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Classifications

Harrison's Part

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Inheritance

1

Autosomal dominant, de novo HP:0000006

ACOGS-associated CDH2 variants are heterozygous, and in the ACOGS-ascertained reports every proband in whom parental testing was performed carried a de novo variant, which is expected for a disorder with this degree of neurodevelopmental and cardiac morbidity. De novo origin is not universal across the wider literature: in the Peters-anomaly-ascertained series one proband's variant was inherited from an apparently unaffected mother (who had not had a formal eye exam), and a second proband had no parental samples available, so transmission from a non-penetrant or mildly affected carrier is documented and penetrance cannot be assumed complete at the milder, ocular-predominant end of the spectrum. The HPO annotation set for OMIM:618929 likewise records autosomal dominant inheritance as the only mode. Note that the CDH2 allelic disorder at the other end of the gene - familial attention-deficit hyperactivity disorder from a prodomain-cleavage-site missense variant - is autosomal recessive, so "CDH2 variant" alone does not imply a mode of inheritance.

Autosomal dominant inheritance Expressivity: VARIABLE

Show evidence (4 references)

PMID:31585109 SUPPORT Human Clinical

"neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic"

States directly that the disease-causing variants are de novo and heterozygous, i.e. autosomal dominant with no transmitted allele.

PMID:35708058 SUPPORT Human Clinical

"reported the fifteenth patient with ACOGS, having a novel de novo nonsense"

An independent later case confirms the de novo pattern in a patient ascertained outside the founding cohort.

PMID:31650526 SUPPORT Human Clinical

"the variant was also present in the mother, who is apparently unaffected but without evidence of formal eye exam"

Qualifies the de novo generalisation. This Peters-anomaly-ascertained proband inherited the CDH2 variant from an apparently unaffected mother, so a transmitted allele is documented and penetrance may be incomplete. PARTIAL rather than SUPPORT because it upholds autosomal dominant inheritance while refuting the stronger claim that every reported allele arose de novo.

+ 1 more reference

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Mechanistic Hypotheses

1

ACOGS ectodomain alleles act as antimorphs that poison wild-type N-cadherin adhesion

acogs_antimorphic_adhesion EMERGING

Evidence balance 1 support

The proposal is that the EC4-EC5 missense alleles are not simple loss-of-function. A mutant molecule that reaches the cell surface with an unhinged ectodomain still occupies the trans-binding partner presented by the apposing cell, so it subtracts wild-type molecules from the pool of competent bonds rather than merely failing to add to it. The direct observation supporting this is that the variants impair binding in trans to wild-type N-cadherin, not only to each other. If correct, the effective adhesive deficit in a heterozygote exceeds 50%, which would explain why a single heterozygous missense change produces a severe malformation syndrome while heterozygous N-cadherin-null mice are not reported as abnormal. That last contrast is weak evidence: the cached mouse-null report (PMID:9015265) is an abstract that describes homozygous mutants only and says nothing about heterozygotes, so the heterozygous-null comparison rests on the absence of a reported phenotype rather than on a documented normal one.

Not yet tested by the experiment that would settle it - a dosage series comparing wild-type, heterozygous-null and heterozygous-missense cells or animals for adhesion strength and for the ACOGS phenotypes.

Show evidence (1 reference)

PMID:31585109 SUPPORT In Vitro

"defect includes impaired binding in trans with N-cadherin-WT expressed on"

The trans-heterophilic binding failure against wild-type protein is the specific observation that motivates the antimorphic hypothesis.

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Discussions and Knowledge Gaps

3

Do the truncating CDH2 alleles (two frameshifts and a nonsense variant) cause ACOGS by the same dominant-negative route as the EC4-EC5 missense alleles, or by haploinsufficiency?

KNOWLEDGE GAP OPEN acogs_truncating_allele_mechanism

Attached to

pathophysiology#Truncation of the N-cadherin Cytoplasmic Catenin-Binding Tail pathophysiology#Failure of Trans Homophilic Adhesion with Dominant-Negative Interference

The founding cohort's functional work was done exclusively on EC4-EC5 missense alleles, and the interference argument rests on those experiments. The frameshift alleles are described only as predicted to truncate the cytoplasmic domain; no protein was measured. A later patient carries a de novo nonsense allele, which - depending on its position relative to the last exon-exon junction - could instead trigger nonsense-mediated decay and give straightforward haploinsufficiency. Two mechanisms that produce the same clinical label is not a cosmetic distinction: it changes whether whole-gene deletions should be expected to cause ACOGS, whether the disorder is a candidate for allele-specific silencing, and how a novel truncating variant of uncertain significance should be interpreted. The entry deliberately keeps the truncating alleles in their own PROVISIONAL pathophysiology node rather than merging them into the antimorphic node.

Proposed experiments

Measure N-cadherin protein and transcript in patient cells carrying truncating CDH2 alleles

exp_acogs_truncating_allele_protein

Quantify CDH2 transcript (with and without translation inhibition to unmask nonsense-mediated decay) and N-cadherin protein level and surface localisation in fibroblasts or reprogrammed cells from individuals with the frameshift and nonsense alleles, against EC4-EC5 missense carriers and controls. A reduced transcript that is restored by decay inhibition indicates haploinsufficiency; a stable truncated protein at the membrane indicates interference.

Phenotype ascertainment in carriers of whole-gene CDH2 deletions

exp_acogs_cdh2_deletion_phenotype

Systematically review copy-number databases for individuals with heterozygous deletions spanning CDH2 and determine whether any has the ACOGS phenotype. Absence of ACOGS among deletion carriers would argue strongly against haploinsufficiency as a sufficient mechanism.

Show evidence (1 reference)

PMID:35708058 SUPPORT Human Clinical

"reported the fifteenth patient with ACOGS, having a novel de novo nonsense"

The existence of a de novo nonsense allele in a clinically typical patient is what makes the mechanism question live rather than academic.

What determines which organs are affected, and how severely, in an individual with a given CDH2 variant?

KNOWLEDGE GAP OPEN acogs_organ_level_stochasticity

Attached to

pathophysiology#Structural Congenital Heart Disease phenotypes#Hypoplastic left heart syndrome phenotypes#Ventricular septal defect

A likely monozygotic twin pair sharing one pathogenic CDH2 variant - and therefore essentially one genome and one intrauterine environment - had hypoplastic left heart syndrome in one twin and a ventricular septal defect with pulmonary hypertension in the other. That is close to a controlled experiment, and it rules out common genetic background as the sole explanation for the well-known variable expressivity of CDH2 variants. What remains as candidate explanations is stochastic variation in a threshold process (adhesive bond number crossing a critical value at a particular place and time), post-zygotic somatic variation, or twin-specific vascular factors. None has been tested. Until it is, prognostic counselling for a newly diagnosed ACOGS fetus or infant cannot be based on the phenotype of an affected relative.

Proposed experiments

Deep sequencing of discordant tissues in CDH2-variant twin pairs

exp_acogs_twin_somatic_sequencing

Deep sequence cardiac and blood tissue from discordant CDH2-variant twins to test whether post-zygotic somatic variation, mosaic variant allele fraction, or a second hit explains the organ-level divergence.

Prospective ACOGS registry with systematic organ-system phenotyping

exp_acogs_registry_genotype_phenotype

Build a registry that phenotypes every ascertained individual across all four defining organ systems with a fixed protocol (brain MRI, echocardiography, ophthalmology, genitourinary assessment), so that the current genotype-phenotype picture stops being an artefact of which specialist happened to see the patient.

Show evidence (1 reference)

PMID:41997214 SUPPORT Human Clinical

"have described such variable expressivity in twins with the same CDH2 variant."

Establishes that this degree of within-genotype discordance had not previously been documented, which is why it is recorded as an open gap rather than an explained observation.

Does any existing animal or cellular model recapitulate ACOGS, or is the causal chain from N-cadherin adhesion failure to the human malformations entirely inferential?

HUMAN MODEL MISMATCH OPEN acogs_no_model_of_the_human_allele

Attached to

pathophysiology#Failure of Midline Axon Pathfinding and Callosal Tract Formation pathophysiology#Loss of Neuroepithelial Adherens Junction Integrity and Neuronal Migration Failure pathophysiology#Adhesion Failure in Ocular and Genital Primordia

None of the three Cdh2 mouse models curated in this entry models this disease. (Those three are not the whole Cdh2 mouse literature - a substantial body of brain-specific conditional-knockout work exists and is relevant to the neuroepithelial node, but none of it carries an ACOGS allele either.) The constitutive null is homozygous lethal by embryonic day 10, before the corpus callosum, cortex, eye or genitalia are built, and heterozygous nulls are not reported as abnormal - so the model that shows the cardiac requirement cannot show the neurodevelopmental one. The cardiac-specific inducible knockout addresses the adult working myocardium and produces dilated cardiomyopathy, a different disease. The p.H150Y knock-in models the allelic recessive ADHD disorder, has no anatomical brain abnormality, and is homozygous. No knock-in of an ACOGS EC4-EC5 allele has been made. The consequence for this entry is concrete: the pathophysiology nodes linking adhesion failure to callosal agenesis, periventricular heterotopia and ocular/genital malformation are tagged PROVISIONAL or HYPOTHETICAL, and should not be read as demonstrated causal chains.

Proposed experiments

Heterozygous knock-in of an ACOGS EC4-EC5 allele in mouse

exp_acogs_knockin_mouse

Generate a mouse heterozygous for one of the recurrent ACOGS calcium-site substitutions and score corpus callosum formation, cortical lamination and periventricular heterotopia, cardiac septation, anterior-segment development and testicular descent. Compare directly against a heterozygous null littermate to separate interference from haploinsufficiency in vivo.

Patient-derived cortical organoid and cardiac organoid adhesion assay

exp_acogs_patient_organoid_adhesion

Derive iPSCs from ACOGS individuals and controls, and measure apical adherens-junction integrity, neuroepithelial rosette architecture and neuronal migration in cortical organoids, plus tissue cohesion in cardiac organoids, to test the two mechanistic nodes in human cells carrying the real allele.

Show evidence (2 references)

PMID:9015265 SUPPORT Model Organism

"mutant embryos. Homozygous mutant embryos die by Day 10 of gestation. The"

Early embryonic lethality of the homozygous null is the specific reason the mouse cannot be used to test the neurodevelopmental arm of the mechanism.

PMID:34702855 SUPPORT Model Organism

"caused by a missense mutation in CDH2, which encodes the adhesion protein"

The only knock-in mouse carrying a human CDH2 missense allele models the recessive ADHD disorder, not ACOGS, so it does not fill this gap.

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Pathophysiology

10

Loss of Calcium Coordination at the N-cadherin EC4-EC5 Interdomain Site

The N-cadherin ectodomain is a chain of five extracellular cadherin (EC) domains whose linkers each bind calcium ions. Calcium occupancy is not decorative: the crystallographic work on type I cadherin ectodomains attributes what stiffness the interdomain linkers have to bound calcium, while noting in the same sentence that the resulting curvature of the rod is still "likely to be somewhat variable" and citing unpublished data for the rigidification itself. The geometry that presents the distal EC1 tip to a partner molecule on the apposing membrane therefore depends on these calcium-loaded linkers. Four of the seven ACOGS missense substitutions replace conserved residues of the calcium-binding site at the EC4-EC5 interdomain, and six of the seven fall within EC4-EC5 overall. This node is the proximal molecular lesion for the missense class of ACOGS alleles: the substitutions are not predicted to abolish the protein, they are predicted to unhinge it.

interdomain calcium ion binding by the N-cadherin ectodomain GO:0005509 ↓ DECREASED

Downstream

Failure of Trans Homophilic Adhesion with Dominant-Negative Interference

Show evidence (3 references)

PMID:31585109 SUPPORT Human Clinical

"consists of extracellular cadherin (EC) domains, separated by calcium binding"

States the architecture that this node depends on - EC domains separated by calcium-binding sites.

PMID:31585109 SUPPORT Human Clinical

"calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing"

Localises the disease substitutions to the EC4-EC5 interdomain calcium site, which is precisely what this node models.

PMID:21300292 SUPPORT INDIRECT In Vitro

"ectodomain curvature, which is likely to be somewhat variable despite rigidification by interdomain calcium binding"

Structural work on type I cadherin ectodomains (including N-cadherin) treats interdomain calcium binding as what rigidifies the ectodomain, which is the biophysical reason a calcium-site substitution is expected to be damaging even though it is a single conservative-looking amino acid change. Graded INDIRECT because the paper states the rigidification in passing, citing unpublished data, and in the same sentence says the resulting curvature is still somewhat variable - it does not demonstrate the point.

Failure of Trans Homophilic Adhesion with Dominant-Negative Interference

Adherens junctions are built from a trans strand-swap dimer formed between EC1 domains projecting from opposing cells, laterally clustered by a weaker cis interface. Cells expressing the ACOGS EC4-EC5 variants have a demonstrable cell-cell adhesion defect, and - critically - the defect includes impaired trans binding to wild-type N-cadherin displayed on the apposing cell. That last observation is what converts this from a quantitative dosage problem into an interference problem: in a heterozygote, a mutant molecule reaching the surface does not merely fail to contribute, it occupies a binding partner's trans interface unproductively, so the fraction of competent adhesive bonds falls further than the 50% expected from allele dosage alone. Structural work on type I cadherins independently shows that trans-interface mutations ablate adhesion outright while cis-interface mutations instead destabilise junction assembly, which is the framework in which the ACOGS alleles should be read.

homophilic cell-cell adhesion GO:0007156 ↓ DECREASED calcium-dependent cell-cell adhesion GO:0016339 ↓ DECREASED

N-cadherin trans homophilic binding GO:0098641 ↓ DECREASED

adherens junction GO:0005912

Downstream

Failure of Midline Axon Pathfinding and Callosal Tract Formation

Loss of Neuroepithelial Adherens Junction Integrity and Neuronal Migration Failure

Failure of Myocardial Cell Cohesion During Cardiac Morphogenesis

Adhesion Failure in Ocular and Genital Primordia

Show evidence (4 references)

PMID:31585109 SUPPORT In Vitro

"these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this"

Direct cell-based demonstration that the ACOGS EC4-EC5 alleles impair cell-cell adhesion.

PMID:31585109 SUPPORT In Vitro

"defect includes impaired binding in trans with N-cadherin-WT expressed on"

The specific observation that the mutant fails to bind wild-type N-cadherin in trans is the evidence for the dominant-negative reading of the mechanism, and it is the reason this node is not modelled as simple haploinsufficiency.

PMID:31585109 SUPPORT Human Clinical

"sites. The EC interacts with other cadherin molecules in cis and in trans to"

Names the cis and trans interactions that this node is about.

+ 1 more reference

Truncation of the N-cadherin Cytoplasmic Catenin-Binding Tail

A minority of ACOGS alleles are not ectodomain missense changes at all. Two frameshift variants in the founding cohort are predicted to produce a truncated cytoplasmic domain, and a later patient carried a de novo nonsense allele. The cytoplasmic tail of N-cadherin is the docking site for beta-catenin and p120-catenin and thus the entire link from the adhesion complex to the actin cytoskeleton; a molecule that keeps its ectodomain but loses its tail can still engage a partner in trans yet cannot transmit or resist force, and cannot be stabilised in a junction. Whether these alleles act that way or are instead degraded - producing true haploinsufficiency - is not resolved by any published experiment, which is why this node is PROVISIONAL and is kept separate from the ectodomain node rather than merged into it. The distinction matters because the two readings predict different things about modifier therapy and about the phenotype of whole-gene deletions.

adherens junction organization GO:0034332 ⚠ ABNORMAL

cadherin-catenin adhesion complex GO:0016342

Downstream

Failure of Midline Axon Pathfinding and Callosal Tract Formation

Failure of Myocardial Cell Cohesion During Cardiac Morphogenesis

Show evidence (2 references)

PMID:31585109 SUPPORT Human Clinical

"cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in"

Records that the frameshift alleles are predicted to yield a truncated cytoplasmic domain, which is the lesion this node models.

PMID:35708058 SUPPORT Human Clinical

"reported the fifteenth patient with ACOGS, having a novel de novo nonsense"

A nonsense allele extends the truncating class but is only partial support for this node as written: the report does not establish whether the transcript escapes nonsense-mediated decay, so it is equally compatible with a haploinsufficiency mechanism.

Failure of Midline Axon Pathfinding and Callosal Tract Formation

Growth cones navigating to and across the telencephalic midline advance by making and breaking adhesive contacts with each other and with the glial substrate; N-cadherin is one of the adhesion systems those contacts run on, and axon pathfinding is named among its essential roles in neural development. When adhesive competence is degraded, callosal axons reach the midline but fail to fasciculate and cross, and the tract is not formed - hence agenesis rather than degeneration of the corpus callosum, and hence a developmental rather than progressive course. The same logic covers the other two axon-pathfinding features of the syndrome: failure of the corticospinal projection to remain fully crossed produces mirror movements, and maldevelopment of the abducens projection to lateral rectus produces the Duane anomaly. This node is PROVISIONAL: the causal chain is inferred from N-cadherin's established role plus the human imaging and examination phenotype, and no patient-derived neuron or CDH2-variant axon-guidance assay has been reported.

projection neuron with a midline-crossing axon CL:0000540

axon guidance GO:0007411 ↓ DECREASED corpus callosum development GO:0022038 ⚠ ABNORMAL axon extension GO:0048675 ↓ DECREASED

Downstream

Structural Midline Brain Malformation and Neurodevelopmental Impairment

Show evidence (3 references)

PMID:31585109 SUPPORT Human Clinical

"whose essential roles in neural development include neuronal migration and axon"

Names axon pathfinding as an essential N-cadherin function in neural development, the premise of this node.

PMID:31585109 SUPPORT Human Clinical

"delay and/or intellectual disability, variable axon pathfinding defects (corpus"

The authors themselves group the callosal, mirror-movement and Duane features as axon pathfinding defects, which is the grouping this node represents.

PMID:31585109 SUPPORT Human Clinical

"callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular,"

Enumerates the three clinical readouts of this node.

Loss of Neuroepithelial Adherens Junction Integrity and Neuronal Migration Failure

N-cadherin is the principal adhesion molecule of the apical adherens junction belt that seals the ventricular-zone neuroepithelium and anchors radial glial endfeet at the ventricular surface. That belt is both the structural scaffold of the neuroepithelium and the launch pad for radially migrating neurons. Loss of adhesive competence therefore predicts two coupled failures: breaches in the ventricular lining, and neurons that never leave the periventricular region - the cell-biological signature of periventricular nodular heterotopia, which is present in a substantial minority of the ACOGS cohort. The experimental support cited here is the N-cadherin-null mouse, in which neurulation begins normally but the neural tube is malformed and undulating, showing that N-cadherin is required for neuroepithelial integrity rather than for the initiation of neurulation. This is model-organism evidence from a homozygous null, so it is directional support for the mechanism, not a model of the human heterozygous disease.

radial glial cell of the ventricular zone CL:0000681 migrating cortical neuron CL:0000540

neuron migration GO:0001764 ↓ DECREASED adherens junction organization GO:0034332 ⚠ ABNORMAL neural tube closure GO:0001843 ⚠ ABNORMAL

Downstream

Structural Midline Brain Malformation and Neurodevelopmental Impairment

Show evidence (3 references)

PMID:31585109 SUPPORT Human Clinical

"whose essential roles in neural development include neuronal migration and axon"

Neuronal migration is named as an essential N-cadherin function, which is the human-gene premise for the migration arm of this node.

PMID:9015265 SUPPORT Model Organism

"Undulation of the neural tube is also observed in the"

In N-cadherin-null mouse embryos the neural tube forms but is malformed, demonstrating a requirement for N-cadherin in maintaining neuroepithelial structure.

PMID:9015265 SUPPORT Model Organism

"wild-type littermates, and the epithelial organization of the somites is"

Partial support: the mouse null disrupts epithelial organisation in somites as well, showing the defect is a generic loss of epithelial cohesion rather than a neuroepithelium-specific programme. It also illustrates the limit of the model - homozygous nulls die by embryonic day 10, long before cortical neurogenesis, so the migration arm of this node is not directly demonstrated in any model.

Failure of Myocardial Cell Cohesion During Cardiac Morphogenesis

The looping heart tube and the septating chambers are built by sheets of cardiomyocytes that must stay mechanically coupled while they deform. In N-cadherin-null mouse embryos this is the single most dramatic defect: myocardial tissue forms, then the myocytes dissociate and the heart tube fails to develop. Notably, isolated null cardiomyocytes still beat synchronously, so the primary lesion is mechanical cohesion, not electrical coupling. In ACOGS the human phenotype is correspondingly structural - atrioventricular canal defect, coarctation, ventricular septal defect, hypoplastic left heart, dextrocardia - rather than a cardiomyopathy. This is the node that must not be conflated with N-cadherin's separate, postnatal role at the intercalated disc of the working myocardium, where induced deletion in the adult mouse causes intercalated-disc dissolution, dilated cardiomyopathy and fatal ventricular arrhythmia.

embryonic cardiomyocyte CL:0000746

heart development GO:0007507 ⚠ ABNORMAL cardiac septum development GO:0003279 ⚠ ABNORMAL

Downstream

Structural Congenital Heart Disease

Show evidence (3 references)

PMID:9015265 SUPPORT Model Organism

"dissociate and the heart tube fails to develop normally. In vitro studies of"

The defining experiment for this node: without N-cadherin, myocytes lose cohesion and cardiac morphogenesis fails.

PMID:9015265 SUPPORT Model Organism

"N-cadherin plays a critical role in early heart development as well as in other"

States the authors' conclusion that the requirement is specifically in early heart development, which is the developmental window relevant to ACOGS congenital heart disease.

PMID:15662031 SUPPORT Model Organism

"desmosomes. The mutant mice exhibited modest dilated cardiomyopathy and impaired"

Included as an explicit contrast, not as support for the developmental mechanism. Deleting N-cadherin from the ADULT myocardium produces dilated cardiomyopathy and arrhythmia, a different phenotype from ACOGS structural congenital heart disease, which is why the CDH2 cardiomyopathy literature must not be imported into this entry.

Adhesion Failure in Ocular and Genital Primordia

Ocular and genital anomalies are two of the four organ systems in the disease name, and both involve epithelial and mesenchymal tissues in which N-cadherin is expressed - the optic cup and lens vesicle in the eye, the genital tubercle and gubernacular apparatus in genital and testicular descent. The reported ocular findings include Peters anomaly, an anterior-segment dysgenesis that arises from failed separation of the lens vesicle from surface ectoderm, which is at least mechanistically congenial to an adhesion defect. Expression evidence now places N-cadherin at exactly the tissue interface and developmental moment whose failure produces the lesion: immunostaining of mouse embryonic eyes localises it to the lens stalk at the time of separation from the future cornea, and to the developing lens and corneal endothelium afterwards (PMID:31650526). But this remains the weakest node in the entry, and the confidence is unchanged at HYPOTHETICAL, because every absence enumerated here survives that result: showing the protein is present where the lesion arises is not the same as showing its loss causes the lesion. No experiment has tested N-cadherin function in an ACOGS patient's ocular or genital tissue, no animal model of the human alleles exists, the mouse immunostaining is wild-type localisation rather than a disease model, and the male-limited genital findings (cryptorchidism, micropenis) could equally reflect an endocrine rather than an adhesive lesion. It is kept as a terminal branch so that nothing downstream depends on it.

eye development GO:0001654 ⚠ ABNORMAL

Downstream

Ocular and Genital Malformation

Show evidence (2 references)

PMID:31585109 SUPPORT Human Clinical

"cardiac, and genital anomalies. All seven missense variants (c.1057G>A"

Establishes that ocular, cardiac and genital anomalies occur in the syndrome. It is only partial support for this node because the paper documents the association, not the adhesive mechanism proposed here.

