Cardiofacioneurodevelopmental Syndrome

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Classifications

Harrison's Part

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Inheritance

1

Autosomal recessive HP:0000007

Biallelic pathogenic CCDC32 variants underlie the reported recessive syndrome. Homozygous frameshift alleles segregated in the two founding consanguineous families; the parents of the 2026 siblings were heterozygous deletion carriers.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:41639596 SUPPORT Human Clinical

"Cardiofacioneurodevelopmental syndrome (CFNDS, MIM:619123) is a rare genetic disorder caused by bi-allelic pathogenic variants in CCDC32."

States the biallelic requirement directly, and anchors the OMIM identifier used for the NEC check.

PMID:32307552 SUPPORT Human Clinical

"we investigated the genetic and mechanistic cause of disease in two independent consanguineous families affected by overlapping craniofacial, cardiac, laterality and neurodevelopmental anomalies"

The founding report ascertained two consanguineous families, the classic setting for a recessive disorder.

url:https://www.nature.com/articles/s41431-026-02023-y/figures/1 SUPPORT Human Clinical

"Parents confirmed as heterozygous carriers."

Parents of the two siblings carried the deletion heterozygously.

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Mechanistic Hypotheses

2

AP-2 assembly and coated-pit function model

ccdc32_ap2_endocytic_model CANONICAL

Evidence balance 3 support

CCDC32 supports AP-2 assembly in knockout/reconstitution studies and also regulates coated-pit stability and invagination under partial-knockdown conditions that preserve AP-2 protein levels. Impaired receptor uptake is demonstrated in engineered cells. These molecular functions are established, while their contribution to each human malformation remains a hypothesis. The engineered CCDC32(1-54) disease mimic is defective in AP-2 binding and uptake rescue but is not the exact frameshift protein predicted in the founding patient.

Show evidence (3 references)

PMID:39145939 SUPPORT In Vitro

"We identified CCDC32 as another chaperone regulating AP2 assembly."

Establishes the core molecular role of the protein.

PMID:39145939 SUPPORT In Vitro

"The AP2-regulating function of CCDC32 is disrupted by a disease-causing mutation."

A disease-mimicking mutant disrupts the AP-2-regulating function in an engineered assay; this is not a direct measurement of patient protein.

PMID:41489497 SUPPORT In Vitro

"These findings show that this loss-of-function nonsense mutation in CCDC32 abolishes its interactions with AP2 and inhibits CME, likely contributing to the development of CFNDS."

The experimental truncation supports a loss-of-function model; the construct omits both an N-terminal segment and the patient frameshift tail.

Ciliary Contribution Model

ccdc32_ciliary_model ALTERNATIVE

Evidence balance 2 support

The founding study found reduced Kupffer vesicle cilia number and length in mosaic CRISPR-edited zebrafish embryos, and impaired ciliogenesis after siRNA knockdown in mouse IMCD3 cells. Abnormal southpaw expression and cardiac looping support a contribution to left-right patterning in fish. A corresponding causal chain has not been demonstrated in patient tissue.

The ciliary and endocytic models need not be mutually exclusive. The 2022 case report cites the 2020 zebrafish experiments; it does not provide independent replication. How CCDC32 affects cilia and whether this depends on AP-2 remain unresolved.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Model Organism

"KV cilia were reduced significantly in both number and length in crispants at the 10 somite stage"

Ciliary number and length were measured in mosaic CRISPR-edited zebrafish embryos.

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT In Vitro

"Cilia formation was similarly impaired in ciliated mouse inner medullary collecting duct cells with GFP-labeled cilia (IMCD3 5-HT6-GFP) following siRNA-mediated knockdown"

The mouse experiment used cultured cells, not an intact mouse model.

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Discussions and Knowledge Gaps

6

Do the craniofacial, cardiac and brain malformations of CFNDS arise from the endocytic consequences of failed AP-2 assembly, from a ciliary defect, or from both?

OPEN QUESTION OPEN ccdc32_ap2_versus_cilia

Attached to

pathophysiology#Defective Ciliogenesis pathophysiology#Deficient Clathrin-Mediated Endocytosis

AP-2 assembly and coated-pit regulation have direct biochemical and cell-biological support. Ciliary changes and altered left-right patterning are demonstrated in the founding zebrafish and mouse-cell experiments. Their relationship remains unknown: neither a cilia-independent developmental route nor endocytosis-dependent disruption of cilia has been established in patient tissue.

Both proposed routes retain indirect edges to organ-level abnormalities.

Show evidence (2 references)

PMID:32307552 SUPPORT Model Organism

"arguing that ciliary defects are at least partially involved in the pathomechanism of this disorder"

The ciliary side of the question, stated by its own authors as a partial explanation, which is the hedge that keeps the question open.

PMID:41489497 SUPPORT In Vitro

"Our results suggest that the inability to bind mature AP2 and hence to be recruited to nascent CCSs inhibits critical early stages of CME and contributes to the development of CFNDS."

The endocytic side of the question, also phrased as a suggestion and a contribution rather than as a demonstrated cause.

Is CCDC32 a transient assembly chaperone that is released before AP-2 matures, or does it also bind the mature complex and act at clathrin-coated pits?

CONTROVERSY OPEN ccdc32_ap2_chaperone_mechanism

Attached to

pathophysiology#Failure of AP-2 Adaptor Complex Assembly pathophysiology#Clathrin-Coated Pit Destabilization

The 2024 reconstitution study describes ordered AAGAB-to-CCDC32 handover and release of CCDC32 during assembly. The 2026 coated-pit study detects recruitment and association with native AP-2, using different tagging and imaging conditions. The structural study adds a membrane-dependent switch: CCDC32 stabilizes alpha/sigma2 and prevents or reverses tetramer assembly in solution, while PIP2 membranes relieve inhibition. These observations allow context-dependent assembly and post-assembly roles. Partial knockdown leaves AP-2 abundance intact despite pit defects, whereas knockout reduces subunit abundance.

Show evidence (2 references)

PMID:42234739 SUPPORT In Vitro

"Unexpectedly, in solution, CCDC32 prevents complex assembly and actively disassembles AP-2 tetramers."

The third and most recent model, in which CCDC32 is inhibitory until membrane relieves the inhibition.

PMID:42234739 SUPPORT In Vitro

"We propose that the membrane acts as a molecular switch to release inhibitory interactions, allowing for full complex assembly to proceed."

The proposed reconciliation, which is itself a hypothesis.

How much CCDC32 protein and activity remains for each patient genotype?

OPEN QUESTION OPEN ccdc32_hypomorph_versus_null

Attached to

pathophysiology#Biallelic CCDC32 Loss of Function

The coated-pit study discusses possible residual function and nonsense-mediated decay, but its 1-54 construct is not an exact patient frameshift product. Patient RNA downregulation and exon skipping are now reported for the 2026 deletion family. These data do not quantify residual protein or AP-2/cilia function across alleles. Elective termination of the affected founding fetus is not evidence of biological lethality.

Constitutive engineered knockout and a patient truncation or exon deletion may have different consequences; matched patient-protein and functional assays would resolve this.

Show evidence (2 references)

PMID:41489497 SUPPORT In Vitro

"our disease mimic construct CCDC32(1-54) does not contain a 9 aa peptide (VRGSCLRFQ) in the N-terminus and an extra 12 aa in the C-terminus when CFNDS patient mutation was described (p.(Glu64Glyfs∗12))"

Explicit limits of transferring results from the engineered construct to the patient protein.

url:https://www.nature.com/articles/s41431-026-02023-y/figures/2 SUPPORT Human Clinical

"(not included in the ID and MCA panels) exhibited notable downregulation with a Z-score of -8.20."

Panel membership explains part of the diagnostic blind spot; the RNA outlier is patient-specific.

What are the verified breakpoints and phase of the reported structural alleles?

KNOWLEDGE GAP OPEN ccdc32_recurrent_15q15_deletion

Attached to

pathophysiology#Biallelic CCDC32 Loss of Function

The 2022 deletion spans 32,583 bp, and the 2026 siblings have an exon-3/4 deletion confirmed by PCR and Sanger sequencing. For the 2024 fourth patient, the paper title and ClinGen assessment differ: ClinGen describes suspected 21-kb and 9.7-kb deletions in trans and excluded the proband from scoring. Near-matching uncertain registry coordinates do not establish a recurrent rearrangement, shared founder allele or a first-line worldwide breakpoint assay.

Primary breakpoint and segregation data are needed before treating different structural records as the same allele.

Show evidence (2 references)

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_29c6c0dd-bbaf-45ce-92af-4c67059cac8f-2024-10-18T16:00:00.000Z SUPPORT Other

"An additional 21 kb deletion was reported in a fourth proband (PMID: 38818818) but was not included in this curation."

ClinGen records an unscored fourth case; the primary report has no accessible abstract in the cache.

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_29c6c0dd-bbaf-45ce-92af-4c67059cac8f-2024-10-18T16:00:00.000Z SUPPORT Other

"the following suspected deletions in trans: a 21 kb deletion ... and a 9.7 kb deletion"

The ClinGen case-level explanation describes two suspected deletions in trans, rather than a proven recurrence of the 2022 allele.

Which factors account for variable expressivity among individuals with predicted loss-of-function alleles?

OPEN QUESTION OPEN ccdc32_expressivity_with_loss_of_function_alleles

Attached to

pathophysiology#Biallelic CCDC32 Loss of Function phenotypes#Hypertelorism

The founding individuals differ in interorbital distance, cardiac lesions and laterality. Their variants are predicted loss-of-function alleles, but equivalent complete loss of every CCDC32 activity has not been measured. Residual transcript or protein, modifier loci and developmental variability are possible explanations, not established mechanisms or prognostic markers.

The discordant facial and cardiac observations are directly described in the 2020 clinical full text.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"Dysmorphic features included hypotelorism, upslanting palpebral fissures, a stiff upper lip, missing teeth attributed to the clefting, vaulted palate with cleft, prominent ears, underdeveloped helices and micrognathia."

A-II-1 had hypotelorism.

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"Dysmorphic features included brachydactyly, hypertelorism, epicanthal folds, broad nasal root, a prominent large nose and malformed protruded ears."

B-II-1 had hypertelorism.

What is the true frequency of each CFNDS feature, and what is the natural history beyond childhood?

KNOWLEDGE GAP OPEN ccdc32_phenotype_denominator_gap

The 2026 review describes six living individuals and one fetus across five families after including its two siblings. Ascertainment and investigations differ between reports. These data do not establish population prevalence, reliable per-feature frequencies, adult outcome or survival. Prospective standardized phenotyping and follow-up would address the gap.

Show evidence (1 reference)

PMID:41639596 SUPPORT Human Clinical

"So far, CFNDS has only been described in four living individuals and one terminated fetus from four families"

Quantifies the denominator problem: no frequency or natural-history claim can be made from a cohort of this size.

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Pathophysiology

10

Biallelic CCDC32 Loss of Function

Mechanism confidence: Established

Biallelic frameshift and deletion alleles disrupt CCDC32. The founding paper describes two frameshifts on NM_001080791.2, c.54dupT and c.189_190dupGG; later reports include a 32,583-bp deletion and a deletion of exons 3 and 4. Predicted loss of function is not proof that every allele abolishes all protein activity. Patient transcript downregulation is documented for the exon-3/4 deletion, while residual protein function across genotypes remains unknown.

CCDC32 hgnc:28295

AP-2 adaptor complex binding GO:0035612 ↓ DECREASED

Downstream

Failure of AP-2 Adaptor Complex Assembly Engineered CCDC32 loss impairs AP-2 assembly; disease-mimicking constructs lose AP-2-regulating activity.

Clathrin-Coated Pit Destabilization Partial knockdown disrupts pit dynamics even when AP-2 protein levels remain normal.

Defective Ciliogenesis Knockdown or mosaic disruption impairs cilia in fish embryos and mouse cells; the intervening molecular mechanism is unknown.

Show evidence (2 references)

PMID:32307552 SUPPORT Human Clinical

"Using whole exome sequencing, we identified homozygous frameshift CCDC32 variants in three affected individuals."

The founding identification of biallelic loss-of-function alleles.

PMID:41489497 SUPPORT In Vitro

"These findings show that this loss-of-function nonsense mutation in CCDC32 abolishes its interactions with AP2 and inhibits CME, likely contributing to the development of CFNDS."

The experimental truncation supports a loss-of-function model; the construct omits both an N-terminal segment and the patient frameshift tail.

Failure of AP-2 Adaptor Complex Assembly

Mechanism confidence: Established

CCDC32 participates in chaperoned AP-2 assembly after AAGAB-dependent stabilization of the alpha/sigma2 intermediate. Reconstitution shows an AAGAB-to-CCDC32 handover. Later structural work shows that CCDC32 can prevent or reverse tetramer assembly in solution, whereas binding to PIP2-containing membranes relieves this inhibition and stabilizes assembled AP-2. Thus assembly depends on membrane context as well as the handover. Engineered CCDC32 knockout reduces AP-2 subunit abundance.

AP-2 clathrin adaptor complex GO:0030122

AP-2 adaptor complex GO:0030122

Downstream

Reduced AP-2 Complex Abundance Failed assembly is associated with loss of AP-2 subunits in CCDC32-knockout cells.

Show evidence (4 references)

PMID:39145939 SUPPORT In Vitro

"These findings demonstrate that AP2 is assembled by a handover mechanism switching from AAGAB-based initiation complexes to CCDC32-based template complexes."

Biochemical reconstitution supports ordered handover between assembly factors.

PMID:42234739 SUPPORT In Vitro

"coiled-coil domain-containing protein 32 (CCDC32), whose deletion causes loss of all AP-2 subunits in vivo"

States the consequence of losing CCDC32 for the complex as a whole, which is the step this node models.

PMID:33859415 SUPPORT In Vitro

"We also show that C15orf57 encodes a protein that binds the AP2 complex, localizes to clathrin-coated pits and enables efficient transferrin uptake."

The unbiased co-essentiality screen that first assigned CCDC32 (C15orf57) to the AP2 module.

+ 1 more reference

Reduced AP-2 Complex Abundance

CCDC32 knockout reduces AP-2 subunits and surface AP-2 puncta in HeLa cells; re-expression restores AP-2. This phenotype is condition-dependent: partial CCDC32 knockdown in the coated-pit study did not lower AP-2 protein levels.

AP-2 adaptor complex GO:0030122

Experimental models

CCDC32-knockout and rescue cell systems CELL LINE

Downstream

Deficient Clathrin-Mediated Endocytosis Reduced AP-2 abundance accompanies impaired receptor internalization in knockout cells; this is distinct from the normal-abundance partial-knockdown condition.

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11348294/ SUPPORT In Vitro

"expression of AP2 subunits was diminished"

AP-2 abundance was reduced in knockout cells.

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11348294/ SUPPORT In Vitro

"AP2 expression was fully restored when a CCDC32 rescue gene was expressed"

Genetic rescue supports specificity of the knockout effect.

PMID:41489497 SUPPORT In Vitro

"Under our conditions of CCDC32 knockdown, we did not detect any decrease in protein levels of the AP2 complex"

Pit defects in this knockdown experiment cannot be attributed to measured AP-2 depletion.

Clathrin-Coated Pit Destabilization

Mechanism confidence: Established

Partial CCDC32 knockdown increases unstable, flat clathrin assemblies and impairs pit invagination in ARPE-HPV cells without reducing AP-2 protein levels. The remaining productive pits and increased initiation provide compensation, so the marked change in pit dynamics produces only a mild reduction in transferrin receptor uptake.

Clathrin-coated pit GO:0005905

Experimental models

CCDC32 knockdown and disease-mimic rescue in ARPE-HPV cells CELL LINE

Downstream

Deficient Clathrin-Mediated Endocytosis Defective pit stabilization and invagination reduce productive internalization, although compensatory dynamics limit the net uptake defect in this assay.

Show evidence (2 references)

PMID:41489497 SUPPORT In Vitro

"We show by quantitative live cell imaging that siRNA-mediated knockdown of CCDC32, a poorly characterized endocytic accessory protein, leads to the accumulation of unstable flat clathrin assemblies."

Direct live-cell demonstration of the coated-pit phenotype caused by loss of CCDC32.

PMID:41489497 SUPPORT In Vitro

"Under our conditions of CCDC32 knockdown, we did not detect any decrease in protein levels of the AP2 complex"

Pit defects in this knockdown experiment cannot be attributed to measured AP-2 depletion.

Deficient Clathrin-Mediated Endocytosis

Mechanism confidence: Established

Engineered CCDC32 loss or depletion impairs receptor-mediated internalization, assessed by transferrin uptake. The magnitude depends on the perturbation and assay. A developmental trafficking defect is plausible, but no specific cargo or signaling pathway has been shown to connect these cell-line findings to a particular human malformation.

Clathrin-dependent endocytosis GO:0072583 ↓ DECREASED

Experimental models

CCDC32-knockout and rescue cell systems CELL LINE

CCDC32 knockdown and disease-mimic rescue in ARPE-HPV cells CELL LINE

Downstream

Abnormal Craniofacial Development A contribution of altered endocytosis to this developmental phenotype is proposed; the relevant cargo, cell population and intermediate signaling steps remain unknown.

Abnormal Cardiac Morphogenesis A contribution of altered endocytosis to this developmental phenotype is proposed; the relevant cargo, cell population and intermediate signaling steps remain unknown.

Abnormal Brain Development A contribution of altered endocytosis to this developmental phenotype is proposed; the relevant cargo, cell population and intermediate signaling steps remain unknown.

Abnormal Left-Right Patterning A contribution of altered endocytosis to this developmental phenotype is proposed; the relevant cargo, cell population and intermediate signaling steps remain unknown.

Show evidence (2 references)

PMID:33859415 SUPPORT In Vitro

"We also show that C15orf57 encodes a protein that binds the AP2 complex, localizes to clathrin-coated pits and enables efficient transferrin uptake."

Establishes that CCDC32 is required for efficient receptor-mediated internalisation, the functional read-out modelled by this node.

PMID:41489497 SUPPORT In Vitro

"Despite these profound alterations in CCP dynamics, CME itself, as measured by TfnR internalization efficiency, is only partially inhibited."

Pit dynamics and net cargo uptake are different readouts; the latter is partially preserved.

Defective Ciliogenesis

Mechanism confidence: Provisional

Loss of ccdc32 reduces cilia number and length in the zebrafish Kupffer vesicle. siRNA depletion also impairs ciliogenesis in cultured mouse IMCD3 cells. These findings support a ciliary contribution but do not establish whether cilia are a primary CCDC32 target or affected through altered membrane trafficking.

Cilium assembly GO:0060271 ↓ DECREASED

Experimental models

Ccdc32 knockdown in IMCD3 cells CELL LINE

Animal models

Mosaic F0 ccdc32 CRISPR/Cas9 disruption using two independent exon-2 sgRNAs Danio rerio Danio rerio partially recapitulates

Downstream

Abnormal Craniofacial Development A ciliary contribution is proposed from experimental and clinical overlap; a complete route to the human organ abnormality has not been demonstrated.

Abnormal Cardiac Morphogenesis A ciliary contribution is proposed from experimental and clinical overlap; a complete route to the human organ abnormality has not been demonstrated.

Abnormal Brain Development A ciliary contribution is proposed from experimental and clinical overlap; a complete route to the human organ abnormality has not been demonstrated.

Abnormal Left-Right Patterning A ciliary contribution is proposed from experimental and clinical overlap; a complete route to the human organ abnormality has not been demonstrated.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Model Organism

"KV cilia were reduced significantly in both number and length in crispants at the 10 somite stage"

Ciliary number and length were measured in mosaic CRISPR-edited zebrafish embryos.

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT In Vitro

"Cilia formation was similarly impaired in ciliated mouse inner medullary collecting duct cells with GFP-labeled cilia (IMCD3 5-HT6-GFP) following siRNA-mediated knockdown"

The mouse experiment used cultured cells, not an intact mouse model.

Abnormal Craniofacial Development

Mechanism confidence: Established

Cleft lip and palate and variable facial and mandibular anomalies are observed in patients. Zebrafish ccdc32 disruption alters craniofacial cartilage geometry; fish do not model human lip or palate fusion directly.

Animal models

Mosaic F0 ccdc32 CRISPR/Cas9 disruption using two independent exon-2 sgRNAs Danio rerio Danio rerio partially recapitulates

Downstream

Cleft lip Observed clinical manifestation of the developmental phenotype.

Cleft palate Observed clinical manifestation of the developmental phenotype.

Micrognathia Observed clinical manifestation of the developmental phenotype.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"Dysmorphic features included hypotelorism, upslanting palpebral fissures, a stiff upper lip, missing teeth attributed to the clefting, vaulted palate with cleft, prominent ears, underdeveloped helices and micrognathia."

Craniofacial abnormalities in individual A-II-1.

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Model Organism

"crispants exhibited significant, reproducible alterations in facial skeletal morphology compared to controls, as measured by the angle of the bilateral ceratohyal cartilages"

The craniofacial readout is cartilage geometry, not human cleft-palate fusion.

Abnormal Brain Development

Mechanism confidence: Established

Reported structural abnormalities include callosal, cerebellar, vermian and pontine hypoplasia. Microcephaly and developmental impairment accompany the variable imaging phenotype. Reduced head size and cerebellar abnormalities in zebrafish support a developmental role without establishing each human intermediate.

Animal models

Mosaic F0 ccdc32 CRISPR/Cas9 disruption using two independent exon-2 sgRNAs Danio rerio Danio rerio partially recapitulates

Downstream

Hypoplasia of the corpus callosum Observed clinical manifestation of the developmental phenotype.

Cerebellar hypoplasia Observed clinical manifestation of the developmental phenotype.

Cerebellar vermis hypoplasia Observed clinical manifestation of the developmental phenotype.

Hypoplasia of the pons Observed clinical manifestation of the developmental phenotype.

Microcephaly Observed clinical manifestation of the developmental phenotype.

Global developmental delay Observed clinical manifestation of the developmental phenotype.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"Brain MRI revealed hypoplastic cerebellar tonsils."

Patient imaging identifies a specific cerebellar abnormality.

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Model Organism

"with either sgRNA resulted in a significant reduction in head size at 3 dpf compared to either uninjected or sgRNA-only (no Cas9 protein) injected controls"

Two independent sgRNA/Cas9 perturbations reduce embryonic head size.

Abnormal Cardiac Morphogenesis

Mechanism confidence: Established

Atrioventricular canal defect, ventricular septal defect and pulmonary valve stenosis are reported in patients. The developmental route from CCDC32 dysfunction to these lesions remains unknown; zebrafish cardiac-looping assays do not model human chamber septation.

Downstream

Atrioventricular canal defect Observed clinical manifestation of the developmental phenotype.

Ventricular septal defect Observed clinical manifestation of the developmental phenotype.

Pulmonic stenosis Observed clinical manifestation of the developmental phenotype.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"atrioventricular (AV) canal defect and abdominal ... situs inversus ... with asplenia. Physical examination revealed borderline microcephaly"

Cardiac and visceral laterality findings in individual A-II-1.

Abnormal Left-Right Patterning

Mechanism confidence: Established

Abdominal situs inversus with asplenia is reported in individual A-II-1. Abnormal southpaw expression and cardiac looping in mosaic ccdc32 zebrafish support an embryonic laterality role, without proving a cilia-mediated route in the patient.

Animal models

Mosaic F0 ccdc32 CRISPR/Cas9 disruption using two independent exon-2 sgRNAs Danio rerio Danio rerio partially recapitulates

Downstream

Abdominal situs inversus Observed clinical manifestation of the developmental phenotype.

Asplenia Observed clinical manifestation of the developmental phenotype.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"atrioventricular (AV) canal defect and abdominal ... situs inversus ... with asplenia. Physical examination revealed borderline microcephaly"

Cardiac and visceral laterality findings in individual A-II-1.

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Model Organism

"using either of our sgRNAs disrupted cardiac looping at 2 dpf"

The cardiac assay measures looping and laterality.

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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

44

Cardiovascular 5

Atrioventricular canal defect HP:0006695

Onset: CONGENITAL

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"atrioventricular (AV) canal defect and abdominal ... situs inversus ... with asplenia. Physical examination revealed borderline microcephaly"

An atrioventricular canal defect was reported in A-II-1. The quoted clinical description does not specify complete versus partial anatomy.

Ventricular septal defect HP:0001629

Onset: CONGENITAL

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"ventricular septal defect and pulmonary valve stenosis."

A ventricular septal defect was reported in B-II-1.

Pulmonic stenosis HP:0001642

Onset: CONGENITAL

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"ventricular septal defect and pulmonary valve stenosis."

Pulmonary valve stenosis was reported in B-II-1.

Asplenia HP:0001746

Onset: CONGENITAL

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"atrioventricular (AV) canal defect and abdominal ... situs inversus ... with asplenia. Physical examination revealed borderline microcephaly"

The clinical description directly documents asplenia with abdominal situs inversus in A-II-1. The prevention implications are supported separately in the treatment section.

Absent right internal carotid artery Abnormal internal carotid artery morphology HP:3000062

Laterality: RIGHT

Coarse binding: no hpo term

Ontology gap: EBI OLS4 HPO search query "internal carotid" on 2026-10-04 returned HP:3000062 and HP:0005290 (Internal carotid artery hypoplasia), but no term specifying absence of this artery. The morphology parent includes the observed absence; hypoplasia or agenesis of the carotid canal would assert a different finding. The preferred term preserves the specific MRI observation.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41431-026-02023-y/figures/1 SUPPORT Human Clinical

"Top-left image reveals no right internal carotid artery."

The 2026 MRI caption reports no right internal carotid artery. The caption does not assign each subpanel unambiguously to a sibling.

Digestive 2

Abdominal situs inversus HP:0003363

Onset: CONGENITAL

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"atrioventricular (AV) canal defect and abdominal ... situs inversus ... with asplenia. Physical examination revealed borderline microcephaly"

Abdominal situs inversus with asplenia was reported in A-II-1; this does not establish the same laterality pattern in every family.

Feeding difficulties in infancy HP:0008872

Onset: INFANTILE

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"He had severe feeding difficulties, moderately delayed motor and language development and hyperactivity."

The examination of B-II-1 describes severe feeding difficulties. The separate A-II-1 quote explicitly establishes infantile onset.

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"global developmental delay, feeding difficulties in infancy and congenital anomalies"

Clinical description of A-II-1 explicitly dates feeding difficulties to infancy.

Ear 3

Conductive hearing impairment HP:0000405

Laterality: BILATERAL

Show evidence (1 reference)

PMID:35451546 SUPPORT Human Clinical

"She had bilateral conductive hearing loss, small hands and feet, and finger abnormalities."

Direct documentation in a genotyped patient.

Protruding ear HP:0000411

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"Dysmorphic features included brachydactyly, hypertelorism, epicanthal folds, broad nasal root, a prominent large nose and malformed protruded ears."

The founding report describes malformed protruded ears in B-II-1.

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"Dysmorphic features included hypotelorism, upslanting palpebral fissures, a stiff upper lip, missing teeth attributed to the clefting, vaulted palate with cleft, prominent ears, underdeveloped helices and micrognathia."

The same report describes prominent ears in A-II-1, supporting involvement in both liveborn founding individuals.

Hypoplastic helices HP:0008589

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"Dysmorphic features included hypotelorism, upslanting palpebral fissures, a stiff upper lip, missing teeth attributed to the clefting, vaulted palate with cleft, prominent ears, underdeveloped helices and micrognathia."

Underdeveloped helices were reported in A-II-1.

Endocrine 1

Anterior pituitary hypoplasia HP:0010627

Show evidence (1 reference)

url:https://www.nature.com/articles/s41431-026-02023-y/figures/1 SUPPORT Human Clinical

"hypoplasia of the adenohypophysis, measuring 2.2 mm."

The 2026 MRI figure documents anterior pituitary hypoplasia; hormone deficiency cannot be inferred from this image alone.

Eye 3

Hypertelorism HP:0000316

Severity: SEVERE

Opposite interorbital-distance findings occur in different patients and are not contradictory measurements in one individual.

Show evidence (1 reference)

PMID:35451546 SUPPORT Human Clinical

"The patient had intellectual disability, marked hypertelorism, bilateral cleft lip and palate, and short stature."

Documents hypertelorism, and its severity qualifier, in a genotyped patient.

Hypotelorism HP:0000601

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"Dysmorphic features included hypotelorism, upslanting palpebral fissures, a stiff upper lip, missing teeth attributed to the clefting, vaulted palate with cleft, prominent ears, underdeveloped helices and micrognathia."

The examination sentence identifies hypotelorism in A-II-1; the opposite finding in B-II-1 is documented in the hypertelorism row.

Thin optic nerve Abnormal optic nerve morphology HP:0000587

Coarse binding: no hpo term

Ontology gap: EBI OLS4 HPO search query "optic nerve" on 2026-10-04 returned HP:0000587, HP:0000609 (Optic nerve hypoplasia), HP:0008058 (Aplasia/Hypoplasia of the optic nerve), and HP:0000648 (Optic atrophy). The figure caption describes thinness without establishing developmental hypoplasia or atrophy. The morphology parent is used with the observed thinness retained in preferred_term.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41431-026-02023-y/figures/1 SUPPORT Human Clinical

"Bottom-left image shows a thin optic nerve."

The 2026 MRI caption describes a thin optic nerve, without establishing optic atrophy or a functional visual deficit.

Genitourinary 1

Cryptorchidism HP:0000028

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"The individual had clinodactyly, nail aplasia on thumbs and toes and cryptorchidism."

The male proband B-II-1 is explicitly described as having cryptorchidism.

Head and Neck 9

Cleft lip HP:0410030

Laterality: BILATERAL Onset: CONGENITAL

The 2022 paper described clefting in the three individuals then known. In the founding girl, missing teeth were attributed to clefting rather than established as primary congenital hypodontia. No population frequency band is inferred.

Show evidence (2 references)

PMID:35451546 SUPPORT Human Clinical

"We describe a core phenotype comprising developmental delay and bilateral cleft lip and palate in the three individuals with CFNDS."

Designates bilateral cleft lip and palate as one of the two core features of the syndrome.

PMID:35451546 SUPPORT Human Clinical

"The patient had intellectual disability, marked hypertelorism, bilateral cleft lip and palate, and short stature."

Documents the finding in the individually reported patient.

Cleft palate HP:0000175

Onset: CONGENITAL

Reported in all three individuals known at the time of PMID:35451546. No frequency band is asserted: the clinical denominator is small and variably investigated.

Show evidence (1 reference)

PMID:35451546 SUPPORT Human Clinical

"The cardiofacioneurodevelopmental syndrome (CFNDS) is characterized by craniofacial anomalies including bilateral cleft lip and palate, cardiac, skeletal, and neurodevelopmental features and additional variable manifestations."

Names bilateral cleft lip and palate as the defining craniofacial anomaly.

Microcephaly HP:0000252

Show evidence (4 references)

PMID:41639596 SUPPORT Human Clinical

"the clinical phenotype can include microcephaly, facial malformations, developmental delay, cerebellar hypoplasia, and cardiac anomalies"

Lists microcephaly among the recurring features.

PMID:35451546 SUPPORT Human Clinical

"Variable abnormalities of the face, brain, heart, fingers, and toes and postnatal growth retardation or microcephaly can be present."

The source identifies microcephaly as a variable feature; this sentence does not establish its presence in an individual patient.

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"Physical examination revealed borderline microcephaly (3rd–5th percentiles), height at 80th percentile and weight at 32nd percentile."

Patient-level head-size measurement in A-II-1 is explicitly described as borderline.

+ 1 more reference

Epicanthus HP:0000286

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"Dysmorphic features included brachydactyly, hypertelorism, epicanthal folds, broad nasal root, a prominent large nose and malformed protruded ears."

Epicanthal folds were described in B-II-1.

Upslanted palpebral fissure HP:0000582

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"Dysmorphic features included hypotelorism, upslanting palpebral fissures, a stiff upper lip, missing teeth attributed to the clefting, vaulted palate with cleft, prominent ears, underdeveloped helices and micrognathia."

Upslanted fissures were described in A-II-1.

Micrognathia HP:0000347

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"Dysmorphic features included hypotelorism, upslanting palpebral fissures, a stiff upper lip, missing teeth attributed to the clefting, vaulted palate with cleft, prominent ears, underdeveloped helices and micrognathia."

Micrognathia was reported in A-II-1.

