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Classifications

Harrison's Part

🔗

Mappings

MONDO

MONDO:0800439 syndromic complex neurodevelopmental disorder Not Yet Curated

ClinGen's Intellectual Disability and Autism GCEP curated the ANKRD17 gene-disease relationship against this umbrella MONDO term rather than against MONDO:0859186, while stating that the curated disease is also known as Chopra-Amiel-Gordon syndrome. The umbrella covers many unrelated genes, so this is recorded as a broader cross-reference, not an equivalence.

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Inheritance

1

Autosomal dominant HP:0000006

Heterozygous ANKRD17 pathogenic variants cause disease in an autosomal dominant manner, typically de novo. In the founding cohort the variant was confirmed de novo in 29 of 34 individuals; one truncating variant was transmitted from a mother with borderline intellectual functioning to her son, and one nonsense variant was present at low level (about 4% of reads) in the blood of a healthy, non-dysmorphic father, consistent with parental somatic and possibly germline mosaicism. GeneReviews therefore describes the recurrence risk to sibs of a proband with an apparently de novo variant as low but above the population risk. Expressivity is variable, including between a transmitting parent and child; no formal penetrance estimate has been published.

Autosomal dominant inheritance Expressivity: VARIABLE De novo rate: 29 of 34 individuals in the founding cohort

Show evidence (5 references)

PMID:36548456 SUPPORT Human Clinical

"ANKRD17-related neurodevelopmental syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant."

GeneReviews states the inheritance pattern and that most cases are de novo.

PMID:36548456 SUPPORT Human Clinical

"If the ANKRD17 pathogenic variant identified in the proband is not identified in either parent, the risk to sibs is low but greater than that of the general population because of the possibility of parental germline mosaicism."

GeneReviews recurrence-risk statement for sibs of a simplex proband.

PMID:33909992 SUPPORT Human Clinical

"The ANKRD17 variants were shown to be de novo in 29 of the 34 individuals."

De novo fraction in the founding cohort.

+ 2 more references

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Mechanistic Hypotheses

3

Reduced ANKRD17 impairs YAP-dependent neural progenitor growth signaling

ankrd17_hippo_yap EMERGING

Evidence balance 1 support

ANKRD17 is a Mask-family co-factor that promotes YAP nuclear import and stability, and it is co-expressed with YAP1 in fetal human radial glia. The hypothesis is that reduced ANKRD17 lowers YAP activity in neural progenitors and so contributes to the neurodevelopmental phenotype. It rests on Drosophila genetics, mammalian cell-line work and expression data; it has not been tested in ANKRD17-deficient neural tissue.

Pathograph links

Reduced ANKRD17 in Developing Neural Progenitors and Neurons -> Disrupted YAP Nuclear Import in Neural Progenitors UNKNOWN

Disrupted YAP Nuclear Import in Neural Progenitors -> Neurodevelopmental Dysfunction UNKNOWN

Show evidence (1 reference)

PMID:33909992 SUPPORT Computational

"raising the possibility that the neurodevelopmental phenotypes associated with ANKRD17 variants may be due to disruption of this pathway"

The founding authors' statement of the hypothesis.

ANKRD17 deficiency impairs synaptic protein composition and mitochondrial function

ankrd17_synaptic_mitochondrial EMERGING

Evidence balance 1 support

Based on one study combining regional knockdown in juvenile mouse brain with proteomics of one ANKRD17-deleted fetal cortex, ANKRD17 deficiency is proposed to reduce excitatory synaptic proteins and mitochondrial respiratory proteins, contributing to intellectual disability and autism.

Pathograph links

Reduced ANKRD17 in Developing Neural Progenitors and Neurons -> Synaptic Protein Deficit and Neural Circuit Dysfunction INDIRECT UNKNOWN INTERMEDIATES

Synaptic Protein Deficit and Neural Circuit Dysfunction -> Neurodevelopmental Dysfunction UNKNOWN

Show evidence (1 reference)

PMID:40604385 SUPPORT Model Organism

"Furthermore, our studies suggest dysregulation of synaptic proteins and mitochondrial function, along with impaired neural circuits following Ankrd17 knockdown."

Statement of the hypothesis from the knockdown study.