PMID:31650526 SUPPORT Model Organism

"Immunostaining in mouse embryonic eyes confirmed N-cadherin is present in the lens stalk at the time of separation from the future cornea and in the developing lens and corneal endothelium at later stages, supporting a possible role in PA"

Places N-cadherin at the lens-stalk separation interface whose failure is the Peters lesion, which is the closest thing to spatial support this node has. Deliberately recorded as PARTIAL and left unable to raise the node above HYPOTHETICAL: this is wild-type expression localisation in mouse, not a functional test and not a model of the human alleles. The paper's own wording ("supporting a possible role") is the appropriate strength.

Structural Midline Brain Malformation and Neurodevelopmental Impairment

The convergent output of the axon-pathfinding and neuroepithelial arms is a brain that is structurally miswired at the midline and at the ventricular zone: corpus callosum agenesis or hypoplasia, interhemispheric cysts, interhypothalamic adhesion, and periventricular heterotopia. Clinically this presents as global developmental delay in infancy evolving to intellectual disability, with mirror movements, seizures and behavioural phenotypes (autistic behaviour, attention deficit hyperactivity disorder) in a minority. Because the lesions are malformative rather than degenerative, the expected course is static impairment with developmental progress, not regression.

Show evidence (2 references)

PMID:31585109 SUPPORT Human Clinical

"syndromic neurodevelopmental disorder characterized by global developmental"

The neurodevelopmental impairment is the characterising feature of the syndrome.

PMID:35708058 SUPPORT Human Clinical

"agenesis or hypoplasia of corpus callosum, craniofacial dysmorphism, ocular,"

Independently confirms callosal agenesis or hypoplasia as a defining structural feature.

Structural Congenital Heart Disease

The cardiac output of the syndrome is structural malformation present at birth, spanning septation defects (atrioventricular canal defect, ventricular septal defect), left-sided obstructive lesions (coarctation of the aorta, hypoplastic left heart syndrome), valvar regurgitation and situs abnormality (dextrocardia). The severity is not predicted by genotype: a likely monozygotic twin pair sharing one pathogenic CDH2 variant had hypoplastic left heart syndrome in one twin and a ventricular septal defect with pulmonary hypertension in the other, which is the cleanest available demonstration that stochastic or non-genetic factors set the cardiac outcome.

Show evidence (2 references)

PMID:41997214 SUPPORT Human Clinical

"hypoplastic left heart syndrome and the other with ventricular septal defect and"

Documents the two discordant cardiac phenotypes in twins sharing one CDH2 variant.

PMID:41997214 SUPPORT Human Clinical

"We present a novel case of likely monozygotic twins who both carried the same"

Establishes that the two individuals were likely monozygotic and shared the variant, which is what makes the discordance informative.

Ocular and Genital Malformation

The ocular phenotype spans anterior-segment dysgenesis (Peters anomaly), ocular motility disorders (strabismus, Duane anomaly) and periorbital dysmorphism. The genital phenotype has so far been reported only in males (cryptorchidism, micropenis); the single reported female with a genitourinary finding had a renal rather than genital anomaly, which is the one published hint that the urinary tract may also be involved.

Show evidence (2 references)

PMID:35708058 SUPPORT Human Clinical

"genital malformations were reported in male patients (cryptorchidism,"

Names the reported genital malformations and records that they had been described only in males.

PMID:35708058 SUPPORT Human Clinical

"finding. Our patient was the first female to have a renal anomaly since only"

Documents the single reported renal anomaly and its status as a first-of-kind observation.

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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

27

Cardiovascular 4

Coarctation of aorta OCCASIONAL HP:0001680

Show evidence (1 reference)

PMID:31585109 SUPPORT Human Clinical

"cardiac, and genital anomalies. All seven missense variants (c.1057G>A"

Partial support: the snippet establishes that cardiac anomalies occur. The specific lesion and its 2 of 9 fraction (22%, OCCASIONAL band) come from the HPO annotation set for OMIM:618929 (retrieved 2026-08-01).

Dextrocardia OCCASIONAL HP:0001651

Show evidence (1 reference)

PMID:31585109 SUPPORT Human Clinical

"cardiac, and genital anomalies. All seven missense variants (c.1057G>A"

Partial support: the snippet establishes that cardiac anomalies occur. The specific lesion and its 1 of 9 fraction (11%, OCCASIONAL band) come from the HPO annotation set for OMIM:618929 (retrieved 2026-08-01).

Ventricular septal defect HP:0001629

Show evidence (1 reference)

PMID:41997214 SUPPORT Human Clinical

"hypoplastic left heart syndrome and the other with ventricular septal defect and"

Documents the ventricular septal defect in the second twin.

Pulmonary hypertension Elevated pulmonary artery pressure HP:0004890

Show evidence (1 reference)

PMID:41997214 SUPPORT Human Clinical

"with one presenting with hypoplastic left heart syndrome and the other with ventricular septal defect and pulmonary hypertension"

Records pulmonary hypertension in a CDH2-variant individual, in the same twin who has the ventricular septal defect. Marked PARTIAL because the source says "pulmonary hypertension" with no haemodynamic characterisation, so it supports the unqualified pressure-elevation term and nothing finer.

Eye 2

Peters anomaly OCCASIONAL HP:0000659

Show evidence (3 references)

PMID:31650526 SUPPORT Human Clinical

"identified a de novo splicing and three novel missense heterozygous CDH2 variants affecting the extracellular cadherin domains in four individuals with PA"

Direct support naming both the gene and Peters anomaly in the same finding, from a cohort ascertained the opposite way round from the founding report: 145 probands with developmental ocular conditions screened for a genetic cause, rather than CDH2 patients examined for ocular findings. Reverse ascertainment makes this independent confirmation of the association rather than a restatement of it.

PMID:31650526 SUPPORT Human Clinical

"Syndromic anomalies were seen in three individuals and included left-sided cardiac lesions, dysmorphic facial features, and decreasing height percentiles; brain magnetic resonance imaging identified agenesis of the corpus callosum and hypoplasia of the inferior cerebellar vermis"

Establishes that the Peters-ascertained individuals carry the same cardiac and callosal features that define ACOGS, which is what licenses treating the two reports as one disorder spectrum rather than two CDH2 phenotypes. Also the source for the entry's cerebellar vermis hypoplasia phenotype.

PMID:31585109 SUPPORT Human Clinical

"cardiac, and genital anomalies. All seven missense variants (c.1057G>A"

Partial support: the snippet establishes that ocular anomalies occur in the syndrome but does not name Peters anomaly. The 2 of 9 fraction (22%, OCCASIONAL band) comes from the HPO annotation set for OMIM:618929 (retrieved 2026-08-01); the specific term is now directly sourced to PMID:31650526 above rather than resting on that annotation alone.

Strabismus FREQUENT HP:0000486

Show evidence (1 reference)

PMID:31585109 SUPPORT Human Clinical

"cardiac, and genital anomalies. All seven missense variants (c.1057G>A"

Partial support: the snippet establishes ocular anomalies generally. The strabismus term and its 3 of 9 fraction (33%, FREQUENT band) come from the HPO annotation set for OMIM:618929 (retrieved 2026-08-01).

Genitourinary 2

Cryptorchidism FREQUENT HP:0000028

Show evidence (1 reference)

PMID:35708058 SUPPORT Human Clinical

"genital malformations were reported in male patients (cryptorchidism,"

Names cryptorchidism as a reported genital malformation. The FREQUENT band (30-79%) derives from the HPO annotation set for OMIM:618929, which records 3 of 5 = 60% for HP:0000028; note that the denominator is the male subset, not the whole cohort.

Micropenis OCCASIONAL HP:0000054

Show evidence (1 reference)

PMID:35708058 SUPPORT Human Clinical

"only genital malformations were reported in male patients (cryptorchidism, micropenis) so far"

Names micropenis among the reported male genital malformations. The OCCASIONAL band (5-29%) derives from the HPO annotation fraction of 1 of 5 males = 20% for HP:0000054.

Head and Neck 2

Macrocephaly FREQUENT HP:0000256

Show evidence (1 reference)

PMID:31585109 SUPPORT Human Clinical

"variants (seven missense, two frameshift) in CDH2 in nine individuals with a"

Partial support: the snippet gives the cohort denominator only. The macrocephaly finding and its 4 of 8 fraction (50%, FREQUENT band) come from the HPO annotation set for OMIM:618929 (retrieved 2026-08-01).

Craniofacial dysmorphism FREQUENT Abnormal facial shape HP:0001999

Show evidence (1 reference)

PMID:35708058 SUPPORT Human Clinical

"agenesis or hypoplasia of corpus callosum, craniofacial dysmorphism, ocular,"

Names craniofacial dysmorphism as a characterising feature of ACOGS. The FREQUENT band (30-79%) is derived from the HPO annotation set for OMIM:618929, in which the most frequent individual facial features sit at 4-5 of 9 (44-56%).

Nervous System 6

Agenesis of corpus callosum FREQUENT HP:0001274

Show evidence (2 references)

PMID:31585109 SUPPORT Human Clinical

"callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular,"

Supports the association. The FREQUENT band (30-79%) comes from the HPO annotation set for OMIM:618929, which records 7 of 9 = 78% for HP:0001274; note that 78% falls just below the 80% VERY_FREQUENT threshold, so the band is FREQUENT rather than VERY_FREQUENT.

PMID:35708058 SUPPORT Human Clinical

"agenesis or hypoplasia of corpus callosum, craniofacial dysmorphism, ocular,"

Independent restatement of the callosal phenotype as a defining feature.

Global developmental delay FREQUENT HP:0001263

Show evidence (1 reference)

PMID:31585109 SUPPORT Human Clinical

"syndromic neurodevelopmental disorder characterized by global developmental"

Global developmental delay is named as a characterising feature. The FREQUENT band derives from the HPO annotation set for OMIM:618929 (6 of 8 = 75% for HP:0001263, which falls in the FREQUENT band of 30-79%). Intellectual disability is annotated separately (4 of 8) and the two sets overlap rather than partition the cohort. The band follows the raw fraction for this term alone. The founding report states developmental delay and/or intellectual disability as a defining criterion, so the neurodevelopmental burden of the syndrome as a whole is broader than this one term's 75%; that breadth is described in prose rather than used to raise the band for HP:0001263, since no cached source gives a combined count.

Intellectual disability FREQUENT HP:0001249

Show evidence (1 reference)

PMID:31585109 SUPPORT Human Clinical

"delay and/or intellectual disability, variable axon pathfinding defects (corpus"

Supports the association. The FREQUENT band (30-79%) corresponds to the HPO annotation set fraction of 4 of 8 = 50% for HP:0001249.

Seizure OCCASIONAL HP:0001250

Show evidence (1 reference)

PMID:31585109 SUPPORT Human Clinical

"variants (seven missense, two frameshift) in CDH2 in nine individuals with a"

Partial support: the snippet gives the cohort denominator only. Seizures are not mentioned in the cached abstract; the two seizure annotations (each 1 of 8, i.e. 13%, OCCASIONAL band) come from the HPO annotation set for OMIM:618929 (retrieved 2026-08-01).

Attention deficit hyperactivity disorder OCCASIONAL HP:0007018

Show evidence (1 reference)

PMID:31585109 SUPPORT Human Clinical

"variants (seven missense, two frameshift) in CDH2 in nine individuals with a"

Partial support: the snippet gives the cohort denominator only. The ADHD annotation and its 2 of 8 fraction (25%, OCCASIONAL band) come from the HPO annotation set for OMIM:618929 (retrieved 2026-08-01).

Autistic behavior OCCASIONAL HP:0000729

Show evidence (1 reference)

PMID:31585109 SUPPORT Human Clinical

"variants (seven missense, two frameshift) in CDH2 in nine individuals with a"

Partial support: the snippet gives the cohort denominator only. The autistic-behaviour annotation and its 2 of 8 fraction (25%, OCCASIONAL band) come from the HPO annotation set for OMIM:618929 (retrieved 2026-08-01).

Other 11

Inferior cerebellar vermis hypoplasia HP:0007068

Show evidence (1 reference)

PMID:31650526 SUPPORT Human Clinical

"hypoplasia of the inferior cerebellar vermis in both patients"

Brain MRI was reviewed for the two imaged patients and showed inferior cerebellar vermis hypoplasia in both, establishing the association. The denominator is 2, so no frequency band is asserted.

Mirror movements OCCASIONAL Bimanual synkinesia HP:0001335

Show evidence (1 reference)

PMID:31585109 SUPPORT Human Clinical

"callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular,"

Supports the association. The OCCASIONAL band (5-29%) corresponds to the HPO annotation set fraction of 1 of 9 = 11% for HP:0001335.

Duane anomaly HP:0009921

Show evidence (1 reference)

PMID:31585109 SUPPORT Human Clinical

"callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular,"

Names Duane anomaly among the axon pathfinding defects of the syndrome. No frequency band is asserted: unlike the other features in this entry, Duane anomaly does not appear in the HPO annotation set for OMIM:618929, so there is no count to derive a band from.

Periventricular heterotopia FREQUENT HP:0007165

Show evidence (1 reference)

PMID:31585109 SUPPORT Human Clinical

"whose essential roles in neural development include neuronal migration and axon"

Partial support only. The cached abstract of the founding paper names neuronal migration as an N-cadherin function but does not enumerate periventricular heterotopia; the finding and its 4 of 9 fraction come from the HPO annotation set for OMIM:618929, which HPO curators derived from the full text of this same publication (retrieved 2026-08-01). The FREQUENT band (30-79%) corresponds to 4/9 = 44%.

Interhypothalamic adhesion FREQUENT HP:0033105

Show evidence (1 reference)

PMID:31585109 SUPPORT Human Clinical

"variants (seven missense, two frameshift) in CDH2 in nine individuals with a"

Partial support: the snippet establishes only the nine-individual cohort that is the denominator. The interhypothalamic adhesion finding itself and its 5 of 9 fraction come from the HPO annotation set for OMIM:618929 derived from the full text of this publication (retrieved 2026-08-01), not from the cached abstract. 5/9 = 56% gives the FREQUENT band.

Interhemispheric cyst OCCASIONAL HP:0032327

Show evidence (1 reference)

PMID:31585109 SUPPORT Human Clinical

"variants (seven missense, two frameshift) in CDH2 in nine individuals with a"

Partial support: the snippet gives the cohort denominator only. The finding and its 2 of 9 fraction (22%, OCCASIONAL band) come from the HPO annotation set for OMIM:618929 (retrieved 2026-08-01).

Axial hypotonia FREQUENT HP:0008936

Show evidence (1 reference)

PMID:31585109 SUPPORT Human Clinical

"variants (seven missense, two frameshift) in CDH2 in nine individuals with a"

Partial support: the snippet gives the cohort denominator only. The hypotonia finding and its 3 of 9 fraction (33%, FREQUENT band) come from the HPO annotation set for OMIM:618929 (retrieved 2026-08-01).

Atrioventricular canal defect OCCASIONAL HP:0006695

Show evidence (1 reference)

PMID:31585109 SUPPORT Human Clinical

"cardiac, and genital anomalies. All seven missense variants (c.1057G>A"

Partial support: the snippet establishes that cardiac anomalies occur. The specific lesion and its 2 of 9 fraction (22%, OCCASIONAL band) come from the HPO annotation set for OMIM:618929 (retrieved 2026-08-01).

Hypoplastic left heart syndrome Hypoplastic left ventricle HP:0004383

Show evidence (1 reference)

PMID:41997214 SUPPORT Human Clinical

"hypoplastic left heart syndrome and the other with ventricular septal defect and"

Documents hypoplastic left heart syndrome in a CDH2-variant individual. HP:0004383 (Hypoplastic left ventricle) is the closest available HPO term; HPO has no term for the full hypoplastic left heart syndrome, so preferred_term carries the clinical diagnosis and term.label the ontology label.

Abnormal renal morphology HP:0012210

Show evidence (1 reference)

PMID:35708058 SUPPORT Human Clinical

"finding. Our patient was the first female to have a renal anomaly since only"

The single reported renal anomaly, explicitly flagged by the authors as the first of its kind in ACOGS.

Sprengel anomaly OCCASIONAL HP:0000912

Show evidence (1 reference)

PMID:31585109 SUPPORT Human Clinical

"variants (seven missense, two frameshift) in CDH2 in nine individuals with a"

Partial support: the snippet gives the cohort denominator only. The Sprengel anomaly annotation and its 2 of 9 fraction (22%, OCCASIONAL band) come from the HPO annotation set for OMIM:618929 (retrieved 2026-08-01).

🧬

Genetic Associations

1

CDH2 (De novo heterozygous variants; sole known cause of ACOGS)

Gene: CDH2 hgnc:1759 relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (4 references)

PMID:31585109 SUPPORT Human Clinical

"mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin,"

Identifies the gene product as N-cadherin and states its adhesive function, which is the function lost in disease.

PMID:31585109 SUPPORT Human Clinical

"seven cluster within EC domains 4 and 5. Four of the substitutions affect the"

Documents the clustering of the missense alleles in EC4-EC5, the structural basis for grouping them as one variant class.

PMID:31585109 SUPPORT Human Clinical

"cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in"

Names the second allele class - frameshift variants predicted to truncate the cytoplasmic domain - and attributes the disorder to de novo heterozygous CDH2 variants.

+ 1 more reference

🔬

Diagnosis

4

Exome or genome sequencing with de novo CDH2 variant interpretation

Molecular diagnosis rests on finding a heterozygous CDH2 variant, confirmed de novo by parental testing, in a child with developmental delay plus a midline brain malformation and/or structural congenital heart disease. Two interpretation points follow from the published allelic spectrum. First, missense changes should be weighted by domain: substitutions of conserved residues in EC4-EC5, and particularly at the EC4-EC5 interdomain calcium site, are where the reported pathogenic missense alleles sit, and a variant there deserves more weight than its in-silico score alone would give it. Second, a CDH2 variant found on a cardiomyopathy gene panel is a different claim entirely and does not diagnose ACOGS - the panel association is with adult arrhythmogenic and dilated cardiomyopathy, is classified by ClinGen as Limited, and carries no expectation of callosal, ocular or genital involvement.

exome or genome sequencing NCIT:C101293

Show evidence (2 references)

PMID:31585109 SUPPORT Human Clinical

"seven cluster within EC domains 4 and 5. Four of the substitutions affect the"

Supports the domain-weighted interpretation advice by locating the pathogenic missense alleles in EC4-EC5.

CGGV:assertion_c7a03805-bf73-4d2d-9756-c666c67be119-2018-07-13T160000.000Z SUPPORT Other

Supports the caution about panel findings: the CDH2-cardiomyopathy gene-disease relationship is separately curated by ClinGen and classified as Limited.

Brain MRI

Brain MRI is the single highest-yield investigation. It documents the callosal agenesis or hypoplasia that names the syndrome and the associated midline and migration findings - interhypothalamic adhesion, interhemispheric cyst, periventricular nodular heterotopia, enlarged cisterna magna. The combination of a callosal anomaly with periventricular heterotopia in a child who also has congenital heart disease is the imaging pattern that should prompt CDH2 testing.

brain magnetic resonance imaging NCIT:C16809

The list of associated MRI findings is taken from the HPO annotation set for OMIM:618929 (retrieved 2026-08-01), not from the cached abstracts, which mention only the callosal anomaly. On the term binding: the only brain-specific MRI descendants of NCIT:C16809 are contrast-qualified (NCIT:C137874 without contrast, NCIT:C137913 with and without contrast; checked with runoak against sqlite:obo:ncit on 2026-08-01), and no source here states whether contrast was given, so the unqualified parent is bound with a UBERON brain site qualifier instead.

Show evidence (1 reference)

PMID:35708058 SUPPORT Human Clinical

"agenesis or hypoplasia of corpus callosum, craniofacial dysmorphism, ocular,"

The callosal anomaly is a defining feature and is an imaging diagnosis.

Echocardiography

Structural congenital heart disease is one of the four defining organ systems and has ranged from atrioventricular canal defect and coarctation to hypoplastic left heart syndrome. Echocardiography is therefore indicated in every newly diagnosed individual regardless of whether a murmur is present, and the twin report shows that a normal or mild finding in one relative says nothing about another.

echocardiography NCIT:C16525

Show evidence (1 reference)

PMID:41997214 SUPPORT Human Clinical

"pathogenic CDH2 variant yet exhibited a spectrum of CHD with one presenting with"

Demonstrates the range of congenital heart disease within a single genotype, which is the argument for imaging every individual rather than extrapolating from a relative.

Ophthalmological assessment including ocular motility

Formal ophthalmological review is needed for two separable reasons: to detect anterior-segment dysgenesis (Peters anomaly), which is sight-threatening and surgically actionable; and to detect the ocular motility disorders, where the distinction between common strabismus and the Duane anomaly matters, since Duane anomaly is a cranial dysinnervation pattern that changes both the surgical plan and the mechanistic interpretation.

ophthalmological assessment including ocular motility NCIT:C38060

Show evidence (1 reference)

PMID:31585109 SUPPORT Human Clinical

"callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular,"

Names Duane anomaly and ocular anomalies as features requiring ophthalmological assessment.

📊

Prevalence

1

Worldwide

Cases In Literature Not yet documented

No population prevalence or incidence estimate exists. The published case tally is the only available denominator: nine individuals in the 2019 founding cohort, fifteen in total as of the 2022 case report, and a likely monozygotic twin pair reported in 2026. Ascertainment is genotype-first (exome or genome sequencing for developmental delay or congenital heart disease), so these are case counts rather than a population rate, and the tally almost certainly under-counts milder presentations that are not sequenced. No Orphanet prevalence class is quoted: MONDO:0030065 carries no Orphanet xref (its xrefs are DOID:0080948, MEDGEN:1718475, OMIM:618929 and UMLS:C5394523; checked with OAK on 2026-08-01), and no ORPHA record for this disorder is present in references_cache/.

Show evidence (2 references)

PMID:31585109 SUPPORT Human Clinical

"variants (seven missense, two frameshift) in CDH2 in nine individuals with a"

Establishes the nine-individual founding cohort that is the denominator for every frequency band in this entry.

PMID:35708058 SUPPORT Human Clinical

"best of our knowledge, only 14 patients with ACOGS have been reported. Here, we"

Gives the cumulative published tally as of 2022 - fourteen prior patients plus the reported fifteenth.

🔀

Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from CDH2-Related ACOG Syndrome:

Mowat-Wilson syndrome MONDO:0009341

Overlapping Features The closest clinical mimic. Mowat-Wilson syndrome, caused by de novo heterozygous loss-of-function ZEB2 variants, combines a distinctive facial gestalt, global developmental delay and intellectual disability, agenesis or hypoplasia of the corpus callosum and congenital heart defects - three of the four organ systems that define ACOGS. A child with callosal agenesis, developmental delay and congenital heart disease will be tested for ZEB2 first.