High palate HP:0000218

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"Dysmorphic features included hypotelorism, upslanting palpebral fissures, a stiff upper lip, missing teeth attributed to the clefting, vaulted palate with cleft, prominent ears, underdeveloped helices and micrognathia."

A vaulted palate with a cleft was described in A-II-1.

Wide nasal bridge HP:0000431

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"Dysmorphic features included brachydactyly, hypertelorism, epicanthal folds, broad nasal root, a prominent large nose and malformed protruded ears."

A broad nasal root was described in B-II-1.

Prominent nose HP:0000448

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"Dysmorphic features included brachydactyly, hypertelorism, epicanthal folds, broad nasal root, a prominent large nose and malformed protruded ears."

A prominent large nose was reported in B-II-1.

Integument 3

Absent fingernail HP:0001817

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"The individual had clinodactyly, nail aplasia on thumbs and toes and cryptorchidism."

The founding report documents aplasia of thumb and toe nails in B-II-1; this row binds the fingernail component.

Abnormal dermatoglyphics HP:0007477

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"She had mild kyphosis and nail clubbing and abnormal dermatoglyphics, bilateral camptodactyly and clinodactyly of the fifth fingers."

Abnormal dermatoglyphics were reported in A-II-1.

Absent toenail HP:0001802

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"The individual had clinodactyly, nail aplasia on thumbs and toes and cryptorchidism."

The clinical description explicitly includes nail aplasia on toes.

Limbs 6

Small hand HP:0200055

Show evidence (1 reference)

PMID:35451546 SUPPORT Human Clinical

"She had bilateral conductive hearing loss, small hands and feet, and finger abnormalities."

Direct documentation in a genotyped patient.

Short foot HP:0001773

Show evidence (1 reference)

PMID:35451546 SUPPORT Human Clinical

"She had bilateral conductive hearing loss, small hands and feet, and finger abnormalities."

Direct documentation in a genotyped patient.

Brachydactyly HP:0001156

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"Dysmorphic features included brachydactyly, hypertelorism, epicanthal folds, broad nasal root, a prominent large nose and malformed protruded ears."

Brachydactyly was reported in B-II-1.

Clinodactyly of the 5th finger HP:0004209

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"She had mild kyphosis and nail clubbing and abnormal dermatoglyphics, bilateral camptodactyly and clinodactyly of the fifth fingers."

The examination of A-II-1 explicitly identifies clinodactyly of the fifth fingers.

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"The individual had clinodactyly, nail aplasia on thumbs and toes and cryptorchidism."

B-II-1 also had clinodactyly; this sentence does not identify the affected digit.

Camptodactyly of finger HP:0100490

Laterality: BILATERAL

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"She had mild kyphosis and nail clubbing and abnormal dermatoglyphics, bilateral camptodactyly and clinodactyly of the fifth fingers."

Bilateral camptodactyly was reported in A-II-1.

Clubbing HP:0001217

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"She had mild kyphosis and nail clubbing and abnormal dermatoglyphics, bilateral camptodactyly and clinodactyly of the fifth fingers."

The clinical examination of A-II-1 explicitly describes nail clubbing, without attributing its cause.

Musculoskeletal 1

Kyphosis HP:0002808

Severity: MILD

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"She had mild kyphosis and nail clubbing and abnormal dermatoglyphics, bilateral camptodactyly and clinodactyly of the fifth fingers."

Mild kyphosis was reported in A-II-1.

Nervous System 7

Global developmental delay HP:0001263

Named as core in PMID:35451546 across the three individuals then known, and listed again among the recurring features in the 2026 review. No frequency band is asserted: the clinical denominator is small and variably investigated.

Show evidence (2 references)

PMID:35451546 SUPPORT Human Clinical

"We describe a core phenotype comprising developmental delay and bilateral cleft lip and palate in the three individuals with CFNDS."

Designates developmental delay as one of the two core features.

PMID:41639596 SUPPORT Human Clinical

"the clinical phenotype can include microcephaly, facial malformations, developmental delay, cerebellar hypoplasia, and cardiac anomalies"

The 2026 review carries developmental delay forward as a recurring feature.

Intellectual disability HP:0001249

Documented in one individually described patient. Because the syndrome is congenital and the reported cohort is largely young, the proportion of affected individuals old enough for a formal cognitive assessment is small, which is a further reason no frequency band is asserted.

Show evidence (1 reference)

PMID:35451546 SUPPORT Human Clinical

"The patient had intellectual disability, marked hypertelorism, bilateral cleft lip and palate, and short stature."

Direct documentation of intellectual disability in a genotyped patient.

Cerebellar vermis hypoplasia HP:0001320

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"A sibling fetus in Family A (A-II-2) had bilateral cleft lip, vermian hypoplasia, hypoplastic pons and abnormal cisterna magna that were detected by ultrasound, and the pregnancy was terminated electively."

Vermian hypoplasia was detected prenatally in fetus A-II-2.

Hypoplasia of the corpus callosum HP:0002079

Show evidence (2 references)

PMID:35451546 SUPPORT Human Clinical

"Brain imaging disclosed hypoplastic corpus callosum."

Direct imaging documentation in a genotyped patient.

url:https://www.nature.com/articles/s41431-026-02023-y/figures/1 SUPPORT Human Clinical

"Bottom-right image indicates a complete but thin corpus callosum with abnormalities in sinuses."

A complete but thin corpus callosum is separately reported in the 2026 MRI figure; this is not agenesis.

Cerebellar hypoplasia HP:0001321

Show evidence (1 reference)

PMID:41639596 SUPPORT Human Clinical

"the clinical phenotype can include microcephaly, facial malformations, developmental delay, cerebellar hypoplasia, and cardiac anomalies"

The review that pooled the published cases lists cerebellar hypoplasia as part of the phenotype.

Hypoplasia of the pons HP:0012110

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"A sibling fetus in Family A (A-II-2) had bilateral cleft lip, vermian hypoplasia, hypoplastic pons and abnormal cisterna magna that were detected by ultrasound, and the pregnancy was terminated electively."

Prenatal ultrasound showed a hypoplastic pons in A-II-2.

Hyperactivity HP:0000752

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"He had severe feeding difficulties, moderately delayed motor and language development and hyperactivity."

The clinical account explicitly names hyperactivity in B-II-1 without diagnosing ADHD.

Growth 2

Postnatal growth retardation HP:0008897

Show evidence (1 reference)

PMID:35451546 SUPPORT Human Clinical

"Variable abnormalities of the face, brain, heart, fingers, and toes and postnatal growth retardation or microcephaly can be present."

Names postnatal growth retardation as a variable feature.

Short stature HP:0004322

Show evidence (1 reference)

PMID:35451546 SUPPORT Human Clinical

"The patient had intellectual disability, marked hypertelorism, bilateral cleft lip and palate, and short stature."

Direct documentation in a genotyped patient.

Other 1

Hypoplastic cerebellar tonsils

Needs precise term: EBI OLS4 HPO search query "cerebellar tonsil" on 2026-10-04 returned Chiari malformation (HP:0002308), Chiari type I malformation (HP:0007099) and Chiari type II malformation (HP:0025660), not a term for tonsillar hypoplasia. Chiari displacement is not the reported finding. The anatomically specific descriptor is therefore left unbound.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"Brain MRI revealed hypoplastic cerebellar tonsils."

MRI showed hypoplastic cerebellar tonsils in A-II-1.

🧬

Genetic Associations

1

CCDC32

Gene: CCDC32 hgnc:28295 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (2 references)

PMID:32307552 SUPPORT Human Clinical

"Using whole exome sequencing, we identified homozygous frameshift CCDC32 variants in three affected individuals."

The founding gene-disease association.

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_29c6c0dd-bbaf-45ce-92af-4c67059cac8f-2024-10-18T16:00:00.000Z SUPPORT Other

"In summary, there is moderate evidence to support this gene-disease relationship."

ClinGen Syndromic Disorders GCEP assessment approved 2024-10-18.

Variants (6)

CCDC32 c.27dup (p.Thr10fs), family A founding frameshift Pathogenic

Gene: CCDC32 hgnc:28295 frameshift duplication 1 bp

The founding family A carried the homozygous single-base frameshift duplication reported as NM_001080791.2:c.54dupT, p.(Thr19Tyrfs*12). ClinGen represents the same allele as NM_001080792.4:c.27dup, p.Thr10TyrfsTer12. The sequence predicts premature termination; patient protein abundance was not measured in that report.

Also known as: NM_001080791.2:c.54dupT p.(Thr19Tyrfs*12) NM_001080792.4:c.27dup p.Thr10fs

Identifiers: ClinVar:VCV000988600 OMIM:618941.0001 dbSNP:rs1890756020 ClinGen:CA1139663846

Functional effects

predicted loss of function

Frameshift with a premature stop, predicted to disrupt CCDC32. Residual patient protein and activity are not established.

External assertions

ClinVar germline classification for CCDC32 c.27dup

ClinVar germline variant classification VCV000988600

Classified Pathogenic for cardiofacioneurodevelopmental syndrome (MedGen:C5436852, MONDO:0030873, OMIM:619123), last evaluated 2020-12-09, review status "no assertion criteria provided" (one submitter, SCV001450459; the OMIM allelic-variant record). Retrieved from the NCBI eutils ClinVar esummary and VCV efetch endpoints on 2026-08-01.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"c.54dupT in Family A and c.189_190dupGG in Family B"

Figure 1 documents the segregating founding alleles.

CCDC32 c.162_163dup (p.Glu55fs), family B founding frameshift Pathogenic

Gene: CCDC32 hgnc:28295 frameshift duplication 2 bp

The founding family B carried the homozygous two-base duplication NM_001080791.2:c.189_190dupGG, p.(Glu64Glyfs*12), represented by ClinGen as NM_001080792.4:c.162_163dup, p.Glu55GlyfsTer12. The CCDC32(1-54) assay construct omits both the nine-residue N-terminal segment of the published sequence and the twelve-residue frameshift tail; it is an informative disease mimic, not an exact patient protein.

Also known as: NM_001080791.2:c.189_190dupGG p.(Glu64Glyfs*12) NM_001080792.4:c.162_163dup p.Glu55fs

Identifiers: ClinVar:VCV000988601 OMIM:618941.0002 dbSNP:rs1890742129 ClinGen:CA1139663845

Functional effects

predicted loss of function

Frameshift with a premature stop, predicted to disrupt CCDC32. Residual patient protein and activity are not established.

External assertions

ClinVar germline classification for CCDC32 c.162_163dup

ClinVar germline variant classification VCV000988601

Classified Pathogenic for cardiofacioneurodevelopmental syndrome (MedGen:C5436852, MONDO:0030873, OMIM:619123), last evaluated 2020-12-09, review status "no assertion criteria provided" (one submitter, SCV001450460; the OMIM allelic-variant record). Retrieved from the NCBI eutils ClinVar esummary and VCV efetch endpoints on 2026-08-01.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"c.54dupT in Family A and c.189_190dupGG in Family B"

Figure 1 documents the segregating founding alleles.

PMID:41489497 SUPPORT In Vitro

"our disease mimic construct CCDC32(1-54) does not contain a 9 aa peptide (VRGSCLRFQ) in the N-terminus and an extra 12 aa in the C-terminus when CFNDS patient mutation was described (p.(Glu64Glyfs∗12))"

Explicit limits of transferring results from the engineered construct to the patient protein.

CCDC32 c.471T>A (p.Tyr157Ter), nonsense variant of uncertain significance Uncertain Significance

Gene: CCDC32 hgnc:28295 nonsense 1 bp

A nonsense variant recorded as uncertain significance in the ClinVar assertion retrieved on 2026-08-01. It is not a confirmed disease allele. Its C-terminal position alone cannot establish whether AP-2 assembly, membrane binding or another function is preserved.

Also known as: NM_001080792.4:c.471T>A p.Tyr157Ter

Identifiers: ClinVar:VCV002580223 dbSNP:rs2543087691 ClinGen:CA391722033

External assertions

ClinVar germline classification for CCDC32 c.471T>A

ClinVar germline variant classification VCV002580223

Classified Uncertain significance for cardiofacioneurodevelopmental syndrome (MedGen:C5436852, MONDO:0030873, OMIM:619123), last evaluated 2023-03-30, review status "criteria provided, single submitter" (SCV004035993). GRCh38 chr15:40554058. Retrieved from the NCBI eutils ClinVar esummary endpoint on 2026-08-01.

CCDC32 32,583-bp deletion (2022 patient) Pathogenic

Gene: CCDC32 hgnc:28295 deletion

The 2022 patient carried a homozygous 32,583-bp deletion affecting CCDC32, predicted to remove protein function independently of transcript choice. The source does not establish that this is the same allele as the later structural variants.

Identifiers: ClinVar:VCV001690313 OMIM:618941.0003

External assertions

ClinVar germline classification for the CCDC32 32.6-kb deletion (Abdalla patient)

ClinVar germline variant classification VCV001690313

NC_000015.10:g.40529942_40562524del, alias "32.6-KB DEL", classified Pathogenic for cardiofacioneurodevelopmental syndrome, last evaluated 2022-11-29, review status "criteria provided, single submitter"; also carried as OMIM allelic variant 618941.0003. GRCh37 coordinates chr15:40822141-40854723. Retrieved from the NCBI eutils ClinVar esummary endpoint on 2026-08-01.

Show evidence (2 references)

PMID:35451546 SUPPORT Human Clinical

"We report a 9-year-old female patient with CFNDS caused by a homozygous 32,583-bp deletion affecting CCDC32."

The first reported structural deletion allele.

PMID:35451546 SUPPORT Human Clinical

"Independent of the affected CCDC32 transcript variant this deletion likely leads to loss of the encoded protein."

Explains why the deletion is interpreted as loss of function regardless of which transcript is considered.

CCDC32 deletion of exons 3 and 4 (2026 siblings)

Gene: CCDC32 hgnc:28295 intragenic deletion

Biallelic genomic deletion of exons 3 and 4 in two siblings, detected through transcript analysis and confirmed by deletion-specific PCR and Sanger breakpoint sequencing. Both parents were heterozygous. The RNA finding revealed a variant missed in the earlier panel-focused diagnostic workflow, rather than proving that the deletion is undetectable by DNA methods.

Identifiers: ClinVar:SCV007113788

Show evidence (2 references)

PMID:41639596 SUPPORT Human Clinical

"Skipping of two exons in CCDC32 transcript was identified, consistent with a bi-allelic deletion including exons 3 and 4 of CCDC32."

An intragenic multi-exon deletion detected through its transcript consequence.

url:https://www.nature.com/articles/s41431-026-02023-y/figures/2 SUPPORT Human Clinical

"Deletion-specific PCR for affected individuals, heterozygous parents, and unrelated control."

Genomic confirmation accompanies the RNA finding.

CCDC32 structural variants in the 2024 fourth patient

Gene: CCDC32 hgnc:28295 suspected deletions in trans

The 2024 report title describes a homozygous deletion, while the ClinGen assessment describes suspected 21-kb and 9.7-kb deletions in trans and excluded this proband from its scoring. This discrepancy should be resolved from primary breakpoint and segregation data before equating the allele with the 2022 deletion.

Identifiers: ClinVar:VCV002431643

Show evidence (2 references)

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_29c6c0dd-bbaf-45ce-92af-4c67059cac8f-2024-10-18T16:00:00.000Z SUPPORT Other

"An additional 21 kb deletion was reported in a fourth proband (PMID: 38818818) but was not included in this curation."

ClinGen records an unscored fourth case; the primary report has no accessible abstract in the cache.

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_29c6c0dd-bbaf-45ce-92af-4c67059cac8f-2024-10-18T16:00:00.000Z SUPPORT Other

"the following suspected deletions in trans: a 21 kb deletion ... and a 9.7 kb deletion"

The ClinGen case-level explanation describes two suspected deletions in trans, rather than a proven recurrence of the 2022 allele.

💊

Medical Actions

10

Antimicrobial prophylaxis and immunisation for asplenia

Action: Asplenia infection-prevention care Ontology label: Supportive Care NCIT:C15747

Platform: Other

Individuals with asplenia need infection-prevention planning, vaccination and prompt assessment of febrile illness under general asplenia care. Antibiotic prophylaxis duration depends on age and individual risk; lifelong infection susceptibility does not mean that every patient requires lifelong daily antibiotics. These are general asplenia recommendations, not CFNDS-specific trial outcomes.

Target Phenotypes: Asplenia HP:0001746

Show evidence (2 references)

PMID:33275684 SUPPORT Human Clinical

"Recommendations for patients with functional or anatomic asplenia include antibiotic prophylaxis, vaccination, and patient and family education to ensure prevention of infections and timely management of febrile illnesses."

General asplenia management extrapolated to affected CFNDS individuals.

PMID:33275684 SUPPORT Human Clinical

"Duration of routine prophylaxis depends on age, time since splenectomy, degree of immunocompromise, or prior episode of sepsis."

The source does not recommend universal lifelong prophylaxis for all patients.

Cleft palate repair

Action: palatorrhaphy Ontology label: Palatorrhaphy NCIT:C168380

Platform: Surgery

Palatoplasty within multidisciplinary cleft care, with timing individualized to anatomy, feeding and speech needs. This is phenotype-directed supportive care; CFNDS-specific comparative surgical outcomes are not established.

Target Phenotypes: Cleft palate HP:0000175

Cleft lip repair

Action: cleft lip repair (cheiloplasty) Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Cheiloplasty as part of multidisciplinary cleft care. This is a phenotype-directed intervention; the cited CFNDS reports do not establish a syndrome-specific timing protocol.

Target Phenotypes: Cleft lip HP:0410030

Nutritional and feeding support in infancy

Action: nutritional support Ontology label: Nutritional Support NCIT:C15433

Platform: Other

Individualized feeding assessment, cleft-adapted feeding support and nutritional monitoring for reported feeding difficulties. This is supportive extrapolation from the phenotype, without CFNDS-specific intervention trial data.

Target Phenotypes: Feeding difficulties in infancy HP:0008872

Orchidopexy for cryptorchidism

Action: orchiopexy Ontology label: Orchiopexy NCIT:C111066

Platform: Surgery

Urological assessment and consideration of orchiopexy for the reported undescended testis phenotype, under general pediatric urology care. A CFNDS-specific protocol or outcome series is not established.

Target Phenotypes: Cryptorchidism HP:0000028

Hearing support

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Platform: Other

Hearing support and treatment of conductive impairment when indicated. Hearing evaluation is part of phenotype assessment; benefit in CFNDS has not been tested in a dedicated trial.

Speech and language therapy

Action: speech therapy Ontology label: Speech Language Therapy NCIT:C159273

Platform: Behavioral / lifestyle

Individualized speech and language support can address developmental and cleft-related needs. This is supportive extrapolation from the reported phenotype.

Developmental and educational therapy

Action: rehabilitation Ontology label: Rehabilitation NCIT:C15315

Platform: Behavioral / lifestyle

Developmental, rehabilitation and educational support directed at the individual pattern of delay or intellectual disability. No disease-modifying efficacy is claimed.

Management of congenital cardiac lesions

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Platform: Other

Cardiology-directed management or repair of the specific congenital cardiac lesion, according to its anatomy and physiology. This is standard phenotype-directed care rather than a CFNDS-specific treatment protocol.

Genetic counselling

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

Platform: Other

For parents confirmed to carry pathogenic variants in the same autosomal recessive gene, standard Mendelian counseling gives a 25% affected-child risk per pregnancy. Familial testing must account for the actual sequence or deletion alleles. This is an inheritance-based calculation, not a measured penetrance estimate; prognosis cannot be predicted reliably from the small clinical series.

🔬

Diagnosis

4

Exome or genome sequencing

Molecular diagnosis requires compatible findings and biallelic pathogenic CCDC32 variants. Exome sequencing identified the founding frameshifts; analysis should also consider exon-level and larger deletions. Developmental delay with orofacial clefting and additional cardiac, laterality or brain findings can prompt consideration of CCDC32, but no formal clinical scoring criteria are established.

Show evidence (1 reference)

PMID:32307552 SUPPORT Human Clinical

"Using whole exome sequencing, we identified homozygous frameshift CCDC32 variants in three affected individuals."

Exome sequencing was the method that established the diagnosis in the founding families.

RNA sequencing when DNA-based testing is uninformative

In the 2026 siblings, RNA sequencing identified marked CCDC32 downregulation and loss of exons 3 and 4 after SNP array and trio exome testing had been uninformative. CCDC32 was absent from the intellectual-disability and congenital-malformation panels used in the earlier analysis. Review of WES tracks and genomic PCR/Sanger sequencing then confirmed the deletion. RNA analysis can complement a negative work-up, but this case does not establish that DNA testing is intrinsically unable to detect the allele.

Show evidence (3 references)

PMID:41639596 SUPPORT Human Clinical

"We present a family with two affected individuals who were diagnosed through clinical RNA sequencing (RNA-seq) after conventional DNA diagnostics did not yield a molecular cause."

States precisely the diagnostic claim made here: RNA sequencing made the diagnosis after DNA-based testing had failed.

PMID:41639596 SUPPORT Human Clinical

"This deletion was not detected in previous SNP array analyses and trio exome sequencing focusing on genes related to intellectual disability and congenital malformations, highlighting the complementary value of RNA-seq."

Documents that both SNP array and trio exome sequencing missed the causal allele, which is the reason RNA sequencing is recommended here.

url:https://www.nature.com/articles/s41431-026-02023-y/figures/2 SUPPORT Human Clinical

"(not included in the ID and MCA panels) exhibited notable downregulation with a Z-score of -8.20."

Panel membership explains part of the diagnostic blind spot; the RNA outlier is patient-specific.

Brain magnetic resonance imaging

Brain MRI can characterize the reported callosal, cerebellar and brainstem abnormalities. The 2026 figure also reports anterior pituitary hypoplasia, a thin optic nerve and absent right internal carotid artery. Imaging observations should not be converted into unmeasured endocrine or visual dysfunction.

Show evidence (2 references)

PMID:35451546 SUPPORT Human Clinical

"Brain imaging disclosed hypoplastic corpus callosum."

Brain imaging revealed a structural anomaly that would otherwise have been missed.

url:https://www.nature.com/articles/s41431-026-02023-y/figures/1 SUPPORT Human Clinical

"Bottom-right image indicates a complete but thin corpus callosum with abnormalities in sinuses."

A complete but thin corpus callosum is separately reported in the 2026 MRI figure; this is not agenesis.

Cardiac, visceral situs and hearing assessment

Phenotype-directed assessment includes cardiac anatomy, abdominal organ position and spleen presence, and hearing. This is inferred from the reported defects rather than a validated CFNDS screening schedule.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"atrioventricular (AV) canal defect and abdominal ... situs inversus ... with asplenia. Physical examination revealed borderline microcephaly"

Asplenia accompanied abdominal situs inversus in A-II-1. Infection prevention is an actionable consequence of this finding.

PMID:35451546 SUPPORT Human Clinical

"She had bilateral conductive hearing loss, small hands and feet, and finger abnormalities."

Direct documentation in a genotyped patient.

📈

Progression

2

Age: Prenatal to birth

Structural malformations can be detected prenatally. Ultrasound in fetus A-II-2 showed bilateral cleft lip, vermian and pontine hypoplasia, and an abnormal cisterna magna. The pregnancy was terminated electively; this observation does not establish fetal lethality.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Human Clinical

"A sibling fetus in Family A (A-II-2) had bilateral cleft lip, vermian hypoplasia, hypoplastic pons and abnormal cisterna magna that were detected by ultrasound, and the pregnancy was terminated electively."

Direct prenatal imaging observations in the founding family.

Age: Infancy through childhood

Feeding difficulties and developmental delay were reported in childhood, and intellectual disability was documented in the nine-year-old patient reported in 2022. Growth, head size and structural findings vary. These small case reports do not establish adult prognosis or a progressive neurodegenerative course.

Show evidence (1 reference)

PMID:35451546 SUPPORT Human Clinical

"Variable abnormalities of the face, brain, heart, fingers, and toes and postnatal growth retardation or microcephaly can be present."

Identifies growth retardation and microcephaly as postnatal rather than necessarily congenital findings.

📊

Prevalence

1

Global

Cases In Literature Ultra Rare

The 2026 report describes two siblings in addition to four living individuals and one electively terminated fetus from four previously reported families: six living individuals and one fetus from five families within that literature review. This is a dated literature count, not a current worldwide census or a population rate.

Show evidence (1 reference)

PMID:41639596 SUPPORT Human Clinical

"So far, CFNDS has only been described in four living individuals and one terminated fetus from four families"

Gives the published denominator immediately before this report, which is the basis for the ultra-rare tier.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Cardiofacioneurodevelopmental Syndrome:

Cardiofaciocutaneous syndrome MONDO:0015280

Overlapping Features A RASopathy caused by heterozygous gain-of-function variants in BRAF, MAP2K1, MAP2K2 or KRAS. It is included here primarily as a NAMING hazard rather than a close clinical mimic: "cardiofaciocutaneous" and "cardiofacioneurodevelopmental" differ by one word element, both abbreviate to a CF acronym, and a literature search or an automated entity resolver can silently substitute one for the other. Clinically the two do share craniofacial dysmorphism, congenital heart disease, growth retardation and intellectual disability, so the distinction also matters at the bedside. The discriminators are the ectodermal features and the inheritance pattern.

Distinguishing Features

Autosomal dominant, usually de novo, versus autosomal recessive for CFNDS
Caused by RAS-MAPK pathway genes (BRAF, MAP2K1, MAP2K2, KRAS), not CCDC32
Cutaneous abnormalities are central to the CFC GeneReviews description; the small CFNDS series does not establish their universal absence.
Bilateral cleft lip and palate is the core craniofacial feature of CFNDS but is not characteristic of cardiofaciocutaneous syndrome
Pulmonic stenosis and hypertrophic cardiomyopathy are the characteristic RASopathy cardiac lesions

Show evidence (3 references)

PMID:20301365 SUPPORT Human Clinical

"CLINICAL CHARACTERISTICS: Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities"

GeneReviews characterizes the different RASopathy, including its cutaneous component; it cannot prove absence of those findings in CFNDS.

PMID:20301365 SUPPORT Human Clinical

"The diagnosis of CFC syndrome is established in a proband with suggestive clinical findings by the identification of a heterozygous pathogenic variant in BRAF, MAP2K1, MAP2K2, or KRAS by molecular genetic testing."

Establishes the genetic discriminator: heterozygous RAS-MAPK pathway variants rather than biallelic CCDC32 variants.

PMID:20301365 SUPPORT Human Clinical

"CFC syndrome is inherited in an autosomal dominant manner."

Establishes the inheritance discriminator.

Ciliopathy with craniofacial, cardiac and laterality involvement

Overlapping Features The founding report explicitly framed CFNDS as overlapping the ciliopathies, on the basis of the laterality anomalies and the craniofacial and brain findings. In practice a child with orofacial clefting, a congenital cardiac lesion, situs abnormality and posterior-fossa anomaly will be worked up for the ciliopathy spectrum, and CCDC32 should be in that differential rather than outside it. No single MONDO grouping term is bound here because the candidate entities span several distinct disorders rather than one, and picking any one of them would assert a specific alternative diagnosis that the source does not support.

Distinguishing Features

Different ciliopathies have different retinal, renal, skeletal and laterality findings; there is no universal distinguishing feature across this group.
Ophthalmologic and renal evaluations were normal in the two liveborn founding CFNDS individuals, which does not establish lifelong or universal absence of disease in these organs.
CCDC32 regulates AP-2 and coated-pit function; the biochemical route to its reported ciliary phenotype remains unresolved.

Show evidence (1 reference)

PMID:32307552 SUPPORT Human Clinical

"Because some of the patient phenotypes overlap defects common to ciliopathies, we asked if loss of CCDC32 might contribute to the dysfunction of this organelle."

The authors themselves note the phenotypic overlap with ciliopathies, which is the reason this differential is listed.

🧫

Experimental Models

4

CCDC32-knockout and rescue cell systems CELL_LINE

The 2024 study deleted CCDC32 in cultured cells, measured AP-2 subunits and receptor uptake, and restored AP-2 with a rescue gene. Additional engineered iPSC and mouse preadipocyte experiments support a role across cell contexts. These are not patient-derived CFNDS lines.

Cell source

Engineered human HeLa cells; additional human iPSCs and mouse preadipocytes

Pathograph links

Reduced AP-2 Complex Abundance perturbs

Limitations: Engineered model; does not establish the complete human developmental mechanism.

Reduced AP-2 Complex Abundance rescues

Limitations: Engineered model; does not establish the complete human developmental mechanism.

Deficient Clathrin-Mediated Endocytosis perturbs

Limitations: Engineered model; does not establish the complete human developmental mechanism.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11348294/ SUPPORT In Vitro

"expression of AP2 subunits was diminished"

AP-2 abundance was reduced in knockout cells.

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11348294/ SUPPORT In Vitro

"AP2 expression was fully restored when a CCDC32 rescue gene was expressed"

Genetic rescue supports specificity of the knockout effect.

CCDC32 knockdown and disease-mimic rescue in ARPE-HPV cells CELL_LINE

Partial siRNA knockdown, live-cell pit imaging and transferrin uptake distinguish pit dynamics from AP-2 abundance. CCDC32(1-54) lacks AP-2 binding and does not restore uptake. The construct differs from the patient frameshift product; intact AP-2 protein levels distinguish this experiment from knockout.

Cell source

Immortalized human retinal pigment epithelial cells

Pathograph links

Clathrin-Coated Pit Destabilization perturbs

Limitations: Engineered model; does not establish the complete human developmental mechanism.

Deficient Clathrin-Mediated Endocytosis perturbs

Limitations: Engineered model; does not establish the complete human developmental mechanism.

Show evidence (2 references)

PMID:41489497 SUPPORT In Vitro

"Under our conditions of CCDC32 knockdown, we did not detect any decrease in protein levels of the AP2 complex"

Pit defects in this knockdown experiment cannot be attributed to measured AP-2 depletion.

PMID:41489497 SUPPORT In Vitro

"our disease mimic construct CCDC32(1-54) does not contain a 9 aa peptide (VRGSCLRFQ) in the N-terminus and an extra 12 aa in the C-terminus when CFNDS patient mutation was described (p.(Glu64Glyfs∗12))"

Explicit limits of transferring results from the engineered construct to the patient protein.

Ccdc32 knockdown in IMCD3 cells CELL_LINE

siRNA-mediated Ccdc32 knockdown impairs cilia formation in a cultured mouse renal epithelial model.

Cell source

Mouse inner medullary collecting duct IMCD3 5-HT6-GFP cells

Pathograph links

Defective Ciliogenesis perturbs

Limitations: Engineered model; does not establish the complete human developmental mechanism.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT In Vitro

"Cilia formation was similarly impaired in ciliated mouse inner medullary collecting duct cells with GFP-labeled cilia (IMCD3 5-HT6-GFP) following siRNA-mediated knockdown"

The mouse experiment used cultured cells, not an intact mouse model.

Patient fibroblast RNA sequencing PRIMARY_CELL_CULTURE

RNA sequencing in cultured patient fibroblasts, with and without cycloheximide, revealed CCDC32 downregulation and loss of exons 3 and 4. Genomic PCR and Sanger sequencing confirmed the deletion. This demonstrates transcript consequences, not a direct patient AP-2 or cilia functional assay.

Cell source

Fibroblasts from individual 1 in the 2026 sibling family, with unrelated controls

Show evidence (2 references)

url:https://www.nature.com/articles/s41431-026-02023-y/figures/2 SUPPORT In Vitro

"locus showing RNA-seq of fibroblast cultured with or without cycloheximide (CHX) for individual 1 and unrelated controls"

Specifies the patient-derived tissue system and experimental condition.

url:https://www.nature.com/articles/s41431-026-02023-y/figures/2 SUPPORT Human Clinical

"(not included in the ID and MCA panels) exhibited notable downregulation with a Z-score of -8.20."

Panel membership explains part of the diagnostic blind spot; the RNA outlier is patient-specific.

🐁

Animal Models

1

Mosaic F0 ccdc32 CRISPR/Cas9 disruption using two independent exon-2 sgRNAs Danio rerio

One 2020 study used two independently targeted mosaic F0 zebrafish cohorts. Findings included reduced head size, altered craniofacial cartilage angle, hypoplastic cerebella, abnormal cardiac looping and southpaw expression, and fewer, shorter Kupffer vesicle cilia. The two sgRNAs are experimental replication within this paper. The 2022 clinical report cites the same study. These fish do not directly model human cleft lip/palate fusion, chamber septation or digital abnormalities.