Reduced ANKRD17 weakens NOD1/NOD2 and RIG-I-like receptor signaling, predisposing to infection

ankrd17_innate_immunity EMERGING

Evidence balance 1 support

Cell-line studies place ANKRD17 in NOD1/NOD2 antibacterial and RIG-I-like receptor antiviral signaling; the founding authors propose this as the basis of recurrent infections. Not tested in patient cells.

Pathograph links

Impaired Innate Immune Pattern-Recognition Signaling -> Recurrent Infections UNKNOWN

Show evidence (1 reference)

PMID:23711367 SUPPORT In Vitro

"In conclusion, this reveals a novel function for Ankrd17 in anti-bacterial innate immune pathways."

Cell-line basis for the immune hypothesis.

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Discussions and Knowledge Gaps

3

Homozygous Ankrd17-null mice die of hemorrhage from failed vascular maturation, yet no vascular features were found in the 34-person founding cohort. Does heterozygous ANKRD17 loss confer any vascular risk in humans, as the single neonatal ruptured-aneurysm case might suggest?

HUMAN MODEL MISMATCH mismatch_ankrd17_null_mouse_vascular

Attached to

animal_models#Mouse phenotypes#Intracranial Aneurysm

The mouse phenotype reflects complete loss, which has no human counterpart, and heterozygous mice were not phenotyped in detail. A single human aneurysm case with a missense variant cannot establish an association, and ClinGen records its significance as unclear. Whether vascular imaging belongs in surveillance depends on the answer.

Proposed experiments

Vascular phenotyping of Ankrd17 heterozygous mice

exp_ankrd17_heterozygous_mouse_vasculature

Examine cerebral and systemic arterial wall structure, smooth muscle coverage and aneurysm formation in aging Ankrd17 heterozygous mice.

Systematic vascular review in the natural history cohort

exp_ankrd17_cohort_vascular_imaging

Review MRI/MRA and clinical vascular events in the NCT05528744 natural history cohort to estimate whether cerebrovascular disease is enriched.

The Mask/Yorkie requirement is established in Drosophila and YAP nuclear import in immortalized mammalian cell lines. Does reduced ANKRD17 dosage actually lower YAP-dependent signaling in human neural progenitors, where the syndrome originates?

HUMAN MODEL MISMATCH mismatch_ankrd17_hippo_yap_model_systems

Attached to

pathophysiology#Disrupted YAP Nuclear Import in Neural Progenitors mechanistic_hypotheses#ankrd17_hippo_yap

Every functional step in this hypothesis comes from a system that is not human neural tissue: fly tissue-growth genetics and cell-line overexpression or knockdown. The only human data are expression, namely that ANKRD17 and YAP1 are co-expressed in fetal radial glia, which establishes opportunity rather than dependence. The paralog ANKHD1 also binds YAP and could buffer the pathway differently in human progenitors than in either model. If reduced ANKRD17 does not lower YAP activity in human neural cells, this node and its hypothesis group are describing a conserved biochemical activity that is not the disease mechanism.

Proposed experiments

YAP localization and activity in ANKRD17-haploinsufficient human neural progenitors

exp_ankrd17_yap_human_neural_progenitors

In patient-derived or isogenic ANKRD17 heterozygous iPSC-derived neural progenitors and cortical organoids, measure nuclear versus cytoplasmic YAP, YAP target-gene expression, and progenitor proliferation against isogenic controls, with ANKHD1 dosage manipulated separately to test paralog buffering.

Perturbations

Heterozygous ANKRD17 loss in human neural progenitors

pathophysiology#ANKRD17 Haploinsufficiency

Readouts

Nuclear YAP and YAP target-gene activity

pathophysiology#Disrupted YAP Nuclear Import in Neural Progenitors

Direction: DECREASED

Interpretation: Reduced nuclear YAP and target-gene output in the haploinsufficient progenitors would support the pathway step in human cells; no change would refute it.

Would support

pathophysiology#Disrupted YAP Nuclear Import in Neural Progenitors

Would refute

pathophysiology#Disrupted YAP Nuclear Import in Neural Progenitors

Supporting outcome

Nuclear YAP and YAP target-gene expression are reduced in ANKRD17 haploinsufficient human neural progenitors relative to isogenic controls.

