 5-6)

Cellular and advanced models

FAT1 knockdown causes nuclear YAP1 accumulation in vitro, providing pathway-level evidence connecting an upstream Hippo regulator to coloboma biology. No syndrome-specific human iPSC, ocular-organoid, craniofacial-organoid, single-cell, spatial-transcriptomic, CRISPR-screen, or multi-omics model was identified. These are major opportunities for future research. (deyoung2022denovoframeshift pages 5-6)

Recent-development and evidence assessment

The latest syndrome-specific clinical evidence retrieved was published in 2022: DeYoung et al., DOI: https://doi.org/10.1080/13816810.2022.2028299, describing a de novo YAP1 frameshift, and Jauss et al., December 2022, DOI: https://doi.org/10.3390/genes13122305, broadening the neurodevelopmental phenotype. The former directly states that its patient had “bilateral uveal coloboma and microphthalmia,” while the latter’s abstract states that routine diagnostics can “broaden the phenotypic spectrum” for genes including YAP1. (deyoung2022denovoframeshift pages 3-5, jauss2022routinediagnosticsconfirm pages 6-7)

No syndrome-specific 2023–2024 clinical cohort, natural-history study, therapeutic trial, or guideline was found. The strongest expert interpretation from the current literature is therefore that YAP1-related disease is a variable, incompletely penetrant developmental spectrum, not a uniform triad. Diagnostic practice should combine detailed phenotyping with sequencing and segregation analysis, while care remains multidisciplinary and manifestation-directed. (oatts2017novelheterozygousmutation pages 1-6, deyoung2022denovoframeshift pages 5-6)

Key limitations for knowledge-base curation

Do not infer phenotype frequencies from single families.
Do not assign an unverified MONDO or Orphanet identifier.
Do not treat every YAP1 variant as pathogenic; missense alleles require rigorous ACMG/AMP and segregation assessment.
Do not extrapolate environmental risks or prevalence from nonspecific coloboma/MAC studies.
Record epidemiology, standardized prognosis, protective factors, pharmacogenomics, targeted treatment, and clinical-trial evidence as not established rather than “none” in an absolute biological sense.
PMID fields should remain blank where a PMID was not directly verified; the DOI URLs above provide stable source links.

References

(deyoung2022denovoframeshift pages 5-6): Charles DeYoung, Bin Guan, Ehsan Ullah, Delphine Blain, Robert B. Hufnagel, and Brian P. Brooks. De novo frameshift mutation in yap1 associated with bilateral uveal coloboma and microphthalmia. Ophthalmic Genetics, 43:513-517, Mar 2022. URL: https://doi.org/10.1080/13816810.2022.2028299, doi:10.1080/13816810.2022.2028299. This article has 9 citations and is from a peer-reviewed journal.
(deyoung2022denovoframeshift pages 6-6): Charles DeYoung, Bin Guan, Ehsan Ullah, Delphine Blain, Robert B. Hufnagel, and Brian P. Brooks. De novo frameshift mutation in yap1 associated with bilateral uveal coloboma and microphthalmia. Ophthalmic Genetics, 43:513-517, Mar 2022. URL: https://doi.org/10.1080/13816810.2022.2028299, doi:10.1080/13816810.2022.2028299. This article has 9 citations and is from a peer-reviewed journal.
(deyoung2022denovoframeshift pages 1-3): Charles DeYoung, Bin Guan, Ehsan Ullah, Delphine Blain, Robert B. Hufnagel, and Brian P. Brooks. De novo frameshift mutation in yap1 associated with bilateral uveal coloboma and microphthalmia. Ophthalmic Genetics, 43:513-517, Mar 2022. URL: https://doi.org/10.1080/13816810.2022.2028299, doi:10.1080/13816810.2022.2028299. This article has 9 citations and is from a peer-reviewed journal.
(deyoung2022denovoframeshift pages 3-5): Charles DeYoung, Bin Guan, Ehsan Ullah, Delphine Blain, Robert B. Hufnagel, and Brian P. Brooks. De novo frameshift mutation in yap1 associated with bilateral uveal coloboma and microphthalmia. Ophthalmic Genetics, 43:513-517, Mar 2022. URL: https://doi.org/10.1080/13816810.2022.2028299, doi:10.1080/13816810.2022.2028299. This article has 9 citations and is from a peer-reviewed journal.
(jauss2022routinediagnosticsconfirm pages 6-7): Robin-Tobias Jauss, Sophia Schließke, and Rami Abou Jamra. Routine diagnostics confirm novel neurodevelopmental disorders. Genes, 13:2305, Dec 2022. URL: https://doi.org/10.3390/genes13122305, doi:10.3390/genes13122305. This article has 13 citations.
(oatts2017novelheterozygousmutation pages 1-6): Julius T. Oatts, Sarah Hull, Michel Michaelides, Gavin Arno, Andrew R. Webster, and Anthony T. Moore. Novel heterozygous mutation in yap1 in a family with isolated ocular colobomas. Ophthalmic Genetics, 38:281-283, May 2017. URL: https://doi.org/10.1080/13816810.2016.1188122, doi:10.1080/13816810.2016.1188122. This article has 22 citations and is from a peer-reviewed journal.
(oatts2017novelheterozygousmutation pages 6-8): Julius T. Oatts, Sarah Hull, Michel Michaelides, Gavin Arno, Andrew R. Webster, and Anthony T. Moore. Novel heterozygous mutation in yap1 in a family with isolated ocular colobomas. Ophthalmic Genetics, 38:281-283, May 2017. URL: https://doi.org/10.1080/13816810.2016.1188122, doi:10.1080/13816810.2016.1188122. This article has 22 citations and is from a peer-reviewed journal.

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1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

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Uveal Coloboma–Cleft Lip/Palate–Intellectual Disability Syndrome

Executive summary

1. Disease information

Definition and nomenclature

2. Etiology

Causal factor

Risk factors

Protective factors

3. Phenotypes

Ocular manifestations

Craniofacial and neurodevelopmental manifestations

Other manifestations

Quality-of-life effects

4. Genetic and molecular information

Gene and protein

Representative variants

5. Environmental information

6. Mechanism and pathophysiology

Proposed causal chain

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical evaluation

Genetic testing strategy

Differential diagnosis

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species and natural disease

15. Model organisms

Zebrafish

Mouse

Cellular and advanced models

Recent-development and evidence assessment

Key limitations for knowledge-base curation

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