Species

Danio rerio

Genotype

Mosaic F0 ccdc32 CRISPR/Cas9 disruption using two independent exon-2 sgRNAs

Pathograph links

Defective Ciliogenesis partially recapitulates

Limitations: Mosaic embryonic disruption; no patient-genotype or human-tissue cilia rescue is demonstrated.

Abnormal Left-Right Patterning partially recapitulates

Limitations: Looping and left-right patterning are assessed; fish do not model human chamber septation.

Abnormal Brain Development partially recapitulates

Limitations: Engineered model; does not establish the complete human developmental mechanism.

Abnormal Craniofacial Development partially recapitulates

Limitations: Engineered model; does not establish the complete human developmental mechanism.

Show evidence (5 references)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Model Organism

"We designed two distinct single guide (sg)RNAs (sgRNA1 and sgRNA2) targeting non-overlapping regions of exon 2 ... and injected each into zebrafish embryos at the one cell stage, along with Cas9 protein."

Direct description of the model-generation method.

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Model Organism

"KV cilia were reduced significantly in both number and length in crispants at the 10 somite stage"

Ciliary number and length were measured in mosaic CRISPR-edited zebrafish embryos.

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/ SUPPORT Model Organism

"with either sgRNA resulted in a significant reduction in head size at 3 dpf compared to either uninjected or sgRNA-only (no Cas9 protein) injected controls"

Two independent sgRNA/Cas9 perturbations reduce embryonic head size.