Refuting outcome

YAP localization, target-gene output and progenitor proliferation are unchanged despite halved ANKRD17, indicating the pathway is buffered in human neural cells.

Show evidence (1 reference)

PMID:31661072 SUPPORT In Vitro

"Mammalian Mask1/2 proteins also promote nuclear import of YAP, as well as stabilising YAP and driving formation of liquid droplets."

The mammalian evidence for the pathway step is cell-line work, not neural tissue, which is the mismatch this discussion records.

Do ANKRD17 missense variants act only by destabilizing the protein, and do they produce a different severity from truncating alleles?

KNOWLEDGE GAP gap_ankrd17_genotype_phenotype

Attached to

pathophysiology#Ankyrin Repeat Destabilization by Missense Variants pathophysiology#ANKRD17 Haploinsufficiency

Missense pathogenicity rests on conservation and homology modeling alone, with no protein-level assay. A later report stated that a genotype-phenotype correlation could not yet be established. If some missense alleles are not simple loss of function, variant interpretation and the single-mechanism model in this entry would need revision.

Proposed experiments

Protein stability assay of patient missense alleles

exp_ankrd17_missense_stability

Express patient missense and in-frame variants and measure protein half-life and steady-state level against wild type and a truncating control; test effect on YAP nuclear localization.

Show evidence (1 reference)

PMID:40604385 SUPPORT Human Clinical

"These findings highlight the difficulty of establishing a clear genotype–phenotype correlation and underscore the need for larger cohort studies to identify potential trends."

Genotype-phenotype correlation remains unresolved.

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Pathophysiology

8

ANKRD17 Haploinsufficiency

A heterozygous germline ANKRD17 variant reduces functional ANKRD17 dosage. In the founding cohort 22 of 32 probands carried a variant expected to cause loss of function (7 nonsense, 12 frameshift, 2 essential splice site, and a 1.16 Mb 4q13.3 deletion including ANKRD17); later reports add a second 4q13.3 deletion removing exons 2-34 and a canonical splice variant shown on RNA to skip exon 32. ANKRD17 is highly constrained against loss-of-function variation in the population, and ClinGen scores it as haploinsufficient. In one proband with a de novo nonsense variant (p.Arg418*), ANKRD17 protein in peripheral blood was about half the parental level.

ANKRD17 hgnc:23575

Genetic context ANKRD17 hgnc:23575 variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Truncating, essential-splice and whole- or multi-exon deletion alleles; most arise de novo.

Animal models

Ankrd17 null mouse Mouse fails to recapitulate The model informs the essential role of Ankrd17 in embryonic vascular maturation, not the heterozygous human neurodevelopmental disorder.

Downstream

Reduced ANKRD17 in Developing Neural Progenitors and Neurons Halving gene dosage reduces ANKRD17 in every tissue that expresses it, including the developing cortex.

Show evidence (7 references)

PMID:33909992 SUPPORT Human Clinical

"The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb)."

The founding cohort's mutational spectrum, dominated by loss-of-function alleles.

PMID:33909992 SUPPORT Human Clinical

"ANKRD17 is highly intolerant to loss of function in the human population"

Population constraint against loss-of-function variants supports a dosage-sensitive gene.

CGDS:HGNC_23575 SUPPORT Other

"ANKRD17 | HGNC:23575 | 26057 | 4q13.3 | chr4:73073376-73258798 | 3 - Sufficient Evidence for Haploinsufficiency | 0 - No Evidence for Triplosensitivity | 2023-04-11"

ClinGen Dosage Sensitivity haploinsufficiency score 3 for ANKRD17 (last evaluated 2023-04-11).

+ 4 more references

Ankyrin Repeat Destabilization by Missense Variants

Mechanism confidence: Hypothetical

Nine of 32 founding-cohort probands carried de novo missense variants and one an in-frame indel, all at highly conserved residues. Five of the seven missense variants inside the ankyrin repeats alter positions that are invariant across all 25 ANKRD17 repeats (the 6th/21st leucines of the hydrophobic core and the 13th glycine of the inter-helix turn). Homology modeling predicts these destabilize the repeat fold rather than a specific binding surface, which would reduce functional protein and converge on haploinsufficiency. No functional assay of any missense allele has been published, so a dominant-negative or other effect is not excluded.