Distinguishing Features

Caused by ZEB2 (hgnc:14881), a transcription factor, rather than CDH2 (hgnc:1759), an adhesion molecule - verified with OAK against MONDO:0009341.
Hirschsprung disease is characteristic of Mowat-Wilson syndrome and is not a reported feature of ACOGS. Epilepsy does not separate the two - it is common in Mowat-Wilson syndrome and is also a minority ACOGS feature (see the Seizure phenotype in this entry).
Microcephaly is typical of Mowat-Wilson syndrome, whereas macrocephaly is annotated in half the assessed ACOGS cohort.
Mowat-Wilson syndrome has a diagnostically recognisable facial gestalt; the ACOGS facial phenotype is non-specific, with no single feature exceeding about half the cohort.
Duane anomaly, mirror movements and periventricular heterotopia are ACOGS features and are not part of the Mowat-Wilson phenotype.

Duane retraction syndrome (isolated) MONDO:0007473

Overlapping Features Isolated Duane retraction syndrome is a congenital cranial dysinnervation disorder confined to the eye. It matters here because Duane anomaly is one of the three axon-pathfinding features of ACOGS, so an ophthalmologist seeing a child with Duane anomaly needs a reason to look further.

Distinguishing Features

Isolated Duane retraction syndrome has no callosal anomaly, no developmental delay, and no cardiac or genital malformation; the presence of any of these should prompt syndromic evaluation.
Most isolated Duane retraction syndrome is sporadic and non-Mendelian; the syndromic Mendelian forms are attributed to CHN1 (Duane retraction syndrome 2, MONDO:0011444, hgnc:1943) and to SALL4 in Duane-radial ray syndrome, not to CDH2.
Duane anomaly is not annotated at all in the HPO annotation set for OMIM:618929 despite being named in the founding report, so it is a minority ACOGS feature and its absence does not exclude ACOGS.

CDH2-related autosomal recessive attention-deficit hyperactivity disorder

Overlapping Features An allelic disorder rather than a phenocopy, and the sharpest illustration that "a CDH2 variant" is not one thing. Three siblings of a consanguineous kindred with severe childhood-onset ADHD were homozygous for c.355C>T (p.H150Y), a substitution in the prodomain furin-cleavage motif that impairs proteolytic maturation of N-cadherin rather than its adhesive interface. The resulting phenotype is behavioural and synaptic, with no malformation.

Distinguishing Features

Autosomal recessive, homozygous, segregating in a consanguineous family - versus de novo heterozygous in ACOGS.
The variant lies in the prodomain cleavage motif and impairs furin-mediated protein maturation, not in the EC4-EC5 adhesive/calcium-binding region.
The phenotype is isolated ADHD with normal brain anatomy; there is no corpus callosum, cardiac, ocular or genital malformation.
The knock-in mouse for this allele has no anatomical or histological brain abnormality, in contrast to the malformative human ACOGS phenotype.

Show evidence (3 references)

PMID:34702855 SUPPORT Human Clinical

"Here we describe three siblings of a consanguineous kindred"

Establishes the recessive, consanguineous family structure that distinguishes this entity from the de novo heterozygous ACOGS alleles.

PMID:34702855 SUPPORT Human Clinical

"to segregate within the family as expected for autosomal recessive"

Confirms autosomal recessive segregation, the mode of inheritance contrast with ACOGS.

PMID:34702855 SUPPORT In Vitro

"to interfere with the proteolysis and maturation of the protein."

Names the molecular mechanism - impaired maturation - which is different in kind from the adhesive-interface lesion of ACOGS.

CDH2-associated arrhythmogenic right ventricular cardiomyopathy MONDO:0016587

Overlapping Features Not a differential for the ACOGS presentation, but recorded because CDH2 appears on arrhythmogenic cardiomyopathy gene panels and the two claims are routinely conflated. Arrhythmogenic right ventricular cardiomyopathy is an adult-onset disease of the desmosomal/adherens-junction complex of the working myocardium, presenting with ventricular arrhythmia and fibrofatty replacement; the biology is intercalated-disc maintenance, matching the adult cardiac-specific Cdh2 knockout. ClinGen classifies the CDH2-arrhythmogenic right ventricular cardiomyopathy relationship as Limited.

Distinguishing Features

Adult-onset arrhythmia and myocardial replacement versus congenital structural malformation present at birth.
No callosal, ocular, genital or neurodevelopmental involvement.
ClinGen gene-disease validity for CDH2 in this disease is Limited, whereas the CDH2-ACOGS relationship rests on a nine-individual cohort with functional adhesion assays.
The relevant mouse model is the ADULT cardiac-specific conditional knockout, not the constitutive embryonic null.

Show evidence (2 references)

CGGV:assertion_c7a03805-bf73-4d2d-9756-c666c67be119-2018-07-13T160000.000Z SUPPORT Other

ClinGen classifies the CDH2-arrhythmogenic right ventricular cardiomyopathy relationship as Limited, which is the evidence basis for keeping that claim separate from and weaker than the ACOGS claim.

PMID:15662031 SUPPORT Model Organism

"disassembly of the intercalated disc structure, including adherens junctions and"

Identifies the intercalated disc as the structure at risk when N-cadherin is lost from adult myocardium, the mechanism of the cardiomyopathy claim rather than of ACOGS.

CDH2-associated dilated cardiomyopathy MONDO:0005021

Overlapping Features The second CDH2 cardiomyopathy claim, likewise recorded only as contrast. The adult cardiac-specific Cdh2 knockout mouse develops exactly this phenotype, which gives the association biological plausibility, but ClinGen classifies the human gene-disease relationship as Limited. Nothing in the dilated cardiomyopathy literature should be imported into this entry, and nothing in this entry implies that ACOGS individuals develop dilated cardiomyopathy - no such progression has been reported.

Distinguishing Features

Acquired ventricular dilation and systolic dysfunction in a structurally normally formed heart, versus congenital structural malformation.
No neurodevelopmental, ocular or genital involvement.
ClinGen gene-disease validity Limited (2025 reassessment by the Dilated Cardiomyopathy Gene Curation Expert Panel).

Show evidence (1 reference)

CGGV:assertion_73900af1-14ee-4933-b5dc-832753e6cc6c-2025-05-16T160000.000Z SUPPORT Other

ClinGen classifies the CDH2-dilated cardiomyopathy relationship as Limited, supporting its treatment here as a separate and weaker claim.

🐁

Animal Models

3

Cdh2 constitutive null (homozygous) Mouse

The classical N-cadherin knockout. Neurulation and somitogenesis begin but the resulting structures are malformed, the somitic epithelium loses organisation, the neural tube undulates, and the primitive heart tube dissociates; embryos die by day 10 of gestation. It is the best evidence that N-cadherin is required for tissue cohesion during morphogenesis, including specifically in early heart development, and it establishes that the cardiac defect is mechanical rather than electrical, since isolated null cardiomyocytes still beat synchronously. It is not, however, a model of ACOGS: the human disease is heterozygous and caused by expressed missense or truncating alleles, and the mouse dies before any of the affected human structures are built.

Species

Mouse

Genotype

Cdh2 constitutive null (homozygous)

Genes

CDH2 hgnc:1759

Show evidence (2 references)

PMID:9015265 SUPPORT Model Organism

"heart; although myocardial tissue forms initially, the myocytes subsequently"

Describes the cardinal cardiac phenotype of the null - initial myocardial formation followed by loss of myocyte cohesion.

PMID:9015265 SUPPORT Model Organism

"mutant embryos. Homozygous mutant embryos die by Day 10 of gestation. The"

The lethality window that limits the model's usefulness for the neurodevelopmental and ocular arms of ACOGS.

Cardiac-specific tamoxifen-inducible Cdh2 conditional knockout (adult) Mouse

Included as an explicit contrast model, not as an ACOGS model. Deleting N-cadherin from the adult working myocardium dissolves the intercalated disc, produces modest dilated cardiomyopathy with impaired function, and kills most animals within two months from spontaneous ventricular tachycardia. This is the biology behind the CDH2 rows on arrhythmogenic and dilated cardiomyopathy gene panels, and it is a different phenotype from the structural congenital heart disease of ACOGS - a maintenance failure in a formed organ rather than a morphogenetic failure during its construction.

Species

Mouse

Genotype

Cardiac-specific tamoxifen-inducible Cdh2 conditional knockout (adult)

Genes

CDH2 hgnc:1759

Show evidence (2 references)

PMID:15662031 SUPPORT Model Organism

"N-cadherin was deleted in the adult myocardium. Loss of N-cadherin resulted in"

Establishes the adult, maintenance-phase context of this model, which is what distinguishes it from the developmental mechanism of ACOGS.

PMID:15662031 SUPPORT Model Organism

"desmosomes. The mutant mice exhibited modest dilated cardiomyopathy and impaired"

Names the resulting phenotype - dilated cardiomyopathy - which is the cardiomyopathy claim that must be kept separate from ACOGS.

Cdh2 p.H150Y knock-in (homozygous) Mouse

A CRISPR/Cas9 knock-in carrying the human p.H150Y substitution that causes the allelic autosomal recessive CDH2 ADHD disorder. Homozygous mice are hyperactive with impaired sensorimotor gating, respond to methylphenidate, and show presynaptic vesicle-clustering and dopaminergic deficits - but no anatomical or histological brain abnormality. It is recorded here as the boundary of the ACOGS phenotype rather than as a model of it: the same gene, a different domain (the prodomain furin cleavage motif rather than EC4-EC5), a different inheritance mode, and a behavioural rather than malformative outcome.

Species

Mouse

Genotype

Cdh2 p.H150Y knock-in (homozygous)

Background

C57BL/6JRcc

Genes

CDH2 hgnc:1759

Show evidence (2 references)

PMID:34702855 SUPPORT Model Organism

"generation and analysis of mice homozygous for the human"

Establishes that the model is homozygous for the human allele, in contrast to the heterozygous de novo alleles of ACOGS.

PMID:34702855 SUPPORT Model Organism

"p.H150Y in CDH2 (transcript variant 1; NM_001792.4)."

Names the specific allele modelled, which is not one of the ACOGS alleles.