+ 2 more references

{ }

Source YAML

click to show

name: Cardiofacioneurodevelopmental Syndrome
creation_date: '2026-08-01T00:00:00Z'
category: Mendelian
synonyms:
- CFNDS
- cardio-facio-neuro-developmental syndrome
- CCDC32-related cardiofacioneurodevelopmental syndrome
- C15orf57-related multiple congenital anomaly syndrome
description: >-
  Cardiofacioneurodevelopmental syndrome (CFNDS) is an ultra-rare autosomal recessive congenital anomaly
  syndrome associated with biallelic CCDC32 loss-of-function variants. Developmental delay and orofacial
  clefting recur alongside variable cardiac, laterality, brain, digital and growth abnormalities. CCDC32
  regulates assembly of the AP-2 clathrin adaptor complex and the stabilization and invagination of clathrin-coated
  pits. Knockout and partial-knockdown experiments reveal distinct effects on AP-2 abundance and pit dynamics.
  Zebrafish and cultured mouse-cell experiments also implicate ciliogenesis, but the links from either
  cellular defect to individual human malformations remain incompletely resolved. Patient fibroblast RNA
  sequencing has demonstrated transcript downregulation and loss of exons 3 and 4 in one family.
disease_term:
  preferred_term: cardiofacioneurodevelopmental syndrome
  term:
    id: MONDO:0030873
    label: cardiofacioneurodevelopmental syndrome
parents:
- Multiple congenital anomaly syndrome
- Orofacial clefting syndrome
- Mendelian neurodevelopmental disorder
- Disorder of clathrin-mediated endocytosis
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:32307552
      reference_title: Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Using whole exome sequencing, we identified homozygous frameshift CCDC32 variants in three affected
        individuals.
      explanation: >-
        A monogenic recessive malformation syndrome defined and diagnosed by
        exome sequencing belongs to the genetics chapter.
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:41639596
      reference_title: Two siblings with CCDC32-related cardiofacioneurodevelopmental syndrome diagnosed by clinical RNA-sequencing and review of literature.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the clinical phenotype can include microcephaly, facial malformations, developmental delay, cerebellar
        hypoplasia, and cardiac anomalies
      explanation: >-
        Developmental delay, microcephaly and cerebellar hypoplasia place the
        entity in the neurology chapter alongside its malformation features.
  - classification_value: CARDIOVASCULAR
    evidence:
    - reference: PMID:32307552
      reference_title: Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        we investigated the genetic and mechanistic cause of disease in two independent consanguineous
        families affected by overlapping craniofacial, cardiac, laterality and neurodevelopmental anomalies
      explanation: >-
        Congenital cardiac and laterality anomalies are part of the defining
        phenotype, so the entry also belongs to the cardiovascular chapter.
notes: >-
  CFNDS (MONDO:0030873, OMIM:619123) is the CCDC32-related recessive syndrome, distinct from cardiofaciocutaneous
  syndrome, a RASopathy. The GeneReviews reference in the differential section concerns that different
  disease. The small, variably investigated clinical series supports individual observations, not population
  frequency bands or genotype-based prognosis. Mechanistic experiments use engineered cell lines or zebrafish
  except for the explicitly identified patient fibroblast RNA study; neither a specific developmental
  receptor nor a complete causal route to the human malformations has been established. Supportive interventions
  are phenotype-directed extrapolations unless a source states otherwise.
inheritance:
- name: Autosomal recessive
  description: >-
    Biallelic pathogenic CCDC32 variants underlie the reported recessive syndrome. Homozygous frameshift
    alleles segregated in the two founding consanguineous families; the parents of the 2026 siblings were
    heterozygous deletion carriers.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:41639596
    reference_title: Two siblings with CCDC32-related cardiofacioneurodevelopmental syndrome diagnosed by clinical RNA-sequencing and review of literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiofacioneurodevelopmental syndrome (CFNDS, MIM:619123) is a rare genetic disorder caused by
      bi-allelic pathogenic variants in CCDC32.
    explanation: >-
      States the biallelic requirement directly, and anchors the OMIM identifier
      used for the NEC check.
  - reference: PMID:32307552
    reference_title: Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we investigated the genetic and mechanistic cause of disease in two independent consanguineous families
      affected by overlapping craniofacial, cardiac, laterality and neurodevelopmental anomalies
    explanation: >-
      The founding report ascertained two consanguineous families, the classic
      setting for a recessive disorder.
  - reference: url:https://www.nature.com/articles/s41431-026-02023-y/figures/1
    reference_title: "Fig. 1: Clinical hallmarks of Cardiofacioneurodevelopmental syndrome (CFNDS). | European Journal of Human Genetics | European Journal of Human Genetics"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Parents confirmed as heterozygous carriers.
    explanation: >-
      Parents of the two siblings carried the deletion heterozygously.
prevalence:
- population: Global
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The 2026 report describes two siblings in addition to four living individuals and one electively terminated
    fetus from four previously reported families: six living individuals and one fetus from five families
    within that literature review. This is a dated literature count, not a current worldwide census or
    a population rate.
  evidence:
  - reference: PMID:41639596
    reference_title: Two siblings with CCDC32-related cardiofacioneurodevelopmental syndrome diagnosed by clinical RNA-sequencing and review of literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      So far, CFNDS has only been described in four living individuals and one terminated fetus from four
      families
    explanation: >-
      Gives the published denominator immediately before this report, which is
      the basis for the ultra-rare tier.
progression:
- age_range: Prenatal to birth
  notes: >-
    Structural malformations can be detected prenatally. Ultrasound in fetus A-II-2 showed bilateral cleft
    lip, vermian and pontine hypoplasia, and an abnormal cisterna magna. The pregnancy was terminated
    electively; this observation does not establish fetal lethality.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A sibling fetus in Family A (A-II-2) had bilateral cleft lip, vermian hypoplasia, hypoplastic pons
      and abnormal cisterna magna that were detected by ultrasound, and the pregnancy was terminated electively.
    explanation: >-
      Direct prenatal imaging observations in the founding family.
- age_range: Infancy through childhood
  notes: >-
    Feeding difficulties and developmental delay were reported in childhood, and intellectual disability
    was documented in the nine-year-old patient reported in 2022. Growth, head size and structural findings
    vary. These small case reports do not establish adult prognosis or a progressive neurodegenerative
    course.
  evidence:
  - reference: PMID:35451546
    reference_title: "Cardiofacioneurodevelopmental syndrome: Report of a novel patient and expansion of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Variable abnormalities of the face, brain, heart, fingers, and toes and postnatal growth retardation
      or microcephaly can be present.
    explanation: >-
      Identifies growth retardation and microcephaly as postnatal rather than
      necessarily congenital findings.
mechanistic_hypotheses:
- hypothesis_group_id: ccdc32_ap2_endocytic_model
  hypothesis_label: AP-2 assembly and coated-pit function model
  status: CANONICAL
  description: >-
    CCDC32 supports AP-2 assembly in knockout/reconstitution studies and also regulates coated-pit stability
    and invagination under partial-knockdown conditions that preserve AP-2 protein levels. Impaired receptor
    uptake is demonstrated in engineered cells. These molecular functions are established, while their
    contribution to each human malformation remains a hypothesis. The engineered CCDC32(1-54) disease
    mimic is defective in AP-2 binding and uptake rescue but is not the exact frameshift protein predicted
    in the founding patient.
  evidence:
  - reference: PMID:39145939
    reference_title: An AAGAB-to-CCDC32 handover mechanism controls the assembly of the AP2 adaptor complex.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We identified CCDC32 as another chaperone regulating AP2 assembly.
    explanation: Establishes the core molecular role of the protein.
  - reference: PMID:39145939
    reference_title: An AAGAB-to-CCDC32 handover mechanism controls the assembly of the AP2 adaptor complex.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The AP2-regulating function of CCDC32 is disrupted by a disease-causing mutation.
    explanation: >-
      A disease-mimicking mutant disrupts the AP-2-regulating function in an engineered assay; this is
      not a direct measurement of patient protein.
  - reference: PMID:41489497
    reference_title: CCDC32 stabilizes clathrin-coated pits and drives their invagination.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These findings show that this loss-of-function nonsense mutation in CCDC32 abolishes its interactions
      with AP2 and inhibits CME, likely contributing to the development of CFNDS.
    explanation: >-
      The experimental truncation supports a loss-of-function model; the construct omits both an N-terminal
      segment and the patient frameshift tail.
- hypothesis_group_id: ccdc32_ciliary_model
  hypothesis_label: Ciliary Contribution Model
  status: ALTERNATIVE
  description: >-
    The founding study found reduced Kupffer vesicle cilia number and length in mosaic CRISPR-edited zebrafish
    embryos, and impaired ciliogenesis after siRNA knockdown in mouse IMCD3 cells. Abnormal southpaw expression
    and cardiac looping support a contribution to left-right patterning in fish. A corresponding causal
    chain has not been demonstrated in patient tissue.
  notes: >-
    The ciliary and endocytic models need not be mutually exclusive. The 2022 case report cites the 2020
    zebrafish experiments; it does not provide independent replication. How CCDC32 affects cilia and whether
    this depends on AP-2 remain unresolved.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      KV cilia were reduced significantly in both number and length in crispants at the 10 somite stage
    explanation: >-
      Ciliary number and length were measured in mosaic CRISPR-edited zebrafish embryos.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cilia formation was similarly impaired in ciliated mouse inner medullary collecting duct cells with
      GFP-labeled cilia (IMCD3 5-HT6-GFP) following siRNA-mediated knockdown
    explanation: >-
      The mouse experiment used cultured cells, not an intact mouse model.
pathophysiology:
- name: Biallelic CCDC32 Loss of Function
  description: >-
    Biallelic frameshift and deletion alleles disrupt CCDC32. The founding paper describes two frameshifts
    on NM_001080791.2, c.54dupT and c.189_190dupGG; later reports include a 32,583-bp deletion and a deletion
    of exons 3 and 4. Predicted loss of function is not proof that every allele abolishes all protein
    activity. Patient transcript downregulation is documented for the exon-3/4 deletion, while residual
    protein function across genotypes remains unknown.
  role: root
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  gene:
    preferred_term: CCDC32
    term:
      id: hgnc:28295
      label: CCDC32
  downstream:
  - target: Failure of AP-2 Adaptor Complex Assembly
    description: >-
      Engineered CCDC32 loss impairs AP-2 assembly; disease-mimicking constructs lose AP-2-regulating
      activity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39145939
      reference_title: An AAGAB-to-CCDC32 handover mechanism controls the assembly of the AP2 adaptor complex.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The AP2-regulating function of CCDC32 is disrupted by a disease-causing mutation.
      explanation: >-
        A disease-mimicking mutant disrupts the AP-2-regulating function in an engineered assay; this
        is not a direct measurement of patient protein.
  - target: Clathrin-Coated Pit Destabilization
    description: >-
      Partial knockdown disrupts pit dynamics even when AP-2 protein levels remain normal.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41489497
      reference_title: CCDC32 stabilizes clathrin-coated pits and drives their invagination.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Under our conditions of CCDC32 knockdown, we did not detect any decrease in protein levels of
        the AP2 complex
      explanation: >-
        Pit defects in this knockdown experiment cannot be attributed to measured AP-2 depletion.
  - target: Defective Ciliogenesis
    description: >-
      Knockdown or mosaic disruption impairs cilia in fish embryos and mouse cells; the intervening molecular
      mechanism is unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
      reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        KV cilia were reduced significantly in both number and length in crispants at the 10 somite stage
      explanation: >-
        Ciliary number and length were measured in mosaic CRISPR-edited zebrafish embryos.
    - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
      reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Cilia formation was similarly impaired in ciliated mouse inner medullary collecting duct cells
        with
        GFP-labeled cilia (IMCD3 5-HT6-GFP) following siRNA-mediated knockdown
      explanation: >-
        The mouse experiment used cultured cells, not an intact mouse model.
  evidence:
  - reference: PMID:32307552
    reference_title: Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using whole exome sequencing, we identified homozygous frameshift CCDC32 variants in three affected
      individuals.
    explanation: The founding identification of biallelic loss-of-function alleles.
  - reference: PMID:41489497
    reference_title: CCDC32 stabilizes clathrin-coated pits and drives their invagination.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These findings show that this loss-of-function nonsense mutation in CCDC32 abolishes its interactions
      with AP2 and inhibits CME, likely contributing to the development of CFNDS.
    explanation: >-
      The experimental truncation supports a loss-of-function model; the construct omits both an N-terminal
      segment and the patient frameshift tail.
  molecular_functions:
  - preferred_term: AP-2 adaptor complex binding
    term:
      id: GO:0035612
      label: AP-2 adaptor complex binding
    modifier: DECREASED
  notes: >-
    The molecular-function annotation identifies AP-2 binding as a normal CCDC32 activity disrupted in
    disease-mimic assays. It does not assert measured abolition of binding in every patient genotype.
- name: Failure of AP-2 Adaptor Complex Assembly
  description: >-
    CCDC32 participates in chaperoned AP-2 assembly after AAGAB-dependent stabilization of the alpha/sigma2
    intermediate. Reconstitution shows an AAGAB-to-CCDC32 handover. Later structural work shows that CCDC32
    can prevent or reverse tetramer assembly in solution, whereas binding to PIP2-containing membranes
    relieves this inhibition and stabilizes assembled AP-2. Thus assembly depends on membrane context
    as well as the handover. Engineered CCDC32 knockout reduces AP-2 subunit abundance.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  cellular_components:
  - preferred_term: AP-2 adaptor complex
    term:
      id: GO:0030122
      label: AP-2 adaptor complex
  protein_complexes:
  - preferred_term: AP-2 clathrin adaptor complex
    term:
      id: GO:0030122
      label: AP-2 adaptor complex
  downstream:
  - target: Reduced AP-2 Complex Abundance
    description: >-
      Failed assembly is associated with loss of AP-2 subunits in CCDC32-knockout cells.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:39145939
    reference_title: An AAGAB-to-CCDC32 handover mechanism controls the assembly of the AP2 adaptor complex.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These findings demonstrate that AP2 is assembled by a handover mechanism switching from AAGAB-based
      initiation complexes to CCDC32-based template complexes.
    explanation: >-
      Biochemical reconstitution supports ordered handover between assembly factors.
  - reference: PMID:42234739
    reference_title: CCDC32 collaborates with the membrane to assemble the AP-2 clathrin adaptor complex.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      coiled-coil domain-containing protein 32 (CCDC32), whose deletion causes loss of all AP-2 subunits
      in vivo
    explanation: >-
      States the consequence of losing CCDC32 for the complex as a whole, which
      is the step this node models.
  - reference: PMID:33859415
    reference_title: A genome-wide atlas of co-essential modules assigns function to uncharacterized genes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We also show that C15orf57 encodes a protein that binds the AP2 complex, localizes to clathrin-coated
      pits and enables efficient transferrin uptake.
    explanation: >-
      The unbiased co-essentiality screen that first assigned CCDC32 (C15orf57)
      to the AP2 module.
  - reference: PMID:42234739
    reference_title: CCDC32 collaborates with the membrane to assemble the AP-2 clathrin adaptor complex.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Unexpectedly, in solution, CCDC32 prevents complex assembly and actively disassembles AP-2 tetramers.
      Inhibition requires the amphipathic helices of CCDC32, which also mediate binding to phosphatidylinositol
      4,5-bisphosphate (PIP2)-containing membranes. The presence of PIP2-containing membrane stabilizes
      the final stages of assembly.
    explanation: >-
      Biochemical reconstitution establishes the membrane dependence of the assembly process; this is
      not a direct patient membrane-binding assay.
- name: Reduced AP-2 Complex Abundance
  biological_scale: MOLECULAR
  description: >-
    CCDC32 knockout reduces AP-2 subunits and surface AP-2 puncta in HeLa cells; re-expression restores
    AP-2. This phenotype is condition-dependent: partial CCDC32 knockdown in the coated-pit study did
    not lower AP-2 protein levels.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11348294/
    reference_title: An AAGAB-to-CCDC32 handover mechanism controls the assembly of the AP2 adaptor complex - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      expression of AP2 subunits was diminished
    explanation: >-
      AP-2 abundance was reduced in knockout cells.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11348294/
    reference_title: An AAGAB-to-CCDC32 handover mechanism controls the assembly of the AP2 adaptor complex - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      AP2 expression was fully restored when a CCDC32 rescue gene was expressed
    explanation: >-
      Genetic rescue supports specificity of the knockout effect.
  - reference: PMID:41489497
    reference_title: CCDC32 stabilizes clathrin-coated pits and drives their invagination.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Under our conditions of CCDC32 knockdown, we did not detect any decrease in protein levels of the
      AP2 complex
    explanation: >-
      Pit defects in this knockdown experiment cannot be attributed to measured AP-2 depletion.
  cellular_components:
  - preferred_term: AP-2 adaptor complex
    term:
      id: GO:0030122
      label: AP-2 adaptor complex
    modifier: DECREASED
  downstream:
  - target: Deficient Clathrin-Mediated Endocytosis
    description: >-
      Reduced AP-2 abundance accompanies impaired receptor internalization in knockout cells; this is
      distinct from the normal-abundance partial-knockdown condition.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Clathrin-Coated Pit Destabilization
  description: >-
    Partial CCDC32 knockdown increases unstable, flat clathrin assemblies and impairs pit invagination
    in ARPE-HPV cells without reducing AP-2 protein levels. The remaining productive pits and increased
    initiation provide compensation, so the marked change in pit dynamics produces only a mild reduction
    in transferrin receptor uptake.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  cellular_components:
  - preferred_term: Clathrin-coated pit
    term:
      id: GO:0005905
      label: clathrin-coated pit
  downstream:
  - target: Deficient Clathrin-Mediated Endocytosis
    causal_link_type: DIRECT
    description: >-
      Defective pit stabilization and invagination reduce productive internalization, although compensatory
      dynamics limit the net uptake defect in this assay.
    evidence:
    - reference: PMID:41489497
      reference_title: CCDC32 stabilizes clathrin-coated pits and drives their invagination.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        our data demonstrate the function of a novel endocytic accessory protein, CCDC32, in regulating
        CCP stabilization and invagination, critical early stages of CME
      explanation: >-
        States the coupling between coated-pit stabilisation and invagination
        and the endocytic pathway as a whole.
  evidence:
  - reference: PMID:41489497
    reference_title: CCDC32 stabilizes clathrin-coated pits and drives their invagination.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show by quantitative live cell imaging that siRNA-mediated knockdown of CCDC32, a poorly characterized
      endocytic accessory protein, leads to the accumulation of unstable flat clathrin assemblies.
    explanation: >-
      Direct live-cell demonstration of the coated-pit phenotype caused by loss
      of CCDC32.
  - reference: PMID:41489497
    reference_title: CCDC32 stabilizes clathrin-coated pits and drives their invagination.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Under our conditions of CCDC32 knockdown, we did not detect any decrease in protein levels of the
      AP2 complex
    explanation: >-
      Pit defects in this knockdown experiment cannot be attributed to measured AP-2 depletion.
- name: Deficient Clathrin-Mediated Endocytosis
  description: >-
    Engineered CCDC32 loss or depletion impairs receptor-mediated internalization, assessed by transferrin
    uptake. The magnitude depends on the perturbation and assay. A developmental trafficking defect is
    plausible, but no specific cargo or signaling pathway has been shown to connect these cell-line findings
    to a particular human malformation.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: Clathrin-dependent endocytosis
    term:
      id: GO:0072583
      label: clathrin-dependent endocytosis
    modifier: DECREASED
  downstream:
  - target: Abnormal Craniofacial Development
    description: >-
      A contribution of altered endocytosis to this developmental phenotype is proposed; the relevant
      cargo, cell population and intermediate signaling steps remain unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal Cardiac Morphogenesis
    description: >-
      A contribution of altered endocytosis to this developmental phenotype is proposed; the relevant
      cargo, cell population and intermediate signaling steps remain unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal Brain Development
    description: >-
      A contribution of altered endocytosis to this developmental phenotype is proposed; the relevant
      cargo, cell population and intermediate signaling steps remain unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal Left-Right Patterning
    description: >-
      A contribution of altered endocytosis to this developmental phenotype is proposed; the relevant
      cargo, cell population and intermediate signaling steps remain unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:33859415
    reference_title: A genome-wide atlas of co-essential modules assigns function to uncharacterized genes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We also show that C15orf57 encodes a protein that binds the AP2 complex, localizes to clathrin-coated
      pits and enables efficient transferrin uptake.
    explanation: >-
      Establishes that CCDC32 is required for efficient receptor-mediated
      internalisation, the functional read-out modelled by this node.
  - reference: PMID:41489497
    reference_title: CCDC32 stabilizes clathrin-coated pits and drives their invagination.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Despite these profound alterations in CCP dynamics, CME itself, as measured by TfnR internalization
      efficiency, is only partially inhibited.
    explanation: >-
      Pit dynamics and net cargo uptake are different readouts; the latter is partially preserved.
- name: Defective Ciliogenesis
  description: >-
    Loss of ccdc32 reduces cilia number and length in the zebrafish Kupffer vesicle. siRNA depletion also
    impairs ciliogenesis in cultured mouse IMCD3 cells. These findings support a ciliary contribution
    but do not establish whether cilia are a primary CCDC32 target or affected through altered membrane
    trafficking.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: Cilium assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: DECREASED
  notes: >-
    The ciliary contribution to human CFNDS remains provisional. The two experimental systems are from
    the same 2020 publication, and no patient cilia assay is reported in the sources used here.
  downstream:
  - target: Abnormal Craniofacial Development
    description: >-
      A ciliary contribution is proposed from experimental and clinical overlap; a complete route to the
      human organ abnormality has not been demonstrated.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal Cardiac Morphogenesis
    description: >-
      A ciliary contribution is proposed from experimental and clinical overlap; a complete route to the
      human organ abnormality has not been demonstrated.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal Brain Development
    description: >-
      A ciliary contribution is proposed from experimental and clinical overlap; a complete route to the
      human organ abnormality has not been demonstrated.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal Left-Right Patterning
    description: >-
      A ciliary contribution is proposed from experimental and clinical overlap; a complete route to the
      human organ abnormality has not been demonstrated.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      KV cilia were reduced significantly in both number and length in crispants at the 10 somite stage
    explanation: >-
      Ciliary number and length were measured in mosaic CRISPR-edited zebrafish embryos.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cilia formation was similarly impaired in ciliated mouse inner medullary collecting duct cells with
      GFP-labeled cilia (IMCD3 5-HT6-GFP) following siRNA-mediated knockdown
    explanation: >-
      The mouse experiment used cultured cells, not an intact mouse model.
- name: Abnormal Craniofacial Development
  biological_scale: ORGANISM
  description: >-
    Cleft lip and palate and variable facial and mandibular anomalies are observed in patients. Zebrafish
    ccdc32 disruption alters craniofacial cartilage geometry; fish do not model human lip or palate fusion
    directly.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysmorphic features included hypotelorism, upslanting palpebral fissures, a stiff upper lip, missing
      teeth attributed to the clefting, vaulted palate with cleft, prominent ears, underdeveloped helices
      and micrognathia.
    explanation: >-
      Craniofacial abnormalities in individual A-II-1.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      crispants exhibited significant, reproducible alterations in facial skeletal morphology compared
      to controls, as measured by the angle of the bilateral ceratohyal cartilages
    explanation: >-
      The craniofacial readout is cartilage geometry, not human cleft-palate fusion.
  role: outcome
  mechanism_confidence: ESTABLISHED
  downstream:
  - target: Cleft lip
    description: >-
      Observed clinical manifestation of the developmental phenotype.
    causal_link_type: DIRECT
  - target: Cleft palate
    description: >-
      Observed clinical manifestation of the developmental phenotype.
    causal_link_type: DIRECT
  - target: Micrognathia
    description: >-
      Observed clinical manifestation of the developmental phenotype.
    causal_link_type: DIRECT
- name: Abnormal Brain Development
  biological_scale: ORGANISM
  description: >-
    Reported structural abnormalities include callosal, cerebellar, vermian and pontine hypoplasia. Microcephaly
    and developmental impairment accompany the variable imaging phenotype. Reduced head size and cerebellar
    abnormalities in zebrafish support a developmental role without establishing each human intermediate.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI revealed hypoplastic cerebellar tonsils.
    explanation: >-
      Patient imaging identifies a specific cerebellar abnormality.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      with either sgRNA resulted in a significant reduction in head size at 3 dpf compared to either uninjected
      or sgRNA-only (no Cas9 protein) injected controls
    explanation: >-
      Two independent sgRNA/Cas9 perturbations reduce embryonic head size.
  role: outcome
  mechanism_confidence: ESTABLISHED
  downstream:
  - target: Hypoplasia of the corpus callosum
    description: >-
      Observed clinical manifestation of the developmental phenotype.
    causal_link_type: DIRECT
  - target: Cerebellar hypoplasia
    description: >-
      Observed clinical manifestation of the developmental phenotype.
    causal_link_type: DIRECT
  - target: Cerebellar vermis hypoplasia
    description: >-
      Observed clinical manifestation of the developmental phenotype.
    causal_link_type: DIRECT
  - target: Hypoplasia of the pons
    description: >-
      Observed clinical manifestation of the developmental phenotype.
    causal_link_type: DIRECT
  - target: Microcephaly
    description: >-
      Observed clinical manifestation of the developmental phenotype.
    causal_link_type: DIRECT
  - target: Global developmental delay
    description: >-
      Observed clinical manifestation of the developmental phenotype.
    causal_link_type: DIRECT
- name: Abnormal Cardiac Morphogenesis
  biological_scale: ORGANISM
  description: >-
    Atrioventricular canal defect, ventricular septal defect and pulmonary valve stenosis are reported
    in patients. The developmental route from CCDC32 dysfunction to these lesions remains unknown; zebrafish
    cardiac-looping assays do not model human chamber septation.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      atrioventricular (AV) canal defect and abdominal ... situs inversus ... with asplenia. Physical
      examination revealed borderline microcephaly
    explanation: >-
      Cardiac and visceral laterality findings in individual A-II-1.
  role: outcome
  mechanism_confidence: ESTABLISHED
  downstream:
  - target: Atrioventricular canal defect
    description: >-
      Observed clinical manifestation of the developmental phenotype.
    causal_link_type: DIRECT
  - target: Ventricular septal defect
    description: >-
      Observed clinical manifestation of the developmental phenotype.
    causal_link_type: DIRECT
  - target: Pulmonic stenosis
    description: >-
      Observed clinical manifestation of the developmental phenotype.
    causal_link_type: DIRECT
- name: Abnormal Left-Right Patterning
  biological_scale: ORGANISM
  description: >-
    Abdominal situs inversus with asplenia is reported in individual A-II-1. Abnormal southpaw expression
    and cardiac looping in mosaic ccdc32 zebrafish support an embryonic laterality role, without proving
    a cilia-mediated route in the patient.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      atrioventricular (AV) canal defect and abdominal ... situs inversus ... with asplenia. Physical
      examination revealed borderline microcephaly
    explanation: >-
      Cardiac and visceral laterality findings in individual A-II-1.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      using either of our sgRNAs disrupted cardiac looping at 2 dpf
    explanation: >-
      The cardiac assay measures looping and laterality.
  role: outcome
  mechanism_confidence: ESTABLISHED
  downstream:
  - target: Abdominal situs inversus
    description: >-
      Observed clinical manifestation of the developmental phenotype.
    causal_link_type: DIRECT
  - target: Asplenia
    description: >-
      Observed clinical manifestation of the developmental phenotype.
    causal_link_type: DIRECT
phenotypes:
- name: Cleft lip
  category: Head and Neck
  description: >-
    Bilateral cleft lip, occurring together with cleft palate, is one of the two
    features that PMID:35451546 designated as the core phenotype of CFNDS.
  diagnostic: true
  notes: >-
    The 2022 paper described clefting in the three individuals then known. In the founding girl, missing
    teeth were attributed to clefting rather than established as primary congenital hypodontia. No population
    frequency band is inferred.
  phenotype_term:
    preferred_term: Bilateral cleft lip
    term:
      id: HP:0410030
      label: Cleft lip
    onset:
      onset_category: CONGENITAL
    laterality: BILATERAL
  evidence:
  - reference: PMID:35451546
    reference_title: "Cardiofacioneurodevelopmental syndrome: Report of a novel patient and expansion of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a core phenotype comprising developmental delay and bilateral cleft lip and palate in
      the three individuals with CFNDS.
    explanation: >-
      Designates bilateral cleft lip and palate as one of the two core features
      of the syndrome.
  - reference: PMID:35451546
    reference_title: "Cardiofacioneurodevelopmental syndrome: Report of a novel patient and expansion of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had intellectual disability, marked hypertelorism, bilateral cleft lip and palate, and
      short stature.
    explanation: Documents the finding in the individually reported patient.
- name: Cleft palate
  category: Head and Neck
  description: >-
    Cleft palate accompanies the recurring cleft-lip phenotype in the liveborn cases described by the
    early reports.
  diagnostic: true
  notes: >-
    Reported in all three individuals known at the time of PMID:35451546. No frequency band is asserted:
    the clinical denominator is small and variably investigated.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:35451546
    reference_title: "Cardiofacioneurodevelopmental syndrome: Report of a novel patient and expansion of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cardiofacioneurodevelopmental syndrome (CFNDS) is characterized by craniofacial anomalies including
      bilateral cleft lip and palate, cardiac, skeletal, and neurodevelopmental features and additional
      variable manifestations.
    explanation: Names bilateral cleft lip and palate as the defining craniofacial anomaly.
- name: Global developmental delay
  category: Nervous System
  description: >-
    Developmental delay was identified as a recurring core feature in the early clinical reports. The
    small ascertainment series does not establish a population frequency.
  diagnostic: true
  notes: >-
    Named as core in PMID:35451546 across the three individuals then known, and listed again among the
    recurring features in the 2026 review. No frequency band is asserted: the clinical denominator is
    small and variably investigated.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:35451546
    reference_title: "Cardiofacioneurodevelopmental syndrome: Report of a novel patient and expansion of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a core phenotype comprising developmental delay and bilateral cleft lip and palate in
      the three individuals with CFNDS.
    explanation: Designates developmental delay as one of the two core features.
  - reference: PMID:41639596
    reference_title: Two siblings with CCDC32-related cardiofacioneurodevelopmental syndrome diagnosed by clinical RNA-sequencing and review of literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the clinical phenotype can include microcephaly, facial malformations, developmental delay, cerebellar
      hypoplasia, and cardiac anomalies
    explanation: The 2026 review carries developmental delay forward as a recurring feature.
- name: Intellectual disability
  category: Nervous System
  description: >-
    Intellectual disability was explicitly documented in the nine-year-old patient reported in 2022; this
    does not establish an inevitable progression from delay in every patient.
  notes: >-
    Documented in one individually described patient. Because the syndrome is congenital and the reported
    cohort is largely young, the proportion of affected individuals old enough for a formal cognitive
    assessment is small, which is a further reason no frequency band is asserted.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:35451546
    reference_title: "Cardiofacioneurodevelopmental syndrome: Report of a novel patient and expansion of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had intellectual disability, marked hypertelorism, bilateral cleft lip and palate, and
      short stature.
    explanation: Direct documentation of intellectual disability in a genotyped patient.
- name: Hypertelorism
  category: Head and Neck
  description: >-
    Hypertelorism was reported in B-II-1 and was marked in the 2022 patient. A-II-1 instead had hypotelorism.
  notes: >-
    Opposite interorbital-distance findings occur in different patients and are not contradictory measurements
    in one individual.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
    severity: SEVERE
  evidence:
  - reference: PMID:35451546
    reference_title: "Cardiofacioneurodevelopmental syndrome: Report of a novel patient and expansion of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had intellectual disability, marked hypertelorism, bilateral cleft lip and palate, and
      short stature.
    explanation: >-
      Documents hypertelorism, and its severity qualifier, in a genotyped
      patient.
- name: Hypotelorism
  category: Head and Neck
  description: >-
    Hypotelorism was observed in individual A-II-1; the unrelated individual B-II-1 had hypertelorism.
  phenotype_term:
    preferred_term: Hypotelorism
    term:
      id: HP:0000601
      label: Hypotelorism
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysmorphic features included hypotelorism, upslanting palpebral fissures, a stiff upper lip, missing
      teeth attributed to the clefting, vaulted palate with cleft, prominent ears, underdeveloped helices
      and micrognathia.
    explanation: >-
      The examination sentence identifies hypotelorism in A-II-1; the opposite finding in B-II-1 is documented
      in the hypertelorism row.
- name: Atrioventricular canal defect
  category: Cardiovascular
  description: >-
    An atrioventricular canal defect was reported in A-II-1. The quoted clinical description does not
    specify complete versus partial anatomy.
  phenotype_term:
    preferred_term: Atrioventricular canal defect
    term:
      id: HP:0006695
      label: Atrioventricular canal defect
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      atrioventricular (AV) canal defect and abdominal ... situs inversus ... with asplenia. Physical
      examination revealed borderline microcephaly
    explanation: >-
      An atrioventricular canal defect was reported in A-II-1. The quoted clinical description does not
      specify complete versus partial anatomy.
- name: Ventricular septal defect
  category: Cardiovascular
  description: >-
    A ventricular septal defect was reported in B-II-1.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ventricular septal defect and pulmonary valve stenosis.
    explanation: >-
      A ventricular septal defect was reported in B-II-1.
- name: Pulmonic stenosis
  category: Cardiovascular
  description: >-
    Pulmonary valve stenosis was reported in B-II-1.
  phenotype_term:
    preferred_term: Pulmonic stenosis
    term:
      id: HP:0001642
      label: Pulmonic stenosis
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ventricular septal defect and pulmonary valve stenosis.
    explanation: >-
      Pulmonary valve stenosis was reported in B-II-1.
- name: Asplenia
  category: Immune System
  description: >-
    Asplenia accompanied abdominal situs inversus in A-II-1. Infection prevention is an actionable consequence
    of this finding.
  phenotype_term:
    preferred_term: Asplenia
    term:
      id: HP:0001746
      label: Asplenia
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      atrioventricular (AV) canal defect and abdominal ... situs inversus ... with asplenia. Physical
      examination revealed borderline microcephaly
    explanation: >-
      The clinical description directly documents asplenia with abdominal situs inversus in A-II-1. The
      prevention implications are supported separately in the treatment section.
- name: Abdominal situs inversus
  category: Prenatal and Birth
  description: >-
    Abdominal situs inversus with asplenia was reported in A-II-1; this does not establish the same laterality
    pattern in every family.
  phenotype_term:
    preferred_term: Abdominal situs inversus
    term:
      id: HP:0003363
      label: Abdominal situs inversus
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      atrioventricular (AV) canal defect and abdominal ... situs inversus ... with asplenia. Physical
      examination revealed borderline microcephaly
    explanation: >-
      Abdominal situs inversus with asplenia was reported in A-II-1; this does not establish the same
      laterality pattern in every family.
- name: Cerebellar vermis hypoplasia
  category: Nervous System
  description: >-
    Vermian hypoplasia was detected prenatally in fetus A-II-2.
  phenotype_term:
    preferred_term: Cerebellar vermis hypoplasia
    term:
      id: HP:0001320
      label: Cerebellar vermis hypoplasia
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A sibling fetus in Family A (A-II-2) had bilateral cleft lip, vermian hypoplasia, hypoplastic pons
      and abnormal cisterna magna that were detected by ultrasound, and the pregnancy was terminated electively.
    explanation: >-
      Vermian hypoplasia was detected prenatally in fetus A-II-2.
- name: Feeding difficulties in infancy
  category: Digestive
  description: >-
    Feeding difficulties were reported in both liveborn individuals in the founding study, explicitly
    in infancy for A-II-1 and as severe difficulties in B-II-1.
  phenotype_term:
    preferred_term: Feeding difficulties in infancy
    term:
      id: HP:0008872
      label: Feeding difficulties in infancy
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had severe feeding difficulties, moderately delayed motor and language development and hyperactivity.
    explanation: >-
      The examination of B-II-1 describes severe feeding difficulties. The separate A-II-1 quote explicitly
      establishes infantile onset.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      global developmental delay, feeding difficulties in infancy and congenital anomalies
    explanation: >-
      Clinical description of A-II-1 explicitly dates feeding difficulties to infancy.
- name: Cryptorchidism
  category: Genitourinary
  description: >-
    Cryptorchidism was reported in the male individual B-II-1.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The individual had clinodactyly, nail aplasia on thumbs and toes and cryptorchidism.
    explanation: >-
      The male proband B-II-1 is explicitly described as having cryptorchidism.
- name: Hypoplasia of the corpus callosum
  category: Nervous System
  description: >-
    A hypoplastic corpus callosum was demonstrated on brain imaging in the
    patient reported in PMID:35451546, and abnormalities of the brain are listed
    among the variable features of the syndrome.
  phenotype_term:
    preferred_term: Hypoplastic corpus callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  evidence:
  - reference: PMID:35451546
    reference_title: "Cardiofacioneurodevelopmental syndrome: Report of a novel patient and expansion of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain imaging disclosed hypoplastic corpus callosum.
    explanation: Direct imaging documentation in a genotyped patient.
  - reference: url:https://www.nature.com/articles/s41431-026-02023-y/figures/1
    reference_title: "Fig. 1: Clinical hallmarks of Cardiofacioneurodevelopmental syndrome (CFNDS). | European Journal of Human Genetics | European Journal of Human Genetics"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bottom-right image indicates a complete but thin corpus callosum with abnormalities in sinuses.
    explanation: >-
      A complete but thin corpus callosum is separately reported in the 2026 MRI figure; this is not agenesis.
- name: Cerebellar hypoplasia
  category: Nervous System
  description: >-
    Cerebellar hypoplasia is listed among the recurring features of CFNDS in the
    2026 literature review, extending the brain phenotype beyond the midline
    callosal anomaly to the posterior fossa.
  phenotype_term:
    preferred_term: Cerebellar hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
  evidence:
  - reference: PMID:41639596
    reference_title: Two siblings with CCDC32-related cardiofacioneurodevelopmental syndrome diagnosed by clinical RNA-sequencing and review of literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the clinical phenotype can include microcephaly, facial malformations, developmental delay, cerebellar
      hypoplasia, and cardiac anomalies
    explanation: >-
      The review that pooled the published cases lists cerebellar hypoplasia as
      part of the phenotype.
- name: Microcephaly
  category: Head and Neck
  description: >-
    The founding report described borderline microcephaly at the 3rd-5th percentiles in A-II-1 and microcephaly
    with a Z score of -2.5 in B-II-1. Later clinical summaries retain microcephaly as a variable feature;
    the borderline and definite measurements are not interchangeable.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:41639596
    reference_title: Two siblings with CCDC32-related cardiofacioneurodevelopmental syndrome diagnosed by clinical RNA-sequencing and review of literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the clinical phenotype can include microcephaly, facial malformations, developmental delay, cerebellar
      hypoplasia, and cardiac anomalies
    explanation: Lists microcephaly among the recurring features.
  - reference: PMID:35451546
    reference_title: "Cardiofacioneurodevelopmental syndrome: Report of a novel patient and expansion of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Variable abnormalities of the face, brain, heart, fingers, and toes and postnatal growth retardation
      or microcephaly can be present.
    explanation: >-
      The source identifies microcephaly as a variable feature; this sentence does not establish its presence
      in an individual patient.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physical examination revealed borderline microcephaly (3rd–5th percentiles), height at 80th percentile
      and weight at 32nd percentile.
    explanation: >-
      Patient-level head-size measurement in A-II-1 is explicitly described as borderline.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physical examination revealed microcephaly ... score − 2.5), height at 97th percentile and weight
      at 64th percentile.
    explanation: >-
      Patient-level measurement in B-II-1 documents a head-size Z score of -2.5; the ellipsis crosses
      italic markup around Z.
- name: Postnatal growth retardation
  category: Growth
  description: >-
    Postnatal growth impairment is a variable feature and is presented in
    PMID:35451546 as an alternative to microcephaly. Short stature was documented
    in the individually reported patient.
  phenotype_term:
    preferred_term: Postnatal growth retardation
    term:
      id: HP:0008897
      label: Postnatal growth retardation
  evidence:
  - reference: PMID:35451546
    reference_title: "Cardiofacioneurodevelopmental syndrome: Report of a novel patient and expansion of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Variable abnormalities of the face, brain, heart, fingers, and toes and postnatal growth retardation
      or microcephaly can be present.
    explanation: Names postnatal growth retardation as a variable feature.
- name: Short stature
  category: Growth
  description: >-
    Short stature was documented in the nine-year-old patient reported in
    PMID:35451546.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:35451546
    reference_title: "Cardiofacioneurodevelopmental syndrome: Report of a novel patient and expansion of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had intellectual disability, marked hypertelorism, bilateral cleft lip and palate, and
      short stature.
    explanation: Direct documentation in a genotyped patient.
- name: Conductive hearing impairment
  category: Ear
  description: >-
    Bilateral conductive hearing loss was documented in the 2022 patient. Its causal relationship to the
    cleft palate was not experimentally established.
  phenotype_term:
    preferred_term: Bilateral conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
    laterality: BILATERAL
  evidence:
  - reference: PMID:35451546
    reference_title: "Cardiofacioneurodevelopmental syndrome: Report of a novel patient and expansion of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had bilateral conductive hearing loss, small hands and feet, and finger abnormalities.
    explanation: Direct documentation in a genotyped patient.
- name: Small hand
  category: Limbs
  description: >-
    Small hands were documented in the patient reported in PMID:35451546, and
    abnormalities of the fingers and toes are listed among the variable features
    of the syndrome.
  phenotype_term:
    preferred_term: Small hand
    term:
      id: HP:0200055
      label: Small hand
  evidence:
  - reference: PMID:35451546
    reference_title: "Cardiofacioneurodevelopmental syndrome: Report of a novel patient and expansion of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had bilateral conductive hearing loss, small hands and feet, and finger abnormalities.
    explanation: Direct documentation in a genotyped patient.
- name: Short foot
  category: Limbs
  description: >-
    Small feet were documented alongside small hands in the patient reported in
    PMID:35451546.
  phenotype_term:
    preferred_term: Small feet
    term:
      id: HP:0001773
      label: Short foot
  evidence:
  - reference: PMID:35451546
    reference_title: "Cardiofacioneurodevelopmental syndrome: Report of a novel patient and expansion of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had bilateral conductive hearing loss, small hands and feet, and finger abnormalities.
    explanation: Direct documentation in a genotyped patient.
- name: Hypoplasia of the pons
  category: Nervous System
  description: >-
    Prenatal ultrasound showed a hypoplastic pons in A-II-2.
  phenotype_term:
    preferred_term: Hypoplasia of the pons
    term:
      id: HP:0012110
      label: Hypoplasia of the pons
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A sibling fetus in Family A (A-II-2) had bilateral cleft lip, vermian hypoplasia, hypoplastic pons
      and abnormal cisterna magna that were detected by ultrasound, and the pregnancy was terminated electively.
    explanation: >-
      Prenatal ultrasound showed a hypoplastic pons in A-II-2.
- name: Epicanthus
  category: Head and Neck
  description: >-
    Epicanthal folds were described in B-II-1.
  phenotype_term:
    preferred_term: Epicanthus
    term:
      id: HP:0000286
      label: Epicanthus
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysmorphic features included brachydactyly, hypertelorism, epicanthal folds, broad nasal root, a
      prominent large nose and malformed protruded ears.
    explanation: >-
      Epicanthal folds were described in B-II-1.
- name: Hyperactivity
  category: Behavioral
  description: >-
    Hyperactivity was reported in B-II-1; an ADHD diagnosis was not established.
  phenotype_term:
    preferred_term: Hyperactivity
    term:
      id: HP:0000752
      label: Hyperactivity
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had severe feeding difficulties, moderately delayed motor and language development and hyperactivity.
    explanation: >-
      The clinical account explicitly names hyperactivity in B-II-1 without diagnosing ADHD.
- name: Protruding ear
  category: Ear
  description: >-
    Prominent or protruding ears were described in both liveborn founding individuals.
  phenotype_term:
    preferred_term: Protruding ear
    term:
      id: HP:0000411
      label: Protruding ear
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysmorphic features included brachydactyly, hypertelorism, epicanthal folds, broad nasal root, a
      prominent large nose and malformed protruded ears.
    explanation: >-
      The founding report describes malformed protruded ears in B-II-1.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysmorphic features included hypotelorism, upslanting palpebral fissures, a stiff upper lip, missing
      teeth attributed to the clefting, vaulted palate with cleft, prominent ears, underdeveloped helices
      and micrognathia.
    explanation: >-
      The same report describes prominent ears in A-II-1, supporting involvement in both liveborn founding
      individuals.
- name: Upslanted palpebral fissure
  category: Head and Neck
  description: >-
    Upslanted fissures were described in A-II-1.
  phenotype_term:
    preferred_term: Upslanted palpebral fissure
    term:
      id: HP:0000582
      label: Upslanted palpebral fissure
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysmorphic features included hypotelorism, upslanting palpebral fissures, a stiff upper lip, missing
      teeth attributed to the clefting, vaulted palate with cleft, prominent ears, underdeveloped helices
      and micrognathia.
    explanation: >-
      Upslanted fissures were described in A-II-1.
- name: Micrognathia
  category: Head and Neck
  description: >-
    Micrognathia was reported in A-II-1.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysmorphic features included hypotelorism, upslanting palpebral fissures, a stiff upper lip, missing
      teeth attributed to the clefting, vaulted palate with cleft, prominent ears, underdeveloped helices
      and micrognathia.
    explanation: >-
      Micrognathia was reported in A-II-1.
- name: Brachydactyly
  category: Limbs
  description: >-
    Brachydactyly was reported in B-II-1.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysmorphic features included brachydactyly, hypertelorism, epicanthal folds, broad nasal root, a
      prominent large nose and malformed protruded ears.
    explanation: >-
      Brachydactyly was reported in B-II-1.
- name: Clinodactyly of the 5th finger
  category: Limbs
  description: >-
    Fifth-finger clinodactyly was reported in A-II-1; B-II-1 also had clinodactyly without a digit specified
    in the clinical sentence.
  phenotype_term:
    preferred_term: Clinodactyly of the 5th finger
    term:
      id: HP:0004209
      label: Clinodactyly of the 5th finger
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had mild kyphosis and nail clubbing and abnormal dermatoglyphics, bilateral camptodactyly and
      clinodactyly of the fifth fingers.
    explanation: >-
      The examination of A-II-1 explicitly identifies clinodactyly of the fifth fingers.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The individual had clinodactyly, nail aplasia on thumbs and toes and cryptorchidism.
    explanation: >-
      B-II-1 also had clinodactyly; this sentence does not identify the affected digit.
- name: Camptodactyly of finger
  category: Limbs
  description: >-
    Bilateral camptodactyly was reported in A-II-1.
  phenotype_term:
    preferred_term: Camptodactyly of finger
    term:
      id: HP:0100490
      label: Camptodactyly of finger
    laterality: BILATERAL
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had mild kyphosis and nail clubbing and abnormal dermatoglyphics, bilateral camptodactyly and
      clinodactyly of the fifth fingers.
    explanation: >-
      Bilateral camptodactyly was reported in A-II-1.
- name: Absent fingernail
  category: Limbs
  description: >-
    Nail aplasia affected the thumbs in B-II-1; toe nails were also involved.
  phenotype_term:
    preferred_term: Absent fingernail
    term:
      id: HP:0001817
      label: Absent fingernail
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The individual had clinodactyly, nail aplasia on thumbs and toes and cryptorchidism.
    explanation: >-
      The founding report documents aplasia of thumb and toe nails in B-II-1; this row binds the fingernail
      component.
- name: Clubbing
  category: Limbs
  description: >-
    Nail clubbing was reported in A-II-1; the cause was not established.
  phenotype_term:
    preferred_term: Clubbing
    term:
      id: HP:0001217
      label: Clubbing
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had mild kyphosis and nail clubbing and abnormal dermatoglyphics, bilateral camptodactyly and
      clinodactyly of the fifth fingers.
    explanation: >-
      The clinical examination of A-II-1 explicitly describes nail clubbing, without attributing its cause.
- name: Abnormal dermatoglyphics
  category: Integument
  description: >-
    Abnormal dermatoglyphics were reported in A-II-1.
  phenotype_term:
    preferred_term: Abnormal dermatoglyphics
    term:
      id: HP:0007477