ANKRD17 hgnc:23575

Genetic context ANKRD17 hgnc:23575 variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

De novo missense and in-frame alleles at conserved ankyrin-repeat core residues; loss of function is predicted by structural modeling only.

Downstream

ANKRD17 Haploinsufficiency Predicted, not demonstrated: destabilized protein would lower functional ANKRD17 to a level comparable with a null allele.

Show evidence (2 references)

PMID:33909992 SUPPORT Computational

"Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues."

Homology modeling of the missense variants.

PMID:33909992 SUPPORT Computational

"Remarkably, five of the seven ankyrin repeat missense variants affect amino acids that are invariant in all 25 repeats"

Conservation analysis across the 25 ANKRD17 ankyrin repeats.

Reduced ANKRD17 in Developing Neural Progenitors and Neurons

Mechanism confidence: Provisional

In single-cell RNA-seq of the fetal human telencephalon ANKRD17 is broadly expressed, including in radial glial progenitors, excitatory neurons and interneurons, whereas its paralog ANKHD1 is more restricted, so the paralog may not compensate in the developing cortex. In adult mouse brain ANKRD17 is expressed in excitatory and inhibitory neurons. Which of ANKRD17's reported molecular activities (Hippo/YAP co-factor, cyclin E/CDK2 interaction, RNA binding through the KH domain) is dosage-critical in these cells is not known.

ANKRD17 deficiency impairs synaptic protein composition and mitochondrial function Reduced ANKRD17 impairs YAP-dependent neural progenitor growth signaling

radial glial cell CL:0000681 neuron CL:0000540

neurogenesis GO:0022008 ⚠ ABNORMAL

Downstream

Disrupted YAP Nuclear Import in Neural Progenitors

Synaptic Protein Deficit and Neural Circuit Dysfunction

Neurodevelopmental Dysfunction Genetic evidence (dosage-reducing variants cause the syndrome) establishes the link; the intermediate cellular steps are unresolved.

Show evidence (3 references)

PMID:33909992 SUPPORT Computational

"indicates broad expression of ANKRD17, including in radial glial progenitors (the neural stem cells of the cortex), excitatory neurons, and interneurons, while ANKHD1 expression appears more limited"

Reanalysis of a public fetal telencephalon scRNA-seq dataset; expression, not function.

PMID:40604385 SUPPORT Model Organism

"ANKRD17 is broadly expressed, particularly in the cytoplasm, of both excitatory and inhibitory neurons in the adult mouse brain"

Neuronal expression in mouse brain.

PMID:19150984 SUPPORT In Vitro

"Overexpression of Ankrd17 promotes S phase entry, whereas depletion of Ankrd17 expression by small interfering RNA inhibits DNA replication and blocks cell cycle progression"

Cell-line evidence for the cyclin E/CDK2-linked cell-cycle role named in this node's description; not tested in neural progenitors.

Disrupted YAP Nuclear Import in Neural Progenitors

Mechanism confidence: Hypothetical

ANKRD17 (Mask2) and its paralog ANKHD1 (Mask1) bind YAP and promote its nuclear import and stability in mammalian cells, and the Drosophila ortholog Mask is required for Yorkie-driven tissue growth. YAP1 and ANKRD17 are co-expressed in fetal human radial glia. That reduced ANKRD17 lowers nuclear YAP activity in neural progenitors, and that this contributes to the neurodevelopmental or growth phenotype, is a hypothesis raised by the founding authors; it has not been tested in ANKRD17-deficient human or mammalian neural tissue.

Reduced ANKRD17 impairs YAP-dependent neural progenitor growth signaling

radial glial cell CL:0000681

hippo signaling GO:0035329 ⚠ ABNORMAL YAP nuclear import GO:0042307 ↓ DECREASED

Downstream

Neurodevelopmental Dysfunction

Show evidence (2 references)

PMID:31661072 SUPPORT In Vitro

"Mammalian Mask1/2 proteins also promote nuclear import of YAP, as well as stabilising YAP and driving formation of liquid droplets."

ANKHD1/ANKRD17 promote YAP nuclear import and stability in mammalian cells.

PMID:33909992 SUPPORT Computational

"raising the possibility that the neurodevelopmental phenotypes associated with ANKRD17 variants may be due to disruption of this pathway"

The founding authors state the Hippo/YAP link as a possibility, based on YAP1/ANKRD17 co-expression in radial glia.