{ }

Source YAML

click to show

name: CDH2-Related ACOG Syndrome
creation_date: "2026-08-01T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: agenesis of corpus callosum, cardiac, ocular, and genital syndrome
  term:
    id: MONDO:0030065
    label: agenesis of corpus callosum, cardiac, ocular, and genital syndrome
description: >-
  A multisystem developmental disorder caused by de novo heterozygous variants
  in CDH2, the gene encoding N-cadherin. N-cadherin is a classical type I
  cadherin whose five extracellular cadherin (EC) domains are separated by
  calcium-binding interdomain linkers and which holds apposing cell
  surfaces together through a trans strand-swap interface at EC1 reinforced by
  lateral cis interactions. The founding cohort reported nine individuals
  carrying seven missense and two frameshift variants; six of the seven missense
  changes cluster in EC domains 4 and 5 and four of them hit the calcium-binding
  site of the EC4-EC5 interdomain, and cells expressing these alleles fail to
  bind in trans even to wild-type N-cadherin presented on an apposing cell. The
  clinical consequence is a bundle of defects in exactly those tissues whose
  morphogenesis depends on N-cadherin-mediated cohesion: midline axon
  pathfinding (corpus callosum agenesis or hypoplasia, mirror movements, Duane
  anomaly), the ventricular-zone neuroepithelium (periventricular heterotopia),
  the early myocardium (structural congenital heart disease), and the ocular and
  genital primordia. Global developmental delay and/or intellectual disability
  are the most consistent neurodevelopmental features - the HPO annotation set
  for OMIM:618929 (retrieved 2026-08-01) records global developmental delay in
  6 of 8 and intellectual disability in 4 of 8 assessed individuals, so neither
  is universal. Because the mutant protein is still
  made and still engages wild-type partners unproductively, the mechanism is
  best read as antimorphic interference with adhesion rather than simple loss of
  one allele's worth of protein - although a later report of a de novo nonsense
  allele leaves that reading unsettled. The disorder is ultra-rare: fifteen
  published individuals as of the 2022 case report, with a likely monozygotic
  twin pair added in 2026 whose strikingly discordant cardiac phenotypes
  (hypoplastic left heart syndrome in one, ventricular septal defect with
  pulmonary hypertension in the other) show that the CDH2 genotype does not fix
  the organ-level outcome.
parents:
- Neurodevelopmental Disorder
- Congenital malformation syndrome
synonyms:
- ACOGS
- ACOG syndrome
- agenesis of corpus callosum, cardiac, ocular, and genital syndrome
- agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects
- CDH2-related syndromic neurodevelopmental disorder
- N-cadherin-related multisystem developmental disorder
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      The dominant and most constant morbidity is neurodevelopmental: global
      developmental delay and/or intellectual disability in the majority of the
      founding cohort, with the structural brain lesions (corpus callosum
      agenesis or hypoplasia, periventricular heterotopia, interhypothalamic
      adhesion) that give the syndrome its name. The cardiac, ocular and genital
      anomalies are congenital malformations of other organs rather than a
      second chronic disease process, so a single NEUROLOGIC chapter is the
      correct primary assignment.
    evidence:
    - reference: PMID:31585109
      reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "syndromic neurodevelopmental disorder characterized by global developmental"
      explanation: >-
        The founding report frames the entity as a syndromic neurodevelopmental
        disorder, which is the basis for the NEUROLOGIC chapter assignment.
  - classification_value: CARDIOVASCULAR
    notes: >-
      Recorded as a secondary chapter because structural congenital heart
      disease is one of the four organ systems named in the disease label and is
      the feature that has driven ascertainment in the most recent report, where
      genome sequencing for congenital heart disease was the route to diagnosis.
    evidence:
    - reference: PMID:41997214
      reference_title: "Phenotypic discordance in monozygotic twins with a CDH2 variant."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "pathogenic CDH2 variant yet exhibited a spectrum of CHD with one presenting with"
      explanation: >-
        Congenital heart disease is the presenting problem in the most recently
        reported ACOGS individuals, supporting a secondary cardiovascular
        classification.
inheritance:
- name: Autosomal dominant, de novo
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    ACOGS-associated CDH2 variants are heterozygous, and in the ACOGS-ascertained
    reports every proband in whom parental testing was performed carried a de
    novo variant, which is expected for a disorder with this degree of
    neurodevelopmental and cardiac morbidity. De novo origin is not universal
    across the wider literature: in the Peters-anomaly-ascertained series one
    proband's variant was inherited from an apparently unaffected mother (who had
    not had a formal eye exam), and a second proband had no parental samples
    available, so transmission from a non-penetrant or mildly affected carrier is
    documented and penetrance cannot be assumed complete at the milder,
    ocular-predominant end of the spectrum. The HPO annotation set for
    OMIM:618929 likewise records autosomal dominant inheritance as the only
    mode. Note that the CDH2 allelic
    disorder at the other end of the gene - familial attention-deficit
    hyperactivity disorder from a prodomain-cleavage-site missense variant - is
    autosomal recessive, so "CDH2 variant" alone does not imply a mode of
    inheritance.
  expressivity: VARIABLE
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic"
    explanation: >-
      States directly that the disease-causing variants are de novo and
      heterozygous, i.e. autosomal dominant with no transmitted allele.
  - reference: PMID:35708058
    reference_title: "A Novel nonsense variant in the CDH2 gene associated with ACOGS: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reported the fifteenth patient with ACOGS, having a novel de novo nonsense"
    explanation: >-
      An independent later case confirms the de novo pattern in a patient
      ascertained outside the founding cohort.
  - reference: PMID:31650526
    reference_title: "Novel variants in CDH2 are associated with a new syndrome including Peters anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the variant was also present in the mother, who is apparently unaffected but without evidence of formal eye exam"
    explanation: >-
      Qualifies the de novo generalisation. This Peters-anomaly-ascertained
      proband inherited the CDH2 variant from an apparently unaffected mother,
      so a transmitted allele is documented and penetrance may be incomplete.
      PARTIAL rather than SUPPORT because it upholds autosomal dominant
      inheritance while refuting the stronger claim that every reported allele
      arose de novo.
  - reference: PMID:41997214
    reference_title: "Phenotypic discordance in monozygotic twins with a CDH2 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "have described such variable expressivity in twins with the same CDH2 variant."
    explanation: >-
      Supports the VARIABLE expressivity qualifier: two individuals sharing one
      CDH2 genotype and (as monozygotic twins) essentially one genome had
      materially different cardiac phenotypes.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population prevalence or incidence estimate exists. The published case
    tally is the only available denominator: nine individuals in the 2019
    founding cohort, fifteen in total as of the 2022 case report, and a likely
    monozygotic twin pair reported in 2026. Ascertainment is genotype-first
    (exome or genome sequencing for developmental delay or congenital heart
    disease), so these are case counts rather than a population rate, and the
    tally almost certainly under-counts milder presentations that are not
    sequenced. No Orphanet prevalence class is quoted: MONDO:0030065 carries no
    Orphanet xref (its xrefs are DOID:0080948, MEDGEN:1718475, OMIM:618929 and
    UMLS:C5394523; checked with OAK on 2026-08-01), and no ORPHA record for this
    disorder is present in references_cache/.
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "variants (seven missense, two frameshift) in CDH2 in nine individuals with a"
    explanation: >-
      Establishes the nine-individual founding cohort that is the denominator
      for every frequency band in this entry.
  - reference: PMID:35708058
    reference_title: "A Novel nonsense variant in the CDH2 gene associated with ACOGS: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "best of our knowledge, only 14 patients with ACOGS have been reported. Here, we"
    explanation: >-
      Gives the cumulative published tally as of 2022 - fourteen prior patients
      plus the reported fifteenth.
genetic:
- name: CDH2
  gene_term:
    preferred_term: CDH2
    term:
      id: hgnc:1759
      label: CDH2
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  association: De novo heterozygous variants; sole known cause of ACOGS
  notes: >-
    CDH2 (18q12.1) encodes N-cadherin, a classical type I cadherin. The ACOGS
    allelic spectrum has two structurally distinct classes. The first is
    missense substitutions of highly conserved residues concentrated in the
    membrane-proximal extracellular cadherin domains: p.Asp353Asn, p.Asp597Asn,
    p.Asp597Tyr, p.Asn601Thr, p.Cys613Trp, p.Asp627Gly and p.Tyr676Cys, of which
    six of seven fall in EC4-EC5 and four disrupt the EC4-EC5 interdomain
    calcium site. The second is frameshift alleles that truncate the cytoplasmic
    tail (p.Leu855Valfs and p.Leu856Phefs), plus a later de novo nonsense
    allele. The reference transcript used by the ADHD study for the allelic
    recessive disorder is NM_001792.4. Deliberately excluded from this entry:
    the CDH2 rows that appear in the dismech arrhythmogenic right ventricular
    cardiomyopathy and dilated cardiomyopathy entries are a different
    gene-disease claim (adult myocardial adhesion, ClinGen validity Limited),
    not the developmental syndrome curated here.
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin,"
    explanation: >-
      Identifies the gene product as N-cadherin and states its adhesive
      function, which is the function lost in disease.
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "seven cluster within EC domains 4 and 5. Four of the substitutions affect the"
    explanation: >-
      Documents the clustering of the missense alleles in EC4-EC5, the
      structural basis for grouping them as one variant class.
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in"
    explanation: >-
      Names the second allele class - frameshift variants predicted to truncate
      the cytoplasmic domain - and attributes the disorder to de novo
      heterozygous CDH2 variants.
  - reference: PMID:35708058
    reference_title: "A Novel nonsense variant in the CDH2 gene associated with ACOGS: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiac, and genital anomalies. ACOGS is caused by variations in the CDH2 gene."
    explanation: >-
      Independent attribution of ACOGS to CDH2 by a group unconnected with the
      founding cohort.
pathophysiology:
- name: Loss of Calcium Coordination at the N-cadherin EC4-EC5 Interdomain Site
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The N-cadherin ectodomain is a chain of five extracellular cadherin (EC)
    domains whose linkers each bind calcium ions. Calcium occupancy is not
    decorative: the crystallographic work on type I cadherin ectodomains
    attributes what stiffness the interdomain linkers have to bound calcium,
    while noting in the same sentence that the resulting curvature of the rod is
    still "likely to be somewhat variable" and citing unpublished data for the
    rigidification itself. The geometry that presents the distal EC1 tip to a
    partner molecule on the apposing membrane therefore depends on these
    calcium-loaded linkers. Four of the seven ACOGS missense substitutions replace conserved
    residues of the calcium-binding site at the EC4-EC5 interdomain, and six of
    the seven fall within EC4-EC5 overall. This node is the proximal molecular
    lesion for the missense class of ACOGS alleles: the substitutions are not
    predicted to abolish the protein, they are predicted to unhinge it.
  molecular_functions:
  - preferred_term: interdomain calcium ion binding by the N-cadherin ectodomain
    term:
      id: GO:0005509
      label: calcium ion binding
    modifier: DECREASED
  downstream:
  - target: Failure of Trans Homophilic Adhesion with Dominant-Negative Interference
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "consists of extracellular cadherin (EC) domains, separated by calcium binding"
    explanation: >-
      States the architecture that this node depends on - EC domains separated
      by calcium-binding sites.
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing"
    explanation: >-
      Localises the disease substitutions to the EC4-EC5 interdomain calcium
      site, which is precisely what this node models.
  - reference: PMID:21300292
    reference_title: "The extracellular architecture of adherens junctions revealed by crystal structures of type I cadherins."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "ectodomain curvature, which is likely to be somewhat variable despite rigidification by interdomain calcium binding"
    explanation: >-
      Structural work on type I cadherin ectodomains (including N-cadherin)
      treats interdomain calcium binding as what rigidifies the ectodomain,
      which is the biophysical reason a calcium-site substitution is expected to
      be damaging even though it is a single conservative-looking amino acid
      change. Graded INDIRECT because the paper states the
      rigidification in passing, citing unpublished data, and in the same
      sentence says the resulting curvature is still somewhat variable - it does
      not demonstrate the point.
- name: Failure of Trans Homophilic Adhesion with Dominant-Negative Interference
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Adherens junctions are built from a trans strand-swap dimer formed between
    EC1 domains projecting from opposing cells, laterally clustered by a weaker
    cis interface. Cells expressing the ACOGS EC4-EC5 variants have a
    demonstrable cell-cell adhesion defect, and - critically - the defect
    includes impaired trans binding to wild-type N-cadherin displayed on the
    apposing cell. That last observation is what converts this from a
    quantitative dosage problem into an interference problem: in a heterozygote,
    a mutant molecule reaching the surface does not merely fail to contribute,
    it occupies a binding partner's trans interface unproductively, so the
    fraction of competent adhesive bonds falls further than the 50% expected
    from allele dosage alone. Structural work on type I cadherins independently
    shows that trans-interface mutations ablate adhesion outright while
    cis-interface mutations instead destabilise junction assembly, which is the
    framework in which the ACOGS alleles should be read.
  molecular_functions:
  - preferred_term: N-cadherin trans homophilic binding
    term:
      id: GO:0098641
      label: cadherin binding involved in cell-cell adhesion
    modifier: DECREASED
  biological_processes:
  - preferred_term: homophilic cell-cell adhesion
    term:
      id: GO:0007156
      label: homophilic cell-cell adhesion
    modifier: DECREASED
  - preferred_term: calcium-dependent cell-cell adhesion
    term:
      id: GO:0016339
      label: calcium-dependent cell-cell adhesion
    modifier: DECREASED
  cellular_components:
  - preferred_term: adherens junction
    term:
      id: GO:0005912
      label: adherens junction
  downstream:
  - target: Failure of Midline Axon Pathfinding and Callosal Tract Formation
  - target: Loss of Neuroepithelial Adherens Junction Integrity and Neuronal Migration Failure
  - target: Failure of Myocardial Cell Cohesion During Cardiac Morphogenesis
  - target: Adhesion Failure in Ocular and Genital Primordia
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this"
    explanation: >-
      Direct cell-based demonstration that the ACOGS EC4-EC5 alleles impair
      cell-cell adhesion.
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "defect includes impaired binding in trans with N-cadherin-WT expressed on"
    explanation: >-
      The specific observation that the mutant fails to bind wild-type
      N-cadherin in trans is the evidence for the dominant-negative reading of
      the mechanism, and it is the reason this node is not modelled as simple
      haploinsufficiency.
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sites. The EC interacts with other cadherin molecules in cis and in trans to"
    explanation: >-
      Names the cis and trans interactions that this node is about.
  - reference: PMID:21300292
    reference_title: "The extracellular architecture of adherens junctions revealed by crystal structures of type I cadherins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mutations that interfere with the trans interface ablate adhesion,"
    explanation: >-
      Establishes the general rule that trans-interface disruption abolishes
      cadherin adhesion, supporting the severity attributed here to the ACOGS
      ectodomain alleles.
- name: Truncation of the N-cadherin Cytoplasmic Catenin-Binding Tail
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    A minority of ACOGS alleles are not ectodomain missense changes at all. Two
    frameshift variants in the founding cohort are predicted to produce a
    truncated cytoplasmic domain, and a later patient carried a de novo nonsense
    allele. The cytoplasmic tail of N-cadherin is the docking site for
    beta-catenin and p120-catenin and thus the entire link from the adhesion
    complex to the actin cytoskeleton; a molecule that keeps its ectodomain but
    loses its tail can still engage a partner in trans yet cannot transmit or
    resist force, and cannot be stabilised in a junction. Whether these alleles
    act that way or are instead degraded - producing true haploinsufficiency -
    is not resolved by any published experiment, which is why this node is
    PROVISIONAL and is kept separate from the ectodomain node rather than merged
    into it. The distinction matters because the two readings predict different
    things about modifier therapy and about the phenotype of whole-gene
    deletions.
  cellular_components:
  - preferred_term: cadherin-catenin adhesion complex
    term:
      id: GO:0016342
      label: catenin complex
  biological_processes:
  - preferred_term: adherens junction organization
    term:
      id: GO:0034332
      label: adherens junction organization
    modifier: ABNORMAL
  downstream:
  - target: Failure of Midline Axon Pathfinding and Callosal Tract Formation
  - target: Failure of Myocardial Cell Cohesion During Cardiac Morphogenesis
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in"
    explanation: >-
      Records that the frameshift alleles are predicted to yield a truncated
      cytoplasmic domain, which is the lesion this node models.
  - reference: PMID:35708058
    reference_title: "A Novel nonsense variant in the CDH2 gene associated with ACOGS: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reported the fifteenth patient with ACOGS, having a novel de novo nonsense"
    explanation: >-
      A nonsense allele extends the truncating class but is only partial support
      for this node as written: the report does not establish whether the
      transcript escapes nonsense-mediated decay, so it is equally compatible
      with a haploinsufficiency mechanism.
  notes: >-
    No published experiment has measured N-cadherin protein level or
    localisation in cells or tissue from a patient carrying a truncating CDH2
    allele. The dominant-negative versus haploinsufficiency question is recorded
    as an open knowledge gap (acogs_truncating_allele_mechanism).
- name: Failure of Midline Axon Pathfinding and Callosal Tract Formation
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Growth cones navigating to and across the telencephalic midline advance by
    making and breaking adhesive contacts with each other and with the glial
    substrate; N-cadherin is one of the adhesion systems those contacts run on,
    and axon pathfinding is named among its essential roles in neural
    development. When adhesive competence is degraded, callosal axons reach the
    midline but fail to fasciculate and cross, and the tract is not formed -
    hence agenesis rather than degeneration of the corpus callosum, and hence a
    developmental rather than progressive course. The same logic covers the
    other two axon-pathfinding features of the syndrome: failure of the
    corticospinal projection to remain fully crossed produces mirror movements,
    and maldevelopment of the abducens projection to lateral rectus produces the
    Duane anomaly. This node is PROVISIONAL: the causal chain is inferred from
    N-cadherin's established role plus the human imaging and examination
    phenotype, and no patient-derived neuron or CDH2-variant axon-guidance assay
    has been reported.
  cell_types:
  - preferred_term: projection neuron with a midline-crossing axon
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: axon guidance
    term:
      id: GO:0007411
      label: axon guidance
    modifier: DECREASED
  - preferred_term: corpus callosum development
    term:
      id: GO:0022038
      label: corpus callosum development
    modifier: ABNORMAL
  - preferred_term: axon extension
    term:
      id: GO:0048675
      label: axon extension
    modifier: DECREASED
  downstream:
  - target: Structural Midline Brain Malformation and Neurodevelopmental Impairment
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "whose essential roles in neural development include neuronal migration and axon"
    explanation: >-
      Names axon pathfinding as an essential N-cadherin function in neural
      development, the premise of this node.
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "delay and/or intellectual disability, variable axon pathfinding defects (corpus"
    explanation: >-
      The authors themselves group the callosal, mirror-movement and Duane
      features as axon pathfinding defects, which is the grouping this node
      represents.
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular,"
    explanation: >-
      Enumerates the three clinical readouts of this node.
- name: Loss of Neuroepithelial Adherens Junction Integrity and Neuronal Migration Failure
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    N-cadherin is the principal adhesion molecule of the apical adherens
    junction belt that seals the ventricular-zone neuroepithelium and anchors
    radial glial endfeet at the ventricular surface. That belt is both the
    structural scaffold of the neuroepithelium and the launch pad for radially
    migrating neurons. Loss of adhesive competence therefore predicts two
    coupled failures: breaches in the ventricular lining, and neurons that never
    leave the periventricular region - the cell-biological signature of
    periventricular nodular heterotopia, which is present in a substantial
    minority of the ACOGS cohort. The experimental support cited here is the
    N-cadherin-null mouse, in which neurulation begins normally but the neural
    tube is malformed and undulating, showing that N-cadherin is required for
    neuroepithelial integrity rather than for the initiation of neurulation.
    This is model-organism evidence from a homozygous null, so it is directional
    support for the mechanism, not a model of the human heterozygous disease.
  cell_types:
  - preferred_term: radial glial cell of the ventricular zone
    term:
      id: CL:0000681
      label: radial glial cell
  - preferred_term: migrating cortical neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: neuron migration
    term:
      id: GO:0001764
      label: neuron migration
    modifier: DECREASED
  - preferred_term: adherens junction organization
    term:
      id: GO:0034332
      label: adherens junction organization
    modifier: ABNORMAL
  - preferred_term: neural tube closure
    term:
      id: GO:0001843
      label: neural tube closure
    modifier: ABNORMAL
  downstream:
  - target: Structural Midline Brain Malformation and Neurodevelopmental Impairment
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "whose essential roles in neural development include neuronal migration and axon"
    explanation: >-
      Neuronal migration is named as an essential N-cadherin function, which is
      the human-gene premise for the migration arm of this node.
  - reference: PMID:9015265
    reference_title: "Developmental defects in mouse embryos lacking N-cadherin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Undulation of the neural tube is also observed in the"
    explanation: >-
      In N-cadherin-null mouse embryos the neural tube forms but is malformed,
      demonstrating a requirement for N-cadherin in maintaining neuroepithelial
      structure.
  - reference: PMID:9015265
    reference_title: "Developmental defects in mouse embryos lacking N-cadherin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "wild-type littermates, and the epithelial organization of the somites is"
    explanation: >-
      Partial support: the mouse null disrupts epithelial organisation in
      somites as well, showing the defect is a generic loss of epithelial
      cohesion rather than a neuroepithelium-specific programme. It also
      illustrates the limit of the model - homozygous nulls die by embryonic
      day 10, long before cortical neurogenesis, so the migration arm of this
      node is not directly demonstrated in any model.
  notes: >-
    Periventricular heterotopia and interhypothalamic adhesion are recorded in
    the HPO annotation set for OMIM:618929 (derived from PMID:31585109), but
    neither appears in the cached abstract, and no neuropathological or
    cell-biological study of an ACOGS brain has been published. The link from
    N-cadherin adhesion failure to periventricular heterotopia is therefore an
    inference from cell biology, recorded here explicitly so it is not read as
    an established finding.
- name: Failure of Myocardial Cell Cohesion During Cardiac Morphogenesis
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    The looping heart tube and the septating chambers are built by sheets of
    cardiomyocytes that must stay mechanically coupled while they deform. In
    N-cadherin-null mouse embryos this is the single most dramatic defect:
    myocardial tissue forms, then the myocytes dissociate and the heart tube
    fails to develop. Notably, isolated null cardiomyocytes still beat
    synchronously, so the primary lesion is mechanical cohesion, not electrical
    coupling. In ACOGS the human phenotype is correspondingly structural -
    atrioventricular canal defect, coarctation, ventricular septal defect,
    hypoplastic left heart, dextrocardia - rather than a cardiomyopathy. This is
    the node that must not be conflated with N-cadherin's separate, postnatal
    role at the intercalated disc of the working myocardium, where induced
    deletion in the adult mouse causes intercalated-disc dissolution, dilated
    cardiomyopathy and fatal ventricular arrhythmia.
  cell_types:
  - preferred_term: embryonic cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: heart development
    term:
      id: GO:0007507
      label: heart development
    modifier: ABNORMAL
  - preferred_term: cardiac septum development
    term:
      id: GO:0003279
      label: cardiac septum development
    modifier: ABNORMAL
  downstream:
  - target: Structural Congenital Heart Disease
  evidence:
  - reference: PMID:9015265
    reference_title: "Developmental defects in mouse embryos lacking N-cadherin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "dissociate and the heart tube fails to develop normally. In vitro studies of"
    explanation: >-
      The defining experiment for this node: without N-cadherin, myocytes lose
      cohesion and cardiac morphogenesis fails.
  - reference: PMID:9015265
    reference_title: "Developmental defects in mouse embryos lacking N-cadherin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "N-cadherin plays a critical role in early heart development as well as in other"
    explanation: >-
      States the authors' conclusion that the requirement is specifically in
      early heart development, which is the developmental window relevant to
      ACOGS congenital heart disease.
  - reference: PMID:15662031
    reference_title: "Induced deletion of the N-cadherin gene in the heart leads to dissolution of the intercalated disc structure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "desmosomes. The mutant mice exhibited modest dilated cardiomyopathy and impaired"
    explanation: >-
      Included as an explicit contrast, not as support for the developmental
      mechanism. Deleting N-cadherin from the ADULT myocardium produces dilated
      cardiomyopathy and arrhythmia, a different phenotype from ACOGS structural
      congenital heart disease, which is why the CDH2 cardiomyopathy literature
      must not be imported into this entry.
- name: Adhesion Failure in Ocular and Genital Primordia
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Ocular and genital anomalies are two of the four organ systems in the
    disease name, and both involve epithelial and mesenchymal tissues in which
    N-cadherin is expressed - the optic cup and lens vesicle in the eye, the
    genital tubercle and gubernacular apparatus in genital and testicular
    descent. The reported ocular findings include Peters anomaly, an
    anterior-segment dysgenesis that arises from failed separation of the lens
    vesicle from surface ectoderm, which is at least mechanistically congenial
    to an adhesion defect. Expression evidence now places N-cadherin at exactly
    the tissue interface and developmental moment whose failure produces the
    lesion: immunostaining of mouse embryonic eyes localises it to the lens
    stalk at the time of separation from the future cornea, and to the
    developing lens and corneal endothelium afterwards (PMID:31650526). But
    this remains the weakest node in the entry, and the confidence is unchanged
    at HYPOTHETICAL, because every absence enumerated here survives that
    result: showing the protein is present where the lesion arises is not the
    same as showing its loss causes the lesion. No experiment has tested
    N-cadherin function in an ACOGS patient's ocular or genital tissue, no
    animal model of the human alleles exists, the mouse immunostaining is
    wild-type localisation rather than a disease model, and the male-limited
    genital findings (cryptorchidism, micropenis) could equally reflect an
    endocrine rather than an adhesive lesion. It is kept as a terminal branch
    so that nothing downstream depends on it.
  biological_processes:
  - preferred_term: eye development
    term:
      id: GO:0001654
      label: eye development
    modifier: ABNORMAL
  downstream:
  - target: Ocular and Genital Malformation
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiac, and genital anomalies. All seven missense variants (c.1057G>A"
    explanation: >-
      Establishes that ocular, cardiac and genital anomalies occur in the
      syndrome. It is only partial support for this node because the paper
      documents the association, not the adhesive mechanism proposed here.
  - reference: PMID:31650526
    reference_title: "Novel variants in CDH2 are associated with a new syndrome including Peters anomaly."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Immunostaining in mouse embryonic eyes confirmed N-cadherin is present in the lens stalk at the time of separation from the future cornea and in the developing lens and corneal endothelium at later stages, supporting a possible role in PA"
    explanation: >-
      Places N-cadherin at the lens-stalk separation interface whose failure is
      the Peters lesion, which is the closest thing to spatial support this
      node has. Deliberately recorded as PARTIAL and left unable to raise the
      node above HYPOTHETICAL: this is wild-type expression localisation in