      label: Abnormal dermatoglyphics
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had mild kyphosis and nail clubbing and abnormal dermatoglyphics, bilateral camptodactyly and
      clinodactyly of the fifth fingers.
    explanation: >-
      Abnormal dermatoglyphics were reported in A-II-1.
- name: Kyphosis
  category: Skeletal
  description: >-
    Mild kyphosis was reported in A-II-1.
  phenotype_term:
    preferred_term: Kyphosis
    term:
      id: HP:0002808
      label: Kyphosis
    severity: MILD
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had mild kyphosis and nail clubbing and abnormal dermatoglyphics, bilateral camptodactyly and
      clinodactyly of the fifth fingers.
    explanation: >-
      Mild kyphosis was reported in A-II-1.
- name: High palate
  category: Head and Neck
  description: >-
    A vaulted palate with a cleft was described in A-II-1.
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysmorphic features included hypotelorism, upslanting palpebral fissures, a stiff upper lip, missing
      teeth attributed to the clefting, vaulted palate with cleft, prominent ears, underdeveloped helices
      and micrognathia.
    explanation: >-
      A vaulted palate with a cleft was described in A-II-1.
- name: Hypoplastic helices
  category: Ear
  description: >-
    Underdeveloped helices were reported in A-II-1.
  phenotype_term:
    preferred_term: Hypoplastic helices
    term:
      id: HP:0008589
      label: Hypoplastic helices
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysmorphic features included hypotelorism, upslanting palpebral fissures, a stiff upper lip, missing
      teeth attributed to the clefting, vaulted palate with cleft, prominent ears, underdeveloped helices
      and micrognathia.
    explanation: >-
      Underdeveloped helices were reported in A-II-1.
- name: Wide nasal bridge
  category: Head and Neck
  description: >-
    A broad nasal root was described in B-II-1.
  phenotype_term:
    preferred_term: Wide nasal bridge
    term:
      id: HP:0000431
      label: Wide nasal bridge
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysmorphic features included brachydactyly, hypertelorism, epicanthal folds, broad nasal root, a
      prominent large nose and malformed protruded ears.
    explanation: >-
      A broad nasal root was described in B-II-1.
- name: Prominent nose
  category: Head and Neck
  description: >-
    A prominent large nose was reported in B-II-1.
  phenotype_term:
    preferred_term: Prominent nose
    term:
      id: HP:0000448
      label: Prominent nose
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysmorphic features included brachydactyly, hypertelorism, epicanthal folds, broad nasal root, a
      prominent large nose and malformed protruded ears.
    explanation: >-
      A prominent large nose was reported in B-II-1.
- name: Anterior pituitary hypoplasia
  category: Nervous System
  description: >-
    The 2026 MRI figure documents anterior pituitary hypoplasia; hormone deficiency cannot be inferred
    from this image alone.
  phenotype_term:
    preferred_term: Anterior pituitary hypoplasia
    term:
      id: HP:0010627
      label: Anterior pituitary hypoplasia
  evidence:
  - reference: url:https://www.nature.com/articles/s41431-026-02023-y/figures/1
    reference_title: "Fig. 1: Clinical hallmarks of Cardiofacioneurodevelopmental syndrome (CFNDS). | European Journal of Human Genetics | European Journal of Human Genetics"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypoplasia of the adenohypophysis, measuring 2.2 mm.
    explanation: >-
      The 2026 MRI figure documents anterior pituitary hypoplasia; hormone deficiency cannot be inferred
      from this image alone.
- name: Absent right internal carotid artery
  category: Cardiovascular
  description: >-
    The 2026 MRI caption reports no right internal carotid artery. The caption does not assign each subpanel
    unambiguously to a sibling.
  phenotype_term:
    preferred_term: Absent right internal carotid artery
    term:
      id: HP:3000062
      label: Abnormal internal carotid artery morphology
    laterality: RIGHT
    coarse_binding_basis: NO_HPO_TERM
    term_gap: >-
      EBI OLS4 HPO search query "internal carotid" on 2026-10-04 returned HP:3000062 and HP:0005290 (Internal
      carotid artery hypoplasia), but no term specifying absence of this artery. The morphology parent
      includes the observed absence; hypoplasia or agenesis of the carotid canal would assert a different
      finding. The preferred term preserves the specific MRI observation.
  evidence:
  - reference: url:https://www.nature.com/articles/s41431-026-02023-y/figures/1
    reference_title: "Fig. 1: Clinical hallmarks of Cardiofacioneurodevelopmental syndrome (CFNDS). | European Journal of Human Genetics | European Journal of Human Genetics"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Top-left image reveals no right internal carotid artery.
    explanation: >-
      The 2026 MRI caption reports no right internal carotid artery. The caption does not assign each
      subpanel unambiguously to a sibling.
- name: Thin optic nerve
  category: Nervous System
  description: >-
    The 2026 MRI caption describes a thin optic nerve, without establishing optic atrophy or a functional
    visual deficit.
  phenotype_term:
    preferred_term: Thin optic nerve
    term:
      id: HP:0000587
      label: Abnormal optic nerve morphology
    coarse_binding_basis: NO_HPO_TERM
    term_gap: >-
      EBI OLS4 HPO search query "optic nerve" on 2026-10-04 returned HP:0000587, HP:0000609 (Optic nerve
      hypoplasia), HP:0008058 (Aplasia/Hypoplasia of the optic nerve), and HP:0000648 (Optic atrophy).
      The figure caption describes thinness without establishing developmental hypoplasia or atrophy.
      The morphology parent is used with the observed thinness retained in preferred_term.
  evidence:
  - reference: url:https://www.nature.com/articles/s41431-026-02023-y/figures/1
    reference_title: "Fig. 1: Clinical hallmarks of Cardiofacioneurodevelopmental syndrome (CFNDS). | European Journal of Human Genetics | European Journal of Human Genetics"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bottom-left image shows a thin optic nerve.
    explanation: >-
      The 2026 MRI caption describes a thin optic nerve, without establishing optic atrophy or a functional
      visual deficit.
- name: Hypoplastic cerebellar tonsils
  category: Nervous System
  description: >-
    MRI showed hypoplastic cerebellar tonsils in A-II-1.
  phenotype_term:
    preferred_term: Hypoplastic cerebellar tonsils
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI revealed hypoplastic cerebellar tonsils.
    explanation: >-
      MRI showed hypoplastic cerebellar tonsils in A-II-1.
  notes: >-
    Needs precise term: EBI OLS4 HPO search query "cerebellar tonsil" on 2026-10-04 returned Chiari malformation
    (HP:0002308), Chiari type I malformation (HP:0007099) and Chiari type II malformation (HP:0025660),
    not a term for tonsillar hypoplasia. Chiari displacement is not the reported finding. The anatomically
    specific descriptor is therefore left unbound.
- name: Absent toenail
  category: Limbs
  description: >-
    Nail aplasia affected the toes as well as the thumbs in B-II-1.
  phenotype_term:
    preferred_term: Absent toenail
    term:
      id: HP:0001802
      label: Absent toenail
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The individual had clinodactyly, nail aplasia on thumbs and toes and cryptorchidism.
    explanation: >-
      The clinical description explicitly includes nail aplasia on toes.
genetic:
- name: CCDC32
  gene_term:
    preferred_term: CCDC32
    term:
      id: hgnc:28295
      label: CCDC32
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: Biallelic loss-of-function variants
  notes: >-
    CCDC32, formerly C15orf57, is located at 15q15.1. The 2020 paper uses NM_001080791.2:c.54dupT, p.(Thr19Tyrfs*12)
    and c.189_190dupGG, p.(Glu64Glyfs*12). The 2024 ClinGen assertion represents the founding alleles
    on NM_001080792.4 as c.27dup, p.Thr10TyrfsTer12 and c.162_163dup, p.Glu55GlyfsTer12. Transcript accession
    and version must accompany comparisons. ClinGen classified the recessive gene-disease relationship
    as Moderate on 2024-10-18; this is a gene-level assessment, not a variant-level classification or
    a claim that all molecular functions are unresolved. Residual protein function and genotype-phenotype
    correlations remain uncertain.
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:41639596
      reference_title: Two siblings with CCDC32-related cardiofacioneurodevelopmental syndrome diagnosed by clinical RNA-sequencing and review of literature.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Cardiofacioneurodevelopmental syndrome (CFNDS, MIM:619123) is a rare genetic disorder caused by
        bi-allelic pathogenic variants in CCDC32.
      explanation: Confirms the biallelic requirement at the gene level.
  evidence:
  - reference: PMID:32307552
    reference_title: Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using whole exome sequencing, we identified homozygous frameshift CCDC32 variants in three affected
      individuals.
    explanation: The founding gene-disease association.
  - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_29c6c0dd-bbaf-45ce-92af-4c67059cac8f-2024-10-18T16:00:00.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In summary, there is moderate evidence to support this gene-disease relationship.
    explanation: >-
      ClinGen Syndromic Disorders GCEP assessment approved 2024-10-18.
  variants:
  - name: CCDC32 c.27dup (p.Thr10fs), family A founding frameshift
    description: >-
      The founding family A carried the homozygous single-base frameshift duplication reported as NM_001080791.2:c.54dupT,
      p.(Thr19Tyrfs*12). ClinGen represents the same allele as NM_001080792.4:c.27dup, p.Thr10TyrfsTer12.
      The sequence predicts premature termination; patient protein abundance was not measured in that
      report.
    type: frameshift duplication
    clinical_significance: PATHOGENIC
    sequence_length: 1
    synonyms:
    - NM_001080791.2:c.54dupT
    - p.(Thr19Tyrfs*12)
    - NM_001080792.4:c.27dup
    - p.Thr10fs
    identifiers:
    - ClinVar:VCV000988600
    - OMIM:618941.0001
    - dbSNP:rs1890756020
    - ClinGen:CA1139663846
    gene:
      preferred_term: CCDC32
      term:
        id: hgnc:28295
        label: CCDC32
    external_assertions:
    - name: ClinVar germline classification for CCDC32 c.27dup
      source: ClinVar
      assertion_type: germline_variant_classification
      external_id: VCV000988600
      url: https://www.ncbi.nlm.nih.gov/clinvar/variation/988600/
      description: >-
        Classified Pathogenic for cardiofacioneurodevelopmental syndrome (MedGen:C5436852, MONDO:0030873,
        OMIM:619123), last evaluated 2020-12-09, review status "no assertion criteria provided" (one submitter,
        SCV001450459; the OMIM allelic-variant record). Retrieved from the NCBI eutils ClinVar esummary
        and VCV efetch endpoints on 2026-08-01.
    functional_effects:
    - type: predicted loss of function
      description: >-
        Frameshift with a premature stop, predicted to disrupt CCDC32. Residual patient protein and activity
        are not established.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
      reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        c.54dupT in Family A and c.189_190dupGG in Family B
      explanation: >-
        Figure 1 documents the segregating founding alleles.
  - name: CCDC32 c.162_163dup (p.Glu55fs), family B founding frameshift
    description: >-
      The founding family B carried the homozygous two-base duplication NM_001080791.2:c.189_190dupGG,
      p.(Glu64Glyfs*12), represented by ClinGen as NM_001080792.4:c.162_163dup, p.Glu55GlyfsTer12. The
      CCDC32(1-54) assay construct omits both the nine-residue N-terminal segment of the published sequence
      and the twelve-residue frameshift tail; it is an informative disease mimic, not an exact patient
      protein.
    type: frameshift duplication
    clinical_significance: PATHOGENIC
    sequence_length: 2
    synonyms:
    - NM_001080791.2:c.189_190dupGG
    - p.(Glu64Glyfs*12)
    - NM_001080792.4:c.162_163dup
    - p.Glu55fs
    identifiers:
    - ClinVar:VCV000988601
    - OMIM:618941.0002
    - dbSNP:rs1890742129
    - ClinGen:CA1139663845
    gene:
      preferred_term: CCDC32
      term:
        id: hgnc:28295
        label: CCDC32
    external_assertions:
    - name: ClinVar germline classification for CCDC32 c.162_163dup
      source: ClinVar
      assertion_type: germline_variant_classification
      external_id: VCV000988601
      url: https://www.ncbi.nlm.nih.gov/clinvar/variation/988601/
      description: >-
        Classified Pathogenic for cardiofacioneurodevelopmental syndrome (MedGen:C5436852, MONDO:0030873,
        OMIM:619123), last evaluated 2020-12-09, review status "no assertion criteria provided" (one submitter,
        SCV001450460; the OMIM allelic-variant record). Retrieved from the NCBI eutils ClinVar esummary
        and VCV efetch endpoints on 2026-08-01.
    functional_effects:
    - type: predicted loss of function
      description: >-
        Frameshift with a premature stop, predicted to disrupt CCDC32. Residual patient protein and activity
        are not established.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
      reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        c.54dupT in Family A and c.189_190dupGG in Family B
      explanation: >-
        Figure 1 documents the segregating founding alleles.
    - reference: PMID:41489497
      reference_title: CCDC32 stabilizes clathrin-coated pits and drives their invagination.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        our disease mimic construct CCDC32(1-54) does not contain a 9 aa peptide (VRGSCLRFQ) in the N-terminus
        and an extra 12 aa in the C-terminus when CFNDS patient mutation was described (p.(Glu64Glyfs∗12))
      explanation: >-
        Explicit limits of transferring results from the engineered construct to the patient protein.
  - name: CCDC32 c.471T>A (p.Tyr157Ter), nonsense variant of uncertain significance
    description: >-
      A nonsense variant recorded as uncertain significance in the ClinVar assertion retrieved on 2026-08-01.
      It is not a confirmed disease allele. Its C-terminal position alone cannot establish whether AP-2
      assembly, membrane binding or another function is preserved.
    type: nonsense
    clinical_significance: UNCERTAIN_SIGNIFICANCE
    sequence_length: 1
    synonyms:
    - NM_001080792.4:c.471T>A
    - p.Tyr157Ter
    identifiers:
    - ClinVar:VCV002580223
    - dbSNP:rs2543087691
    - ClinGen:CA391722033
    gene:
      preferred_term: CCDC32
      term:
        id: hgnc:28295
        label: CCDC32
    external_assertions:
    - name: ClinVar germline classification for CCDC32 c.471T>A
      source: ClinVar
      assertion_type: germline_variant_classification
      external_id: VCV002580223
      url: https://www.ncbi.nlm.nih.gov/clinvar/variation/2580223/
      description: >-
        Classified Uncertain significance for cardiofacioneurodevelopmental
        syndrome (MedGen:C5436852, MONDO:0030873, OMIM:619123), last evaluated
        2023-03-30, review status "criteria provided, single submitter"
        (SCV004035993). GRCh38 chr15:40554058. Retrieved from the NCBI eutils
        ClinVar esummary endpoint on 2026-08-01.
  - name: CCDC32 32,583-bp deletion (2022 patient)
    description: >-
      The 2022 patient carried a homozygous 32,583-bp deletion affecting CCDC32, predicted to remove protein
      function independently of transcript choice. The source does not establish that this is the same
      allele as the later structural variants.
    type: deletion
    clinical_significance: PATHOGENIC
    identifiers:
    - ClinVar:VCV001690313
    - OMIM:618941.0003
    gene:
      preferred_term: CCDC32
      term:
        id: hgnc:28295
        label: CCDC32
    external_assertions:
    - name: ClinVar germline classification for the CCDC32 32.6-kb deletion (Abdalla patient)
      source: ClinVar
      assertion_type: germline_variant_classification
      external_id: VCV001690313
      url: https://www.ncbi.nlm.nih.gov/clinvar/variation/1690313/
      description: >-
        NC_000015.10:g.40529942_40562524del, alias "32.6-KB DEL", classified
        Pathogenic for cardiofacioneurodevelopmental syndrome, last evaluated
        2022-11-29, review status "criteria provided, single submitter"; also
        carried as OMIM allelic variant 618941.0003. GRCh37 coordinates
        chr15:40822141-40854723. Retrieved from the NCBI eutils ClinVar esummary
        endpoint on 2026-08-01.
    evidence:
    - reference: PMID:35451546
      reference_title: "Cardiofacioneurodevelopmental syndrome: Report of a novel patient and expansion of the phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report a 9-year-old female patient with CFNDS caused by a homozygous 32,583-bp deletion affecting
        CCDC32.
      explanation: The first reported structural deletion allele.
    - reference: PMID:35451546
      reference_title: "Cardiofacioneurodevelopmental syndrome: Report of a novel patient and expansion of the phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Independent of the affected CCDC32 transcript variant this deletion likely leads to loss of the
        encoded protein.
      explanation: >-
        Explains why the deletion is interpreted as loss of function regardless
        of which transcript is considered.
  - name: CCDC32 deletion of exons 3 and 4 (2026 siblings)
    type: intragenic deletion
    gene:
      preferred_term: CCDC32
      term:
        id: hgnc:28295
        label: CCDC32
    description: >-
      Biallelic genomic deletion of exons 3 and 4 in two siblings, detected through transcript analysis
      and confirmed by deletion-specific PCR and Sanger breakpoint sequencing. Both parents were heterozygous.
      The RNA finding revealed a variant missed in the earlier panel-focused diagnostic workflow, rather
      than proving that the deletion is undetectable by DNA methods.
    identifiers:
    - ClinVar:SCV007113788
    evidence:
    - reference: PMID:41639596
      reference_title: Two siblings with CCDC32-related cardiofacioneurodevelopmental syndrome diagnosed by clinical RNA-sequencing and review of literature.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Skipping of two exons in CCDC32 transcript was identified, consistent with a bi-allelic deletion
        including exons 3 and 4 of CCDC32.
      explanation: An intragenic multi-exon deletion detected through its transcript consequence.
    - reference: url:https://www.nature.com/articles/s41431-026-02023-y/figures/2
      reference_title: "Fig. 2: Deletion of exon 3 and 4 of CCDC32 in affected individuals. | European Journal of Human Genetics | European Journal of Human Genetics"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Deletion-specific PCR for affected individuals, heterozygous parents, and unrelated control.
      explanation: >-
        Genomic confirmation accompanies the RNA finding.
  - name: CCDC32 structural variants in the 2024 fourth patient
    type: suspected deletions in trans
    gene:
      preferred_term: CCDC32
      term:
        id: hgnc:28295
        label: CCDC32
    description: >-
      The 2024 report title describes a homozygous deletion, while the ClinGen assessment describes suspected
      21-kb and 9.7-kb deletions in trans and excluded this proband from its scoring. This discrepancy
      should be resolved from primary breakpoint and segregation data before equating the allele with
      the 2022 deletion.
    identifiers:
    - ClinVar:VCV002431643
    evidence:
    - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_29c6c0dd-bbaf-45ce-92af-4c67059cac8f-2024-10-18T16:00:00.000Z
      reference_title: curation results for Gene-Disease Validity
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        An additional 21 kb deletion was reported in a fourth proband (PMID: 38818818) but was not included
        in this curation.
      explanation: >-
        ClinGen records an unscored fourth case; the primary report has no accessible abstract in the
        cache.
    - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_29c6c0dd-bbaf-45ce-92af-4c67059cac8f-2024-10-18T16:00:00.000Z
      reference_title: curation results for Gene-Disease Validity
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        the following suspected deletions in trans: a 21 kb deletion ... and a 9.7 kb deletion
      explanation: >-
        The ClinGen case-level explanation describes two suspected deletions in trans, rather than a proven
        recurrence of the 2022 allele.
diagnosis:
- name: Exome or genome sequencing
  description: >-
    Molecular diagnosis requires compatible findings and biallelic pathogenic CCDC32 variants. Exome sequencing
    identified the founding frameshifts; analysis should also consider exon-level and larger deletions.
    Developmental delay with orofacial clefting and additional cardiac, laterality or brain findings can
    prompt consideration of CCDC32, but no formal clinical scoring criteria are established.
  evidence:
  - reference: PMID:32307552
    reference_title: Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using whole exome sequencing, we identified homozygous frameshift CCDC32 variants in three affected
      individuals.
    explanation: >-
      Exome sequencing was the method that established the diagnosis in the
      founding families.
- name: RNA sequencing when DNA-based testing is uninformative
  description: >-
    In the 2026 siblings, RNA sequencing identified marked CCDC32 downregulation and loss of exons 3 and
    4 after SNP array and trio exome testing had been uninformative. CCDC32 was absent from the intellectual-disability
    and congenital-malformation panels used in the earlier analysis. Review of WES tracks and genomic
    PCR/Sanger sequencing then confirmed the deletion. RNA analysis can complement a negative work-up,
    but this case does not establish that DNA testing is intrinsically unable to detect the allele.
  evidence:
  - reference: PMID:41639596
    reference_title: Two siblings with CCDC32-related cardiofacioneurodevelopmental syndrome diagnosed by clinical RNA-sequencing and review of literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present a family with two affected individuals who were diagnosed through clinical RNA sequencing
      (RNA-seq) after conventional DNA diagnostics did not yield a molecular cause.
    explanation: >-
      States precisely the diagnostic claim made here: RNA sequencing made the
      diagnosis after DNA-based testing had failed.
  - reference: PMID:41639596
    reference_title: Two siblings with CCDC32-related cardiofacioneurodevelopmental syndrome diagnosed by clinical RNA-sequencing and review of literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This deletion was not detected in previous SNP array analyses and trio exome sequencing focusing
      on genes related to intellectual disability and congenital malformations, highlighting the complementary
      value of RNA-seq.
    explanation: >-
      Documents that both SNP array and trio exome sequencing missed the causal
      allele, which is the reason RNA sequencing is recommended here.
  - reference: url:https://www.nature.com/articles/s41431-026-02023-y/figures/2
    reference_title: "Fig. 2: Deletion of exon 3 and 4 of CCDC32 in affected individuals. | European Journal of Human Genetics | European Journal of Human Genetics"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      (not included in the ID and MCA panels) exhibited notable downregulation with a Z-score of -8.20.
    explanation: >-
      Panel membership explains part of the diagnostic blind spot; the RNA outlier is patient-specific.
- name: Brain magnetic resonance imaging
  description: >-
    Brain MRI can characterize the reported callosal, cerebellar and brainstem abnormalities. The 2026
    figure also reports anterior pituitary hypoplasia, a thin optic nerve and absent right internal carotid
    artery. Imaging observations should not be converted into unmeasured endocrine or visual dysfunction.
  evidence:
  - reference: PMID:35451546
    reference_title: "Cardiofacioneurodevelopmental syndrome: Report of a novel patient and expansion of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain imaging disclosed hypoplastic corpus callosum.
    explanation: >-
      Brain imaging revealed a structural anomaly that would otherwise have been
      missed.
  - reference: url:https://www.nature.com/articles/s41431-026-02023-y/figures/1
    reference_title: "Fig. 1: Clinical hallmarks of Cardiofacioneurodevelopmental syndrome (CFNDS). | European Journal of Human Genetics | European Journal of Human Genetics"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bottom-right image indicates a complete but thin corpus callosum with abnormalities in sinuses.
    explanation: >-
      A complete but thin corpus callosum is separately reported in the 2026 MRI figure; this is not agenesis.
- name: Cardiac, visceral situs and hearing assessment
  description: >-
    Phenotype-directed assessment includes cardiac anatomy, abdominal organ position and spleen presence,
    and hearing. This is inferred from the reported defects rather than a validated CFNDS screening schedule.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      atrioventricular (AV) canal defect and abdominal ... situs inversus ... with asplenia. Physical
      examination revealed borderline microcephaly
    explanation: >-
      Asplenia accompanied abdominal situs inversus in A-II-1. Infection prevention is an actionable consequence
      of this finding.
  - reference: PMID:35451546
    reference_title: "Cardiofacioneurodevelopmental syndrome: Report of a novel patient and expansion of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had bilateral conductive hearing loss, small hands and feet, and finger abnormalities.
    explanation: Direct documentation in a genotyped patient.
treatments:
- name: Antimicrobial prophylaxis and immunisation for asplenia
  description: >-
    Individuals with asplenia need infection-prevention planning, vaccination and prompt assessment of
    febrile illness under general asplenia care. Antibiotic prophylaxis duration depends on age and individual
    risk; lifelong infection susceptibility does not mean that every patient requires lifelong daily antibiotics.
    These are general asplenia recommendations, not CFNDS-specific trial outcomes.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Asplenia infection-prevention care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Asplenia
    term:
      id: HP:0001746
      label: Asplenia
  evidence:
  - reference: PMID:33275684
    reference_title: Preventing infections in children and adults with asplenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recommendations for patients with functional or anatomic asplenia include antibiotic prophylaxis,
      vaccination, and patient and family education to ensure prevention of infections and timely management
      of febrile illnesses.
    explanation: >-
      General asplenia management extrapolated to affected CFNDS individuals.
  - reference: PMID:33275684
    reference_title: Preventing infections in children and adults with asplenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Duration of routine prophylaxis depends on age, time since splenectomy, degree of immunocompromise,
      or prior episode of sepsis.
    explanation: >-
      The source does not recommend universal lifelong prophylaxis for all patients.
- name: Cleft palate repair
  description: >-
    Palatoplasty within multidisciplinary cleft care, with timing individualized to anatomy, feeding and
    speech needs. This is phenotype-directed supportive care; CFNDS-specific comparative surgical outcomes
    are not established.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: palatorrhaphy
    term:
      id: NCIT:C168380
      label: Palatorrhaphy
  target_phenotypes:
  - preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
- name: Cleft lip repair
  description: >-
    Cheiloplasty as part of multidisciplinary cleft care. This is a phenotype-directed intervention; the
    cited CFNDS reports do not establish a syndrome-specific timing protocol.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cleft lip repair (cheiloplasty)
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Cleft lip
    term:
      id: HP:0410030
      label: Cleft lip
- name: Nutritional and feeding support in infancy
  description: >-
    Individualized feeding assessment, cleft-adapted feeding support and nutritional monitoring for reported
    feeding difficulties. This is supportive extrapolation from the phenotype, without CFNDS-specific
    intervention trial data.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: nutritional support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  target_phenotypes:
  - preferred_term: Feeding difficulties in infancy
    term:
      id: HP:0008872
      label: Feeding difficulties in infancy
- name: Orchidopexy for cryptorchidism
  description: >-
    Urological assessment and consideration of orchiopexy for the reported undescended testis phenotype,
    under general pediatric urology care. A CFNDS-specific protocol or outcome series is not established.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: orchiopexy
    term:
      id: NCIT:C111066
      label: Orchiopexy
  target_phenotypes:
  - preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
- name: Hearing support
  description: >-
    Hearing support and treatment of conductive impairment when indicated. Hearing evaluation is part
    of phenotype assessment; benefit in CFNDS has not been tested in a dedicated trial.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Speech and language therapy
  description: >-
    Individualized speech and language support can address developmental and cleft-related needs. This
    is supportive extrapolation from the reported phenotype.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
- name: Developmental and educational therapy
  description: >-
    Developmental, rehabilitation and educational support directed at the individual pattern of delay
    or intellectual disability. No disease-modifying efficacy is claimed.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
- name: Management of congenital cardiac lesions
  description: >-
    Cardiology-directed management or repair of the specific congenital cardiac lesion, according to its
    anatomy and physiology. This is standard phenotype-directed care rather than a CFNDS-specific treatment
    protocol.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Genetic counselling
  description: >-
    For parents confirmed to carry pathogenic variants in the same autosomal recessive gene, standard
    Mendelian counseling gives a 25% affected-child risk per pregnancy. Familial testing must account
    for the actual sequence or deletion alleles. This is an inheritance-based calculation, not a measured
    penetrance estimate; prognosis cannot be predicted reliably from the small clinical series.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
differential_diagnoses:
- name: Cardiofaciocutaneous syndrome
  description: >-
    A RASopathy caused by heterozygous gain-of-function variants in BRAF,
    MAP2K1, MAP2K2 or KRAS. It is included here primarily as a NAMING hazard
    rather than a close clinical mimic: "cardiofaciocutaneous" and
    "cardiofacioneurodevelopmental" differ by one word element, both abbreviate
    to a CF acronym, and a literature search or an automated entity resolver can
    silently substitute one for the other. Clinically the two do share
    craniofacial dysmorphism, congenital heart disease, growth retardation and
    intellectual disability, so the distinction also matters at the bedside. The
    discriminators are the ectodermal features and the inheritance pattern.
  distinguishing_features:
  - Autosomal dominant, usually de novo, versus autosomal recessive for CFNDS
  - Caused by RAS-MAPK pathway genes (BRAF, MAP2K1, MAP2K2, KRAS), not CCDC32
  - Cutaneous abnormalities are central to the CFC GeneReviews description; the small CFNDS series does not establish their universal absence.
  - Bilateral cleft lip and palate is the core craniofacial feature of CFNDS but is not characteristic of cardiofaciocutaneous syndrome
  - Pulmonic stenosis and hypertrophic cardiomyopathy are the characteristic RASopathy cardiac lesions
  disease_term:
    preferred_term: cardiofaciocutaneous syndrome
    term:
      id: MONDO:0015280
      label: cardiofaciocutaneous syndrome
  evidence:
  - reference: PMID:20301365
    reference_title: Cardiofaciocutaneous Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CLINICAL CHARACTERISTICS: Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities
      (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm
      disturbances), distinctive craniofacial appearance, and cutaneous abnormalities
    explanation: >-
      GeneReviews characterizes the different RASopathy, including its cutaneous component; it cannot
      prove absence of those findings in CFNDS.
  - reference: PMID:20301365
    reference_title: Cardiofaciocutaneous Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of CFC syndrome is established in a proband with suggestive clinical findings by the
      identification of a heterozygous pathogenic variant in BRAF, MAP2K1, MAP2K2, or KRAS by molecular
      genetic testing.
    explanation: >-
      Establishes the genetic discriminator: heterozygous RAS-MAPK pathway
      variants rather than biallelic CCDC32 variants.
  - reference: PMID:20301365
    reference_title: Cardiofaciocutaneous Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CFC syndrome is inherited in an autosomal dominant manner.
    explanation: Establishes the inheritance discriminator.
- name: AP2M1-related intellectual developmental disorder with seizures
  description: >-
    AP2M1 encodes the mu2 subunit of AP-2. A recurrent heterozygous de novo p.Arg170Trp allele causes
    a developmental and epileptic encephalopathy, providing a mechanistic differential. Different AP-2
    pathway defects need not produce identical organ phenotypes.
  distinguishing_features:
  - Autosomal dominant de novo, versus autosomal recessive for CFNDS
  - Caused by AP2M1 (HGNC:564), an AP-2 subunit, rather than CCDC32, the AP-2 assembly chaperone
  - Generalized epilepsy is central to the cited AP2M1 series; absence of seizures is not established as an exclusion criterion for CFNDS.
  disease_term:
    preferred_term: AP2M1-related intellectual developmental disorder with seizures
    term:
      id: MONDO:0032823
      label: intellectual developmental disorder 60 with seizures
  evidence:
  - reference: PMID:31104773
    reference_title: A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We subsequently found the same de novo variant in two individuals with neurodevelopmental disorders
      and generalized epilepsy in a cohort of 2,310 individuals who underwent diagnostic whole-exome sequencing.
    explanation: >-
      Establishes the de novo dominant inheritance and the epilepsy-dominated
      phenotype that discriminate this disorder from CFNDS.
  - reference: PMID:31104773
    reference_title: A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a de novo c.508C>T (p.Arg170Trp) variant in AP2M1 in two individuals with a phenotypic
      similarity that was higher than expected by chance (p = 0.003) and a phenotype related to epilepsy
      with myoclonic-atonic seizures.
    explanation: >-
      Identifies the recurrent AP2M1 allele and its seizure phenotype.
- name: Ciliopathy with craniofacial, cardiac and laterality involvement
  description: >-
    The founding report explicitly framed CFNDS as overlapping the ciliopathies,
    on the basis of the laterality anomalies and the craniofacial and brain
    findings. In practice a child with orofacial clefting, a congenital cardiac
    lesion, situs abnormality and posterior-fossa anomaly will be worked up for
    the ciliopathy spectrum, and CCDC32 should be in that differential rather
    than outside it. No single MONDO grouping term is bound here because the
    candidate entities span several distinct disorders rather than one, and
    picking any one of them would assert a specific alternative diagnosis that
    the source does not support.
  distinguishing_features:
  - Different ciliopathies have different retinal, renal, skeletal and laterality findings; there is no universal distinguishing feature across this group.
  - Ophthalmologic and renal evaluations were normal in the two liveborn founding CFNDS individuals, which does not establish lifelong or universal absence of disease in these organs.
  - CCDC32 regulates AP-2 and coated-pit function; the biochemical route to its reported ciliary phenotype remains unresolved.
  evidence:
  - reference: PMID:32307552
    reference_title: Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Because some of the patient phenotypes overlap defects common to ciliopathies, we asked if loss
      of CCDC32 might contribute to the dysfunction of this organelle.
    explanation: >-
      The authors themselves note the phenotypic overlap with ciliopathies, which
      is the reason this differential is listed.
animal_models:
- species: Danio rerio
  genotype: Mosaic F0 ccdc32 CRISPR/Cas9 disruption using two independent exon-2 sgRNAs
  description: >-
    One 2020 study used two independently targeted mosaic F0 zebrafish cohorts. Findings included reduced
    head size, altered craniofacial cartilage angle, hypoplastic cerebella, abnormal cardiac looping and
    southpaw expression, and fewer, shorter Kupffer vesicle cilia. The two sgRNAs are experimental replication
    within this paper. The 2022 clinical report cites the same study. These fish do not directly model
    human cleft lip/palate fusion, chamber septation or digital abnormalities.
  associated_phenotypes:
  - Reduced head size
  - Altered craniofacial cartilage angle
  - Hypoplastic cerebellum
  - Abnormal cardiac looping
  - Abnormal southpaw expression
  - Reduced Kupffer vesicle cilia number and length
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We designed two distinct single guide (sg)RNAs (sgRNA1 and sgRNA2) targeting non-overlapping regions
      of exon 2 ... and injected each into zebrafish embryos at the one cell stage, along with Cas9 protein.
    explanation: >-
      Direct description of the model-generation method.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      KV cilia were reduced significantly in both number and length in crispants at the 10 somite stage
    explanation: >-
      Ciliary number and length were measured in mosaic CRISPR-edited zebrafish embryos.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      with either sgRNA resulted in a significant reduction in head size at 3 dpf compared to either uninjected
      or sgRNA-only (no Cas9 protein) injected controls
    explanation: >-
      Two independent sgRNA/Cas9 perturbations reduce embryonic head size.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      crispants exhibited significant, reproducible alterations in facial skeletal morphology compared
      to controls, as measured by the angle of the bilateral ceratohyal cartilages
    explanation: >-
      The craniofacial readout is cartilage geometry, not human cleft-palate fusion.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      using either of our sgRNAs disrupted cardiac looping at 2 dpf
    explanation: >-
      The cardiac assay measures looping and laterality.
  modeled_mechanisms:
  - target: Defective Ciliogenesis
    relationship: PARTIALLY_RECAPITULATES
    limitations: >-
      Mosaic embryonic disruption; no patient-genotype or human-tissue cilia rescue is demonstrated.
  - target: Abnormal Left-Right Patterning
    relationship: PARTIALLY_RECAPITULATES
    limitations: >-
      Looping and left-right patterning are assessed; fish do not model human chamber septation.
  - target: Abnormal Brain Development
    relationship: PARTIALLY_RECAPITULATES
    limitations: >-
      Engineered model; does not establish the complete human developmental mechanism.
  - target: Abnormal Craniofacial Development
    relationship: PARTIALLY_RECAPITULATES
    limitations: >-
      Engineered model; does not establish the complete human developmental mechanism.
discussions:
- discussion_id: ccdc32_ap2_versus_cilia
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Do the craniofacial, cardiac and brain malformations of CFNDS arise from the
    endocytic consequences of failed AP-2 assembly, from a ciliary defect, or
    from both?
  attaches_to:
  - pathophysiology#Defective Ciliogenesis
  - pathophysiology#Deficient Clathrin-Mediated Endocytosis
  rationale: >-
    AP-2 assembly and coated-pit regulation have direct biochemical and cell-biological support. Ciliary
    changes and altered left-right patterning are demonstrated in the founding zebrafish and mouse-cell
    experiments. Their relationship remains unknown: neither a cilia-independent developmental route nor
    endocytosis-dependent disruption of cilia has been established in patient tissue.
  notes: >-
    Both proposed routes retain indirect edges to organ-level abnormalities.
  evidence:
  - reference: PMID:32307552
    reference_title: Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      arguing that ciliary defects are at least partially involved in the pathomechanism of this disorder
    explanation: >-
      The ciliary side of the question, stated by its own authors as a partial
      explanation, which is the hedge that keeps the question open.
  - reference: PMID:41489497
    reference_title: CCDC32 stabilizes clathrin-coated pits and drives their invagination.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our results suggest that the inability to bind mature AP2 and hence to be recruited to nascent CCSs
      inhibits critical early stages of CME and contributes to the development of CFNDS.
    explanation: >-
      The endocytic side of the question, also phrased as a suggestion and a
      contribution rather than as a demonstrated cause.
- discussion_id: ccdc32_ap2_chaperone_mechanism
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Is CCDC32 a transient assembly chaperone that is released before AP-2
    matures, or does it also bind the mature complex and act at clathrin-coated
    pits?
  attaches_to:
  - pathophysiology#Failure of AP-2 Adaptor Complex Assembly
  - pathophysiology#Clathrin-Coated Pit Destabilization
  rationale: >-
    The 2024 reconstitution study describes ordered AAGAB-to-CCDC32 handover and release of CCDC32 during
    assembly. The 2026 coated-pit study detects recruitment and association with native AP-2, using different
    tagging and imaging conditions. The structural study adds a membrane-dependent switch: CCDC32 stabilizes
    alpha/sigma2 and prevents or reverses tetramer assembly in solution, while PIP2 membranes relieve
    inhibition. These observations allow context-dependent assembly and post-assembly roles. Partial knockdown
    leaves AP-2 abundance intact despite pit defects, whereas knockout reduces subunit abundance.
  evidence:
  - reference: PMID:42234739
    reference_title: CCDC32 collaborates with the membrane to assemble the AP-2 clathrin adaptor complex.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Unexpectedly, in solution, CCDC32 prevents complex assembly and actively disassembles AP-2 tetramers.
    explanation: >-
      The third and most recent model, in which CCDC32 is inhibitory until
      membrane relieves the inhibition.
  - reference: PMID:42234739
    reference_title: CCDC32 collaborates with the membrane to assemble the AP-2 clathrin adaptor complex.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We propose that the membrane acts as a molecular switch to release inhibitory interactions, allowing
      for full complex assembly to proceed.
    explanation: The proposed reconciliation, which is itself a hypothesis.
- discussion_id: ccdc32_hypomorph_versus_null
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    How much CCDC32 protein and activity remains for each patient genotype?
  attaches_to:
  - pathophysiology#Biallelic CCDC32 Loss of Function
  rationale: >-
    The coated-pit study discusses possible residual function and nonsense-mediated decay, but its 1-54
    construct is not an exact patient frameshift product. Patient RNA downregulation and exon skipping
    are now reported for the 2026 deletion family. These data do not quantify residual protein or AP-2/cilia
    function across alleles. Elective termination of the affected founding fetus is not evidence of biological
    lethality.
  notes: >-
    Constitutive engineered knockout and a patient truncation or exon deletion may have different consequences;
    matched patient-protein and functional assays would resolve this.
  evidence:
  - reference: PMID:41489497
    reference_title: CCDC32 stabilizes clathrin-coated pits and drives their invagination.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      our disease mimic construct CCDC32(1-54) does not contain a 9 aa peptide (VRGSCLRFQ) in the N-terminus
      and an extra 12 aa in the C-terminus when CFNDS patient mutation was described (p.(Glu64Glyfs∗12))
    explanation: >-
      Explicit limits of transferring results from the engineered construct to the patient protein.
  - reference: url:https://www.nature.com/articles/s41431-026-02023-y/figures/2
    reference_title: "Fig. 2: Deletion of exon 3 and 4 of CCDC32 in affected individuals. | European Journal of Human Genetics | European Journal of Human Genetics"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      (not included in the ID and MCA panels) exhibited notable downregulation with a Z-score of -8.20.
    explanation: >-
      Panel membership explains part of the diagnostic blind spot; the RNA outlier is patient-specific.
- discussion_id: ccdc32_recurrent_15q15_deletion
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What are the verified breakpoints and phase of the reported structural alleles?
  attaches_to:
  - pathophysiology#Biallelic CCDC32 Loss of Function
  rationale: >-
    The 2022 deletion spans 32,583 bp, and the 2026 siblings have an exon-3/4 deletion confirmed by PCR
    and Sanger sequencing. For the 2024 fourth patient, the paper title and ClinGen assessment differ:
    ClinGen describes suspected 21-kb and 9.7-kb deletions in trans and excluded the proband from scoring.
    Near-matching uncertain registry coordinates do not establish a recurrent rearrangement, shared founder
    allele or a first-line worldwide breakpoint assay.
  notes: >-
    Primary breakpoint and segregation data are needed before treating different structural records as
    the same allele.
  evidence:
  - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_29c6c0dd-bbaf-45ce-92af-4c67059cac8f-2024-10-18T16:00:00.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      An additional 21 kb deletion was reported in a fourth proband (PMID: 38818818) but was not included
      in this curation.
    explanation: >-
      ClinGen records an unscored fourth case; the primary report has no accessible abstract in the cache.
  - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_29c6c0dd-bbaf-45ce-92af-4c67059cac8f-2024-10-18T16:00:00.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the following suspected deletions in trans: a 21 kb deletion ... and a 9.7 kb deletion
    explanation: >-
      The ClinGen case-level explanation describes two suspected deletions in trans, rather than a proven
      recurrence of the 2022 allele.
- discussion_id: ccdc32_expressivity_with_loss_of_function_alleles
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Which factors account for variable expressivity among individuals with predicted loss-of-function
    alleles?
  attaches_to:
  - pathophysiology#Biallelic CCDC32 Loss of Function
  - phenotypes#Hypertelorism
  rationale: >-
    The founding individuals differ in interorbital distance, cardiac lesions and laterality. Their variants
    are predicted loss-of-function alleles, but equivalent complete loss of every CCDC32 activity has
    not been measured. Residual transcript or protein, modifier loci and developmental variability are
    possible explanations, not established mechanisms or prognostic markers.
  notes: >-
    The discordant facial and cardiac observations are directly described in the 2020 clinical full text.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysmorphic features included hypotelorism, upslanting palpebral fissures, a stiff upper lip, missing
      teeth attributed to the clefting, vaulted palate with cleft, prominent ears, underdeveloped helices
      and micrognathia.
    explanation: >-
      A-II-1 had hypotelorism.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysmorphic features included brachydactyly, hypertelorism, epicanthal folds, broad nasal root, a
      prominent large nose and malformed protruded ears.
    explanation: >-
      B-II-1 had hypertelorism.
- discussion_id: ccdc32_phenotype_denominator_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the true frequency of each CFNDS feature, and what is the natural
    history beyond childhood?
  rationale: >-
    The 2026 review describes six living individuals and one fetus across five families after including
    its two siblings. Ascertainment and investigations differ between reports. These data do not establish
    population prevalence, reliable per-feature frequencies, adult outcome or survival. Prospective standardized
    phenotyping and follow-up would address the gap.
  evidence:
  - reference: PMID:41639596
    reference_title: Two siblings with CCDC32-related cardiofacioneurodevelopmental syndrome diagnosed by clinical RNA-sequencing and review of literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      So far, CFNDS has only been described in four living individuals and one terminated fetus from four
      families
    explanation: >-
      Quantifies the denominator problem: no frequency or natural-history claim
      can be made from a cohort of this size.
references:
- reference: PMID:32307552
  title: Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies.
- reference: PMID:35451546
  title: "Cardiofacioneurodevelopmental syndrome: Report of a novel patient and expansion of the phenotype."
- reference: PMID:38818818
  title: "A novel homozygous deletion in CCDC32 gene causing cardiofacioneurodevelopmental syndrome: the fourth patient reported."
- reference: PMID:41639596
  title: Two siblings with CCDC32-related cardiofacioneurodevelopmental syndrome diagnosed by clinical RNA-sequencing and review of literature.
- reference: PMID:33859415
  title: A genome-wide atlas of co-essential modules assigns function to uncharacterized genes.
- reference: PMID:39145939
  title: An AAGAB-to-CCDC32 handover mechanism controls the assembly of the AP2 adaptor complex.
- reference: PMID:41489497
  title: CCDC32 stabilizes clathrin-coated pits and drives their invagination.
- reference: PMID:42234739
  title: CCDC32 collaborates with the membrane to assemble the AP-2 clathrin adaptor complex.
- reference: PMID:31104773
  title: A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy.
- reference: PMID:20301365
  title: Cardiofaciocutaneous Syndrome.
  tags:
  - GeneReviews
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
  title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11348294/
  title: An AAGAB-to-CCDC32 handover mechanism controls the assembly of the AP2 adaptor complex - PMC
- reference: url:https://www.nature.com/articles/s41431-026-02023-y/figures/1
  title: "Fig. 1: Clinical hallmarks of Cardiofacioneurodevelopmental syndrome (CFNDS). | European Journal of Human Genetics | European Journal of Human Genetics"
- reference: url:https://www.nature.com/articles/s41431-026-02023-y/figures/2
  title: "Fig. 2: Deletion of exon 3 and 4 of CCDC32 in affected individuals. | European Journal of Human Genetics | European Journal of Human Genetics"
- reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_29c6c0dd-bbaf-45ce-92af-4c67059cac8f-2024-10-18T16:00:00.000Z
  title: curation results for Gene-Disease Validity
- reference: PMID:33275684
  title: Preventing infections in children and adults with asplenia.
experimental_models:
- name: CCDC32-knockout and rescue cell systems
  experimental_model_type: CELL_LINE
  cell_source: Engineered human HeLa cells; additional human iPSCs and mouse preadipocytes
  description: >-
    The 2024 study deleted CCDC32 in cultured cells, measured AP-2 subunits and receptor uptake, and restored
    AP-2 with a rescue gene. Additional engineered iPSC and mouse preadipocyte experiments support a role
    across cell contexts. These are not patient-derived CFNDS lines.
  modeled_mechanisms:
  - target: Reduced AP-2 Complex Abundance
    relationship: PERTURBS
    limitations: >-
      Engineered model; does not establish the complete human developmental mechanism.
  - target: Reduced AP-2 Complex Abundance
    relationship: RESCUES
    limitations: >-
      Engineered model; does not establish the complete human developmental mechanism.
  - target: Deficient Clathrin-Mediated Endocytosis
    relationship: PERTURBS
    limitations: >-
      Engineered model; does not establish the complete human developmental mechanism.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11348294/
    reference_title: An AAGAB-to-CCDC32 handover mechanism controls the assembly of the AP2 adaptor complex - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      expression of AP2 subunits was diminished
    explanation: >-
      AP-2 abundance was reduced in knockout cells.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11348294/
    reference_title: An AAGAB-to-CCDC32 handover mechanism controls the assembly of the AP2 adaptor complex - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      AP2 expression was fully restored when a CCDC32 rescue gene was expressed
    explanation: >-
      Genetic rescue supports specificity of the knockout effect.
- name: CCDC32 knockdown and disease-mimic rescue in ARPE-HPV cells
  experimental_model_type: CELL_LINE
  cell_source: Immortalized human retinal pigment epithelial cells
  description: >-
    Partial siRNA knockdown, live-cell pit imaging and transferrin uptake distinguish pit dynamics from
    AP-2 abundance. CCDC32(1-54) lacks AP-2 binding and does not restore uptake. The construct differs
    from the patient frameshift product; intact AP-2 protein levels distinguish this experiment from knockout.
  modeled_mechanisms:
  - target: Clathrin-Coated Pit Destabilization
    relationship: PERTURBS
    limitations: >-
      Engineered model; does not establish the complete human developmental mechanism.
  - target: Deficient Clathrin-Mediated Endocytosis
    relationship: PERTURBS
    limitations: >-
      Engineered model; does not establish the complete human developmental mechanism.
  evidence:
  - reference: PMID:41489497
    reference_title: CCDC32 stabilizes clathrin-coated pits and drives their invagination.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Under our conditions of CCDC32 knockdown, we did not detect any decrease in protein levels of the
      AP2 complex
    explanation: >-
      Pit defects in this knockdown experiment cannot be attributed to measured AP-2 depletion.
  - reference: PMID:41489497
    reference_title: CCDC32 stabilizes clathrin-coated pits and drives their invagination.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      our disease mimic construct CCDC32(1-54) does not contain a 9 aa peptide (VRGSCLRFQ) in the N-terminus
      and an extra 12 aa in the C-terminus when CFNDS patient mutation was described (p.(Glu64Glyfs∗12))
    explanation: >-
      Explicit limits of transferring results from the engineered construct to the patient protein.
- name: Ccdc32 knockdown in IMCD3 cells
  experimental_model_type: CELL_LINE
  cell_source: Mouse inner medullary collecting duct IMCD3 5-HT6-GFP cells
  description: >-
    siRNA-mediated Ccdc32 knockdown impairs cilia formation in a cultured mouse renal epithelial model.
  modeled_mechanisms:
  - target: Defective Ciliogenesis
    relationship: PERTURBS
    limitations: >-
      Engineered model; does not establish the complete human developmental mechanism.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/
    reference_title: "Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cilia formation was similarly impaired in ciliated mouse inner medullary collecting duct cells with
      GFP-labeled cilia (IMCD3 5-HT6-GFP) following siRNA-mediated knockdown
    explanation: >-
      The mouse experiment used cultured cells, not an intact mouse model.
- name: Patient fibroblast RNA sequencing
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Fibroblasts from individual 1 in the 2026 sibling family, with unrelated controls
  description: >-
    RNA sequencing in cultured patient fibroblasts, with and without cycloheximide, revealed CCDC32 downregulation
    and loss of exons 3 and 4. Genomic PCR and Sanger sequencing confirmed the deletion. This demonstrates
    transcript consequences, not a direct patient AP-2 or cilia functional assay.
  evidence:
  - reference: url:https://www.nature.com/articles/s41431-026-02023-y/figures/2
    reference_title: "Fig. 2: Deletion of exon 3 and 4 of CCDC32 in affected individuals. | European Journal of Human Genetics | European Journal of Human Genetics"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      locus showing RNA-seq of fibroblast cultured with or without cycloheximide (CHX) for individual
      1 and unrelated controls
    explanation: >-
      Specifies the patient-derived tissue system and experimental condition.
  - reference: url:https://www.nature.com/articles/s41431-026-02023-y/figures/2
    reference_title: "Fig. 2: Deletion of exon 3 and 4 of CCDC32 in affected individuals. | European Journal of Human Genetics | European Journal of Human Genetics"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      (not included in the ID and MCA panels) exhibited notable downregulation with a Z-score of -8.20.
    explanation: >-
      Panel membership explains part of the diagnostic blind spot; the RNA outlier is patient-specific.