Synaptic Protein Deficit and Neural Circuit Dysfunction

Mechanism confidence: Hypothetical

After AAV-shRNA knockdown of Ankrd17 in the medial prefrontal cortex or hippocampal CA1 of juvenile mice, the NMDA-receptor subunit GluN2A, the AMPA-receptor subunit GluA1, PSD-95 and synapsin I were reduced, fewer excitatory neurons were activated during behavioral testing, and mitochondrial genes (Sdha, Sdhb, Sdhc, Ogdh, Akr1a1) were down-regulated; the mice showed reduced sociability, increased anxiety and impaired spatial memory. Proteomics of cortex from one ANKRD17-deleted fetus against one control fetus showed down-regulation of mitochondrial proteins. The model is a regional, postnatal knockdown rather than germline heterozygosity, and the human proteomic comparison is one case against one control, so this node is a hypothesis for the cognitive and social phenotype, not an established mechanism.

ANKRD17 deficiency impairs synaptic protein composition and mitochondrial function

neuron CL:0000540

chemical synaptic transmission GO:0007268 ↓ DECREASED mitochondrion organization GO:0007005 ⚠ ABNORMAL

Animal models

Regional Ankrd17 AAV-shRNA knockdown mouse Mouse partially recapitulates Partial Ankrd17 reduction in juvenile cortex or hippocampus reduces synaptic proteins and neuronal activation and produces social, anxiety and spatial-memory deficits.

Downstream

Neurodevelopmental Dysfunction

Show evidence (3 references)

PMID:40604385 SUPPORT Model Organism

"Our findings revealed a decrease in the expression of the NMDAR subunit GluN2A, the AMPAR subunit GluA1, the excitatory synaptic scaffolding protein PSD-95 and Synapsin I"

Synaptic protein reduction after regional Ankrd17 knockdown in mouse brain.

PMID:40604385 SUPPORT Model Organism

"In both the mPFC and CA1 regions, Sdha, Sdhb, Sdhc, Akr1a1, and Ogdh were significantly decreased following Ankrd17 knockdown"

Mitochondrial gene down-regulation in knockdown mouse brain.

PMID:40604385 SUPPORT Human Clinical

"Collectively, these findings suggest an inhibition of mitochondria-related functions in embryonic human brain tissue with ANKRD17 deficiency."

Proteomics of one ANKRD17-deleted fetal cortex against one control fetus; a single comparison.

Impaired Innate Immune Pattern-Recognition Signaling

Mechanism confidence: Hypothetical

In cell lines ANKRD17 binds NOD2 and contributes to NOD1- and NOD2-mediated pro-inflammatory responses to bacteria, and separately binds RIG-I, MDA5 and VISA to enhance RIG-I-like receptor antiviral signaling. The founding authors propose these roles as a plausible basis for the recurrent, mostly bacterial, infections seen in about a third of patients. Immunology assessments in five patients found no obvious immunodeficiency, and no innate-immune assay has been done in patient cells.

Reduced ANKRD17 weakens NOD1/NOD2 and RIG-I-like receptor signaling, predisposing to infection

NOD2 signaling GO:0070431 ↓ DECREASED NOD1 signaling GO:0070427 ↓ DECREASED RIG-I signaling GO:0039529 ↓ DECREASED

Downstream

Recurrent Infections

Show evidence (3 references)

PMID:23711367 SUPPORT In Vitro

"Knock-down and overexpression analysis revealed that Ankrd17 is functionally involved in Nod2- and Nod1-mediated responses in human myeloid and epithelial cells."

Knockdown in human cell lines impairs NOD1/NOD2 responses.

PMID:22328336 SUPPORT In Vitro

"Consistently, knockdown of ankrd17 impairs RLR signaling."

Knockdown impairs RIG-I-like receptor antiviral signaling in cell lines.

PMID:33909992 SUPPORT Human Clinical

"Immunology assessments were recorded in five individuals, details of which can be found in Table S2, with no obvious immunodeficiency identified in these individuals."

Limited patient immunology did not identify an immunodeficiency, so the mechanism of infection susceptibility is unproven.