      mouse, not a functional test and not a model of the human alleles. The
      paper's own wording ("supporting a possible role") is the appropriate
      strength.
- name: Structural Midline Brain Malformation and Neurodevelopmental Impairment
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    The convergent output of the axon-pathfinding and neuroepithelial arms is a
    brain that is structurally miswired at the midline and at the ventricular
    zone: corpus callosum agenesis or hypoplasia, interhemispheric cysts,
    interhypothalamic adhesion, and periventricular heterotopia. Clinically this
    presents as global developmental delay in infancy evolving to intellectual
    disability, with mirror movements, seizures and behavioural phenotypes
    (autistic behaviour, attention deficit hyperactivity disorder) in a minority.
    Because the lesions are malformative rather than degenerative, the expected
    course is static impairment with developmental progress, not regression.
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "syndromic neurodevelopmental disorder characterized by global developmental"
    explanation: >-
      The neurodevelopmental impairment is the characterising feature of the
      syndrome.
  - reference: PMID:35708058
    reference_title: "A Novel nonsense variant in the CDH2 gene associated with ACOGS: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "agenesis or hypoplasia of corpus callosum, craniofacial dysmorphism, ocular,"
    explanation: >-
      Independently confirms callosal agenesis or hypoplasia as a defining
      structural feature.
- name: Structural Congenital Heart Disease
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    The cardiac output of the syndrome is structural malformation present at
    birth, spanning septation defects (atrioventricular canal defect,
    ventricular septal defect), left-sided obstructive lesions (coarctation of
    the aorta, hypoplastic left heart syndrome), valvar regurgitation and
    situs abnormality (dextrocardia). The severity is not predicted by
    genotype: a likely monozygotic twin pair sharing one pathogenic CDH2
    variant had hypoplastic left heart syndrome in one twin and a ventricular
    septal defect with pulmonary hypertension in the other, which is the
    cleanest available demonstration that stochastic or non-genetic factors set
    the cardiac outcome.
  evidence:
  - reference: PMID:41997214
    reference_title: "Phenotypic discordance in monozygotic twins with a CDH2 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypoplastic left heart syndrome and the other with ventricular septal defect and"
    explanation: >-
      Documents the two discordant cardiac phenotypes in twins sharing one CDH2
      variant.
  - reference: PMID:41997214
    reference_title: "Phenotypic discordance in monozygotic twins with a CDH2 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present a novel case of likely monozygotic twins who both carried the same"
    explanation: >-
      Establishes that the two individuals were likely monozygotic and shared
      the variant, which is what makes the discordance informative.
- name: Ocular and Genital Malformation
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  description: >-
    The ocular phenotype spans anterior-segment dysgenesis (Peters anomaly),
    ocular motility disorders (strabismus, Duane anomaly) and periorbital
    dysmorphism. The genital phenotype has so far been reported only in males
    (cryptorchidism, micropenis); the single reported female with a
    genitourinary finding had a renal rather than genital anomaly, which is the
    one published hint that the urinary tract may also be involved.
  evidence:
  - reference: PMID:35708058
    reference_title: "A Novel nonsense variant in the CDH2 gene associated with ACOGS: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "genital malformations were reported in male patients (cryptorchidism,"
    explanation: >-
      Names the reported genital malformations and records that they had been
      described only in males.
  - reference: PMID:35708058
    reference_title: "A Novel nonsense variant in the CDH2 gene associated with ACOGS: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "finding. Our patient was the first female to have a renal anomaly since only"
    explanation: >-
      Documents the single reported renal anomaly and its status as a
      first-of-kind observation.
phenotypes:
- name: Agenesis of corpus callosum
  description: >-
    Complete absence or hypoplasia of the corpus callosum on brain MRI, the
    lesion that names the syndrome. In the HPO annotation set for OMIM:618929
    (derived from the founding cohort) agenesis of the corpus callosum is
    recorded in 7 of 9 individuals.
  phenotype_term:
    preferred_term: Agenesis or hypoplasia of the corpus callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
  frequency: FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular,"
    explanation: >-
      Supports the association. The FREQUENT band (30-79%) comes from the HPO
      annotation set for OMIM:618929, which records 7 of 9 = 78% for
      HP:0001274; note that 78% falls just below the 80% VERY_FREQUENT
      threshold, so the band is FREQUENT rather than VERY_FREQUENT.
  - reference: PMID:35708058
    reference_title: "A Novel nonsense variant in the CDH2 gene associated with ACOGS: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "agenesis or hypoplasia of corpus callosum, craniofacial dysmorphism, ocular,"
    explanation: >-
      Independent restatement of the callosal phenotype as a defining feature.
- name: Inferior cerebellar vermis hypoplasia
  description: >-
    Underdevelopment of the inferior cerebellar vermis on sagittal brain MRI,
    seen alongside the callosal agenesis in the Peters-anomaly-ascertained
    series. Reported in both of the two individuals whose brain imaging was
    formally reviewed in that report; no frequency is recorded in the HPO
    annotation set for OMIM:618929, and the denominator here (2 imaged
    individuals) is too small to support a frequency band.
  phenotype_term:
    preferred_term: Inferior cerebellar vermis hypoplasia
    term:
      id: HP:0007068
      label: Inferior cerebellar vermis hypoplasia
  evidence:
  - reference: PMID:31650526
    reference_title: "Novel variants in CDH2 are associated with a new syndrome including Peters anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypoplasia of the inferior cerebellar vermis in both patients"
    explanation: >-
      Brain MRI was reviewed for the two imaged patients and showed inferior
      cerebellar vermis hypoplasia in both, establishing the association. The
      denominator is 2, so no frequency band is asserted.
- name: Global developmental delay
  description: >-
    Delay across motor, language and cognitive domains in infancy and early
    childhood, recorded in 6 of 8 assessed individuals in the HPO annotation set
    for OMIM:618929. The founding report treats developmental delay and/or
    intellectual disability as a defining criterion of the syndrome, and
    intellectual disability is annotated separately (4 of 8), so this term's
    fraction describes only one of the two ways the neurodevelopmental
    phenotype is coded.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "syndromic neurodevelopmental disorder characterized by global developmental"
    explanation: >-
      Global developmental delay is named as a characterising feature. The
      FREQUENT band derives from the HPO annotation set for OMIM:618929
      (6 of 8 = 75% for HP:0001263, which falls in the FREQUENT band of 30-79%).
      Intellectual disability is annotated separately (4 of 8) and the two sets
      overlap rather than partition the cohort. The band follows the raw
      fraction for this term alone. The founding report states developmental
      delay and/or intellectual disability as a defining criterion, so the
      neurodevelopmental burden of the syndrome
      as a whole is broader than this one term's 75%; that breadth is described
      in prose rather than used to raise the band for HP:0001263, since no
      cached source gives a combined count.
- name: Intellectual disability
  description: >-
    Cognitive impairment persisting beyond early childhood, the older-child
    correlate of the global developmental delay above. Recorded in 4 of 8
    assessed individuals in the HPO annotation set for OMIM:618929.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: FREQUENT
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "delay and/or intellectual disability, variable axon pathfinding defects (corpus"
    explanation: >-
      Supports the association. The FREQUENT band (30-79%) corresponds to the
      HPO annotation set fraction of 4 of 8 = 50% for HP:0001249.
- name: Mirror movements
  description: >-
    Involuntary movements of one hand mirroring intentional movements of the
    other, the clinical signature of an incompletely lateralised corticospinal
    projection. Recorded in 1 of 9 individuals in the HPO annotation set for
    OMIM:618929, so it is a minority feature despite being one of the three
    axon-pathfinding defects the founding paper highlights.
  phenotype_term:
    preferred_term: Mirror movements
    term:
      id: HP:0001335
      label: Bimanual synkinesia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular,"
    explanation: >-
      Supports the association. The OCCASIONAL band (5-29%) corresponds to the
      HPO annotation set fraction of 1 of 9 = 11% for HP:0001335.
- name: Duane anomaly
  description: >-
    Congenital restriction of horizontal eye movement with globe retraction on
    adduction, caused by maldevelopment of the abducens nerve and aberrant
    innervation of lateral rectus by the oculomotor nerve. In ACOGS it is
    classified by the founding authors as an axon-pathfinding defect rather than
    an ocular malformation, which is why it is modelled downstream of the
    midline axon-pathfinding node.
  phenotype_term:
    preferred_term: Duane anomaly
    term:
      id: HP:0009921
      label: Duane anomaly
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular,"
    explanation: >-
      Names Duane anomaly among the axon pathfinding defects of the syndrome. No
      frequency band is asserted: unlike the other features in this entry, Duane
      anomaly does not appear in the HPO annotation set for OMIM:618929, so
      there is no count to derive a band from.
- name: Periventricular heterotopia
  description: >-
    Nodules of grey matter lining the lateral ventricles, representing neurons
    that never left the ventricular zone. Recorded in 4 of 9 individuals in the
    HPO annotation set for OMIM:618929. Mechanistically this is the most
    informative of the brain findings, because periventricular nodular
    heterotopia is the canonical consequence of a breached
    neuroepithelial/adherens-junction belt at the ventricular surface.
  phenotype_term:
    preferred_term: Periventricular nodular heterotopia
    term:
      id: HP:0007165
      label: Periventricular heterotopia
  frequency: FREQUENT
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "whose essential roles in neural development include neuronal migration and axon"
    explanation: >-
      Partial support only. The cached abstract of the founding paper names
      neuronal migration as an N-cadherin function but does not enumerate
      periventricular heterotopia; the finding and its 4 of 9 fraction come from
      the HPO annotation set for OMIM:618929, which HPO curators derived from
      the full text of this same publication (retrieved 2026-08-01). The
      FREQUENT band (30-79%) corresponds to 4/9 = 44%.
- name: Interhypothalamic adhesion
  description: >-
    An abnormal band of tissue crossing the third ventricle between the
    hypothalami, a midline fusion anomaly. Recorded in 5 of 9 individuals in the
    HPO annotation set for OMIM:618929, making it one of the more frequent
    imaging findings and a further midline correlate of the adhesion defect.
  phenotype_term:
    preferred_term: Interhypothalamic adhesion
    term:
      id: HP:0033105
      label: Interhypothalamic adhesion
  frequency: FREQUENT
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "variants (seven missense, two frameshift) in CDH2 in nine individuals with a"
    explanation: >-
      Partial support: the snippet establishes only the nine-individual cohort
      that is the denominator. The interhypothalamic adhesion finding itself and
      its 5 of 9 fraction come from the HPO annotation set for OMIM:618929
      derived from the full text of this publication (retrieved 2026-08-01), not
      from the cached abstract. 5/9 = 56% gives the FREQUENT band.
- name: Interhemispheric cyst
  description: >-
    A midline cyst, a recognised companion of callosal agenesis. Recorded in
    2 of 9 individuals in the HPO annotation set for OMIM:618929.
  phenotype_term:
    preferred_term: Interhemispheric cyst
    term:
      id: HP:0032327
      label: Interhemispheric cyst
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "variants (seven missense, two frameshift) in CDH2 in nine individuals with a"
    explanation: >-
      Partial support: the snippet gives the cohort denominator only. The
      finding and its 2 of 9 fraction (22%, OCCASIONAL band) come from the HPO
      annotation set for OMIM:618929 (retrieved 2026-08-01).
- name: Macrocephaly
  description: >-
    Occipitofrontal circumference above the normal range, recorded in 4 of 8
    assessed individuals in the HPO annotation set for OMIM:618929. Its presence
    is a useful negative discriminator against Mowat-Wilson syndrome, in which
    microcephaly is typical.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  frequency: FREQUENT
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "variants (seven missense, two frameshift) in CDH2 in nine individuals with a"
    explanation: >-
      Partial support: the snippet gives the cohort denominator only. The
      macrocephaly finding and its 4 of 8 fraction (50%, FREQUENT band) come
      from the HPO annotation set for OMIM:618929 (retrieved 2026-08-01).
- name: Axial hypotonia
  description: >-
    Reduced truncal tone, recorded in 3 of 9 individuals in the HPO annotation
    set for OMIM:618929, and part of the early motor presentation.
  phenotype_term:
    preferred_term: Axial hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
  frequency: FREQUENT
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "variants (seven missense, two frameshift) in CDH2 in nine individuals with a"
    explanation: >-
      Partial support: the snippet gives the cohort denominator only. The
      hypotonia finding and its 3 of 9 fraction (33%, FREQUENT band) come from
      the HPO annotation set for OMIM:618929 (retrieved 2026-08-01).
- name: Seizure
  description: >-
    Epileptic seizures are a minority feature. The HPO annotation set for
    OMIM:618929 records infantile spasms in 1 of 8 and focal impaired awareness
    seizures in 1 of 8, so no single seizure semiology predominates and the
    generic parent term is used.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "variants (seven missense, two frameshift) in CDH2 in nine individuals with a"
    explanation: >-
      Partial support: the snippet gives the cohort denominator only. Seizures
      are not mentioned in the cached abstract; the two seizure annotations
      (each 1 of 8, i.e. 13%, OCCASIONAL band) come from the HPO annotation set
      for OMIM:618929 (retrieved 2026-08-01).
- name: Attention deficit hyperactivity disorder
  description: >-
    Recorded in 2 of 8 assessed individuals in the HPO annotation set for
    OMIM:618929. This is worth flagging because a separate, autosomal recessive
    CDH2 disorder consists of ADHD without malformation, so the behavioural
    phenotype is one place where the two CDH2 entities touch.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "variants (seven missense, two frameshift) in CDH2 in nine individuals with a"
    explanation: >-
      Partial support: the snippet gives the cohort denominator only. The ADHD
      annotation and its 2 of 8 fraction (25%, OCCASIONAL band) come from the
      HPO annotation set for OMIM:618929 (retrieved 2026-08-01).
- name: Autistic behavior
  description: >-
    Recorded in 2 of 8 assessed individuals in the HPO annotation set for
    OMIM:618929.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "variants (seven missense, two frameshift) in CDH2 in nine individuals with a"
    explanation: >-
      Partial support: the snippet gives the cohort denominator only. The
      autistic-behaviour annotation and its 2 of 8 fraction (25%, OCCASIONAL
      band) come from the HPO annotation set for OMIM:618929 (retrieved
      2026-08-01).
- name: Peters anomaly
  description: >-
    Central corneal opacity with iridocorneal or lenticulocorneal adhesion, an
    anterior-segment dysgenesis attributed to failed separation of the lens
    vesicle from surface ectoderm. Recorded in 2 of 9 individuals in the HPO
    annotation set for OMIM:618929, and independently the defining feature of a
    second, separately ascertained CDH2 cohort (PMID:31650526), which found
    de novo CDH2 variants in four individuals ascertained through Peters
    anomaly rather than through the neurodevelopmental phenotype. It is the most
    mechanistically suggestive ocular finding in the syndrome, because the
    lesion is literally a failure of two epithelia to separate.
  phenotype_term:
    preferred_term: Peters anomaly
    term:
      id: HP:0000659
      label: Peters anomaly
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31650526
    reference_title: "Novel variants in CDH2 are associated with a new syndrome including Peters anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified a de novo splicing and three novel missense heterozygous CDH2 variants affecting the extracellular cadherin domains in four individuals with PA"
    explanation: >-
      Direct support naming both the gene and Peters anomaly in the same
      finding, from a cohort ascertained the opposite way round from the
      founding report: 145 probands with developmental ocular conditions
      screened for a genetic cause, rather than CDH2 patients examined for
      ocular findings. Reverse ascertainment makes this independent
      confirmation of the association rather than a restatement of it.
  - reference: PMID:31650526
    reference_title: "Novel variants in CDH2 are associated with a new syndrome including Peters anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Syndromic anomalies were seen in three individuals and included left-sided cardiac lesions, dysmorphic facial features, and decreasing height percentiles; brain magnetic resonance imaging identified agenesis of the corpus callosum and hypoplasia of the inferior cerebellar vermis"
    explanation: >-
      Establishes that the Peters-ascertained individuals carry the same
      cardiac and callosal features that define ACOGS, which is what licenses
      treating the two reports as one disorder spectrum rather than two CDH2
      phenotypes. Also the source for the entry's cerebellar vermis hypoplasia
      phenotype.
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiac, and genital anomalies. All seven missense variants (c.1057G>A"
    explanation: >-
      Partial support: the snippet establishes that ocular anomalies occur in
      the syndrome but does not name Peters anomaly. The 2 of 9 fraction (22%,
      OCCASIONAL band) comes from the HPO annotation set for OMIM:618929
      (retrieved 2026-08-01); the specific term is now directly sourced to
      PMID:31650526 above rather than resting on that annotation alone.
- name: Strabismus
  description: >-
    Ocular misalignment, recorded in 3 of 9 individuals in the HPO annotation
    set for OMIM:618929. Recorded separately from Duane anomaly, which is a
    specific cranial dysinnervation pattern rather than generic strabismus.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  frequency: FREQUENT
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiac, and genital anomalies. All seven missense variants (c.1057G>A"
    explanation: >-
      Partial support: the snippet establishes ocular anomalies generally. The
      strabismus term and its 3 of 9 fraction (33%, FREQUENT band) come from the
      HPO annotation set for OMIM:618929 (retrieved 2026-08-01).
- name: Atrioventricular canal defect
  description: >-
    A defect of endocardial cushion fusion producing a common atrioventricular
    junction. Recorded in 2 of 9 individuals in the HPO annotation set for
    OMIM:618929, and mechanistically the most on-message cardiac lesion, since
    cushion fusion is an adhesion-dependent event.
  phenotype_term:
    preferred_term: Atrioventricular canal defect
    term:
      id: HP:0006695
      label: Atrioventricular canal defect
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiac, and genital anomalies. All seven missense variants (c.1057G>A"
    explanation: >-
      Partial support: the snippet establishes that cardiac anomalies occur. The
      specific lesion and its 2 of 9 fraction (22%, OCCASIONAL band) come from
      the HPO annotation set for OMIM:618929 (retrieved 2026-08-01).
- name: Coarctation of aorta
  description: >-
    Narrowing of the aortic isthmus, recorded in 2 of 9 individuals in the HPO
    annotation set for OMIM:618929.
  phenotype_term:
    preferred_term: Coarctation of aorta
    term:
      id: HP:0001680
      label: Coarctation of aorta
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiac, and genital anomalies. All seven missense variants (c.1057G>A"
    explanation: >-
      Partial support: the snippet establishes that cardiac anomalies occur. The
      specific lesion and its 2 of 9 fraction (22%, OCCASIONAL band) come from
      the HPO annotation set for OMIM:618929 (retrieved 2026-08-01).
- name: Dextrocardia
  description: >-
    Rightward position of the cardiac apex, recorded in 1 of 9 individuals in
    the HPO annotation set for OMIM:618929. A single observation, but notable
    because it points at a laterality rather than a septation defect.
  phenotype_term:
    preferred_term: Dextrocardia
    term:
      id: HP:0001651
      label: Dextrocardia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiac, and genital anomalies. All seven missense variants (c.1057G>A"
    explanation: >-
      Partial support: the snippet establishes that cardiac anomalies occur. The
      specific lesion and its 1 of 9 fraction (11%, OCCASIONAL band) come from
      the HPO annotation set for OMIM:618929 (retrieved 2026-08-01).
- name: Hypoplastic left heart syndrome
  description: >-
    Severe underdevelopment of the left ventricle and outflow, reported in one
    of a likely monozygotic twin pair sharing a pathogenic CDH2 variant. No
    frequency band is asserted: this is a single individual outside the
    nine-person cohort from which every other band in this entry derives, and
    it does not appear in the HPO annotation set for OMIM:618929.
  phenotype_term:
    preferred_term: Hypoplastic left heart syndrome
    term:
      id: HP:0004383
      label: Hypoplastic left ventricle
  evidence:
  - reference: PMID:41997214
    reference_title: "Phenotypic discordance in monozygotic twins with a CDH2 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypoplastic left heart syndrome and the other with ventricular septal defect and"
    explanation: >-
      Documents hypoplastic left heart syndrome in a CDH2-variant individual.
      HP:0004383 (Hypoplastic left ventricle) is the closest available HPO term;
      HPO has no term for the full hypoplastic left heart syndrome, so
      preferred_term carries the clinical diagnosis and term.label the ontology
      label.
- name: Ventricular septal defect
  description: >-
    Reported in the co-twin of the individual above, who shared the same
    pathogenic CDH2 variant. No frequency band is asserted for the same reason.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:41997214
    reference_title: "Phenotypic discordance in monozygotic twins with a CDH2 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypoplastic left heart syndrome and the other with ventricular septal defect and"
    explanation: >-
      Documents the ventricular septal defect in the second twin.
- name: Pulmonary hypertension
  description: >-
    Reported in the twin with the ventricular septal defect. The report does not
    give a haemodynamic classification, and in the setting of an unrepaired
    left-to-right shunt the pressure elevation is at least as likely to be
    post-capillary or shunt-driven as pre-capillary. HP:0004890 "Elevated
    pulmonary artery pressure" is therefore bound rather than HP:0002092
    "Pulmonary arterial hypertension": HP:0002092 is a descendant of HP:0033578
    "Pre-capillary pulmonary hypertension" (checked with OAK on 2026-08-01,
    `runoak -i sqlite:obo:hp ancestors -p i HP:0002092`), so binding it would
    assert exactly the haemodynamic category the source does not establish.
    HP:0004890 is the unqualified common ancestor of the pre- and post-capillary
    branches.
  phenotype_term:
    preferred_term: Pulmonary hypertension
    term:
      id: HP:0004890
      label: Elevated pulmonary artery pressure
  evidence:
  - reference: PMID:41997214
    reference_title: "Phenotypic discordance in monozygotic twins with a CDH2 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with one presenting with hypoplastic left heart syndrome and the other with ventricular septal defect and pulmonary hypertension"
    explanation: >-
      Records pulmonary hypertension in a CDH2-variant individual, in the same
      twin who has the ventricular septal defect. Marked PARTIAL because the
      source says "pulmonary hypertension" with no haemodynamic
      characterisation, so it supports the unqualified pressure-elevation term
      and nothing finer.
- name: Cryptorchidism
  description: >-
    Undescended testis, the commonest of the genital anomalies and recorded in
    3 of the 5 males in the HPO annotation set for OMIM:618929.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  frequency: FREQUENT
  evidence:
  - reference: PMID:35708058
    reference_title: "A Novel nonsense variant in the CDH2 gene associated with ACOGS: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "genital malformations were reported in male patients (cryptorchidism,"
    explanation: >-
      Names cryptorchidism as a reported genital malformation. The FREQUENT band
      (30-79%) derives from the HPO annotation set for OMIM:618929, which
      records 3 of 5 = 60% for HP:0000028; note that the denominator is the
      male subset, not the whole cohort.
- name: Micropenis
  description: >-
    Recorded in 1 of the 5 males in the HPO annotation set for OMIM:618929.
  phenotype_term:
    preferred_term: Micropenis
    term:
      id: HP:0000054
      label: Micropenis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:35708058
    reference_title: "A Novel nonsense variant in the CDH2 gene associated with ACOGS: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "only genital malformations were reported in male patients (cryptorchidism, micropenis) so far"
    explanation: >-
      Names micropenis among the reported male genital malformations. The
      OCCASIONAL band (5-29%) derives from the HPO annotation fraction of 1 of
      5 males = 20% for HP:0000054.
- name: Abnormal renal morphology
  description: >-
    A renal anomaly was reported in a single female patient and described by the
    authors as a novel finding for the syndrome. No frequency band is asserted:
    n=1, and the finding does not appear in the HPO annotation set for
    OMIM:618929. It is recorded because it is the only published suggestion that
    the urinary tract, and not only the genital tract, may be affected, and
    because it is the kind of single observation that is either a real extension
    of the phenotype or a coincidence - which cannot yet be told apart.
  phenotype_term:
    preferred_term: Renal anomaly
    term:
      id: HP:0012210
      label: Abnormal renal morphology
  evidence:
  - reference: PMID:35708058
    reference_title: "A Novel nonsense variant in the CDH2 gene associated with ACOGS: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "finding. Our patient was the first female to have a renal anomaly since only"
    explanation: >-
      The single reported renal anomaly, explicitly flagged by the authors as
      the first of its kind in ACOGS.
- name: Craniofacial dysmorphism
  description: >-
    A recognisable but non-specific facial gestalt. The individual components
    recorded in the HPO annotation set for OMIM:618929 are prominent forehead
    (4 of 9), downslanted palpebral fissures (4 of 9), thin upper lip vermilion
    (5 of 9), low-set ears (4 of 9) and posteriorly rotated ears (4 of 9), with
    a scatter of single-patient findings. No component reaches the level of a
    diagnostic gestalt, so the parent term is used rather than a list of
    individual features.
  phenotype_term:
    preferred_term: Craniofacial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  frequency: FREQUENT
  evidence:
  - reference: PMID:35708058
    reference_title: "A Novel nonsense variant in the CDH2 gene associated with ACOGS: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "agenesis or hypoplasia of corpus callosum, craniofacial dysmorphism, ocular,"
    explanation: >-
      Names craniofacial dysmorphism as a characterising feature of ACOGS. The
      FREQUENT band (30-79%) is derived from the HPO annotation set for
      OMIM:618929, in which the most frequent individual facial features sit at
      4-5 of 9 (44-56%).
- name: Sprengel anomaly
  description: >-
    Congenital elevation of the scapula, recorded in 2 of 9 individuals in the
    HPO annotation set for OMIM:618929. The only skeletal feature annotated for
    the syndrome.
  phenotype_term:
    preferred_term: Sprengel anomaly
    term:
      id: HP:0000912
      label: Sprengel anomaly
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "variants (seven missense, two frameshift) in CDH2 in nine individuals with a"
    explanation: >-
      Partial support: the snippet gives the cohort denominator only. The
      Sprengel anomaly annotation and its 2 of 9 fraction (22%, OCCASIONAL band)
      come from the HPO annotation set for OMIM:618929 (retrieved 2026-08-01).
diagnosis:
- name: Exome or genome sequencing with de novo CDH2 variant interpretation
  description: >-
    Molecular diagnosis rests on finding a heterozygous CDH2 variant, confirmed
    de novo by parental testing, in a child with developmental delay plus a
    midline brain malformation and/or structural congenital heart disease. Two
    interpretation points follow from the published allelic spectrum. First,
    missense changes should be weighted by domain: substitutions of conserved
    residues in EC4-EC5, and particularly at the EC4-EC5 interdomain calcium
    site, are where the reported pathogenic missense alleles sit, and a variant
    there deserves more weight than its in-silico score alone would give it.
    Second, a CDH2 variant found on a cardiomyopathy gene panel is a different
    claim entirely and does not diagnose ACOGS - the panel association is with
    adult arrhythmogenic and dilated cardiomyopathy, is classified by ClinGen as
    Limited, and carries no expectation of callosal, ocular or genital
    involvement.
  diagnosis_term:
    preferred_term: exome or genome sequencing
    term:
      id: NCIT:C101293
      label: Next Generation Sequencing
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: CDH2
        term:
          id: hgnc:1759
          label: CDH2
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "seven cluster within EC domains 4 and 5. Four of the substitutions affect the"
    explanation: >-
      Supports the domain-weighted interpretation advice by locating the
      pathogenic missense alleles in EC4-EC5.
  - reference: CGGV:assertion_c7a03805-bf73-4d2d-9756-c666c67be119-2018-07-13T160000.000Z
    reference_title: "CDH2 / arrhythmogenic right ventricular cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CDH2 | HGNC:1759 | arrhythmogenic right ventricular cardiomyopathy | MONDO:0016587 | AD | Limited"
    explanation: >-
      Supports the caution about panel findings: the CDH2-cardiomyopathy
      gene-disease relationship is separately curated by ClinGen and classified
      as Limited.
- name: Brain MRI
  description: >-
    Brain MRI is the single highest-yield investigation. It documents the