📚

References & Deep Research

References

16

PMID:32307552

Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies.

No top-level findings curated for this source.

PMID:35451546

Cardiofacioneurodevelopmental syndrome: Report of a novel patient and expansion of the phenotype.

No top-level findings curated for this source.

PMID:38818818

A novel homozygous deletion in CCDC32 gene causing cardiofacioneurodevelopmental syndrome: the fourth patient reported.

No top-level findings curated for this source.

PMID:41639596

Two siblings with CCDC32-related cardiofacioneurodevelopmental syndrome diagnosed by clinical RNA-sequencing and review of literature.

No top-level findings curated for this source.

PMID:33859415

A genome-wide atlas of co-essential modules assigns function to uncharacterized genes.

No top-level findings curated for this source.

PMID:39145939

An AAGAB-to-CCDC32 handover mechanism controls the assembly of the AP2 adaptor complex.

No top-level findings curated for this source.

PMID:41489497

CCDC32 stabilizes clathrin-coated pits and drives their invagination.

No top-level findings curated for this source.

PMID:42234739

CCDC32 collaborates with the membrane to assemble the AP-2 clathrin adaptor complex.

No top-level findings curated for this source.

PMID:31104773

A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy.

No top-level findings curated for this source.

PMID:20301365

Cardiofaciocutaneous Syndrome.

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788/

Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies - PMC

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11348294/

An AAGAB-to-CCDC32 handover mechanism controls the assembly of the AP2 adaptor complex - PMC

No top-level findings curated for this source.

url:https://www.nature.com/articles/s41431-026-02023-y/figures/1

Fig. 1: Clinical hallmarks of Cardiofacioneurodevelopmental syndrome (CFNDS). | European Journal of Human Genetics | European Journal of Human Genetics

No top-level findings curated for this source.

url:https://www.nature.com/articles/s41431-026-02023-y/figures/2

Fig. 2: Deletion of exon 3 and 4 of CCDC32 in affected individuals. | European Journal of Human Genetics | European Journal of Human Genetics

No top-level findings curated for this source.

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_29c6c0dd-bbaf-45ce-92af-4c67059cac8f-2024-10-18T16:00:00.000Z

curation results for Gene-Disease Validity

No top-level findings curated for this source.

PMID:33275684

Preventing infections in children and adults with asplenia.

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (3)

Review CCDC32 clinical and mechanistic evidence against full texts · 2026-10-04T07:35:39Z · View source

Reviewed the complete existing entry against cached primary sources and the matching claude_code deep-research report and citation list. Eligible Mendelian entry with no prior REVIEW event; infectious, environmental and poisoning entries remain excluded. The isolated branch was created from and rebased onto origin/main dc36c5202f4. Recovered the full 2020 clinical/model paper and full 2024 PNAS paper through the NCBI PMC URL fetcher. Refetched PMID:42234739 as full_text_xml and read its structural mechanism alongside the cached full eLife article. Used the public 2026 Nature figure captions for MRI, fibroblast RNA and genomic-confirmation findings. The PMID:41639596 cache is labeled full_text_html but contains a landing-page abstract, not the full paper; primary full texts for the 2022 and 2024 clinical reports and the complete 2026 clinical article remained inaccessible. Cached ClinGen's dated gene-validity assertion. Every cache file was generated/refreshed by repository reference-fetching tools; no reference-cache Markdown was manually created or edited. Content-completeness cross-check: - Phenotypes: replaced nine HPO-only assertions with primary full-text evidence and expanded the entry from 26 to 44 specific observations, removing broad duplicate facial, cardiac, laterality and finger rows. Included pontine hypoplasia, hyperactivity, epicanthus, additional facial/digital findings, anterior pituitary hypoplasia, absent right internal carotid artery and a thin optic nerve. Did not infer hormone deficiency, optic atrophy, primary hypodontia or population frequencies. - Subtypes: no source-defined mechanistically distinct CFNDS subtypes justified. - Pathophysiology: separated knockout-associated AP-2 abundance loss from coated-pit defects under partial knockdown with normal AP-2 levels. Retained the membrane-dependent assembly model and indirect human developmental links; separated organ outcomes. - Treatments/trials: retained explicitly extrapolated supportive care, removed unsupported fixed ages and universal lifelong antibiotics, and cited the asplenia review for risk-dependent prevention. No verified disease-modifying trial surfaced. - Genetics: corrected exact patient allele versus 1-54 experimental construct, used transcript-version-aware nomenclature, preserved VUS uncertainty, distinguished structural alleles and documented ClinGen's unscored fourth case. Removed ungrounded recurrent-deletion/founder and fetal-lethality inferences and title-only evidence. - Diagnostics/biomarkers: added patient fibroblast RNA findings and PCR/Sanger confirmation; explained the earlier gene-panel omission instead of claiming DNA invisibility. - References: incorporated recovered clinical, experimental and figure material; unavailable PMID:38818818 remains a bibliographic lead only. New evidence titles were read against the cache and matched to their attached findings. - Overall: incorporated central quotable research leads while rejecting unsupported prevalence, carrier-frequency, universal-absence and protocol claims in the report. Corrected the zebrafish model to mosaic F0 CRISPR/Cas9, two sgRNAs within one study; the 2022 report is a citation, not independent replication. Added engineered human cell, mouse IMCD3 and patient-fibroblast systems with explicit translational limits. The GeneReviews check returns TAGGED for the differential-only cardiofaciocutaneous chapter; it is not a clinical baseline for CCDC32-related CFNDS. Live HPO term/definition lookups were used for new bindings; unmatched anatomy remained explicitly unbound. Moved curation-session narrative out of the disease notes. The deep-research reference validation resolved all 20 references (zero off-topic findings). Offline snippet validation verified 141/141 evidence items with none unavailable or mismatched. Final batched schema, live-term and reference validation passed: 141 snippets and 157 titles checked, zero skipped/unavailable snippets or issues. Rendering passed; causal targets, coarse phenotypes, entity references, qualifier terms and node-class examples resolved. Gene activity grounding is 1/1. The single added HPO cache row is HP:0001802 (Absent toenail), generated by term validation.

Address PR #7726 review: allele-level variant curation, NCIT specificity, NAHR knowledge gap · 2026-08-01T19:42:03Z · View source

Response to the ai4c-reviewer REQUEST_CHANGES review on PR #7726 (1 IMPORTANT, 6 SUGGESTIONS). BLOCKING ITEM 1 - genetic.variants lacked allele-level detail. Added three new allele-level Variant blocks (CCDC32 c.27dup / p.Thr10fs family A; c.162_163dup / p.Glu55fs family B; c.471T>A / p.Tyr157Ter VUS) carrying synonyms for both published and current HGVS nomenclatures, identifiers (ClinVar VCV, OMIM allelic variant, dbSNP, ClinGen CAID), and external_assertions recording each ClinVar germline classification with review status and evaluation date. Added ClinVar accessions plus external_assertions for the two large deletions. Every identifier was verified live against the NCBI eutils ClinVar esummary and VCV efetch endpoints on 2026-08-01, not taken from the deep-research artifact. Transcript hazard: the research artifact framed the c.54dupT vs c.27dup discrepancy as a transcript-CHOICE difference (NM_001080791.2 vs NM_001080792.4). The ClinVar VCV XML shows this is wrong - all thirteen current RefSeq transcripts, including NM_001080791.4, number the alleles c.27dup and c.162_163dup. It is a transcript-VERSION artefact with a 9-codon offset, the same offset that explains the 194 vs 185 aa protein-length discrepancy. Curated as such in genetic[0].notes, with the direct documentation quoted from PMID:41489497 (the 9 aa VRGSCLRFQ N-terminal peptide sentence). Gene constraint: recorded pLI 0.16 / LOEUF 0.78 (obs 9 / exp 20.1 LoF) from a live gnomAD GraphQL query on 2026-08-01, explicitly noting these differ from the research artifact's pLI 0.19 / LOEUF 0.76 and that the verified values are the ones recorded. SUGGESTION 2 - replaced generic NCIT:C15329 on the cleft treatment with NCIT:C168380 Palatorrhaphy and split the treatment into cleft palate repair and cleft lip repair. SUGGESTION 3 - added Nutritional and feeding support in infancy (NCIT:C15433) and Orchidopexy for cryptorchidism (NCIT:C111066 Orchiopexy, verified reachable from NCIT:C25218), closing the promote-then-manage loop for HP:0008872 and HP:0000028. SUGGESTION 4 - added the ccdc32_recurrent_15q15_deletion KNOWLEDGE_GAP discussion covering the possible NAHR-mediated or founder recurrent deletion, with the ClinVar breakpoint coordinates and an explicit statement that the coordinates are ClinVar record fields rather than author claims, and that the Fernandes da Rocha breakpoints are HGVS-uncertain. SUGGESTION 5 - DECLINED. The three-organ outcome node is left unsplit; reasoning recorded as entry note (13). SUGGESTION 6 - DECLINED promotion of HP:0012110, HP:0000286, HP:0000752. Neither route into the entry is available: the HPO API was re-queried on 2026-08-01 and returns 25 terms, none of them these three; PMID:32307552 was re-fetched and remains abstract_only, and a grep across all cached references for this entry finds no clinical hit. Reasoning recorded as entry note (10a) with the verified HP identifiers preserved for a future curator. SUGGESTION 7 - replaced the mid-clause PMID:39145939 fragment with a complete ASCII sentence carrying the same claim. Validation: just validate / validate-terms / validate-references all pass; both snippet checkers report 88/88 verbatim; check_folded_hyphens --check OK; validate-history-all passes. references_cache/ churn from the validator was reverted and no new cache file was needed.

Create: cardiofacioneurodevelopmental syndrome · 2026-08-01T17:06:57Z · View source

Created kb/disorders/Cardiofacioneurodevelopmental_Syndrome.yaml for MONDO:0030873 (OMIM:619123), causal gene CCDC32 (hgnc:28295), toward epic #1079. NEC preflight PASSED before any deep-research content was used: runoak on MONDO:0030873 returned RO:0004003 HGNC:28295 CCDC32 and xref OMIM:619123, and runoak relationships on HGNC:28295 returned MONDO:0030873 as the only linked disease; a gene-mention count over the claude_code deep-research report returned 123 CCDC32/C15orf57 hits against 3 genuine BRAF hits (all inside a cardiofaciocutaneous differential row), with OMIM:619123 asserted 10 times. The entry was nevertheless drafted from primary literature before the report finished; the report was used only as a coverage cross-check and as the source of two leads (the HPO annotation set and the ClinGen classification), each of which was then re-verified independently against ontology.jax.org and search.clinicalgenome.org respectively. Curated eight PMIDs, all fetched with just fetch-reference: PMID:32307552 (founding report, zebrafish, ciliary arm), PMID:35451546 (phenotype expansion and core phenotype), PMID:38818818 (fourth patient; PubMed-indexed WITHOUT an abstract, so the single evidence item citing it quotes the article title and no clinical detail from it is asserted), PMID:41639596 (two siblings, RNA-seq diagnosis, 2026 review), PMID:33859415 (co-essentiality screen linking C15orf57 to AP2), PMID:39145939 (AAGAB-to-CCDC32 handover), PMID:41489497 (clathrin-coated pit stabilization; patient-derived truncation), PMID:42234739 (membrane-switch AP-2 assembly), plus PMID:31104773 and PMID:20301365 cited ONLY inside differential-diagnosis blocks. Modelled a six-node pathograph with two competing mechanism arms recorded as mechanistic_hypotheses (AP-2 assembly chaperone / CME, CANONICAL, ESTABLISHED; ciliary contribution, ALTERNATIVE, PROVISIONAL) and both edges into the morphogenesis outcome typed INDIRECT_UNKNOWN_INTERMEDIATES because neither arm has been connected to a human malformation. Four discussions capture the open questions (AP2 vs cilia, the three-way disagreement between the 2024-2026 AP-2 mechanism papers, hypomorph vs null, and the denominator/natural-history gap). NO frequency band is asserted on any phenotype and no prevalence rate is given, because the total published denominator is fewer than ten individuals; raw counts are recorded in per-phenotype notes instead. Nine phenotypes derived from the HPO annotation for OMIM:619123 are curated WITHOUT evidence items and each says so explicitly in its notes, because the underlying counts come from the full text of PMID:32307552, which returned HTTP 403 from both the publisher and PMC. Validated: just validate (schema, terms, references) PASS with 83/83 snippets verified; scripts/check_snippets_verbatim.py PASS 83/83; just validate-terms PASS; check_folded_hyphens PASS; linkml-data-qc compliance 91.7 percent global, 92.1 percent weighted; 5292 targeted pytest data tests pass.

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-opus-5[1m] 28 citations 2026-08-01T09:53:10.150078

1. Disease Information

Overview

Cardiofacioneurodevelopmental syndrome (CFNDS) is an autosomal recessive multiple-congenital-anomaly syndrome caused by biallelic loss-of-function variants in CCDC32. Its recognized core is global developmental delay plus bilateral cleft lip and palate, with a variable constellation of craniofacial dysmorphism, congenital heart disease, hindbrain (cerebellar vermian) hypoplasia, microcephaly, digital/nail anomalies, postnatal growth restriction, and — in one individual — laterality disturbance (abdominal situs inversus with asplenia).

The MedGen/OMIM clinical definition:

"Characterized by microcephaly, midline facial defects, developmental delay, and cerebellar hypoplasia. Variable cardiac defects may be present, including atrioventricular canal and ventricular septal defects. Heterotaxy has also been reported." — MedGen UID 1721861

Abdalla et al. proposed the two-feature core:

"We describe a core phenotype comprising developmental delay and bilateral cleft lip and palate in the three individuals with CFNDS." — PMID:35451546 (verbatim, abstract)

Key identifiers

Resource	Identifier
MONDO	MONDO:0030873 (label: "Cardiofacioneurodevelopmental syndrome"; exact synonym "CFNDS")
OMIM (phenotype)	619123
OMIM (gene)	618941 (CCDC32)
MedGen	UID 1721861
UMLS	C5436852
Orphanet	No ORPHA code identified. Direct Orphanet query returned no matching entry; MONDO:0030873 carries no Orphanet xref. Flag as an ontology-coverage gap.
ICD-10	No specific code. Best fits Q87.8 (other specified congenital malformation syndromes NEC). No dedicated code assigned.
ICD-11	No specific code. Best fits LD2F.1Y / LD2F (other specified syndromes with multiple structural anomalies). Not formally assigned.
MeSH	No dedicated descriptor. Indexed under MeSH terms of the source papers: Craniofacial Abnormalities, Heart Defects, Congenital, Neurodevelopmental Disorders, Ciliopathies, Cleft Lip, Cleft Palate, Loss of Function Mutation.
GARD	Not identified.
ClinGen	Gene-disease validity curated (see §4).

Synonyms / alternative names

CFNDS (standard abbreviation)
CCDC32-related cardiofacioneurodevelopmental syndrome (usage in Albuainain et al. 2026, PMID:41639596)
CCDC32 deficiency / CCDC32-related syndrome (informal)
Historical gene alias in older literature: C15orf57-related syndrome

Provenance of information

Entirely aggregated disease-level and case-level literature. All data derive from individual published case reports and one review; there is no EHR-derived cohort, no patient registry, no natural-history study, and no biobank cohort for CFNDS. No ICEES/COHD-style co-occurrence data exist for this entity (it has no ICD code to key on).

2. Etiology

Disease causal factors

Purely monogenic and germline. CFNDS is caused by biallelic (homozygous, in all published families) loss-of-function variants in CCDC32. No environmental, infectious, or acquired etiology is known or plausible.

"Using whole exome sequencing, we identified homozygous frameshift CCDC32 variants in three affected individuals." — PMID:32307552 (verbatim, abstract)

All reported probands to date are homozygous, arising in the context of parental consanguinity in at least two of the founding families. Compound heterozygosity is theoretically expected but has not yet been reported.

Risk factors

Genetic (causal): - Biallelic CCDC32 LoF variants (frameshift, whole-gene/multi-exon deletion, nonsense) — see §4. - Carrier parents (obligate heterozygotes are unaffected; no heterozygous phenotype reported).

Non-genetic modifier of risk: - Consanguinity is the dominant epidemiological risk factor, as for essentially all ultra-rare AR disorders. Family A was a consanguineous Arab Muslim pedigree (first cousins once removed); Family B a consanguineous Iranian (Isfahan) pedigree [PMC7268788, full text]. - Founder/population endogamy may explain the apparently recurrent large deletion allele (§4).

Environmental risk factors: none identified. No toxin, teratogen, maternal exposure, occupational, dietary, or lifestyle risk factor has been implicated. Given complete genetic determinism at the causal level, none is expected.

Age / sex / family history: Disease is congenital; sex distribution is unremarkable in the tiny cohort (roughly balanced). Family history of consanguinity or an affected sib is the actionable risk signal.

Protective factors

None identified. No protective allele, modifier allele, or environmental protective factor has been reported. gnomAD contains no reported homozygous LoF individuals that would suggest incomplete penetrance or a protective background.

Gene–environment interactions

None identified. No GxE data exist for CFNDS. CTD contains no CCDC32–chemical–disease interaction of relevance to this phenotype.

Curation note / open question: Harel et al. explicitly raised genetic modifiers as a candidate explanation for the incomplete ciliopathy phenotype (absence of cystic kidney disease and polydactyly), citing possible "cis/trans genetic interactions" [PMC7268788, full text]. This is an appropriate KNOWLEDGE_GAP discussion item.

3. Phenotypes

3.1 HPO annotation set (authoritative, from HPOA)

Retrieved from the HPO API for OMIM:619123. Sole annotation source: PMID:32307552 (2 individuals). Frequencies are literal patient counts.

HP ID	Label	Freq	HPO organ system
HP:0001263	Global developmental delay	2/2	Nervous system
HP:0000252	Microcephaly	2/2	Head and neck
HP:0410030	Cleft lip	2/2	Head and neck
HP:0000175	Cleft palate	2/2	Head and neck
HP:0000411	Protruding ear	2/2	Ear
HP:0004209	Clinodactyly of the 5th finger	2/2	Limbs
HP:0008872	Feeding difficulties in infancy	2/2	Digestive
HP:0003577	Congenital onset	2/2	Clinical course
HP:0001320	Cerebellar vermis hypoplasia	1/1	Nervous system
HP:0000028	Cryptorchidism	1/1	Male-specific
HP:0006695	Atrioventricular canal defect	1/2	Cardiovascular
HP:0001629	Ventricular septal defect	1/2	Cardiovascular
HP:0001642	Pulmonic stenosis	1/2	Cardiovascular
HP:0001746	Asplenia	1/2	Cardiovascular
HP:0003363	Abdominal situs inversus	1/2	Digestive
HP:0000316	Hypertelorism	1/2	Eye
HP:0000601	Hypotelorism	1/2	Eye
HP:0000582	Upslanted palpebral fissure	1/2	Head and neck
HP:0000347	Micrognathia	1/2	Head and neck
HP:0001156	Brachydactyly	1/2	Limbs
HP:0012385	Camptodactyly	1/2	Connective tissue
HP:0008386	Aplasia/Hypoplasia of the nails	1/2	Skin, hair, nails
HP:0007477	Abnormal dermatoglyphics	1/2	Skin, hair, nails
HP:0002808	Kyphosis	1/2	Skeletal
HP:0000007	Autosomal recessive inheritance	—	Inheritance

Note the hypertelorism/hypotelorism split (1/2 each) — this is genuine phenotypic discordance between the two index patients, not an annotation error: Individual A-II-1 had hypotelorism, Individual B-II-1 had hypertelorism [PMC7268788, full text]. This is mechanistically interesting (both are midline-patterning readouts in opposite directions) and worth a curation note.

3.2 Additional phenotypes from later reports (not yet in HPOA)

Suggested HPO terms below were verified against OLS:

HP ID	Label	Source	Notes
HP:0001249	Intellectual disability	PMID:35451546	9-y-o girl, Abdalla patient
HP:0002079	Hypoplasia of the corpus callosum	PMID:35451546	"Brain imaging disclosed hypoplastic corpus callosum"
HP:0000405	Conductive hearing impairment	PMID:35451546	Bilateral
HP:0004322	Short stature	PMID:35451546
HP:0012110	Hypoplasia of the pons	PMID:32307552 (fetus A-II-2)	[full text]
HP:0001321	Cerebellar hypoplasia	PMID:41639596	Review-level phenotype statement
HP:0000286	Epicanthus	PMID:32307552	Individual B-II-1 [full text]
HP:0000752	Hyperactivity	PMID:32307552	Individual B-II-1 [full text]

Additional descriptive features from full text, without a crisply matching specific HP term, best captured as free-text preferred_term on a broader parent: stiff upper lip, vaulted palate, underdeveloped helices, broad nasal root, prominent large nose, nail clubbing, small hands and feet, abnormal cisterna magna, missing teeth (HP:0000670 Carious teeth / HP:0000668 Hypodontia — verify against the exact clinical description before assigning).

3.3 Phenotype characteristics

Type distribution: Predominantly congenital structural malformations (craniofacial, cardiac, CNS, limb) plus neurodevelopmental/behavioral features. There are no reported disease-specific laboratory abnormalities — no biomarker, no metabolic derangement, no characteristic biochemical signature. This is important: CFNDS has no biochemical diagnostic handle.

Age of onset: Congenital (HP:0003577), 2/2. Structural anomalies are present prenatally — the terminated fetus A-II-2 was ascertained on prenatal imaging with bilateral cleft lip, vermian hypoplasia, hypoplastic pons, and abnormal cisterna magna [PMC7268788, full text]. Developmental delay declares itself in infancy; feeding difficulties are an early-infancy presentation (2/2).

Severity: Variable. Structural anomalies range from lethal-in-utero-decision severity (fetus) through moderate (VSD + pulmonic stenosis, moderate motor/language delay) to comparatively mild growth findings (one patient at 80th centile height). Neurodevelopmental severity spans "moderately delayed motor and language development" to frank intellectual disability.

Progression: The malformations are static (non-progressive congenital structural defects). The neurodevelopmental phenotype is developmental, not neurodegenerative — no regression, no progressive neurological decline has been reported in any patient. Cerebellar and callosal hypoplasia are developmental (hypoplasia), not atrophic.

Frequency: See table. All frequencies are n/2 or n/6 and are not generalizable. Only DD and bilateral cleft lip/palate approach "obligate" status, and even that is a proposal from a three-patient series.

3.4 Quality-of-life impact

No CFNDS-specific QoL data exist. No EQ-5D, SF-36, PROMIS, or disease-specific PROM has been administered. The following are reasoned extrapolations from the constituent phenotypes and should be curated as such (not as CFNDS evidence):

Bilateral cleft lip/palate (2/2 → likely near-obligate): feeding difficulty in infancy, speech/resonance impairment, recurrent otitis media and conductive hearing loss, multiple staged surgeries through childhood, facial-appearance psychosocial burden. Highest-burden single feature.
Global developmental delay / ID: dominant long-term determinant of independence and caregiver burden.
Congenital heart disease (AVSD/VSD/PS): surgical morbidity; AVSD in particular carries meaningful operative and long-term valve-function burden.
Conductive hearing loss: compounds the speech impact of cleft palate.
Feeding difficulties (2/2): early-infancy nutritional and caregiver burden.
Asplenia (with heterotaxy): lifelong invasive-infection risk requiring prophylaxis — see §12/§13.

4. Genetic / Molecular Information

4.1 Causal gene

Field	Value
Symbol	CCDC32
HGNC	HGNC:28295 → CURIE `hgnc:28295` (lowercase prefix per dismech convention)
Approved name	"coiled-coil domain containing 32"
Previous symbol	C15orf57 (appears in older literature and in Abdalla 2022)
Alias	MGC20481
Locus	15q15.1
Ensembl	ENSG00000128891
NCBI Gene	90416
UniProt	Q9BV29
OMIM (gene)	618941
RefSeq	NM_052849 (HGNC canonical); NM_001080791.2 used by Harel 2020; NM_001080792.4 used by ClinVar
Locus type	gene with protein product
Protein	194-amino-acid polypeptide (isoform reported by Harel et al.); multiple transcript variants exist

⚠️ Transcript-nomenclature hazard. Published HGVS for the two founding frameshifts is on NM_001080791.2, but ClinVar reports the same alleles on NM_001080792.4 with different numbering. Curate both and note the transcript explicitly:

Family	Published (NM_001080791.2)	ClinVar (NM_001080792.4)
A	c.54dupT, p.(Thr19Tyrfs*12)	c.27dup, p.(Thr10fs)
B	c.189_190dupGG, p.(Glu64Glyfs*12)	c.162_163dup, p.(Glu55fs)

4.2 Pathogenic variants reported

#	Variant	Type	HGVS / coordinates	Zygosity	Family / origin	Reference
1	c.54dupT	Frameshift (1-bp dup)	NM_001080791.2:c.54dupT, p.(Thr19Tyrfs*12); chr15:g.40855188dupA (hg19)	Homozygous	Family A, consanguineous Arab Muslim	PMID:32307552
2	c.189_190dupGG	Frameshift (2-bp dup)	NM_001080791.2:c.189_190dupGG, p.(Glu64Glyfs*12); chr15:g.40855052dupCC	Homozygous	Family B, consanguineous Iranian (Isfahan)	PMID:32307552
3	~32.6-kb deletion	Multi-exon/whole-gene deletion	NC_000015.10:g.40529942_40562524del (ClinVar VCV001690313, Pathogenic, condition = CFNDS)	Homozygous	Abdalla patient (9-y-o female)	PMID:35451546
4	~32.6-kb deletion	Deletion	NC_000015.10:g.(40529939_40562522)del (ClinVar VCV002431643, Pathogenic, condition = CFNDS)	Homozygous	Fernandes da Rocha patient (Portugal)	PMID:38818818
5	Deletion of exons 3–4	Intragenic multi-exon deletion, detected as exon skipping on RNA-seq	Exons 3 and 4 of CCDC32	Biallelic	Two siblings, Rotterdam	PMID:41639596
6	p.Tyr157Ter	Nonsense	ClinVar VCV002580223, VUS, condition = CFNDS	Not stated	ClinVar submission	ClinVar

Verbatim support for variant 3:

"We report a 9-year-old female patient with CFNDS caused by a homozygous 32,583-bp deletion affecting CCDC32. Independent of the affected CCDC32 transcript variant this deletion likely leads to loss of the encoded protein." — PMID:35451546 (verbatim, abstract)

🔬 Novel observation worth flagging (hypothesis, needs verification): ClinVar records VCV001690313 and VCV002431643 have near-identical breakpoints (g.40529942_40562524 vs g.40529939_40562522) yet correspond to patients reported independently from different centres (Abdalla et al., Egypt/Hamburg; Fernandes da Rocha et al., Porto). This is consistent with a recurrent, likely repeat-mediated (NAHR) deletion allele at 15q15.1, or possibly a founder allele. I could not confirm the Fernandes da Rocha breakpoints directly — that paper has no abstract in PubMed and the full text is paywalled. Curate this as a KNOWLEDGE_GAP/hypothesis, not as an established fact.

Variant classification (ACMG/AMP): ClinVar carries 4 Pathogenic CFNDS-associated CCDC32 alleles (two frameshift dups, two large deletions), all with the criteria-provided or no-assertion review status — none are expert-panel reviewed. One nonsense VUS exists. There are no ClinGen variant-curation assertions for CCDC32.

Variant class distribution: exclusively loss-of-function — frameshift duplications, whole-gene/multi-exon deletions, and (VUS) nonsense. No pathogenic missense variant has been reported. This matters mechanistically: the disease is a pure LoF/hypomorph disorder, not a gain-of-function or dominant-negative one.

Allele frequency: Both founding frameshifts were:

"Absent from gnomAD, TOPMed, Geno2MP, and GME Variome" [PMC7268788, full text]

Gene-level constraint (gnomAD v4.0): pLI = 0.19, LOEUF = 0.76. Both indicate CCDC32 is tolerant of heterozygous LoF — exactly the expected signature for a recessive disease gene, and a useful reassurance that carriers are unaffected. (LOEUF 0.76 sits above the conventional <0.6 Mendelian-dominant threshold.)

Somatic vs germline: Germline only. No somatic role. COSMIC/TCGA report no recurrent driver role for CCDC32.

Functional consequence: Loss of function. Mechanistic work (§6) shows the disease-associated truncations remove the α-helical AP-2-binding region:

"Disease-causing mutations…lack the α-helix encoded by residues 78–98…defective in AP2 binding" [PMC12768407, eLife, full text] "The CCDC32 mutant was defective in binding AP2 α and σ2 when expressed at similar levels as WT" [PMC11348294, PNAS, full text] "The AP2-regulating function of CCDC32 is disrupted by a disease-causing mutation" [PMC11348294, full text]

4.3 ClinGen gene–disease validity

Field	Value
Gene	CCDC32 (HGNC:28295)
Disease	Cardiofacioneurodevelopmental syndrome (MONDO:0030873)
MOI	Autosomal recessive (AR)
Classification	MODERATE
Expert panel	Syndromic Disorders GCEP
Date	2024-10-18

This is a CGGV-citable structured assertion for dismech evidence. Note it is Moderate, not Definitive — appropriate epistemic humility for a 5-family disease. (Structured-source citation would take the form CGGV:<assertion_id>; the assertion ID must be resolved from the ClinGen CSV via just clingen-rebuild before citing.)

ClinGen dosage sensitivity: no curation exists (0 classifications) — so no CGDS citation is available.

4.4 Modifier genes

None identified. Harel et al. invoke unspecified modifiers to explain absent classical ciliopathy features, but no modifier locus has been mapped.

4.5 Epigenetic information

No data. No methylation episignature has been described for CFNDS. (This is a plausible future study — episignatures now exist for many Mendelian NDDs — and is a reasonable KNOWLEDGE_GAP.)

4.6 Chromosomal abnormalities

The pathogenic alleles include intragenic and whole-gene deletions at 15q15.1, i.e. CNVs rather than SNVs, in 3 of 5 families. Critically:

"This deletion was not detected in previous SNP array analyses and trio exome sequencing" [PMID:41639596]

No CFNDS case has been attributed to aneuploidy, translocation, inversion, or a contiguous-gene 15q15 microdeletion syndrome. Larger 15q duplications/gains overlapping CCDC32 appear in ClinVar but are unrelated pathogenic CNVs of other phenotypes.

5. Environmental Information

Environmental factors: Not applicable. No toxin, radiation, pollutant, or occupational exposure is implicated. CTD contains no relevant CCDC32–chemical–disease axis for this phenotype.
Lifestyle factors: Not applicable. No smoking, diet, exercise, or alcohol association. (Note: general periconceptional folate status modifies non-syndromic orofacial clefting risk in the population — this is not established as relevant to the syndromic, monogenic clefting in CFNDS and should not be curated as a CFNDS factor.)
Infectious agents: Not applicable. No infectious etiology or trigger.

The only non-genetic factor with real epidemiological traction is consanguinity (§2, §9), which is a population-structure variable rather than an environmental exposure.

6. Mechanism / Pathophysiology

CFNDS has a genuinely contested and rapidly evolving mechanism, which is the most scientifically interesting aspect of this entry. Two models exist; the second has largely overtaken the first in molecular support, but the first carries the developmental-phenotype evidence.

6.1 Model A — Ciliopathy (Harel et al. 2020; the original proposal)

The founding paper framed CFNDS as a ciliopathy on the basis of phenotype overlap (laterality defect, cerebellar hypoplasia, craniofacial anomalies) plus direct functional data.

Full verbatim abstract (PMID:32307552) — safe for evidence snippets:

"Despite the wide use of genomics to investigate the molecular basis of rare congenital malformations, a significant fraction of patients remains bereft of diagnosis. As part of our continuous effort to recruit and perform genomic and functional studies on such cohorts, we investigated the genetic and mechanistic cause of disease in two independent consanguineous families affected by overlapping craniofacial, cardiac, laterality and neurodevelopmental anomalies. Using whole exome sequencing, we identified homozygous frameshift CCDC32 variants in three affected individuals. Functional analysis in a zebrafish model revealed that ccdc32 depletion recapitulates the human phenotypes. Because some of the patient phenotypes overlap defects common to ciliopathies, we asked if loss of CCDC32 might contribute to the dysfunction of this organelle. Consistent with this hypothesis, we show that ccdc32 is required for normal cilia formation in zebrafish embryos and mammalian cell culture, arguing that ciliary defects are at least partially involved in the pathomechanism of this disorder."

Supporting evidence: - Kupffer's vesicle (the zebrafish left-right organizer) cilia reduced in both number (P<0.001) and length (P<0.05) in ccdc32 crispants [MODEL_ORGANISM] - Ciliogenesis impaired in mouse IMCD3 cells on siRNA knockdown: reduced % ciliated cells (P<0.01) and reduced cilium length [IN_VITRO] - Human Protein Atlas independently localizes CCDC32 to the primary cilium, centrosome, and basal body (as well as plasma membrane and microtubules) - CCDC-family precedent: CCDC39, CCDC40, CCDC103, CCDC114 all cause primary ciliary dyskinesia

Authors' own caveats (important for balanced curation):

"Some of the hallmark ciliopathy pathologies were absent from the described individuals, such as cystic renal disease and polydactyly" [full text] "Whether this molecule also performs non-ciliary roles relevant to the human pathology remain unclear" [full text]

6.2 Model B — AP-2 adaptor assembly chaperone / clathrin-mediated endocytosis (2024–2026; now the dominant molecular model)

Three independent structural/cell-biological studies since 2024 have assigned CCDC32 a precise, non-ciliary molecular function: it is a dedicated assembly chaperone for the AP-2 clathrin adaptor complex.

The assembly pathway (PNAS 2024, PMID:39145939):

AAGAB binds the AP-2 α subunit, then recruits σ2 → AAGAB:α:σ2 ternary complex
CCDC32 recognizes AAGAB:α:σ2, displacing AAGAB → α:σ2:CCDC32 template complex
The template sequentially recruits μ2, then β2
β2 binding completes AP-2 and releases CCDC32

"AP2 assembly is controlled by a handover mechanism, switching from AAGAB-based initiation complexes to CCDC32-based template complexes" [PMC11348294, full text] "In mammalian cells deficient in AAGAB or CCDC32, all AP2 subunits are degraded" [full text] "CCDC32 is a general regulator of CME" [full text]

CCDC32 directly binds α, σ2, and μ2 — but not β2 (β2 binding is what evicts it). It is selective for AP-2 and does not regulate AP-1/AP-3/AP-4 assembly.

Cellular consequences of CCDC32 loss: AP-2 subunit degradation; loss of plasma-membrane AP-2 puncta; strongly reduced transferrin-receptor endocytosis with elevated surface TfR; impaired GLUT4 internalization.

Coated-pit dynamics (eLife 2026, PMID:41489497 / PMC12768407):

"siRNA-mediated knockdown of CCDC32 leads to the accumulation of unstable flat clathrin assemblies" [full text] "CCDC32 knockdown strongly inhibited CCP invagination" [full text] "CCDC32 interacts with AP2 via the α-AD [appendage domain]" [full text]

Notably, in this system knockdown "does not affect AP2 expression level" [full text] — an apparent tension with the PNAS degradation result, likely reflecting knockdown vs knockout depth. Worth curating as a hypothesis_groups distinction rather than smoothing over.

Structural mechanism and the membrane switch (Science Advances 2026, PMID:42234739):

"CCDC32 binds to α/σ2 in a multivalent manner, using at least three (extended FxDxF, dileucine, and AH1)" [full text] "CCDC32 uses a noncanonical WAPL (Wxxϕ) motif to bind in the same location as other tyrosine-containing cargo" [full text] "In solution, CCDC32 prevents complex assembly and actively disassembles AP-2 tetramers" [full text] "The presence of PIP2–containing membrane stabilizes the final stages of assembly" [full text] "Loss of CCDC32 significantly decreases the steady-state level of all four AP-2 subunits in HeLa cells" [full text]

So CCDC32 is a cargo-mimicking, membrane-gated chaperone: it occupies the cargo-binding sites of α/σ2 and μ2 to hold AP-2 in an assembly-competent but inactive state, and PI(4,5)P₂-containing membrane acts as the molecular switch that licenses final assembly at the plasma membrane. This elegantly couples AP-2 biogenesis to its site of action.

6.3 Reconciling the two models

These are not mutually exclusive, and the most defensible curated position is that AP-2/CME dysfunction is the primary molecular lesion, with ciliary phenotypes as a plausible downstream consequence:

Clathrin-mediated endocytosis governs surface-receptor turnover, including receptors that traffic through the ciliary pocket and regulate Hedgehog/Wnt signalling — so CME failure can secondarily impair ciliogenesis and cilium-dependent signalling.
The absence of classical ciliopathy features (no cystic kidney disease, no polydactyly, no retinal degeneration reported) argues against a primary, canonical ciliopathy.
Independent genetic support for AP-2 hypofunction as a cause of exactly this phenotype spectrum: Ap2b1 (β2) null mice "survive until birth but then die shortly afterwards, the only obvious abnormality being that they have a cleft palate" [JCS review, full text]. Abdalla et al. made precisely this argument:

"Cleft palate and cardiac defects observed in mice deficient of different AP2 subunits support a CCDC32 function in the AP2 complex." — PMID:35451546 (verbatim, abstract)
AP2σ (σ2) and AP2μ (μ2) nulls are early embryonic lethal; complete AP-2 loss is embryonic lethal. CCDC32 loss is compatible with birth — consistent with CFNDS being a partial/hypomorphic AP-2 deficiency, i.e. residual AP-2 assembly persists (AAGAB-dependent, CCDC32-independent). The Sci Adv authors make this point:

"Mutation of CCDC32 does not prevent embryonic development but results in patients with craniofacial malformations" [full text]

Another reported interaction: CCDC32 binds the C-terminus of annexin A2, itself a membrane–cytoskeleton and endocytosis protein [PMC7268788, full text] — consistent with the trafficking model.

6.4 Proposed causal chain (for a dismech pathograph)

Biallelic CCDC32 LoF (frameshift / multi-exon deletion)          [MOLECULAR]
  → Loss of CCDC32 α-helix aa78–98; failure to bind AP-2 α/σ2     [MOLECULAR]
    → Failure of the AAGAB→CCDC32 handover; no α:σ2:CCDC32 template [MOLECULAR]
      → Impaired AP-2 heterotetramer assembly; AP-2 subunit degradation [MOLECULAR]
→ Destabilized, flat, non-invaginating clathrin-coated pits [CELLULAR]
  → Reduced clathrin-mediated endocytosis / receptor internalization [CELLULAR]
    ├→ Impaired ciliogenesis (reduced cilium number and length)  [CELLULAR]  (hypothesis group: ciliary)
    │    → Defective left-right organizer (Kupffer's vesicle) function [TISSUE]
    │      → Aberrant southpaw/NODAL laterality signalling
    │        → Situs inversus, asplenia, cardiac looping defect  [ORGANISM]
    ├→ Impaired cranial neural crest / facial primordium morphogenesis [TISSUE]
    │    → Failure of lip and palatal shelf fusion
    │      → Bilateral cleft lip and palate; midline facial defects [ORGANISM]
    ├→ Impaired cardiac morphogenesis (septation / AV canal)     [TISSUE]
    │    → AVSD, VSD, pulmonic stenosis                          [ORGANISM]
    └→ Impaired cerebral/cerebellar growth and midline patterning [TISSUE]
 → Microcephaly, cerebellar vermis hypoplasia, hypoplastic
   corpus callosum, hypoplastic pons
     → Global developmental delay / intellectual disability [ORGANISM]

Upstream vs downstream: The AP-2 assembly failure is unambiguously upstream. The ciliary branch is contested in its position — Harel's model places cilia upstream of laterality/cerebellar defects directly; the newer model places cilia downstream of CME failure. Curate as two hypothesis_groups on the relevant edges (e.g. ciliary_primary vs cme_primary), with the AP-2 chain as the canonical/emerging model.

6.5 Ontology term suggestions for mechanism

GO biological process / cellular component (all verified via OLS):

GO ID	Label	Use
GO:0072583	clathrin-dependent endocytosis	Core process, DECREASED
GO:0030122	AP-2 adaptor complex	CC — the assembled target
GO:0030131	clathrin adaptor complex	CC — parent
GO:0035612	AP-2 adaptor complex binding	MF — CCDC32's molecular function
GO:0030119	AP-type membrane coat adaptor complex	CC — parent
GO:0030136	clathrin-coated vesicle	CC
GO:0060271	cilium assembly	Ciliary branch, DECREASED
GO:0007368	determination of left/right symmetry	Laterality branch, DECREASED

Additional GO candidates to verify before use: protein-containing complex assembly (GO:0065003), chaperone-mediated protein complex assembly, phosphatidylinositol-4,5-bisphosphate binding, palate development, heart looping, cerebellum development.

CL cell types (verified):

CL ID	Label	Relevance
CL:0000008	migratory cranial neural crest cell	Craniofacial/cleft branch
CL:2000073	migratory cardiac neural crest cell	Cardiac outflow branch
CL:0011012	neural crest cell	Parent

Additional candidates (verify): ciliated epithelial cell, kidney collecting duct epithelial cell (the IMCD3 in-vitro model), cardiac myocyte, Purkinje cell, neuroepithelial cell.

UBERON (verified): UBERON:0004720 cerebellar vermis. Additional candidates to verify: secondary palate, upper lip, interventricular septum, atrioventricular canal, pulmonary valve, spleen, corpus callosum, pons, Kupffer's vesicle (zebrafish-specific).

CHEBI: phosphatidylinositol 4,5-bisphosphate (the membrane switch lipid) — verify the exact CHEBI ID before use.

6.6 Other mechanism dimensions

Metabolic changes: None reported. No metabolic phenotype. (Note the GLUT4 internalization defect in CCDC32-deficient cells is a cell-biological observation, not a reported clinical metabolic phenotype in patients — do not over-read it into a diabetes claim.)
Immune involvement: No primary immune mechanism. However, asplenia (1/2 in HPOA) produces functional hyposplenism with encapsulated-organism susceptibility — a secondary, anatomically-mediated immunodeficiency, clinically important (§12/§13).
Tissue damage mechanisms: Not applicable in the classical sense — CFNDS is a developmental morphogenesis disorder, not a tissue-injury disorder. There is no oxidative stress, ischemia, fibrosis, or necrosis mechanism.
Biochemical abnormalities: No enzyme deficiency, no channelopathy, no receptor defect measurable in patient fluids. The defect is a protein-complex assembly failure.
Molecular profiling: No CFNDS transcriptomic, proteomic, metabolomic, or lipidomic patient study exists. The one transcriptomic application is diagnostic, not mechanistic — clinical RNA-seq of patient cells detecting exon 3–4 skipping (PMID:41639596).
Single-cell / spatial / multi-omics: None for CFNDS. CCDC32 shows "low tissue specificity" and "low cell type specificity" in Human Protein Atlas, with mass-spec enhancement in lymphoid tissue and single-cell enhancement in fallopian tube — none of which maps onto the disease phenotype, reinforcing that the phenotype specificity comes from developmental context, not expression restriction.
Functional genomics screens: No published CRISPR/RNAi screen result specific to CFNDS. CCDC32 is not a common-essential gene in DepMap-style screens (consistent with LOEUF 0.76 and viability of KO cell lines used in the mechanism papers).

7. Anatomical Structures Affected

Organ level

Primary (directly malformed): | System | Structures | HPO/UBERON anchor | |---|---|---| | Craniofacial | Upper lip, primary and secondary palate, mandible, external ear, orbits/interorbital distance, nose | HP:0410030, HP:0000175, HP:0000347, HP:0000411 | | Central nervous | Cerebellum (vermis), pons, corpus callosum, cerebral cortex (volume — microcephaly) | HP:0001320, HP:0012110, HP:0002079, HP:0000252; UBERON:0004720 | | Cardiovascular | Atrioventricular canal, interventricular septum, pulmonary valve | HP:0006695, HP:0001629, HP:0001642 | | Skeletal / limb | Digits (5th finger, phalanges), nails, spine (kyphosis), hands/feet size | HP:0004209, HP:0001156, HP:0012385, HP:0008386, HP:0002808 | | Genitourinary | Testis (descent) | HP:0000028 |

Secondary / complication-driven: - Spleen — asplenia (HP:0001746), in the context of the laterality defect - Abdominal viscera — situs inversus (HP:0003363) - Middle ear — conductive hearing loss, mechanistically secondary to cleft palate/eustachian dysfunction (HP:0000405) - Upper GI / feeding apparatus — feeding difficulties (HP:0008872), largely secondary to cleft and neurological status - Growth axis — postnatal growth restriction / short stature (HP:0004322)

Notably spared: Kidneys (normal renal ultrasound in both index patients), eyes/retina (normal ophthalmology in both), EEG normal in individual B-II-1 [PMC7268788, full text]. The renal and retinal sparing is the key argument against classical ciliopathy.

Body systems involved: cardiovascular, nervous, musculoskeletal, digestive, integumentary (nails/dermatoglyphics), reproductive, immune (via asplenia), sensory (auditory).

Tissue and cell level

Cranial neural crest–derived mesenchyme of the frontonasal and maxillary/mandibular prominences — the presumptive lesion site for cleft lip/palate and the facial/ear/jaw dysmorphism (CL:0000008)
Cardiac neural crest and second-heart-field derivatives — outflow/septation defects (CL:2000073)
Left-right organizer ciliated epithelium (Kupffer's vesicle in fish; embryonic node in mammals) — laterality
Cerebellar and pontine neuroepithelium / rhombic lip derivatives — vermian and pontine hypoplasia
Palatal shelf epithelium and mesenchyme — fusion failure
Epithelial tissue broadly, given CME is a general epithelial/all-cell process

Subcellular level (GO cellular component)

CCDC32 and its pathway localize to: - Plasma membrane and clathrin-coated pit / clathrin-coated vesicle (GO:0030136) — the principal site of action - AP-2 adaptor complex (GO:0030122) itself - Primary cilium, centrosome, basal body — per Human Protein Atlas - Microtubules - Cytosol (site of the AAGAB/CCDC32 pre-assembly intermediates)

Localization / lateralization

Facial clefting is bilateral in the reported patients ("bilateral cleft lip and palate" is the emphasized core feature) — a midline/bilateral pattern, not unilateral.
Digital anomalies are bilateral (bilateral camptodactyly and clinodactyly of fifth fingers).
The laterality defect is, by definition, an asymmetry disorder: abdominal situs inversus with asplenia, plus abnormal cardiac looping in the zebrafish model with "bilateral or right-sided" southpaw expression replacing normal left-sided expression.

This combination — bilateral/midline structural defects plus a stochastic laterality defect — is characteristic and diagnostically useful.

8. Temporal Development

Onset

Congenital (HP:0003577), 2/2. All structural anomalies are established in embryogenesis.
Detectable prenatally: the terminated fetus (A-II-2) was identified antenatally with bilateral cleft lip, vermian hypoplasia, hypoplastic pons, and abnormal cisterna magna — establishing that CFNDS can be recognized on second-trimester ultrasound/fetal MRI in an at-risk family.
Onset pattern: chronic/static from birth. Not acute, not subacute, not insidious.
Sequence of clinical declaration: prenatal structural findings (if imaged) → neonatal cleft and cardiac diagnosis → infantile feeding difficulty (2/2) → toddler-age developmental delay → school-age intellectual disability, hearing, and growth concerns.

Progression

Disease stages: No staging system exists and none is applicable — CFNDS is not a staged/progressive disease.
Progression rate: Non-progressive. The malformations are fixed. Developmental delay evolves into a stable intellectual disability profile rather than deteriorating.
Course pattern: Static/stable with age-dependent emergence of developmental phenotypes. No episodic, relapsing-remitting, or degenerative course has been reported in any patient.
Duration: Lifelong, chronic. Not self-limited.

Patterns

Remission: Not applicable — no spontaneous remission; "treatment-induced improvement" refers only to surgical correction of individual anomalies (cleft repair, cardiac repair), not disease remission.
Critical periods:
Weeks 4–7 post-conception — lip fusion; weeks 6–12 — secondary palate fusion. These windows are already passed at diagnosis; no prenatal intervention is possible.
Weeks 3–4 — left-right axis determination and cardiac looping.
Postnatal intervention windows are the actionable ones: cleft lip repair ~3–6 months, palate repair ~9–18 months (speech-outcome critical period), cardiac repair timed to lesion (AVSD typically 3–6 months), early intervention/speech therapy from infancy, and hearing surveillance from the neonatal period because unrecognized conductive loss compounds the cleft-related speech deficit.

Longitudinal data: No natural-history study, no registry, no longitudinal cohort exists. The oldest reported patient is 9 years old. Adult outcomes for CFNDS are entirely unknown. This is arguably the single largest knowledge gap.

9. Inheritance and Population

Epidemiology

Prevalence: Not established. With ~6 living individuals reported worldwide from 5 families since 2020, the observed prevalence is far below 1 in 1,000,000.
For structured curation: measure_type: CASES_IN_LITERATURE, prevalence_class: BELOW_1_IN_1000000 (or ULTRA_RARE), population: Worldwide. Do not assign a rate_per_100000 — no denominator-based estimate exists.
Supporting statement: "CFNDS has only been described in four living individuals and one terminated fetus from four families" (PMID:41639596) — that count precedes the two siblings in the same report.
Incidence: Not established. No birth-prevalence estimate exists.
Ascertainment caveat: True prevalence is almost certainly higher than reported. Three of five families' variants are deletions, and one was missed by both SNP array and trio exome sequencing — meaning conventional diagnostic pipelines systematically under-ascertain this disease (§10).

Genetic epidemiology

Parameter	Status
Inheritance pattern	Autosomal recessive (HP:0000007). ClinGen AR, MODERATE. All published probands homozygous.
Penetrance	Appears complete in biallelic LoF homozygotes (all reported homozygotes are affected), but n is far too small to exclude reduced penetrance. Heterozygous carriers (parents) are unaffected.
Expressivity	Variable — clearly so. Compare: one patient with AVSD + situs inversus + asplenia; another with VSD + pulmonic stenosis and normal situs; the fetus with no cardiac defect at all. Hypertelorism vs hypotelorism between the two index patients. Intrafamilial variability is untested except in the sibling pair.
Genetic anticipation	Not applicable — no repeat expansion mechanism.
Germline mosaicism	Not reported. Standard AR recurrence counselling applies; no mosaicism-specific caveat documented.
Founder effects	Suspected but unproven. The near-identical ~32.6-kb deletion in two independently reported patients (§4.2) raises either a recurrent (repeat-mediated) deletion or a founder allele. Requires breakpoint-level and haplotype confirmation.
Consanguinity	Central. Both founding families were consanguineous (Arab Muslim first cousins once removed; Iranian). Homozygosity mapping was the discovery route: ~9.06 Mb ROH in Family A, 5.23 Mb ROH in Family B [full text].
Carrier frequency	Not established. No pathogenic CCDC32 allele is reported at appreciable frequency in gnomAD; the two founding frameshifts were absent from gnomAD, TOPMed, Geno2MP, and GME Variome. Carrier frequency is presumptively <1/1,000 in unselected populations, potentially higher in specific endogamous groups.

Population demographics

Reported ancestries: Arab Muslim (Israel/Palestine region), Iranian (Isfahan), Egyptian (Abdalla cohort context), Portuguese, Dutch (Rotterdam sibling pair). This is a broad, non-clustered geographic spread — no single ethnic predilection can be claimed, though ascertainment is biased toward centres with consanguineous referral populations and toward European tertiary genetics services.
Geographic distribution: No endemic region. Cases from the Middle East, North Africa, Southern Europe, and Northwestern Europe.
Variant geography: The two founding frameshifts are each private to one Middle Eastern family. The ~32.6-kb deletion allele appears in at least two unrelated Southern-European/North-African-context patients — the only candidate for a geographically structured allele.
Sex ratio: Approximately balanced in a cohort far too small to estimate (reported: female, male, female, plus the 2024 patient and sibling pair). No sex bias is expected for an autosomal recessive disorder; do not curate a sex ratio.
Age distribution of affected individuals: All reported living patients were children at the time of report (ages 3, 6, 9 years, plus the sibling pair). No adult patient has been described. This reflects the disease's recent delineation, not necessarily a survival ceiling — but it means adult phenotype and survival are unknown.

10. Diagnostics

Clinical tests

Laboratory tests: No disease-specific laboratory test exists. There is no enzyme assay, no metabolite, no biochemical marker for CFNDS. Standard labs are non-diagnostic.
The one lab investigation with real value is functional asplenia screening in patients with laterality defects: peripheral smear for Howell-Jolly bodies, correlated with abdominal imaging.
Biomarkers: None. No FDA-listed or research biomarker. Neither diagnostic, prognostic, nor monitoring biomarkers exist. (Speculatively, surface transferrin receptor levels or AP-2 subunit abundance in patient fibroblasts could serve as a functional assay — this has been demonstrated in engineered cells but never applied to a patient sample. This is a concrete, actionable research gap.)
Imaging studies (essential, high-yield):
Brain MRI — required. Detects cerebellar vermis hypoplasia (HP:0001320), hypoplastic corpus callosum (HP:0002079), hypoplastic pons (HP:0012110), abnormal cisterna magna. This is the highest-yield single imaging study.
Echocardiography — required in all patients. Detects AVSD, VSD, pulmonic stenosis, and cardiac looping/positional abnormality.
Abdominal ultrasound / cross-sectional imaging — for situs and spleen presence. Given asplenia carries life-threatening infection risk, this is not optional in a patient with any laterality clue.
Renal ultrasound — normal in reported patients, but reasonable to exclude the ciliopathy differential.
Skeletal survey / hand radiographs — brachydactyly, clinodactyly, phalangeal anomalies, kyphosis.
Fetal ultrasound / fetal MRI — for prenatal detection in at-risk pregnancies (proven effective: the A-II-2 fetus).
Functional tests: Audiometry / tympanometry — mandatory and repeated, given bilateral conductive hearing loss and cleft palate. Feeding/swallow evaluation (videofluoroscopy) for the 2/2 infantile feeding difficulty.
Electrophysiology: EEG was normal in individual B-II-1. Seizures are not a reported CFNDS feature — a useful negative that distinguishes CFNDS from the AP2M1-related developmental and epileptic encephalopathy (see differential below). ECG accompanies echocardiography.
Biopsy / pathology: No characteristic histopathology. No diagnostic biopsy exists. Nasal brush biopsy for ciliary ultrastructure/beat frequency (the PCD workup) has not been reported in CFNDS and there is no evidence of a motile-ciliary/PCD-type respiratory phenotype — do not curate a PCD-style workup as indicated.

Genetic testing — the only definitive diagnostic modality

Recommended approach, in order of yield:

Trio exome sequencing (ES) with explicit CNV calling, or preferably
Genome sequencing (GS) — better structural-variant resolution, and
RNA sequencing (RNA-seq) as a complementary second-tier test when DNA testing is negative.

The single most important practical lesson from the literature is that conventional testing fails in this disease:

"This deletion was not detected in previous SNP array analyses and trio exome sequencing" — PMID:41639596 "highlighting the complementary value of RNA-seq" — PMID:41639596

WES utility: Established — it discovered the gene ("Using whole exome sequencing, we identified homozygous frameshift CCDC32 variants," PMID:32307552). But ES alone missed a causal intragenic deletion in one family. ES must be paired with CNV analysis, and a negative ES does not exclude CFNDS.
WGS utility: Superior for the deletion alleles that constitute the majority of reported pathogenic variation (3/5 families). Preferred first-line where available.
RNA-seq: Proven diagnostic in CFNDS — exon 3–4 skipping revealed the biallelic deletion the DNA tests missed. This makes CFNDS a genuine exemplar of RNA-seq's complementary diagnostic value.
Gene panels: CCDC32 should be included on orofacial clefting, syndromic congenital heart disease, heterotaxy/laterality, cerebellar hypoplasia/pontocerebellar, and intellectual disability/multiple congenital anomaly panels. Verify inclusion before relying on a panel — as a 2020 gene with Moderate ClinGen validity, panel coverage is inconsistent.
Single-gene testing: Reasonable only for targeted familial-variant testing (carrier testing of relatives, prenatal diagnosis) once the family's variant is known. Not appropriate as a primary diagnostic given phenotypic nonspecificity.
Chromosomal microarray (CMA)/SNP array: Documented to fail — the exon 3–4 deletion escaped SNP array. CMA remains a reasonable first-tier test for MCA/DD generally, but a normal CMA does not exclude CFNDS.
Homozygosity mapping: High value in consanguineous families — it was the discovery route (9.06 Mb and 5.23 Mb ROH). Should be run alongside ES/GS in consanguineous pedigrees.
Karyotyping / FISH: No role. No CFNDS case involves a visible chromosomal rearrangement.
Mitochondrial DNA testing: Not applicable.
Repeat expansion testing: Not applicable.

Omics-based diagnostics

RNA sequencing: the one validated omics diagnostic (above).
Proteomics / metabolomics / epigenomics / liquid biopsy: No established role. No episignature. No metabolomic signature.

Clinical criteria

No standardized diagnostic criteria, no consensus guideline, no society statement exists for CFNDS. Diagnosis is molecular: biallelic pathogenic CCDC32 variants in a compatible phenotype.
Proposed clinical gestalt prompting testing (from Abdalla's core phenotype): developmental delay + bilateral cleft lip and palate, with any of — microcephaly, cerebellar vermis hypoplasia, congenital heart defect, digital/nail anomalies, laterality anomaly, postnatal growth restriction. Consanguinity substantially raises prior probability.

Differential diagnosis

Condition	Gene(s)	Distinguishing features
Cardiofaciocutaneous syndrome (CFC)	BRAF, MAP2K1/2, KRAS	AD/de novo, RASopathy; ectodermal/hair/skin findings, HCM; cleft lip/palate not typical. The critical name-confusion pitfall.
Kabuki syndrome	KMT2D, KDM6A	AD/XL; long palpebral fissures with lower-lid eversion, persistent fetal fingerpads, CHD; cleft palate common but cleft lip less so
CHARGE syndrome	CHD7	AD; coloboma, choanal atresia, semicircular canal hypoplasia, hypogonadotropic hypogonadism
22q11.2 deletion	TBX1 region	Conotruncal CHD, palatal insufficiency/cleft palate, hypocalcemia, immune deficiency; CMA-detectable
Primary ciliary dyskinesia / heterotaxy syndromes	DNAH5, DNAI1, CCDC39, CCDC40, ZIC3, etc.	Chronic sinopulmonary disease, neonatal respiratory distress, bronchiectasis — absent in CFNDS; clefting atypical
Joubert syndrome / other cerebellar-vermis ciliopathies	AHI1, CEP290, TMEM67, etc.	Molar tooth sign, oculomotor apraxia, retinal dystrophy, nephronophthisis — renal and retinal disease absent in CFNDS
Pontocerebellar hypoplasias	TSEN54, EXOSC3, etc.	Progressive microcephaly and neurodegeneration; CFNDS is static
AP2M1-related DEE	AP2M1	Same molecular pathway (AP-2/CME) but AD de novo p.Arg170Trp, dominated by epilepsy (myoclonic-atonic); no clefting, no CHD. EEG normal in CFNDS.
Oral-facial-digital syndromes	OFD1 et al.	Oral frenula, lingual hamartomas, polydactyly (absent in CFNDS)
Non-syndromic bilateral CL/P	multifactorial	Absence of DD, CHD, cerebellar anomaly, microcephaly

Screening

Newborn screening: Not applicable and not feasible — no biochemical marker. CFNDS is not on any NBS panel.
Carrier screening: CCDC32 is not on standard expanded carrier screening panels. Given the ultra-rare status, population carrier screening is not indicated. Targeted carrier testing of relatives is indicated once a family variant is known.
Cascade screening: Appropriate for at-risk relatives in a known family (siblings of probands; extended family in consanguineous pedigrees).

11. Outcome / Prognosis

Global caveat: there is no natural-history study, no survival analysis, and no adult patient reported. Everything below is either directly observed in ≤6 children or explicitly labelled as extrapolation.

Survival and mortality

5-year / 10-year survival: Not established. No survival data.
Life expectancy: Unknown. All reported living patients were alive at last report at ages 3, 6, and 9 years, plus the sibling pair. No death of a liveborn CFNDS patient has been reported.
Mortality rate / disease-specific mortality: Not established.
One pregnancy was electively terminated following prenatal detection of anomalies (fetus A-II-2) — this is a reproductive decision, not a measure of intrinsic lethality, and should not be curated as a mortality statistic.
Reasoned prognostic drivers of mortality risk (extrapolated, not CFNDS-observed): severity of the congenital heart defect (AVSD carries the greatest operative burden), and overwhelming post-splenectomy-type sepsis risk in asplenic patients — the latter is a preventable cause of death and the single most important actionable prognostic factor.