    callosal agenesis or hypoplasia that names the syndrome and the associated
    midline and migration findings - interhypothalamic adhesion,
    interhemispheric cyst, periventricular nodular heterotopia, enlarged
    cisterna magna. The combination of a callosal anomaly with periventricular
    heterotopia in a child who also has congenital heart disease is the imaging
    pattern that should prompt CDH2 testing.
  diagnosis_term:
    preferred_term: brain magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: brain
        term:
          id: UBERON:0000955
          label: brain
  evidence:
  - reference: PMID:35708058
    reference_title: "A Novel nonsense variant in the CDH2 gene associated with ACOGS: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "agenesis or hypoplasia of corpus callosum, craniofacial dysmorphism, ocular,"
    explanation: >-
      The callosal anomaly is a defining feature and is an imaging diagnosis.
  notes: >-
    The list of associated MRI findings is taken from the HPO annotation set for
    OMIM:618929 (retrieved 2026-08-01), not from the cached abstracts, which
    mention only the callosal anomaly. On the term binding: the only
    brain-specific MRI descendants of NCIT:C16809 are contrast-qualified
    (NCIT:C137874 without contrast, NCIT:C137913 with and without contrast;
    checked with runoak against sqlite:obo:ncit on 2026-08-01), and no source
    here states whether contrast was given, so the unqualified parent is bound
    with a UBERON brain site qualifier instead.
- name: Echocardiography
  description: >-
    Structural congenital heart disease is one of the four defining organ
    systems and has ranged from atrioventricular canal defect and coarctation to
    hypoplastic left heart syndrome. Echocardiography is therefore indicated in
    every newly diagnosed individual regardless of whether a murmur is present,
    and the twin report shows that a normal or mild finding in one relative says
    nothing about another.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:41997214
    reference_title: "Phenotypic discordance in monozygotic twins with a CDH2 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pathogenic CDH2 variant yet exhibited a spectrum of CHD with one presenting with"
    explanation: >-
      Demonstrates the range of congenital heart disease within a single
      genotype, which is the argument for imaging every individual rather than
      extrapolating from a relative.
- name: Ophthalmological assessment including ocular motility
  description: >-
    Formal ophthalmological review is needed for two separable reasons: to
    detect anterior-segment dysgenesis (Peters anomaly), which is
    sight-threatening and surgically actionable; and to detect the ocular
    motility disorders, where the distinction between common strabismus and the
    Duane anomaly matters, since Duane anomaly is a cranial dysinnervation
    pattern that changes both the surgical plan and the mechanistic
    interpretation.
  diagnosis_term:
    preferred_term: ophthalmological assessment including ocular motility
    term:
      id: NCIT:C38060
      label: Eye Examination
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular,"
    explanation: >-
      Names Duane anomaly and ocular anomalies as features requiring
      ophthalmological assessment.
mechanistic_hypotheses:
- hypothesis_group_id: acogs_antimorphic_adhesion
  hypothesis_label: ACOGS ectodomain alleles act as antimorphs that poison wild-type N-cadherin adhesion
  status: EMERGING
  description: >-
    The proposal is that the EC4-EC5 missense alleles are not simple
    loss-of-function. A mutant molecule that reaches the cell surface with an
    unhinged ectodomain still occupies the trans-binding partner presented by
    the apposing cell, so it subtracts wild-type molecules from the pool of
    competent bonds rather than merely failing to add to it. The direct
    observation supporting this is that the variants impair binding in trans to
    wild-type N-cadherin, not only to each other. If correct, the effective
    adhesive deficit in a heterozygote exceeds 50%, which would explain why a
    single heterozygous missense change produces a severe malformation syndrome
    while heterozygous N-cadherin-null mice are not reported as abnormal. That
    last contrast is weak evidence: the cached mouse-null report (PMID:9015265)
    is an abstract that describes homozygous mutants only and says nothing
    about heterozygotes, so the heterozygous-null comparison rests on the
    absence of a reported phenotype rather than on a documented normal one.
  evidence:
  - reference: PMID:31585109
    reference_title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "defect includes impaired binding in trans with N-cadherin-WT expressed on"
    explanation: >-
      The trans-heterophilic binding failure against wild-type protein is the
      specific observation that motivates the antimorphic hypothesis.
  notes: >-
    Not yet tested by the experiment that would settle it - a dosage series
    comparing wild-type, heterozygous-null and heterozygous-missense cells or
    animals for adhesion strength and for the ACOGS phenotypes.
discussions:
- discussion_id: acogs_truncating_allele_mechanism
  prompt: >-
    Do the truncating CDH2 alleles (two frameshifts and a nonsense variant)
    cause ACOGS by the same dominant-negative route as the EC4-EC5 missense
    alleles, or by haploinsufficiency?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Truncation of the N-cadherin Cytoplasmic Catenin-Binding Tail
  - pathophysiology#Failure of Trans Homophilic Adhesion with Dominant-Negative Interference
  rationale: >-
    The founding cohort's functional work was done exclusively on EC4-EC5
    missense alleles, and the interference argument rests on those experiments.
    The frameshift alleles are described only as predicted to truncate the
    cytoplasmic domain; no protein was measured. A later patient carries a de
    novo nonsense allele, which - depending on its position relative to the last
    exon-exon junction - could instead trigger nonsense-mediated decay and give
    straightforward haploinsufficiency. Two mechanisms that produce the same
    clinical label is not a cosmetic distinction: it changes whether whole-gene
    deletions should be expected to cause ACOGS, whether the disorder is a
    candidate for allele-specific silencing, and how a novel truncating variant
    of uncertain significance should be interpreted. The entry deliberately
    keeps the truncating alleles in their own PROVISIONAL pathophysiology node
    rather than merging them into the antimorphic node.
  proposed_experiments:
  - experiment_id: exp_acogs_truncating_allele_protein
    name: Measure N-cadherin protein and transcript in patient cells carrying truncating CDH2 alleles
    description: >-
      Quantify CDH2 transcript (with and without translation inhibition to
      unmask nonsense-mediated decay) and N-cadherin protein level and surface
      localisation in fibroblasts or reprogrammed cells from individuals with
      the frameshift and nonsense alleles, against EC4-EC5 missense carriers and
      controls. A reduced transcript that is restored by decay inhibition
      indicates haploinsufficiency; a stable truncated protein at the membrane
      indicates interference.
  - experiment_id: exp_acogs_cdh2_deletion_phenotype
    name: Phenotype ascertainment in carriers of whole-gene CDH2 deletions
    description: >-
      Systematically review copy-number databases for individuals with
      heterozygous deletions spanning CDH2 and determine whether any has the
      ACOGS phenotype. Absence of ACOGS among deletion carriers would argue
      strongly against haploinsufficiency as a sufficient mechanism.
  evidence:
  - reference: PMID:35708058
    reference_title: "A Novel nonsense variant in the CDH2 gene associated with ACOGS: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reported the fifteenth patient with ACOGS, having a novel de novo nonsense"
    explanation: >-
      The existence of a de novo nonsense allele in a clinically typical patient
      is what makes the mechanism question live rather than academic.
- discussion_id: acogs_organ_level_stochasticity
  prompt: >-
    What determines which organs are affected, and how severely, in an
    individual with a given CDH2 variant?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Structural Congenital Heart Disease
  - phenotypes#Hypoplastic left heart syndrome
  - phenotypes#Ventricular septal defect
  rationale: >-
    A likely monozygotic twin pair sharing one pathogenic CDH2 variant - and
    therefore essentially one genome and one intrauterine environment - had
    hypoplastic left heart syndrome in one twin and a ventricular septal defect
    with pulmonary hypertension in the other. That is close to a controlled
    experiment, and it rules out common genetic background as the sole
    explanation for the well-known variable expressivity of CDH2 variants. What
    remains as candidate explanations is stochastic variation in a threshold
    process (adhesive bond number crossing a critical value at a particular
    place and time), post-zygotic somatic variation, or twin-specific vascular
    factors. None has been tested. Until it is, prognostic counselling for a
    newly diagnosed ACOGS fetus or infant cannot be based on the phenotype of an
    affected relative.
  proposed_experiments:
  - experiment_id: exp_acogs_twin_somatic_sequencing
    name: Deep sequencing of discordant tissues in CDH2-variant twin pairs
    description: >-
      Deep sequence cardiac and blood tissue from discordant CDH2-variant twins
      to test whether post-zygotic somatic variation, mosaic variant allele
      fraction, or a second hit explains the organ-level divergence.
  - experiment_id: exp_acogs_registry_genotype_phenotype
    name: Prospective ACOGS registry with systematic organ-system phenotyping
    description: >-
      Build a registry that phenotypes every ascertained individual across all
      four defining organ systems with a fixed protocol (brain MRI,
      echocardiography, ophthalmology, genitourinary assessment), so that the
      current genotype-phenotype picture stops being an artefact of which
      specialist happened to see the patient.
  evidence:
  - reference: PMID:41997214
    reference_title: "Phenotypic discordance in monozygotic twins with a CDH2 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "have described such variable expressivity in twins with the same CDH2 variant."
    explanation: >-
      Establishes that this degree of within-genotype discordance had not
      previously been documented, which is why it is recorded as an open gap
      rather than an explained observation.
- discussion_id: acogs_no_model_of_the_human_allele
  prompt: >-
    Does any existing animal or cellular model recapitulate ACOGS, or is the
    causal chain from N-cadherin adhesion failure to the human malformations
    entirely inferential?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Failure of Midline Axon Pathfinding and Callosal Tract Formation
  - pathophysiology#Loss of Neuroepithelial Adherens Junction Integrity and Neuronal Migration Failure
  - pathophysiology#Adhesion Failure in Ocular and Genital Primordia
  rationale: >-
    None of the three Cdh2 mouse models curated in this entry models this
    disease. (Those three are not the whole Cdh2 mouse literature - a
    substantial body of brain-specific conditional-knockout work exists and is
    relevant to the neuroepithelial node, but none of it carries an ACOGS
    allele either.) The
    constitutive null is homozygous lethal by embryonic day 10, before the
    corpus callosum, cortex, eye or genitalia are built, and heterozygous nulls
    are not reported as abnormal - so the model that shows the cardiac
    requirement cannot show the neurodevelopmental one. The cardiac-specific
    inducible knockout addresses the adult working myocardium and produces
    dilated cardiomyopathy, a different disease. The p.H150Y knock-in models the
    allelic recessive ADHD disorder, has no anatomical brain abnormality, and is
    homozygous. No knock-in of an ACOGS EC4-EC5 allele has been made. The
    consequence for this entry is concrete: the pathophysiology nodes linking
    adhesion failure to callosal agenesis, periventricular heterotopia and
    ocular/genital malformation are tagged PROVISIONAL or HYPOTHETICAL, and
    should not be read as demonstrated causal chains.
  proposed_experiments:
  - experiment_id: exp_acogs_knockin_mouse
    name: Heterozygous knock-in of an ACOGS EC4-EC5 allele in mouse
    description: >-
      Generate a mouse heterozygous for one of the recurrent ACOGS calcium-site
      substitutions and score corpus callosum formation, cortical lamination and
      periventricular heterotopia, cardiac septation, anterior-segment
      development and testicular descent. Compare directly against a
      heterozygous null littermate to separate interference from
      haploinsufficiency in vivo.
  - experiment_id: exp_acogs_patient_organoid_adhesion
    name: Patient-derived cortical organoid and cardiac organoid adhesion assay
    description: >-
      Derive iPSCs from ACOGS individuals and controls, and measure apical
      adherens-junction integrity, neuroepithelial rosette architecture and
      neuronal migration in cortical organoids, plus tissue cohesion in cardiac
      organoids, to test the two mechanistic nodes in human cells carrying the
      real allele.
  evidence:
  - reference: PMID:9015265
    reference_title: "Developmental defects in mouse embryos lacking N-cadherin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "mutant embryos. Homozygous mutant embryos die by Day 10 of gestation. The"
    explanation: >-
      Early embryonic lethality of the homozygous null is the specific reason
      the mouse cannot be used to test the neurodevelopmental arm of the
      mechanism.
  - reference: PMID:34702855
    reference_title: "CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "caused by a missense mutation in CDH2, which encodes the adhesion protein"
    explanation: >-
      The only knock-in mouse carrying a human CDH2 missense allele models the
      recessive ADHD disorder, not ACOGS, so it does not fill this gap.
animal_models:
- species: Mouse
  genotype: Cdh2 constitutive null (homozygous)
  genes:
  - preferred_term: CDH2
    term:
      id: hgnc:1759
      label: CDH2
  description: >-
    The classical N-cadherin knockout. Neurulation and somitogenesis begin but
    the resulting structures are malformed, the somitic epithelium loses
    organisation, the neural tube undulates, and the primitive heart tube
    dissociates; embryos die by day 10 of gestation. It is the best evidence
    that N-cadherin is required for tissue cohesion during morphogenesis,
    including specifically in early heart development, and it establishes that
    the cardiac defect is mechanical rather than electrical, since isolated null
    cardiomyocytes still beat synchronously. It is not, however, a model of
    ACOGS: the human disease is heterozygous and caused by expressed missense or
    truncating alleles, and the mouse dies before any of the affected human
    structures are built.
  evidence:
  - reference: PMID:9015265
    reference_title: "Developmental defects in mouse embryos lacking N-cadherin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "heart; although myocardial tissue forms initially, the myocytes subsequently"
    explanation: >-
      Describes the cardinal cardiac phenotype of the null - initial myocardial
      formation followed by loss of myocyte cohesion.
  - reference: PMID:9015265
    reference_title: "Developmental defects in mouse embryos lacking N-cadherin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "mutant embryos. Homozygous mutant embryos die by Day 10 of gestation. The"
    explanation: >-
      The lethality window that limits the model's usefulness for the
      neurodevelopmental and ocular arms of ACOGS.
- species: Mouse
  genotype: Cardiac-specific tamoxifen-inducible Cdh2 conditional knockout (adult)
  genes:
  - preferred_term: CDH2
    term:
      id: hgnc:1759
      label: CDH2
  description: >-
    Included as an explicit contrast model, not as an ACOGS model. Deleting
    N-cadherin from the adult working myocardium dissolves the intercalated
    disc, produces modest dilated cardiomyopathy with impaired function, and
    kills most animals within two months from spontaneous ventricular
    tachycardia. This is the biology behind the CDH2 rows on arrhythmogenic and
    dilated cardiomyopathy gene panels, and it is a different phenotype from the
    structural congenital heart disease of ACOGS - a maintenance failure in a
    formed organ rather than a morphogenetic failure during its construction.
  evidence:
  - reference: PMID:15662031
    reference_title: "Induced deletion of the N-cadherin gene in the heart leads to dissolution of the intercalated disc structure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "N-cadherin was deleted in the adult myocardium. Loss of N-cadherin resulted in"
    explanation: >-
      Establishes the adult, maintenance-phase context of this model, which is
      what distinguishes it from the developmental mechanism of ACOGS.
  - reference: PMID:15662031
    reference_title: "Induced deletion of the N-cadherin gene in the heart leads to dissolution of the intercalated disc structure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "desmosomes. The mutant mice exhibited modest dilated cardiomyopathy and impaired"
    explanation: >-
      Names the resulting phenotype - dilated cardiomyopathy - which is the
      cardiomyopathy claim that must be kept separate from ACOGS.
- species: Mouse
  genotype: Cdh2 p.H150Y knock-in (homozygous)
  background: C57BL/6JRcc
  genes:
  - preferred_term: CDH2
    term:
      id: hgnc:1759
      label: CDH2
  description: >-
    A CRISPR/Cas9 knock-in carrying the human p.H150Y substitution that causes
    the allelic autosomal recessive CDH2 ADHD disorder. Homozygous mice are
    hyperactive with impaired sensorimotor gating, respond to methylphenidate,
    and show presynaptic vesicle-clustering and dopaminergic deficits - but no
    anatomical or histological brain abnormality. It is recorded here as the
    boundary of the ACOGS phenotype rather than as a model of it: the same gene,
    a different domain (the prodomain furin cleavage motif rather than EC4-EC5),
    a different inheritance mode, and a behavioural rather than malformative
    outcome.
  evidence:
  - reference: PMID:34702855
    reference_title: "CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "generation and analysis of mice homozygous for the human"
    explanation: >-
      Establishes that the model is homozygous for the human allele, in contrast
      to the heterozygous de novo alleles of ACOGS.
  - reference: PMID:34702855
    reference_title: "CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "p.H150Y in CDH2 (transcript variant 1; NM_001792.4)."
    explanation: >-
      Names the specific allele modelled, which is not one of the ACOGS alleles.
differential_diagnoses:
- name: Mowat-Wilson syndrome
  disease_term:
    preferred_term: Mowat-Wilson syndrome
    term:
      id: MONDO:0009341
      label: Mowat-Wilson syndrome
  description: >-
    The closest clinical mimic. Mowat-Wilson syndrome, caused by de novo
    heterozygous loss-of-function ZEB2 variants, combines a distinctive facial
    gestalt, global developmental delay and intellectual disability, agenesis or
    hypoplasia of the corpus callosum and congenital heart defects - three of
    the four organ systems that define ACOGS. A child with callosal agenesis,
    developmental delay and congenital heart disease will be tested for ZEB2
    first.
  distinguishing_features:
  - Caused by ZEB2 (hgnc:14881), a transcription factor, rather than CDH2 (hgnc:1759), an adhesion molecule - verified with OAK against MONDO:0009341.
  - Hirschsprung disease is characteristic of Mowat-Wilson syndrome and is not a reported feature of ACOGS. Epilepsy does not separate the two - it is common in Mowat-Wilson syndrome and is also a minority ACOGS feature (see the Seizure phenotype in this entry).
  - Microcephaly is typical of Mowat-Wilson syndrome, whereas macrocephaly is annotated in half the assessed ACOGS cohort.
  - Mowat-Wilson syndrome has a diagnostically recognisable facial gestalt; the ACOGS facial phenotype is non-specific, with no single feature exceeding about half the cohort.
  - Duane anomaly, mirror movements and periventricular heterotopia are ACOGS features and are not part of the Mowat-Wilson phenotype.
  notes: >-
    MONDO:0009341 and the ZEB2 gene assignment (HGNC:14881) were both verified
    with OAK on 2026-08-01; the term matches the disease_term already bound in
    kb/disorders/Mowat-Wilson_syndrome.yaml. The distinguishing features are
    reasoned contrasts drawn from that existing entry and from the HPO
    annotation set for OMIM:618929, not quotations, so no evidence item is
    attached. Each Mowat-Wilson side of a contrast is curated in that entry:
    distinctive facial features, developmental delay/intellectual disability and
    Hirschsprung disease in its description and phenotypes, and Microcephaly as
    its own phenotype. Claims that are true of Mowat-Wilson syndrome in the
    literature but are not curated in that entry (hypospadias, the specific
    uplifted-earlobe/prominent-chin gestalt) were removed rather than asserted
    without a source.
- name: DCC-related mirror movements and/or agenesis of the corpus callosum
  disease_term:
    preferred_term: mirror movements 1 and/or agenesis of the corpus callosum
    term:
      id: MONDO:0100515
      label: mirror movements 1 and/or agenesis of the corpus callosum
  description: >-
    The mechanistically closest differential rather than merely the clinically
    closest. Heterozygous DCC variants produce congenital mirror movements
    and/or agenesis of the corpus callosum - exactly the two axon-pathfinding
    readouts that ACOGS shares - and DCC is the netrin-1 receptor, i.e. the
    guidance-receptor arm of the same midline-crossing decision that N-cadherin
    contributes adhesion to. The pair is instructive: a receptor lesion and an
    adhesion lesion converge on the same commissural failure.
  distinguishing_features:
  - Caused by DCC (hgnc:2701) rather than CDH2 (hgnc:1759).
  - DCC disease is usually familial and transmitted with reduced penetrance; ACOGS variants are predominantly de novo, with one documented transmission from an apparently unaffected mother (PMID:31650526).
  - DCC disease is confined to the callosal/mirror-movement axis, with no cardiac, ocular-anterior-segment or genital malformation.
  - Intellectual disability is not a consistent feature of DCC-related disease, whereas neurodevelopmental impairment is the characterising feature of ACOGS.
  notes: >-
    MONDO:0100515 was verified with OAK on 2026-08-01; its definition names DCC
    as the causal gene, and hgnc:2701 was independently verified as the DCC
    HGNC identifier. The dismech entry Familial Congenital Mirror Movements
    (MONDO:0016558) is the parent term of MONDO:0100515. No evidence item is
    attached: the contrast is a reasoned cross-reference, not a quoted finding.
    The two clinical contrasts trace to that entry:
    kb/disorders/Familial_Congenital_Mirror_Movements.yaml describes the
    disorder as "typically autosomal dominant" with DCC penetrance "incomplete
    (~68%, higher in males)", and states that "Intelligence and life expectancy
    are typically normal in isolated CMM".
- name: Duane retraction syndrome (isolated)
  disease_term:
    preferred_term: Duane retraction syndrome
    term:
      id: MONDO:0007473
      label: Duane retraction syndrome
  description: >-
    Isolated Duane retraction syndrome is a congenital cranial dysinnervation
    disorder confined to the eye. It matters here because Duane anomaly is one
    of the three axon-pathfinding features of ACOGS, so an ophthalmologist
    seeing a child with Duane anomaly needs a reason to look further.
  distinguishing_features:
  - Isolated Duane retraction syndrome has no callosal anomaly, no developmental delay, and no cardiac or genital malformation; the presence of any of these should prompt syndromic evaluation.
  - Most isolated Duane retraction syndrome is sporadic and non-Mendelian; the syndromic Mendelian forms are attributed to CHN1 (Duane retraction syndrome 2, MONDO:0011444, hgnc:1943) and to SALL4 in Duane-radial ray syndrome, not to CDH2.
  - Duane anomaly is not annotated at all in the HPO annotation set for OMIM:618929 despite being named in the founding report, so it is a minority ACOGS feature and its absence does not exclude ACOGS.
  notes: >-
    MONDO:0007473 matches the disease_term bound in
    kb/disorders/Duane_Retraction_Syndrome.yaml; MONDO:0011444 and its CHN1
    gene assignment (HGNC:1943) were verified with OAK on 2026-08-01. No
    evidence item is attached; the contrast is reasoned. The sporadic/Mendelian
    split traces to that entry, which describes isolated Duane retraction
    syndrome as mostly sporadic with roughly 10% familial and the identified
    Mendelian forms autosomal dominant, citing GeneReviews.
- name: CDH2-related autosomal recessive attention-deficit hyperactivity disorder
  description: >-
    An allelic disorder rather than a phenocopy, and the sharpest illustration
    that "a CDH2 variant" is not one thing. Three siblings of a consanguineous
    kindred with severe childhood-onset ADHD were homozygous for c.355C>T
    (p.H150Y), a substitution in the prodomain furin-cleavage motif that impairs
    proteolytic maturation of N-cadherin rather than its adhesive interface. The
    resulting phenotype is behavioural and synaptic, with no malformation.
  distinguishing_features:
  - Autosomal recessive, homozygous, segregating in a consanguineous family - versus de novo heterozygous in ACOGS.
  - The variant lies in the prodomain cleavage motif and impairs furin-mediated protein maturation, not in the EC4-EC5 adhesive/calcium-binding region.
  - The phenotype is isolated ADHD with normal brain anatomy; there is no corpus callosum, cardiac, ocular or genital malformation.
  - The knock-in mouse for this allele has no anatomical or histological brain abnormality, in contrast to the malformative human ACOGS phenotype.
  notes: >-
    No MONDO term was found for this entity, so no disease_term is bound rather
    than binding an approximate one. OMIM does not list it as a separate
    phenotype series entry in the MONDO record for MONDO:0030065.
  evidence:
  - reference: PMID:34702855
    reference_title: "CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe three siblings of a consanguineous kindred"
    explanation: >-
      Establishes the recessive, consanguineous family structure that
      distinguishes this entity from the de novo heterozygous ACOGS alleles.
  - reference: PMID:34702855
    reference_title: "CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "to segregate within the family as expected for autosomal recessive"
    explanation: >-
      Confirms autosomal recessive segregation, the mode of inheritance contrast
      with ACOGS.
  - reference: PMID:34702855
    reference_title: "CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "to interfere with the proteolysis and maturation of the protein."
    explanation: >-
      Names the molecular mechanism - impaired maturation - which is different
      in kind from the adhesive-interface lesion of ACOGS.
- name: CDH2-associated arrhythmogenic right ventricular cardiomyopathy
  disease_term:
    preferred_term: arrhythmogenic right ventricular cardiomyopathy
    term:
      id: MONDO:0016587
      label: arrhythmogenic right ventricular cardiomyopathy
  description: >-
    Not a differential for the ACOGS presentation, but recorded because CDH2
    appears on arrhythmogenic cardiomyopathy gene panels and the two claims are
    routinely conflated. Arrhythmogenic right ventricular cardiomyopathy is an
    adult-onset disease of the desmosomal/adherens-junction complex of the
    working myocardium, presenting with ventricular arrhythmia and fibrofatty
    replacement; the biology is intercalated-disc maintenance, matching the
    adult cardiac-specific Cdh2 knockout. ClinGen classifies the
    CDH2-arrhythmogenic right ventricular cardiomyopathy relationship as
    Limited.
  distinguishing_features:
  - Adult-onset arrhythmia and myocardial replacement versus congenital structural malformation present at birth.
  - No callosal, ocular, genital or neurodevelopmental involvement.
  - ClinGen gene-disease validity for CDH2 in this disease is Limited, whereas the CDH2-ACOGS relationship rests on a nine-individual cohort with functional adhesion assays.
  - The relevant mouse model is the ADULT cardiac-specific conditional knockout, not the constitutive embryonic null.
  evidence:
  - reference: CGGV:assertion_c7a03805-bf73-4d2d-9756-c666c67be119-2018-07-13T160000.000Z
    reference_title: "CDH2 / arrhythmogenic right ventricular cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CDH2 | HGNC:1759 | arrhythmogenic right ventricular cardiomyopathy | MONDO:0016587 | AD | Limited"
    explanation: >-
      ClinGen classifies the CDH2-arrhythmogenic right ventricular
      cardiomyopathy relationship as Limited, which is the evidence basis for
      keeping that claim separate from and weaker than the ACOGS claim.
  - reference: PMID:15662031
    reference_title: "Induced deletion of the N-cadherin gene in the heart leads to dissolution of the intercalated disc structure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "disassembly of the intercalated disc structure, including adherens junctions and"
    explanation: >-
      Identifies the intercalated disc as the structure at risk when N-cadherin
      is lost from adult myocardium, the mechanism of the cardiomyopathy claim
      rather than of ACOGS.
- name: CDH2-associated dilated cardiomyopathy
  disease_term:
    preferred_term: dilated cardiomyopathy
    term:
      id: MONDO:0005021
      label: dilated cardiomyopathy
  description: >-
    The second CDH2 cardiomyopathy claim, likewise recorded only as contrast.
    The adult cardiac-specific Cdh2 knockout mouse develops exactly this
    phenotype, which gives the association biological plausibility, but ClinGen
    classifies the human gene-disease relationship as Limited. Nothing in the
    dilated cardiomyopathy literature should be imported into this entry, and
    nothing in this entry implies that ACOGS individuals develop dilated
    cardiomyopathy - no such progression has been reported.
  distinguishing_features:
  - Acquired ventricular dilation and systolic dysfunction in a structurally normally formed heart, versus congenital structural malformation.
  - No neurodevelopmental, ocular or genital involvement.
  - ClinGen gene-disease validity Limited (2025 reassessment by the Dilated Cardiomyopathy Gene Curation Expert Panel).
  evidence:
  - reference: CGGV:assertion_73900af1-14ee-4933-b5dc-832753e6cc6c-2025-05-16T160000.000Z
    reference_title: "CDH2 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CDH2 | HGNC:1759 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
    explanation: >-
      ClinGen classifies the CDH2-dilated cardiomyopathy relationship as
      Limited, supporting its treatment here as a separate and weaker claim.
notes: >-
  Scope and boundary. This entry covers the developmental syndrome caused by de
  novo heterozygous CDH2 variants (ACOGS, OMIM:618929, MONDO:0030065). It is
  deliberately kept separate from four other CDH2 claims elsewhere in dismech
  that share the gene and little else. (1) The CDH2 rows in
  kb/disorders/Arrhythmogenic_Right_Ventricular_Cardiomyopathy.yaml and
  kb/disorders/Dilated_Cardiomyopathy.yaml are adult myocardial-maintenance
  claims that ClinGen classifies as Limited; both are cited above as explicit
  contrast and neither file was modified. (2) The CDH2 mention in
  kb/disorders/Chronic_Myeloid_Leukemia.yaml concerns N-cadherin in a
  neoplastic-signalling context and has no bearing on this disorder. (3) The
  autosomal recessive CDH2 ADHD entity (p.H150Y, prodomain cleavage motif) is
  curated above as an allelic differential, not as part of this disease. (4)
  kb/modules/reelin_terminal_translocation_lamination_failure.yaml binds
  hgnc:1759 as part of the Reelin-dependent cortical-lamination mechanism; that
  is the same adhesion biology this entry's neuroepithelial node touches, but
  the module makes no ACOGS claim and was not modified.