Morbidity and function

Morbidity: Substantial and multi-domain — cognitive, speech, hearing, feeding, cardiac, and surgical.
Disability outcomes: Global developmental delay in 2/2 and frank intellectual disability in the oldest reported patient (age 9). Long-term functional independence is unknown but likely to require support. No ICF-coded outcome data exist.
Quality of life: No measured QoL data. No EQ-5D/SF-36/PROMIS administration reported.

Disease course and complications

Observed and anticipated complications: - Cleft-related: feeding failure in infancy (observed 2/2, "severe feeding difficulties" in one), velopharyngeal insufficiency, speech disorder, recurrent otitis media, bilateral conductive hearing loss (observed), dental anomalies (missing teeth observed) - Cardiac: heart failure from unrepaired AVSD/VSD, right-ventricular consequences of pulmonic stenosis, operative and post-operative morbidity - Neurological: developmental delay → intellectual disability; cerebellar signs (ataxia/coordination) plausible from vermian hypoplasia but not explicitly reported; seizures not reported - Infectious: encapsulated-organism sepsis in the asplenic patient — the highest-acuity preventable complication - Growth: postnatal growth restriction/short stature in some, but not universal (one patient at 80th centile height, another at 97th) - Behavioral: hyperactivity reported in one patient

Recovery potential

Structural anomalies are surgically correctable, not spontaneously recoverable. Cleft repair and cardiac repair yield good anatomical outcomes by general paediatric standards.
Neurodevelopmental impairment is not recoverable — it is amenable to habilitation/early intervention but not to reversal.
No disease-modifying therapy exists, so there is no "with vs without treatment" survival comparison to report.

Prediction

Prognostic factors: No validated prognostic model, no prognostic biomarker, no clinical calculator exists. Reasoned (unvalidated) determinants: severity of CHD; presence of asplenia; degree of microcephaly and hindbrain hypoplasia; adequacy/timing of cleft and hearing management.
Genotype–phenotype correlation: None established. All reported variants are complete LoF (frameshift or deletion) yet produce a variable phenotype — arguing that modifiers or stochastic developmental variation, not allele severity, drive expressivity. This is a well-posed research question.

12. Treatment

There is no disease-specific, disease-modifying, or targeted therapy for CFNDS. Management is entirely symptomatic, anatomical, and habilitative, delivered by a multidisciplinary craniofacial/genetics/cardiology team. No treatment guideline exists for CFNDS specifically; care follows the guidelines for each constituent anomaly.

Pharmacotherapy

No disease-specific pharmacotherapy.
Antibiotic prophylaxis in asplenia is the one pharmacological intervention with a strong, specific indication in the subset with asplenia/heterotaxy: penicillin prophylaxis plus a low threshold for empiric treatment of febrile illness (standard asplenia protocols).
Peri-operative and heart-failure medications as dictated by the specific cardiac lesion (diuretics, afterload reduction) — lesion-directed, not disease-directed.
Pharmacogenomics: No CPIC or PharmGKB guidance applies to CCDC32. No PGx relevance identified.

Suggested NCIT annotation:

- name: Antimicrobial Prophylaxis for Asplenia
  treatment_term:
    preferred_term: Pharmacotherapy
    term: {id: NCIT:C15986, label: Pharmacotherapy}
  therapeutic_modality: SMALL_MOLECULE

Advanced therapeutics

Gene therapy: None. Not in development. No preclinical program exists. (Conceptually challenged: the pathology is established during embryogenesis and is structural — postnatal gene replacement could not correct a cleft palate or a septal defect.)
Cell therapy: None.
RNA-based therapies (ASO/siRNA/mRNA): None. Note that despite the exon 3–4 deletion, exon-skipping/splice-modulating ASO strategies are not applicable — the lesion is a genomic deletion producing loss of protein, not a correctable splice defect, and the therapeutic window is prenatal.
Targeted therapy: None. No druggable node has been proposed. (The AP-2 assembly pathway is not currently a therapeutic target for any indication.)
Immunotherapy: Not applicable.

Surgical and interventional (the principal therapeutic modality)

Intervention	Typical timing	Purpose
Cleft lip repair (cheiloplasty)	~3–6 months	Lip closure, feeding, appearance
Cleft palate repair (palatoplasty)	~9–18 months	Palatal closure; timed to speech development
Alveolar bone grafting	~8–11 years	Alveolar continuity, dental eruption
Secondary speech surgery (pharyngoplasty)	as needed	Velopharyngeal insufficiency
Cardiac surgical repair — AVSD repair, VSD closure, pulmonary valvotomy/valvuloplasty	lesion-dependent; AVSD typically 3–6 months	Hemodynamic correction
Tympanostomy tube placement	as needed, often at cleft repair	Middle-ear effusion, conductive hearing loss
Orchidopexy	6–18 months	Cryptorchidism
Gastrostomy	if feeding failure severe	Nutrition
Orthopedic/spinal management	as needed	Kyphosis

Suggested NCIT annotations (verified via OLS unless noted):

- name: Cleft Palate Repair
  treatment_term:
    preferred_term: palatorrhaphy
    term: {id: NCIT:C168380, label: Palatorrhaphy}
  therapeutic_modality: SURGERY

- name: Congenital Heart Defect Surgical Repair
  treatment_term:
    preferred_term: surgical procedure
    term: {id: NCIT:C15329, label: Surgical Procedure}   # safe, reachable from NCIT:C25218
  therapeutic_modality: SURGERY

⚠️ NCIT:C157806 "Cardiac Surgery" also exists but may sit outside the NCIT:C25218 (Clinical Intervention or Procedure) subtree used by the dismech TreatmentTerm dynamic enum — validate with just validate-terms before using it; NCIT:C15329 is the safe fallback.

Supportive and rehabilitative

Intervention	NCIT	Modality
Speech and language therapy — high priority (cleft + DD + hearing)	NCIT:C159273	BEHAVIORAL
Physical therapy	NCIT:C15302	BEHAVIORAL
Occupational therapy	NCIT:C121351	BEHAVIORAL
Nutritional/feeding support	NCIT:C15433 (Nutritional Support) — see CLAUDE.md caution on modality tagging	—
Supportive care (general)	NCIT:C15747	—
Genetic counseling	NCIT:C15240	—
Hearing amplification / hearing aids	No suitable NCIT clinical-action term — omit `term:`, keep free-text `preferred_term`; `therapeutic_modality: DEVICE`	DEVICE
Developmental early intervention / special education	NCIT:C15315 (Rehabilitation)	BEHAVIORAL

Experimental treatments

No clinical trials exist for CFNDS. A ClinicalTrials.gov search yields no interventional or observational study recruiting CFNDS or CCDC32 patients. No NCT identifiers to report. Do not curate a clinical_trials: block for this entry.

Treatment outcomes

Response rates: No CFNDS-specific outcome data. Outcomes of cleft repair and CHD repair in CFNDS patients have not been separately reported.
Side effects / adverse events: No disease-specific pharmacovigilance signal (no disease-specific drug). Surgical risks are the standard risks of the respective procedures.

Treatment strategy

Algorithm: No CFNDS-specific pathway. Practical approach: (1) confirm molecular diagnosis; (2) complete the baseline evaluation — echocardiogram, brain MRI, abdominal imaging for situs/spleen, audiology, ophthalmology, renal ultrasound, feeding assessment, developmental assessment; (3) refer to a multidisciplinary craniofacial team; (4) stage cleft and cardiac surgery per standard protocols; (5) institute early intervention and hearing surveillance; (6) if asplenic, start antibiotic prophylaxis and asplenia vaccination immediately; (7) genetic counselling for the family.
Combination therapies: Not applicable in the pharmacological sense; management is inherently multimodal/multidisciplinary.
Personalized/genotype-guided treatment: None available. No genotype-guided management stratification exists — and with all reported alleles being complete LoF, none is currently plausible.

13. Prevention

Prevention levels

Primary prevention (preventing occurrence): The only effective primary prevention is reproductive — genetic counselling, carrier testing, and reproductive options in at-risk (typically consanguineous) families. There is no modifiable exposure to target. Population-level consanguinity counselling programs reduce the aggregate burden of AR disease but are not CFNDS-specific.
Secondary prevention (early detection): Prenatal ultrasound/fetal MRI in at-risk pregnancies is proven to detect the phenotype (fetus A-II-2). Targeted prenatal molecular testing (CVS/amniocentesis for the known familial variant) is definitive. Postnatally, early molecular diagnosis enables timely baseline evaluation.
Tertiary prevention (preventing complications in affected individuals) — this is where the highest-value, concrete actions lie:
Asplenia protocol: lifelong antibiotic prophylaxis + immunization + fever action plan. Prevents the most likely preventable death.
Audiology surveillance from birth: prevents hearing loss compounding speech/language deficit.
Timely palatoplasty within the speech-critical window: prevents durable velopharyngeal speech impairment.
Cardiac surveillance and timely repair: prevents pulmonary vascular disease and heart failure.
Feeding/nutrition management: prevents failure to thrive.
Early developmental intervention: optimizes attainable function.

Immunization

Highly relevant in the asplenic subset. Standard functional-asplenia immunization: pneumococcal (conjugate + polysaccharide), meningococcal (ACWY and B), and Haemophilus influenzae type b, plus annual influenza. Otherwise, routine childhood immunization per national schedule.

Suggested annotation: treatment_term: NCIT:C15346 (Vaccination), therapeutic_modality: VACCINE.

Screening and early detection

Population screening programs: None applicable. Not newborn-screenable (no biochemical marker); too rare for population carrier screening.
Genetic screening in families: Carrier testing of at-risk relatives; preimplantation genetic testing for monogenic disease (PGT-M) and prenatal diagnosis (CVS/amniocentesis) are both technically available once the familial variant is characterized. For families whose variant is a deletion, ensure the prenatal assay is deletion-capable (targeted MLPA/ddPCR or breakpoint-spanning PCR — a standard variant-specific Sanger assay will fail).
Risk stratification: Prior risk is driven by consanguinity and by an affected sibling (1 in 4 recurrence).

Behavioral interventions

Not applicable to disease occurrence. Standard periconceptional care (folic acid, avoidance of teratogens) is appropriate general practice but has no established effect on CFNDS risk and should not be curated as a CFNDS protective factor.

Counseling

Genetic counselling is the cornerstone of prevention. Content should include: - Autosomal recessive inheritance; 25% recurrence risk for each pregnancy of carrier parents - Carrier parents are unaffected (supported by gnomAD constraint: pLI 0.19, LOEUF 0.76) - Extended-family carrier risk in consanguineous pedigrees; offer cascade testing - Availability of PGT-M and prenatal diagnosis - Honest communication of prognostic uncertainty — with ~6 published patients and no adult data, families must be told that long-term outcome is genuinely unknown - Consanguinity counselling for the wider kindred where culturally appropriate

NCIT: NCIT:C15240 Genetic Counseling.

Public health / environmental interventions

Not applicable. No environmental determinant. The only population-level lever is consanguinity-related genetic services and premarital/preconception carrier screening programs in high-consanguinity populations — a general AR-disease intervention, not CFNDS-specific.

Prophylaxis

Antibiotic prophylaxis for asplenia — the one strongly indicated prophylactic medication (see above).
Endocarditis prophylaxis per standard cardiology guidelines for the specific repaired/unrepaired cardiac lesion.

14. Other Species / Natural Disease

Taxonomy of species with relevant biology

Species	NCBI Taxon	Relevance
Homo sapiens	NCBITaxon:9606	The only species with naturally occurring CFNDS
Danio rerio (zebrafish)	NCBITaxon:7955	Principal experimental model (§15)
Mus musculus (mouse)	NCBITaxon:10090	Cell-line source (IMCD3); no published whole-animal Ccdc32 model

Breed

Not applicable. No breed-associated CFNDS-equivalent disorder has been described. No VBO identifiers apply.

Orthologous genes

Zebrafish ccdc32: a single ortholog, with 46% amino-acid identity and 64% similarity to human CCDC32 [PMC7268788, full text]. Modest conservation, but functionally sufficient — depletion recapitulates the human phenotype.
Mouse Ccdc32: ortholog exists (used for the IMCD3 siRNA experiments, targeted via siCcdc32). MGI record exists; I could not retrieve an IMPC phenotype page (404), and no IMPC null-allele phenotype data were located.
Human NCBI Gene ID 90416 is the anchor for ortholog lookup (Alliance of Genome Resources / HomoloGene).

Natural disease in other species

None known. No OMIA entry, no veterinary case series, no spontaneous animal disorder corresponding to CFNDS has been reported. There is no companion-animal or wildlife counterpart, and no veterinary health importance.

Comparative biology

Evolutionary conservation of mechanism: Strong. Harel et al. concluded that "CCDC32 plays an evolutionarily conserved role in cilia formation in the vertebrate left/right organizing center" [full text]. The AP-2 adaptor complex and its assembly chaperones (AAGAB, CCDC32) are deeply conserved across eukaryotes, and the AP-2 assembly mechanism described in human cells is expected to be broadly conserved.
Comparative pathology — concordances: zebrafish ccdc32 crispants reproduce reduced head size (≈ microcephaly), altered facial cartilage morphology (≈ craniofacial dysmorphism/clefting), cerebellar hypoplasia, disrupted cardiac looping, and laterality randomization (≈ situs inversus).
Comparative pathology — divergences: the zebrafish model shows no global developmental delay (normal body length), and clefting per se cannot be modelled in fish (no secondary palate) — only the homologous pharyngeal cartilage patterning.

Transmission

Not applicable. CFNDS is a germline monogenic disorder. No zoonotic potential, no cross-species transmission, no infectious component.

15. Model Organisms

15.1 Zebrafish (Danio rerio, NCBITaxon:7955) — the primary and best-characterized model

Model type: vertebrate, mammalian-adjacent developmental model; F0 CRISPR crispant (mosaic knockout).

Construction: Two distinct sgRNAs (sgRNA1, sgRNA2) targeting non-overlapping regions of exon 2, injected with Cas9 protein at the one-cell stage. Editing efficiency: 85% (sgRNA1) and 70% (sgRNA2) mosaic alterations in F0 crispants [PMC7268788, full text]. Two independent guides is good practice and substantially strengthens the specificity of the result.

Expression pattern in zebrafish: ccdc32 detected as early as 1 hour post-fertilization; localized to the developing head and neural tube throughout embryogenesis, and particularly concentrated in the Kupffer's vesicle region — a spatial pattern that closely prefigures the human phenotype (head, CNS, laterality).

Phenotypes observed [all MODEL_ORGANISM evidence]:

Zebrafish phenotype	Human counterpart	Statistics
Significant reduction in head size at 3 dpf	Microcephaly (HP:0000252)	Significant vs uninjected and sgRNA-only controls
Altered facial cartilage morphology (ceratohyal angle)	Craniofacial dysmorphism / clefting	P < 0.05
Hypoplastic cerebellum (anti-α-acetylated tubulin)	Cerebellar vermis hypoplasia (HP:0001320)	Qualitative + morphometric
Disrupted cardiac looping at 2 dpf (normal/midline/reversed)	Cardiac malformation, looping abnormality	Both sgRNAs
Aberrant *southpaw (spaw)* expression at 18-somite stage — bilateral or right-sided instead of left	Situs inversus, asplenia (HP:0003363, HP:0001746)	Qualitative scoring
Kupffer's vesicle cilia reduced in number and length at 10-somite stage	Ciliary mechanism hypothesis	Number P<0.001; length P<0.05; one-way ANOVA + Tukey
Normal body length	—	Explicitly noted: no global developmental delay

"ccdc32 depletion recapitulates the human phenotypes" — PMID:32307552 (verbatim, abstract)

Phenotype recapitulation quality: Good for craniofacial, cerebellar, cardiac-looping, and laterality domains. This is a genuinely convergent model — four independent human phenotype domains reproduced.

Limitations: - F0 crispants are mosaic, not stable germline nulls — a stable mutant line has not been reported and is an obvious next step. - Cleft lip/palate cannot be modelled — zebrafish have no secondary palate; only homologous pharyngeal cartilage patterning is assessable. - Intellectual disability/global developmental delay cannot be modelled; body length was explicitly normal. - Situs inversus and asplenia are assessed indirectly (spaw expression, cardiac looping) rather than as terminal organ situs. - Crispant phenotypes can carry p53-dependent off-target/toxicity artefacts; the two-independent-guide design mitigates but does not eliminate this. - Modest human–fish protein identity (46%) limits inference about specific residues/motifs.

Resource: ZFIN (the ZFIN publication record ZDB-PUB-220423-8 exists for the Abdalla paper; I was unable to retrieve the ccdc32 gene record — ZFIN returned a CAPTCHA/traffic page — so the ZFIN gene ID should be looked up before curation).

15.2 Mammalian cell models

mIMCD3 5-HT6-GFP (mouse inner medullary collecting duct, ciliated reporter line) [IN_VITRO] - siRNA against Ccdc32 (5 nM) vs non-targeting control; 24 h serum starvation to induce ciliogenesis; knockdown validated by qRT-PCR with three primer sets - Result: significantly reduced % ciliated cells (P<0.01) and reduced cilium length (P<0.05 to P<0.001) - Rigor: >500 cells per replicate, 4 replicates, >1000 cilia measured, imaging blinded to condition — a well-controlled experiment

"Cilia formation is similarly impaired in ciliated mouse inner medullary collecting duct cells" [full text]

HeLa and other human cell lines (2024–2026 mechanism studies) [IN_VITRO] - CCDC32 knockout HeLa cells: loss of all four AP-2 subunits at steady state; loss of plasma-membrane AP-2 puncta; strongly reduced transferrin-receptor endocytosis with elevated surface TfR; impaired GLUT4 internalization - siRNA knockdown: accumulation of unstable flat clathrin assemblies; inhibited CCP invagination; reduced TfnR uptake - Structure–function: deletion constructs (e.g. CCDC32(1-54), mimicking the patient truncations) fail to rescue CCP stabilization; patient-mutant CCDC32 is defective in binding AP-2 α and σ2 — this is the closest thing to a direct functional validation of patient alleles - In vitro reconstitution with PIP2-containing liposomes — the membrane-switch experiments (Sci Adv 2026)

Patient-derived cells: None reported beyond the RNA-seq performed on patient material for diagnosis (PMID:41639596). No patient fibroblast, iPSC, organoid, or neuronal model of CFNDS exists. This is a major and readily addressable gap.

15.3 Mouse (Mus musculus, NCBITaxon:10090)

No published Ccdc32 whole-animal knockout or knock-in mouse model exists. I found no IMPC phenotype data (the queried IMPC gene page returned 404) and no MGI-recorded allele phenotype for a Ccdc32 null.
A commercially available conditional (flox) allele exists — a Ccdc32-flox C57BL/6 line (Cyagen Ccdc32em1flox) is catalogued — but no phenotype has been published from it. Curate as "resource available, phenotype unpublished," not as a characterized model.
Highly informative surrogate models — the AP-2 subunit knockouts:
Ap2b1 (β2) null: "mice lacking the single-copy AP-2 β subunit gene AP2B1 survive until birth but then die shortly afterwards, the only obvious abnormality being that they have a cleft palate" [JCS review, full text] — strikingly convergent with the CFNDS core phenotype. Survival is attributed to partial redundancy with the AP-1 β paralog.
Ap2s1 (σ2) null: early embryonic lethal (~E3.5–E9.5).
Ap2m1 (μ2) null: early embryonic lethal.
Complete AP-2 loss: "Complete loss of AP-2 is early embryonic lethal" [JCS review, full text]
Interpretive value: these establish a dosage/severity gradient in which CFNDS sits at the mild, viable end — consistent with CCDC32 loss producing partial rather than complete AP-2 deficiency, and directly supporting the cleft palate and cardiac phenotypes as AP-2-attributable. ⚠️ Do not conflate the AP-2 adaptor complex α subunit (AP2A1/AP2A2) with the AP-2α transcription factor (TFAP2A) — searches readily mix them, and TFAP2A knockouts also produce cleft palate and cardiovascular defects for entirely unrelated reasons.

15.4 Applications and gaps

What current models support: ciliogenesis assays; left-right patterning; craniofacial cartilage morphometry; cardiac looping; AP-2 assembly biochemistry and structural biology; CCP dynamics by TIRF; transferrin-uptake functional readouts; direct testing of patient alleles in rescue assays.

What no current model supports: the neurodevelopmental/cognitive phenotype; cleft lip and palate morphogenesis in a mammal; longitudinal/adult natural history; therapeutic testing.

Highest-value next models: (1) a stable germline zebrafish ccdc32 mutant line; (2) a constitutive or neural-crest-conditional mouse Ccdc32 knockout using the existing flox allele — with explicit assessment of palate, cardiac septation, situs, and brain; (3) patient-derived iPSC neural crest cells and cerebral/cardiac organoids; (4) patient fibroblast AP-2 abundance and transferrin-uptake assays as a candidate functional diagnostic for VUS resolution.

Model databases: ZFIN (zebrafish), MGI / IMPC / IMSR / KOMP (mouse), Alliance of Genome Resources (ortholog integration), Cellosaurus (HeLa, mIMCD3 lines).

Appendix A — Consolidated Reference List

PMID	Citation	Type	Role
32307552	Harel T, Griffin JN, Arbogast T, Monroe TO, Palombo F, Martinelli M, Seri M, Pippucci T, Elpeleg O, Katsanis N. Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies. Hum Mol Genet. 2020;29(9):1489-1497. DOI 10.1093/hmg/ddaa073. PMC7268788	HUMAN_CLINICAL + MODEL_ORGANISM + IN_VITRO	Founding paper. Gene discovery, 2 families/3 individuals, zebrafish, ciliary model. Sole HPOA annotation source.
35451546	Abdalla E, Alawi M, Meinecke P, Kutsche K, Harms FL. Cardiofacioneurodevelopmental syndrome: Report of a novel patient and expansion of the phenotype. Am J Med Genet A. 2022;188(8):2448-2453. DOI 10.1002/ajmg.a.62762	HUMAN_CLINICAL	3rd patient; defines the core phenotype; first to propose the AP-2 link.
38818818	Fernandes da Rocha D, Quental R, Grangeia A, Pinto Moura C. A novel homozygous deletion in CCDC32 gene causing cardiofacioneurodevelopmental syndrome: the fourth patient reported. Clin Dysmorphol. 2024;33(3):114-117. DOI 10.1097/MCD.0000000000000501	HUMAN_CLINICAL	4th patient. ⚠️ No abstract in PubMed; full text paywalled — no quotable snippet obtainable.
41639596	Albuainain F, Venema M, Schot R, Huigen G, Mancini GMS, van Ham TJ, Barakat TS. Two siblings with CCDC32-related cardiofacioneurodevelopmental syndrome diagnosed by clinical RNA-sequencing and review of literature. Eur J Hum Genet. 2026. DOI 10.1038/s41431-026-02023-y. PMC13046869	HUMAN_CLINICAL	Most recent + only review. Sibling pair; RNA-seq diagnosis; literature synthesis. ⚠️ Full text not retrievable (403/paywall) — the feature-by-feature review table could not be extracted.
39145939	Wan C, Puscher H, Ouyang Y, Wu J, Tian Y, Li S, Yin Q, Shen J. An AAGAB-to-CCDC32 handover mechanism controls the assembly of the AP2 adaptor complex. PNAS. 2024. PMC11348294	IN_VITRO	Defines CCDC32's molecular function. Tests a CFNDS patient mutant.
41489497	Yang Z, Yang C, Huang Z, Xu P, Li Y, Han L, Peng L, Wei X, Pak JE, Svitkina T, Schmid SL, Chen Z. CCDC32 stabilizes clathrin-coated pits and drives their invagination. eLife. 2026. PMC12768407 (preprint: PMID 38979322)	IN_VITRO	CCP dynamics; maps the aa78-98 α-helix removed by disease alleles.
42234739	Sloan DE, Matthews AE, Yanagisawa H, Tedamrongwanish T, Cannon K, Simmons J, Chappell G, Nicely NI, Berlow R, Kikkawa M, Baker RW. CCDC32 collaborates with the membrane to assemble the AP-2 clathrin adaptor complex. Sci Adv. 2026. PMC13267310 (preprint: PMID 40799577)	IN_VITRO / structural	Structural mechanism; PIP2 membrane as molecular switch.
39250673	Stepwise assembly of the AP2 endocytic clathrin adaptor complex. PNAS. 2024. PMC11420168	Commentary	Contextual commentary on the assembly pathway.
—	Sanger JM et al. Adaptor protein complexes and disease at a glance. J Cell Sci. 2019;132(20):jcs222992	Review	AP-2 subunit KO phenotypes; AP2S1/AP2M1 human disease.

Structured / database sources: MONDO:0030873 (OLS/EBI); MedGen UID 1721861; HPO API annotations for OMIM:619123; HGNC:28295; ClinGen gene-disease validity (Syndromic Disorders GCEP, 2024-10-18, MODERATE); ClinVar (VCV001690313, VCV002431643, VCV000988600, VCV000988601, VCV002580223); gnomAD v4.0 constraint; Human Protein Atlas ENSG00000128891.

Appendix B — Explicit "No Data" Register

For honest curation, these are confirmed absences, not unsearched areas:

Domain	Status
Orphanet entry / ORPHA code	Not found — ontology coverage gap
ICD-10 / ICD-11 specific code	None assigned
Dedicated MeSH descriptor	None
GARD entry	Not identified
Prevalence / incidence estimate	None — literature case count only
Natural history study, registry, longitudinal cohort	None
Adult patient reported	None — oldest is 9 years
Survival / mortality data	None
QoL instrument data (EQ-5D/SF-36/PROMIS)	None
Diagnostic criteria / consensus guideline / society statement	None
Biomarker (diagnostic, prognostic, monitoring)	None
Prognostic model or genotype-phenotype correlation	None
Clinical trials (ClinicalTrials.gov)	None
Disease-modifying / targeted / gene / RNA therapy	None; none in development
Pharmacogenomics (CPIC/PharmGKB)	Not applicable
Methylation episignature	None
Patient transcriptomics/proteomics/metabolomics (mechanistic)	None (RNA-seq used diagnostically only)
Patient-derived fibroblast / iPSC / organoid model	None
Published mouse model phenotype	None (flox allele commercially available, unpublished)
IMPC data for Ccdc32	Not found
Naturally occurring disease in other species / OMIA entry	None
Environmental, infectious, lifestyle, or GxE factor	None; not applicable
ClinGen dosage sensitivity / variant / actionability curation	None (validity curation only)
Newborn or population carrier screening	Not applicable / not indicated

Appendix C — Suggested High-Priority `discussions` Entries for the KB Record

kind: KNOWLEDGE_GAP — Adult phenotype, survival, and natural history are entirely unknown (oldest reported patient age 9).
kind: KNOWLEDGE_GAP — Are the two ~32.6-kb deletions (ClinVar VCV001690313 / VCV002431643) the same recurrent, repeat-mediated allele? Breakpoint and haplotype analysis needed. Proposed experiment: breakpoint-junction sequencing and SNP-haplotype comparison across reported deletion carriers.
kind: HUMAN_MODEL_MISMATCH — The zebrafish ccdc32 crispant supports a primary ciliary mechanism, but the 2024–2026 human-cell structural/biochemical work assigns CCDC32 a primary AP-2 assembly function, and patients lack the cardinal ciliopathy features (cystic kidney disease, polydactyly, retinal dystrophy). Whether the ciliary defect is primary or secondary to CME failure is unresolved. Proposed experiments: test ciliogenesis in CCDC32-KO human cells with AP-2 rescue; assay ciliary receptor trafficking; characterize a stable zebrafish mutant line and a neural-crest-conditional mouse KO.
kind: KNOWLEDGE_GAP — All reported alleles are complete LoF yet expressivity is markedly variable (hypertelorism vs hypotelorism; AVSD+heterotaxy vs isolated VSD; fetus with no cardiac defect). Modifiers, stochastic developmental variation, or both?
kind: KNOWLEDGE_GAP — No functional assay exists to classify CCDC32 VUS (e.g. the p.Tyr157Ter ClinVar VUS). Proposed experiment: validate patient-fibroblast AP-2 subunit abundance and transferrin-uptake as a clinical-grade functional readout.

Suggested conforms_to candidates: none of the existing dismech modules is a clean fit. pharyngeal_arch_patterning_serial_homology is a partial conceptual neighbour (cranial-neural-crest-derived multi-element craniofacial malformation) but CFNDS's lesion is a trafficking/assembly chaperone rather than an arch-patterning or ribosome/spliceosome lesion, and the CFNDS bundle is not confined to arch derivatives — do not force conformance. If a module is created, the natural one is a new "AP-2 adaptor assembly / clathrin-mediated endocytosis deficiency" module, which would already have three worked conformers across the pathway (CCDC32→CFNDS, AP2M1→DEE, AP2S1→FHH3, AAGAB→punctate PPK type 1) — a genuinely reusable conserved mechanism.

Sources: - OMIM #619123 — CARDIOFACIONEURODEVELOPMENTAL SYNDROME; CFNDS - OMIM *618941 — CCDC32 - Harel et al. 2020, Hum Mol Genet (PMID:32307552) · full text PMC7268788 · publisher - Abdalla et al. 2022, Am J Med Genet A (PMID:35451546) · Wiley - Fernandes da Rocha et al. 2024, Clin Dysmorphol (PMID:38818818) · journal - Albuainain et al. 2026, Eur J Hum Genet (PMID:41639596) - Wan et al. 2024, PNAS — AAGAB-to-CCDC32 handover (PMC11348294) - Yang et al. 2026, eLife — CCDC32 stabilizes clathrin-coated pits (PMC12768407) - Sloan et al. 2026, Sci Adv — CCDC32 collaborates with the membrane (PMC13267310) - Stepwise assembly of the AP2 endocytic clathrin adaptor complex, PNAS 2024 (PMC11420168) - Adaptor protein complexes and disease at a glance, J Cell Sci 2019 - MedGen UID 1721861 — CFNDS - HPO annotations for OMIM:619123 - MONDO:0030873 via EBI OLS4 - HGNC:28295 — CCDC32 - ClinGen curation results for CCDC32 (HGNC:28295) - ClinVar — CCDC32 variants - gnomAD v4.0 gene constraint - Human Protein Atlas — CCDC32 (ENSG00000128891) - GeneCards — CCDC32 - Cyagen Ccdc32-flox mouse model - AAGAB mutations in punctate palmoplantar keratoderma (PMC4282079) - Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3, Nat Genet - Modeling AP2M1 developmental and epileptic encephalopathy in Drosophila, DMM

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome	Count
References checked	20
Resolved	20
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	20
On topic	7
Off topic	0

All extracted references resolved successfully.

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OpenScientist Report

Classifications

Inheritance

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

Overview

Key identifiers

Synonyms / alternative names

Provenance of information

2. Etiology

Disease causal factors

Risk factors

Protective factors

Gene–environment interactions

3. Phenotypes

3.1 HPO annotation set (authoritative, from HPOA)

3.2 Additional phenotypes from later reports (not yet in HPOA)

3.3 Phenotype characteristics

3.4 Quality-of-life impact

4. Genetic / Molecular Information

4.1 Causal gene

4.2 Pathogenic variants reported

4.3 ClinGen gene–disease validity

4.4 Modifier genes

4.5 Epigenetic information

4.6 Chromosomal abnormalities

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 Model A — Ciliopathy (Harel et al. 2020; the original proposal)

6.2 Model B — AP-2 adaptor assembly chaperone / clathrin-mediated endocytosis (2024–2026; now the dominant molecular model)

6.3 Reconciling the two models

6.4 Proposed causal chain (for a dismech pathograph)

6.5 Ontology term suggestions for mechanism

6.6 Other mechanism dimensions

7. Anatomical Structures Affected

Organ level

Tissue and cell level

Subcellular level (GO cellular component)

Localization / lateralization

8. Temporal Development

Onset

Progression

Patterns

9. Inheritance and Population

Epidemiology

Genetic epidemiology

Population demographics

10. Diagnostics

Clinical tests

Genetic testing — the only definitive diagnostic modality

Omics-based diagnostics

Clinical criteria

Differential diagnosis

Screening

11. Outcome / Prognosis

Survival and mortality

Morbidity and function

Disease course and complications

Recovery potential

Prediction

12. Treatment

Pharmacotherapy

Advanced therapeutics

Appendix C — Suggested High-Priority `discussions` Entries for the KB Record