  Entity verification. MONDO:0030065 was verified with OAK before any content
  was written: `runoak -i sqlite:obo:mondo info MONDO:0030065 -O obo` returns
  the OMIM xref OMIM:618929 and the synonym ACOGS, and `runoak -i
  sqlite:obo:mondo relationships -p RO:0004003 MONDO:0030065` returns exactly
  one gene, HGNC:1759 CDH2. Every literature source used here names CDH2 as the
  causal gene; no competing gene appears in any of them. Every ontology
  identifier in this entry - HP, GO, CL, MONDO and HGNC - was looked up with
  OAK on 2026-08-01 before being written.

  Frequency provenance, and a caveat that applies to the whole entry. Only the
  abstracts of the three ACOGS clinical papers were retrievable into
  references_cache; the founding report (PMID:31585109) cached as
  abstract_only despite a full-text attempt. Every per-feature count in this
  entry therefore comes from the HPO annotation set for OMIM:618929, retrieved
  from the Human Phenotype Ontology annotation API on 2026-08-01, which HPO
  curators derived from the full text of PMID:31585109 and which is attributed
  to that PMID in every row. Where a feature is named in the cached abstract,
  the evidence item is SUPPORT and the band is stated in the explanation. Where
  the feature exists only in the HPO annotation set, the evidence item is
  deliberately marked PARTIAL, the snippet carries only what it actually
  supports (usually the nine-individual cohort denominator or the
  organ-system-level statement), and the explanation says plainly that the
  per-feature count is not in the cached text. No count in this entry was
  inferred, rounded up, or carried over from a related disorder. The
  denominators differ between features (9 for imaging and examination findings,
  8 for neurobehavioural assessments, 5 for male genital findings) because the
  HPO annotations use whichever subset was assessed; this is stated on each
  phenotype rather than smoothed into a single cohort size.

  Every band now follows its raw fraction. Global developmental delay is
  annotated 6 of 8 (75%) and is banded FREQUENT (30-79%) accordingly. An earlier
  revision of this entry set it to VERY_FREQUENT on the argument that the
  founding report makes developmental delay and/or intellectual disability a
  defining criterion; that argument is retained in the phenotype's description
  and explanation, but it is prose about the syndrome rather than a count for
  HP:0001263, so it no longer overrides the band. No cached source gives a
  combined delay-or-disability numerator.

  Why there is no treatments section. No ACOGS-specific management has been
  published. Care is organ-directed and generic - surgical repair of the
  cardiac lesion, developmental and educational support, strabismus and
  anterior-segment surgery, orchidopexy - and none of it is attested for a
  named ACOGS patient in any cached reference. Writing that list would mean
  asserting management that no source in this entry supports, so it is omitted
  and the diagnosis section carries the assessment recommendations instead. If
  a case report documenting what was actually done for an ACOGS patient
  appears, the treatments section should be added.

  What is genuinely uncertain. Three things, each curated as an open
  discussion rather than smoothed over: whether the truncating alleles work by
  interference or by haploinsufficiency
  (acogs_truncating_allele_mechanism); what determines organ-level severity,
  given that monozygotic twins with one variant had radically different hearts
  (acogs_organ_level_stochasticity); and the fact that no model system carries
  an ACOGS allele at all, so the chain from adhesion failure to callosal
  agenesis, periventricular heterotopia and ocular/genital malformation is
  inference (acogs_no_model_of_the_human_allele). The ocular/genital node is
  tagged HYPOTHETICAL for that reason and is a terminal branch.

  Sources deliberately not used. PubMed searches on 2026-08-01 for CDH2 with
  "agenesis of corpus callosum" and for "CDH2 AND ACOGS" each returned only the
  three clinical papers cited here, so the entire clinical literature is
  curated. A large N-cadherin literature exists in cancer biology
  (epithelial-mesenchymal transition, prostate and neuroblastoma metastasis,
  the N-cadherin/beta-catenin axis in blast-crisis CML); it is dominated by
  somatic and expression-level biology in tumours and says nothing about
  germline developmental disease, so none of it was used. No GeneReviews
  chapter is cited: PubMed searches on 2026-08-01 with "CDH2 AND
  GeneReviews[All Fields]" and "ACOGS AND GeneReviews[All Fields]" each
  returned 0 records. That is a statement about those two searches on that
  date, not a verified fact about the GeneReviews catalogue. No ORPHA record
  for this disorder is present in references_cache/ (and MONDO:0030065 has no
  Orphanet xref), and no ClinGen gene-disease
  validity assertion for CDH2-ACOGS exists in the cached ClinGen snapshot
  (2026-01-24), which holds only the two CDH2 cardiomyopathy assertions cited
  above as contrast.
references:
- reference: PMID:31585109
  title: "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects."
- reference: PMID:31650526
  title: "Novel variants in CDH2 are associated with a new syndrome including Peters anomaly."
- reference: PMID:35708058
  title: "A Novel nonsense variant in the CDH2 gene associated with ACOGS: A case report."
- reference: PMID:41997214
  title: "Phenotypic discordance in monozygotic twins with a CDH2 variant."
- reference: PMID:34702855
  title: "CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice."
- reference: PMID:9015265
  title: "Developmental defects in mouse embryos lacking N-cadherin."
- reference: PMID:15662031
  title: "Induced deletion of the N-cadherin gene in the heart leads to dissolution of the intercalated disc structure."
- reference: PMID:21300292
  title: "The extracellular architecture of adherens junctions revealed by crystal structures of type I cadherins."
- reference: CGGV:assertion_c7a03805-bf73-4d2d-9756-c666c67be119-2018-07-13T160000.000Z
  title: "CDH2 / arrhythmogenic right ventricular cardiomyopathy (Limited)"
- reference: CGGV:assertion_73900af1-14ee-4933-b5dc-832753e6cc6c-2025-05-16T160000.000Z
  title: "CDH2 / dilated cardiomyopathy (Limited)"

📚

References & Deep Research

References

10

PMID:31585109

De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects.

No top-level findings curated for this source.

PMID:31650526

Novel variants in CDH2 are associated with a new syndrome including Peters anomaly.

No top-level findings curated for this source.

PMID:35708058

A Novel nonsense variant in the CDH2 gene associated with ACOGS: A case report.

No top-level findings curated for this source.

PMID:41997214

Phenotypic discordance in monozygotic twins with a CDH2 variant.

No top-level findings curated for this source.

PMID:34702855

CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice.

No top-level findings curated for this source.

PMID:9015265

Developmental defects in mouse embryos lacking N-cadherin.

No top-level findings curated for this source.

PMID:15662031

Induced deletion of the N-cadherin gene in the heart leads to dissolution of the intercalated disc structure.

No top-level findings curated for this source.

PMID:21300292

The extracellular architecture of adherens junctions revealed by crystal structures of type I cadherins.

No top-level findings curated for this source.

CGGV:assertion_c7a03805-bf73-4d2d-9756-c666c67be119-2018-07-13T160000.000Z

CDH2 / arrhythmogenic right ventricular cardiomyopathy (Limited)

No top-level findings curated for this source.

CGGV:assertion_73900af1-14ee-4933-b5dc-832753e6cc6c-2025-05-16T160000.000Z

CDH2 / dilated cardiomyopathy (Limited)

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

CDH2-Related ACOG Syndrome: Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 13 citations 2026-08-03T00:44:15.499481

CDH2-Related ACOG Syndrome: Comprehensive Research Report

Executive Summary

CDH2-related ACOG syndrome (Agenesis of Corpus Callosum, Ocular, Cardiac, and Genital syndrome; also referred to in OMIM as ACOGS) is an ultra-rare, autosomal dominant, multisystem neurodevelopmental disorder caused by de novo heterozygous pathogenic variants in CDH2, the gene encoding N-cadherin (neuronal cadherin). It was first delineated as a distinct Mendelian syndrome in 2019 by Accogli, Srour, Charron, and colleagues (PMID:31585109), who proposed the name "ACOG syndrome" for the pentad of axon-pathfinding defects, corpus callosum anomalies, and ocular, cardiac, and genital malformations. As of the most recent case series (2022), only ~15 individuals have been reported worldwide (PMID:35708058), making this one of the rarest entries in the cadherinopathy spectrum.

1. Disease Information

Overview: CDH2-related ACOG syndrome is a syndromic neurodevelopmental disorder resulting from de novo heterozygous loss-of-function or dominant-negative missense variants in CDH2. The disorder was defined by Accogli et al. (2019), who identified nine individuals with de novo CDH2 variants (seven missense, two frameshift) presenting with "global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies" (PMID:31585109). The authors coined the acronym "ACOG syndrome" — Agenesis of corpus callosum, axon pathfinding, Cardiac, Ocular, and Genital defects.

A related, overlapping presentation with a prominent anterior-segment eye phenotype was independently reported as "a new syndrome including Peters anomaly" caused by CDH2 variants (Peters Anomaly Spectrum group, PMID:31650526, Clinical Genetics 2020;97(3):502-508), describing four individuals with de novo CDH2 variants (splicing + missense) and Peters anomaly, three of whom had syndromic features overlapping ACOG syndrome (agenesis of the corpus callosum, cerebellar vermis hypoplasia, left-sided cardiac lesions, dysmorphic facies). These two reports are now generally regarded as describing the same CDH2-related disorder spectrum.

Key identifiers: - OMIM (phenotype): #618929 — "Agenesis of Corpus Callosum, Cardiac, Ocular, and Genital Syndrome; ACOGS" - OMIM (gene): 114020 — CADHERIN 2; CDH2 - MONDO: MONDO:0030065 - Disease Ontology: DOID:0080948 - NCBI GTR condition: C5394523 - Gene identifiers: HGNC:1759; NCBI Gene ID: 1000; chromosome 18q12.1 - ICD-10/11: No dedicated ICD code exists; typically coded under Q04.0 (agenesis of corpus callosum) or Q89.7 (multiple congenital malformations, not elsewhere classified) in practice — no CDH2-specific ICD-11 entry was identified. - MeSH:* No dedicated MeSH heading; indexed under "Agenesis of Corpus Callosum" (D019112) and "Cadherins" (D029464).

Synonyms: ACOGS; ACOG syndrome; CDH2-related neurodevelopmental disorder; "N-cadherinopathy"; the Peters-anomaly-predominant presentation is sometimes referenced separately as "CDH2-related Peters anomaly syndrome."

Evidence base: All currently published information derives from aggregated case series/case reports (human clinical, aggregated across ~15 patients total in the two founding cohorts plus subsequent single case reports) rather than large-scale EHR data, reflecting the extreme rarity of the condition.

2. Etiology

Disease causal factors: ACOG syndrome is caused exclusively by de novo heterozygous pathogenic variants in CDH2 (autosomal dominant, essentially 100% de novo in reported cases). No environmental, infectious, or multifactorial causes have been implicated; this is a purely monogenic disorder.

Genetic risk factors: - All reported pathogenic variants are heterozygous and arose de novo — no inherited/familial transmission has been documented, consistent with a severe, likely-reproductively-limiting phenotype. - Variant spectrum from the founding cohort: seven missense variants and two frameshift variants (PMID:31585109). "Six of the seven missense variants localize to extracellular cadherin domains 4–5 (EC4–EC5), with four affecting calcium-binding sites" — functional studies showed these EC4–EC5 variants impair cell-cell adhesion. - The Peters-anomaly cohort (PMID:31650526) added a de novo splicing variant and additional missense variants in the extracellular cadherin domains. - ClinVar-documented variants associated with ACOGS include NM_001792.5(CDH2):c.1057G>A (p.Asp353Asn), c.1808C>G (p.Pro603Arg), and c.2027A>G (p.Tyr676Cys), among others. - The Kanjee et al. (2022) case (PMID:35708058) reported a novel de novo nonsense variant, expanding the mutational mechanism beyond missense/frameshift to include premature-stop-codon variants.

Modifier/susceptibility factors: No modifier genes have been identified; given the extremely small number of reported cases, genotype-phenotype correlation is preliminary. Variants clustering in EC4–EC5 appear to correlate with the more classic ACOG presentation (CNS/axon-pathfinding-predominant), while some variants correlate more with the Peters-anomaly/anterior-segment ocular phenotype, but sample sizes are too small for robust correlation.

Protective factors: None identified — no protective genetic or environmental factors have been reported for this ultra-rare monogenic disorder.

Gene-environment interactions: None reported; the disorder behaves as a fully penetrant (or near-fully penetrant), single-gene Mendelian condition with no documented environmental modifiers.

3. Phenotypes

Phenotype frequencies below are drawn from the aggregated cohort of the two founding reports (approximately 9–13 evaluable individuals per feature; PMID:31585109, PMID:31650526) plus subsequent case reports (PMID:35708058).

Neurodevelopmental / Neurological

Global developmental delay / intellectual disability — reported in ~10/12 evaluable patients; variable severity (mild–moderate most common). Suggested HPO: HP:0001263 (Global developmental delay), HP:0001249 (Intellectual disability)
Agenesis or hypoplasia of the corpus callosum — reported in ~11/13; the defining CNS feature, reflecting failure of interhemispheric axon pathfinding. Suggested HPO: HP:0001274 (Agenesis of corpus callosum), HP:0002079 (Hypoplasia of the corpus callosum)
Cerebellar vermis hypoplasia — described in both cohorts. Suggested HPO: HP:0001320 (Cerebellar vermis hypoplasia)
Incomplete hippocampal rotation — noted as an additional brain malformation. Suggested HPO: HP:0030050 (Abnormal hippocampus morphology, most specific available term)
Absent septum pellucidum — reported in a subset. Suggested HPO: HP:0030754 (Absent septum pellucidum, if available) or HP:0001300 (Cavum septum pellucidum, note as related structural anomaly)
Mirror movements — an axon-pathfinding/corticospinal-miswiring sign consistent with N-cadherin's role in axon guidance. Suggested HPO: HP:0007301 (Mirror movements of the hand) or HP:0002378 (Mirror movements)
Hypotonia (axial) with hypertonic extremities — mixed tone abnormality. Suggested HPO: HP:0001252 (Hypotonia), HP:0001276 (Hypertonia)
Cognitive/behavioral delay — variable severity, described qualitatively as "cognitive delays."

Ocular

Duane anomaly / Duane retraction syndrome — a specific ocular motility axon-pathfinding defect (cranial nerve VI miswiring), directly reflecting N-cadherin's axon-guidance role. Suggested HPO: HP:0009921 (Duane anomaly)
Peters anomaly — anterior-segment dysgenesis with corneal opacity/iridocorneal-lenticular adhesions, prominent in the PMID:31650526 cohort. Suggested HPO: HP:0007756 (Peters anomaly)
Other ocular anomalies collectively reported in ~11/13 evaluable individuals (exact sub-phenotypes not fully itemized in available abstracts beyond Duane anomaly and Peters anomaly).

Cardiac

Congenital cardiac anomalies — reported in ~9/13; left-sided cardiac lesions specifically noted in the Peters-anomaly cohort. Suggested HPO: HP:0001631 (Atrial septal defect), HP:0001629 (Ventricular septal defect) — specific lesion types not uniformly itemized across all published cases; "left-sided cardiac lesions" suggests possible left ventricular outflow tract anomalies. Broader term: HP:0001627 (Abnormal heart morphology)

Genital / Genitourinary

Cryptorchidism (males) — a recurring genital anomaly. Suggested HPO: HP:0000028 (Cryptorchidism)
Micropenis (males) — reported ("micropesis" in one source is a likely OCR error for "micropenis"). Suggested HPO: HP:0000054 (Micropenis)
Renal anomaly (ureteropelvic junction obstruction, UPJO) — reported in the first female patient (Kanjee et al. 2022, PMID:35708058), noted as the first genitourinary/renal finding described in a female with ACOGS, since prior reports documented only male-specific genital malformations. Suggested HPO: HP:0000072 (Hydronephrosis) / HP:0100957 (Ureteropelvic junction obstruction, if using UPJO-specific term)

Craniofacial dysmorphism

Hypertelorism (HP:0000316), flat nasal bridge (HP:0005280), low-set or posteriorly rotated ears (HP:0000369 / HP:0000368), upturned earlobes, thin upper lip (HP:0000219), small mouth with downturned corners (HP:0000175 / HP:0002714), low anterior hairline (HP:0000294).

Onset/severity/progression: All reported phenotypes are congenital/present from birth or early infancy (structural brain, cardiac, ocular, and genital malformations). Developmental delay becomes apparent in infancy/early childhood. The disorder does not appear to be progressive in the neurodegenerative sense — it is a static structural/developmental malformation syndrome, though longitudinal follow-up data are sparse given the small number of reported patients.

Quality of life impact: Not formally studied (no EQ-5D/SF-36 data identified); qualitatively, impact stems from intellectual disability, visual impairment (Duane anomaly, Peters anomaly with corneal opacity), and, when present, cardiac and renal complications requiring surgical/medical management.

4. Genetic / Molecular Information

Causal gene: CDH2 (cadherin 2, HGNC:1759, NCBI Gene 1000, OMIM 114020, chromosome 18q12.1), encoding N-cadherin (neuronal cadherin, cadherin-2)*, a classical type I transmembrane cadherin.

Variant classification and type: - Missense variants (majority; six of seven in the founding cohort cluster in EC4–EC5), frameshift variants, a splicing variant, and at least one nonsense variant (PMID:35708058) have been reported — spanning a broader range of variant classes than initially described. - ACMG/AMP classification: reported variants are generally classified pathogenic/likely pathogenic in ClinVar given de novo occurrence, absence from population databases, and functional evidence of impaired adhesion. - Allele frequency: Given all reported variants are de novo and disease-causing, they are essentially absent from gnomAD/population databases (consistent with severe, non-transmitted Mendelian disease); specific gnomAD allele counts were not available in the sources reviewed. - Origin: Exclusively germline, de novo (no somatic CDH2-ACOGS association reported).

Functional consequences: Rutherford/Accogli et al. demonstrated that "cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion" (PMID:31585109) — i.e., the mechanism is loss of N-cadherin-mediated homophilic adhesion, acting in a dominant-negative and/or haploinsufficient manner. A separate report on ACOGS variants found that "de novo mutations in the CDH2 gene impair the cell adhesion function of N-cadherin by affecting self-binding as well as trans-binding with wildtype N-cadherin" — indicating a dominant-negative mechanism in which mutant protein interferes with wild-type N-cadherin function in trans, in addition to any haploinsufficiency.

Protein structure context: N-cadherin is composed of five extracellular cadherin (EC1–EC5) repeat domains (each ~110 amino acids), a transmembrane domain, and a cytoplasmic tail that binds β-catenin/p120-catenin linking to the actin cytoskeleton. Calcium ions bind at interdomain linker regions between EC repeats and rigidify the ectodomain into an extended rod required for trans-adhesion between apposing cell surfaces; EC1–EC2 mediate the primary trans-dimer "strand-swap" interaction, while EC4–EC5 (where most ACOG-syndrome variants cluster) contribute to maintaining the correct ectodomain length/rigidity required for productive trans-dimerization, and calcium-binding-site disruption at EC4–EC5 destabilizes this trans-adhesive interface.

Epigenetic information: No CDH2-ACOGS-specific epigenetic (DNA methylation/histone) data were identified in the literature reviewed.

Chromosomal abnormalities: ACOG syndrome is caused by point mutations/small indels, not by large chromosomal rearrangements; no recurrent CNV/deletion mechanism has been reported (distinguishing it from contiguous-gene 18q12 deletion syndromes, which are a different, unrelated entity).

Related but genetically/mechanistically distinct CDH2 disease associations (important for differential diagnosis and module design — these are separate CDH2 phenotypes, not part of ACOG syndrome per se): - Arrhythmogenic right ventricular cardiomyopathy (ARVC): CDH2 mutations were identified as a novel non-desmosomal genetic cause of ARVC (first reported in a South African family, 2017; PMID:28280076, Circ Cardiovasc Genet). This is an adult-onset, isolated cardiac arrhythmia/cardiomyopathy phenotype, mechanistically and clinically distinct from ACOG syndrome's developmental malformation presentation, though both stem from N-cadherin dysfunction (ARVC-associated variants are hypothesized to act primarily through desmosome/intercalated-disc destabilization in cardiomyocytes rather than broad developmental adhesion failure). - Dilated cardiomyopathy (DCM): A novel CDH2 variant has also been associated with DCM (PMC9468813, Front Med 2022). - Attention-Deficit/Hyperactivity Disorder 8: GeneCards lists CDH2 as associated with an ADHD susceptibility phenotype, distinct from full-syndrome ACOGS.

5. Environmental Information

No environmental factors, toxin exposures, lifestyle factors, or infectious agents have been implicated in CDH2-related ACOG syndrome — it is a purely genetic (de novo monogenic) disorder. No gene-environment interaction data exist.

6. Mechanism / Pathophysiology

Causal chain (from molecular lesion to clinical phenotype):

Molecular lesion: De novo heterozygous CDH2 variant (missense in EC4–EC5 calcium-binding sites, frameshift, nonsense, or splice-altering) →
Protein dysfunction: Impaired N-cadherin ectodomain rigidity/calcium coordination → defective homophilic trans-adhesion between N-cadherin molecules on apposing cell membranes, with evidence of a dominant-negative effect on wild-type N-cadherin trans-binding (not pure haploinsufficiency) →
Cellular process disruption: Failure of N-cadherin-dependent processes across multiple developing tissues — neuroepithelial integrity, radial glial scaffold confinement, growth-cone/axon-guidance receptor complex function, cardiomyocyte adherens-junction/intercalated-disc assembly, and periocular/anterior-segment mesenchymal-neural-crest adhesion →
Tissue-level consequence: Failure of commissural/callosal axons to cross the midline (agenesis/hypoplasia of the corpus callosum), miswiring of cranial motor axons (Duane anomaly), anterior-segment dysgenesis (Peters anomaly), cardiac septation/outflow anomalies, and disrupted genital tubercle/urogenital tract morphogenesis →
Organism-level phenotype: The multisystem ACOG syndrome presentation (global developmental delay/ID, callosal agenesis, axon-pathfinding defects, ocular anomalies, cardiac anomalies, genital anomalies, craniofacial dysmorphism).

Molecular pathways/cellular processes: N-cadherin functions at the head of a "cadherin–catenin–actin" adhesion complex: the cytoplasmic tail binds p120-catenin and β-catenin, which in turn links to α-catenin and the actin cytoskeleton, stabilizing adherens junctions and simultaneously modulating Wnt/β-catenin signaling availability. In neurons, N-cadherin also interacts with growth-cone guidance-receptor machinery relevant to netrin/DCC and other axon-pathfinding pathways (consistent with senior-author Frédéric Charron's expertise in axon guidance) and is implicated in growth-cone adhesion-dependent turning responses.

The 2022 review "Flying under the radar: CDH2 (N-cadherin), an important hub molecule in neurodevelopmental and neurodegenerative diseases" (Njoo & Charron lab collaborators, PMID:36213737, Front Neurosci 2022;16:972059) summarizes that during CNS development CDH2/N-cadherin is required for: "maintenance of neuroepithelial integrity, neural tube closure, confinement of radial glia progenitor cells to the ventricular zone and maintaining their proliferation-differentiation balance, postmitotic neural precursor migration, axon guidance, synaptic development and maintenance."

Cell types involved (suggested CL terms): - Neuroepithelial cells / radial glial cells (CL:0000681, radial glial cell) - Commissural/callosal projection neurons (CL:0000679, glutamatergic neuron; or CL:0011005, callosal neuron if available) - Cardiomyocytes (CL:0000746, cardiac muscle cell) - Cranial neural crest-derived mesenchyme (CL:0000333, migratory neural crest cell) — relevant to anterior-segment (Peters anomaly) and craniofacial dysmorphism - Growth cones of developing axons (structure rather than cell type; consider GO cellular component GO:0030426, growth cone)

Suggested GO Biological Process terms: - GO:0007156 (homophilic cell adhesion via plasma membrane adhesion molecules) - GO:0007411 (axon guidance) - GO:0021801 (cerebral cortex radial glia guided migration) / GO:0021795 (cerebral cortex cell migration) - GO:0007043 (cell-cell junction assembly) - GO:0060976 (coronary vasculature development) — less specific; better: GO:0003231 (cardiac ventricle development) or GO:0003179 (heart valve morphogenesis) depending on the specific cardiac lesion - GO:0021952 (central nervous system projection neuron axonogenesis) - GO:0060997 (dendritic spine morphogenesis) — for the synaptic maintenance role noted in the review

Suggested GO Cellular Component / Molecular Function terms: - GO:0005913 (cell-cell adherens junction) - GO:0098641 (cadherin binding involved in cell-cell adhesion) - GO:0008014 (obsolete/legacy) — prefer GO:0005509 (calcium ion binding) for the EC-domain calcium coordination function

Protein dysfunction mechanism: Predominantly dominant-negative — mutant N-cadherin monomers interfere with wild-type N-cadherin's ability to form productive trans-dimers at apposing cell surfaces ("affecting self-binding as well as trans-binding with wildtype N-cadherin"), rather than simple haploinsufficiency, though partial loss-of-function contribution cannot be excluded for frameshift/nonsense alleles predicted to trigger nonsense-mediated decay.

Immune system involvement: Not implicated; this is a developmental structural disorder, not an immune-mediated one.

Molecular profiling / omics: No transcriptomic, proteomic, metabolomic, or single-cell/spatial datasets specific to human CDH2-ACOG-syndrome patient tissue were identified in the literature reviewed; mechanistic data derive from in vitro cell-adhesion assays (e.g., aggregation assays in transfected cell lines) rather than patient-derived omics.

7. Anatomical Structures Affected

Organ level: - Primary: Brain (corpus callosum, cerebellar vermis, hippocampus, septum pellucidum), eyes (anterior segment/cornea, extraocular muscles/cranial nerve VI), heart, external/internal genitalia, kidneys/urinary tract. - Secondary: Craniofacial skeleton (dysmorphic features). - Body systems: Nervous system, cardiovascular system, ocular/visual system, genitourinary system, musculoskeletal/craniofacial system.

Suggested UBERON terms: - UBERON:0002336 (corpus callosum) - UBERON:0002037 (cerebellum) / UBERON:0002264 (cerebellar vermis, if available) - UBERON:0002421 (hippocampal formation) - UBERON:0000955 (brain) - UBERON:0000970 (eye) - UBERON:0000006 (islet of Langerhans — not relevant; disregard) — correct ocular term: UBERON:0000964 (cornea) for Peters anomaly; UBERON:0001776 (extraocular muscle) for Duane anomaly - UBERON:0000948 (heart) - UBERON:0000992 (gonad) / UBERON:0000473 (testis) for cryptorchidism; UBERON:0000030 (penis) for micropenis - UBERON:0002113 (kidney) / UBERON:0001222 (ureteropelvic junction, if available) for UPJO

Tissue/cell level: Neuroepithelium and radial glial scaffold of the ventricular zone; commissural axon tracts; cardiac myocardium and intercalated discs; corneal endothelium/anterior-segment mesenchyme (neural-crest derived).

Subcellular level (GO Cellular Component): Adherens junctions (GO:0005913), plasma membrane (site of N-cadherin's homophilic adhesive function), growth cone (GO:0030426).

Lateralization: No consistent lateralization pattern reported; corpus callosum agenesis is inherently a midline defect, and cardiac lesions described as "left-sided" in the Peters-anomaly cohort suggest some left-sided predilection for cardiac involvement specifically, but this is based on very small numbers.

8. Temporal Development

Onset: Congenital — all core structural anomalies (brain, cardiac, ocular, genital, craniofacial) are present from birth/prenatally, as expected for a developmental malformation syndrome. Developmental delay/intellectual disability becomes clinically apparent during infancy and early childhood as milestones are missed.

Onset pattern: Insidious recognition in infancy for the neurodevelopmental component; acute/immediately apparent at birth for structural anomalies (e.g., cardiac defects, genital anomalies, corneal opacity in Peters anomaly).

Progression: The disorder is best characterized as a static structural malformation syndrome rather than a progressive neurodegenerative one — no reports of regression or progressive deterioration were identified. However, given only ~15 patients have ever been reported and longitudinal follow-up is limited, the full natural history (e.g., adult outcomes, aging-related complications) remains poorly characterized.

Disease course pattern: Chronic, lifelong (congenital malformations and associated intellectual disability persist), not relapsing-remitting or episodic.

Critical periods: The pathophysiology implicates disruption during early embryonic/fetal development — specifically during neural tube closure, midline commissural axon crossing (corpus callosum formation, ~12–20 weeks gestation in humans), cardiac septation/looping (weeks 3–8 gestation), anterior-segment/ocular morphogenesis, and genital tubercle differentiation — all first-trimester-to-mid-second-trimester embryonic windows.

Remission: Not applicable — no remission pattern described for a congenital structural malformation syndrome.

9. Inheritance and Population

Epidemiology: Extremely rare — as of the most recent published case report (2022), "only 14 patients with ACOGS had been reported" prior to the fifteenth patient described by Kanjee et al. (PMID:35708058). No formal prevalence or incidence rate (cases per 100,000) has been established; the disorder is far below the threshold of most registry-based epidemiological reporting, consistent with its very recent (2019) delineation as a distinct syndrome and its de novo, non-transmitted genetic basis.

Inheritance pattern: Autosomal dominant, with essentially all reported cases arising from de novo variants (no vertical transmission reported to date, consistent with reduced reproductive fitness typical of severe multisystem developmental syndromes).

Penetrance: Presumed high/complete for the core neurodevelopmental and structural phenotype, though formal penetrance estimates are not available given the small cohort and absence of inherited (non-de-novo) transmission data.

Expressivity: Notably variable — patients show a spectrum from ACOG-syndrome-predominant (axon-pathfinding/callosal-predominant) to Peters-anomaly-predominant (anterior-segment ocular-predominant) presentations, and individual features (cardiac, genital, renal) are present in only a subset of patients (e.g., renal/UPJO reported in only one patient to date). This variable expressivity may partly correlate with variant location/type but sample sizes are too small for firm genotype-phenotype rules.

Genetic anticipation: Not applicable/not reported (not a repeat-expansion disorder).

Germline mosaicism: Not specifically documented in the literature reviewed, though it remains a theoretical possibility relevant to recurrence-risk counseling for parents of an affected child, as with other de novo dominant disorders.

Founder effects: None reported; cases have been identified across North America, Europe, and Turkey (Kanjee et al., first reported case from Turkey), consistent with pan-ethnic occurrence and no population-specific founder variant.

Consanguinity: Not implicated — consistent with the de novo dominant mechanism (consanguinity is relevant to recessive disease, not de novo dominant disease).

Carrier frequency: Not applicable for a de novo dominant, non-carrier-based condition.

Population demographics: - Sex ratio: Both males and females affected; genital anomalies (cryptorchidism, micropenis) were initially described only in males, but Kanjee et al. (2022) reported "the first female patient" with ACOGS, presenting instead with a renal anomaly (UPJO), suggesting genitourinary tract involvement in females manifests differently (upper urinary tract rather than external genitalia). - Geographic distribution: Cases reported from North America, Europe, and Turkey; no endemic or regionally clustered pattern identified — consistent with a pan-ethnic de novo disorder. - Age distribution: All reported cases are pediatric at time of publication (diagnosis in infancy/childhood); no adult natural-history cohort has been published.

10. Diagnostics

Clinical/laboratory tests: No CDH2-ACOGS-specific biochemical biomarker exists; diagnosis relies on recognition of the clinical/imaging phenotype plus molecular confirmation.

Imaging studies: - Brain MRI: Essential for detecting agenesis/hypoplasia of the corpus callosum, cerebellar vermis hypoplasia, incomplete hippocampal rotation, and absent septum pellucidum. - Echocardiography: For detection of congenital cardiac anomalies (including left-sided lesions). - Renal/abdominal ultrasound: For detection of urinary tract anomalies (e.g., UPJO/hydronephrosis), as illustrated by the female patient reported by Kanjee et al. - Ophthalmologic exam (slit-lamp, anterior-segment imaging): For Duane anomaly and Peters anomaly detection.

Genetic testing: - Recommended approach: Given the phenotypic overlap with numerous other syndromic corpus callosum agenesis/neurodevelopmental disorders, exome sequencing (WES) or genome sequencing (WGS), typically as a trio (proband + both parents) to establish de novo status, is the diagnostic approach used in all reported cases (the founding cohort was largely ascertained through the NIH Undiagnosed Diseases Network and international WES/WGS collaborations). - Gene panels: CDH2 is increasingly included on clinical "corpus callosum agenesis," "intellectual disability," and "malformations of cortical development" gene panels (e.g., Genomics England PanelApp lists CDH2 under "Malformations of cortical development" and "Paediatric disorders — additional genes" panels). - Single-gene testing: Feasible once a specific familial variant is known, but as a first-tier test is unlikely to be efficient given phenotypic overlap with many other genes. - Chromosomal microarray (CMA)/karyotyping: Not diagnostic for CDH2 point variants but often performed first-line to exclude copy-number/chromosomal causes of corpus callosum agenesis or multiple congenital anomalies before sequencing.

Clinical/diagnostic criteria: No formal consensus diagnostic criteria (e.g., DSM/ICD-style) have been published; diagnosis is currently based on the combination of (1) characteristic multisystem phenotype (callosal/axon-pathfinding + ocular + cardiac + genital + craniofacial dysmorphism) and (2) identification of a de novo heterozygous CDH2 variant.

Differential diagnosis: Other syndromic corpus callosum agenesis disorders (e.g., Mowat-Wilson syndrome, Acrocallosal syndrome, other Duane-anomaly-associated syndromes such as Okihiro/Duane-radial ray syndrome [SALL4], and other cadherin/catenin-pathway disorders), isolated Peters anomaly (PAX6, PITX2, FOXC1, CYP1B1, COL6A3, B3GLCT, DOP1B and other genes), and other causes of syndromic developmental delay with cardiac and genital anomalies (e.g., CHARGE syndrome, VACTERL association).

Screening: No population-based or newborn screening applicable — the disorder is not detectable by standard biochemical newborn screening panels and is far too rare for targeted population screening; diagnosis occurs reactively based on clinical presentation.

11. Outcome / Prognosis

Survival/mortality: No mortality data specific to CDH2-ACOGS were identified; the disorder has not been reported as inherently life-limiting, though outcomes will depend heavily on the severity of associated cardiac and renal anomalies in individual patients, which can independently carry morbidity/mortality risk if uncorrected.

Morbidity/function: Long-term functional outcomes are not well characterized given the small number of reported, largely pediatric, cases. Anticipated morbidity domains include: cognitive/intellectual disability (variable, generally mild-to-moderate based on available descriptions), visual impairment (from Peters anomaly's corneal opacity and/or Duane anomaly's motility restriction), and any sequelae of unrepaired/repaired structural cardiac or renal anomalies.

Complications: Congenital cardiac lesions and renal/urinary tract anomalies (e.g., UPJO leading to hydronephrosis) may require surgical intervention and carry their own complication profiles independent of the neurodevelopmental features.

Recovery potential: Structural malformations (cardiac, renal, ocular) may be amenable to surgical correction with resulting improvement in organ-specific function; the neurodevelopmental/intellectual disability component is not expected to "recover" but may improve functionally with early intervention (standard practice for developmental delay, not disease-specific).

Prognostic factors: Not formally established; qualitatively, the presence and severity of cardiac and renal anomalies, and the degree of corpus callosum abnormality/associated brain malformation burden, would be expected to influence overall prognosis, but no quantitative prognostic model exists given the rarity of the condition.

12. Treatment

There is no disease-modifying or CDH2-targeted therapy for ACOG syndrome; management is entirely symptomatic, supportive, and multidisciplinary, following standard-of-care approaches for each organ-system manifestation (this mirrors management of other syndromic multiple-congenital-anomaly/intellectual disability disorders where no gene-specific therapy exists).

Suggested multidisciplinary management approach (NCIT terms in parentheses where applicable): - Neurodevelopmental/rehabilitative: Early intervention services, physical therapy (NCIT:C15302), occupational therapy (NCIT:C121351), speech-language therapy (NCIT:C159273), special education support for intellectual disability. - Ophthalmologic: Surgical management of Peters anomaly (e.g., penetrating keratoplasty for corneal opacity in severe cases) (NCIT:C15329, Surgical Procedure); strabismus/Duane anomaly management may include observation or extraocular muscle surgery depending on severity and functional impact. - Cardiac: Standard congenital heart disease management per lesion type — may range from surveillance to surgical repair (NCIT:C15329, Surgical Procedure; cardiology follow-up). - Genitourinary: Urologic evaluation/management of cryptorchidism (orchiopexy) and UPJO (pyeloplasty if obstructive/symptomatic) (NCIT:C15329, Surgical Procedure). - Genetic counseling: Recommended for all families given the de novo autosomal dominant mechanism, to discuss low (but non-zero, due to theoretical germline mosaicism) recurrence risk for future pregnancies and to facilitate cascade/predictive considerations (NCIT:C15240, Genetic Counseling). - Supportive care: Routine surveillance/supportive care coordinated across specialists (NCIT:C15747, Supportive Care).

Experimental treatments: No CDH2-ACOGS-specific clinical trials (ClinicalTrials.gov) were identified — the extreme rarity of the condition (~15 reported patients) makes disease-specific trials unlikely at this stage. No gene therapy, RNA-based therapy, or targeted molecular therapy has been proposed or is in development for this disorder in the literature reviewed.

Treatment outcomes: No systematic data on treatment response rates or adverse events specific to this population exist, again reflecting the very small published cohort.

13. Prevention

Primary prevention: Not applicable in a conventional sense — the disorder results from de novo germline mutation with no known modifiable environmental trigger, so there are no primary-prevention (risk-factor-modification) strategies.

Secondary prevention / screening: No population or targeted screening program exists or would be practical given the extreme rarity and de novo nature of the disorder. Prenatal detection is theoretically possible via detailed fetal anatomy ultrasound (identifying corpus callosum agenesis, cardiac anomalies, or genital anomalies) followed by diagnostic prenatal exome sequencing if a syndromic picture is suspected, but this is not a formal screening recommendation specific to CDH2.

Genetic counseling: The main "preventive" intervention available is reproductive genetic counseling for parents of an affected child — given de novo dominant inheritance, recurrence risk for future pregnancies is low but not zero (accounting for theoretical parental germline mosaicism, as is standard counseling practice for de novo dominant conditions); prenatal diagnosis via chorionic villus sampling/amniocentesis with targeted variant testing would be available once the familial pathogenic variant is known.

Public health interventions: None specific to this ultra-rare monogenic disorder.

14. Other Species / Natural Disease

Taxonomy: No naturally occurring CDH2-ACOG-syndrome-like disease has been reported in non-human species (e.g., in OMIA, the animal-disease counterpart of OMIM). CDH2/N-cadherin is highly evolutionarily conserved across vertebrates (relevant orthologs exist in mouse, zebrafish, chick, Xenopus), but no spontaneous veterinary case series analogous to human ACOG syndrome was identified.

Orthologous gene: Mouse Cdh2 (MGI:88355), located on a syntenic region; extensively studied in developmental biology (see Model Organisms, below).

Comparative biology: N-cadherin's role in neural tube closure, cardiac morphogenesis, and axon guidance is deeply conserved across vertebrate models, supporting strong mechanistic plausibility that mouse/zebrafish CDH2 loss-of-function models recapitulate aspects of the human phenotype, even though a naturally occurring animal ACOG-syndrome phenocopy has not been documented.

Zoonotic potential: Not applicable (non-infectious, genetic disorder).

15. Model Organisms

Mouse (Mus musculus, Cdh2, MGI:88355): - Constitutive knockout: Global Cdh2-null mice are embryonic lethal around E10, due to severe cardiac developmental defects. Reported abnormalities include growth retardation, an enlarged/malformed heart, distended pericardial sac, abnormal heart tube looping, a "wavy" (undulated) neural tube, irregular somite shape, and abnormal embryonic turning — precluding assessment of later CNS developmental roles in the constitutive knockout (JAX strain 003179). - Conditional/cardiac-specific knockout: Because global knockout is embryonic lethal via cardiac failure, cardiac-specific conditional deletion strategies have been used. Non-inducible cardiomyocyte-specific deletion (αMHC-Cre) is also embryonic lethal; an inducible cardiac-specific Cre was required to bypass the embryonic requirement. Inducible postnatal cardiomyocyte-specific Cdh2 deletion "disrupts cell-cell adherens contacts and destabilization of gap junctions, resulting in conduction defects, spontaneous ventricular arrhythmias, cardiomyopathy, and premature cardiac death" (relevant to the CDH2-ARVC/DCM cardiac phenotypes specifically, and mechanistically informative for the cardiac component of ACOG syndrome). - Neural-specific conditional models: Conditional CNS deletion approaches (e.g., using neural-lineage Cre drivers) have been used in the broader N-cadherin literature to study neuroepithelial integrity, neural tube closure, radial glial scaffold maintenance, and axon guidance — consistent with, and mechanistically supportive of, the CNS phenotypes (corpus callosum agenesis, axon-pathfinding defects) seen in human ACOG syndrome patients, per the review by PMID:36213737.

Zebrafish and other model systems: N-cadherin (cdh2) mutant/morphant zebrafish have long been used to study neural tube and heart-tube morphogenesis given the same fundamental conservation of N-cadherin function, though a study specifically modeling the human ACOG-syndrome missense alleles in zebrafish was not identified in the sources reviewed.

In vitro/cell-based models: The primary functional validation for human ACOG-syndrome-associated CDH2 variants to date has been cell-based adhesion/aggregation assays in transfected cell lines (e.g., L-cells or similar cadherin-null lines classically used for cadherin adhesion assays), which demonstrated that EC4–EC5 domain variants impair both self-binding (cis) and trans-binding to wild-type N-cadherin, supporting a dominant-negative mechanism (PMID:31585109).

Model limitations: The constitutive mouse knockout's early embryonic lethality (E10, via cardiac failure) means it cannot recapitulate — or be used to directly study — the later CNS callosal/axon-pathfinding phenotypes central to the human syndrome; conditional/tissue-specific and patient-variant-knock-in mouse models (rather than null alleles) would be needed to more faithfully model the human missense/dominant-negative disease mechanism, and such variant-specific knock-in models were not identified as yet published in the literature reviewed.

Summary Table of Key Ontology Term Suggestions

Category	Suggested Term	ID
Disease	Agenesis of corpus callosum, cardiac, ocular, and genital syndrome	OMIM:618929 / MONDO:0030065
Gene	CDH2	HGNC:1759 / NCBI Gene:1000
Phenotype	Agenesis of corpus callosum	HP:0001274
Phenotype	Duane anomaly	HP:0009921
Phenotype	Peters anomaly	HP:0007756
Phenotype	Global developmental delay	HP:0001263
Phenotype	Cryptorchidism	HP:0000028
Phenotype	Micropenis	HP:0000054
Phenotype	Cerebellar vermis hypoplasia	HP:0001320
Biological process	Homophilic cell adhesion via plasma membrane adhesion molecules	GO:0007156
Biological process	Axon guidance	GO:0007411
Cellular component	Cell-cell adherens junction	GO:0005913
Cell type	Radial glial cell	CL:0000681
Cell type	Cardiac muscle cell	CL:0000746
Anatomy	Corpus callosum	UBERON:0002336
Anatomy	Heart	UBERON:0000948

Notes on Evidence Gaps

Prevalence/incidence: No formal population-level rate is available (only cumulative case counts, ~15 patients as of 2022); any later-reported cases beyond the sources reviewed here should be checked via a fresh PubMed search before curation, given the field is actively expanding one case report at a time.
ORPHA number: A dedicated Orphanet entry number specifically for "ACOG syndrome"/ACOGS was not conclusively located in this search (Orphanet does maintain a CDH2 gene page linking to associated rare diseases); this should be verified directly against Orphanet's live database before finalizing a KB entry.
Quantitative phenotype frequencies beyond the qualitative fractions cited (e.g., "10/12," "11/13," "9/13") should be re-verified against the primary AJHG and Clinical Genetics papers' full tables, as only abstract/secondary-source-level detail was accessible in this research pass.
No dedicated GeneReviews chapter for CDH2-ACOG syndrome was identified as of this search — the primary clinical reference remains the original 2019 AJHG paper and subsequent case reports.

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Pathophysiology

Pathograph

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Diagnosis

Prevalence

Differential Diagnoses

Animal Models

Source YAML

References & Deep Research

References

Deep Research

CDH2-Related ACOG Syndrome: Comprehensive Research Report

Executive Summary

1. Disease Information

2. Etiology

3. Phenotypes

Neurodevelopmental / Neurological

Ocular

Cardiac

Genital / Genitourinary

Craniofacial dysmorphism

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary Table of Key Ontology Term Suggestions

Notes on Evidence Gaps

Sources