Neurodevelopmental Dysfunction

The shared clinical consequence of reduced ANKRD17 dosage in the developing brain, expressed as global developmental delay or intellectual disability with disproportionate speech impairment, motor delay, behavioral comorbidity, epilepsy and non-specific structural brain findings. The course is developmental rather than degenerative; no regression has been reported.

Downstream

Global Developmental Delay

Intellectual Disability

Delayed Speech and Language Development

Absent Speech

Motor Delay

Autism Spectrum Disorder

Attention Deficit Hyperactivity Disorder

Seizures

EEG Abnormality

Gait or Balance Disturbance

Spasticity

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech"

Summary of the core neurodevelopmental phenotype.

Abnormal Brain Development

Mechanism confidence: Provisional

Structural brain findings on MRI are present in about half of imaged patients but are heterogeneous (reduced white matter volume, thin corpus callosum, optic nerve hypoplasia, periventricular nodular heterotopia, focal hyperintensities, cysts); one deleted fetus had cerebellar hypoplasia. There is no consistent malformation pattern and no study linking a specific molecular step to any of them.

Downstream

Abnormal Brain Morphology

Reduced Cerebral White Matter Volume

Thin Corpus Callosum

Optic Nerve Hypoplasia

Neurodevelopmental Dysfunction

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"Neuroimaging abnormalities were identified in 11 of the 23 individuals in whom an MRI was recorded."

Frequency and heterogeneity of MRI findings.

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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

49

Cardiovascular 2

Prominent Superficial Blood Vessels HP:0007394

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"abnormality of bone mineralization (n = 2), and cutaneous prominence of blood vessels (n = 2)"

Two cohort members had cutaneous prominence of blood vessels.

Intracranial Aneurysm Dilatation of the cerebral artery HP:0004944

Onset: NEONATAL

Show evidence (3 references)

PMID:36277850 SUPPORT Human Clinical

"who experienced subarachnoid hemorrhage from a ruptured aneurysm involving the left middle cerebral artery. He experienced acute symptomatic seizures and required clipping of his aneurysm at 35 days of life"

Single case report of a term male neonate with a heterozygous de novo ANKRD17 missense variant (c.6988C>G, p.Pro2330Ala).

CGGV:assertion_48a9765c-f7ae-46f4-aa6f-7fa95f81404f-2024-12-12T170000.000Z NO_EVIDENCE Other

"The significance of these reports is unclear."

ClinGen regards the intracranial hemorrhage case as an atypical phenotype of unclear significance.

PMID:33909992 REFUTE Human Clinical

"There were no clinical features suggestive of vascular abnormalities in our cohort."

No vascular features in the founding cohort, arguing that vascular disease is not a regular feature.

Digestive 1

Feeding Difficulties FREQUENT HP:0011968

Onset: INFANTILE

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"Feeding difficulties, especially reduced oral intake, were reported at some stage in 11 individuals, 5 of whom required G-tube nutritional supplementation."

11 of 27 (41%) with feeding difficulties; 5 needed a G-tube.

Ear 2

Recurrent Otitis Media HP:0000403

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"The source of bacterial infection was primarily the upper and lower respiratory system and the middle ear (nine individuals) and in some cases required hospitalization."

Middle-ear and respiratory infections dominate; the split between the two sites is not given.

Low-Set Ears HP:0000369

Show evidence (1 reference)

PMID:36548456 SUPPORT Human Clinical

"deep-set and/or almond-shaped eyes with periorbital fullness, low-set ears, thick nasal alae and flared nostrils"

GeneReviews lists low-set ears.

Eye 5

Optic Nerve Hypoplasia HP:0000609

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"Abnormalities include decreased white matter volume (individuals 14, 16, and 18), thinning of the corpus callosum (individuals 14 and 19), optic nerve hypoplasia (individuals 18 and 19)"

Two individuals had optic nerve hypoplasia.

Ophthalmological Abnormalities FREQUENT Abnormality of the eye HP:0000478

Coarse binding: source unspecified

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"Ophthalmological abnormalities were reported in 13/23 individuals."

57% had ophthalmological abnormalities, not further specified.

Strabismus HP:0000486

Show evidence (1 reference)

PMID:36548456 SUPPORT Human Clinical

"ophthalmologic abnormalities (strabismus and refractive errors)"

GeneReviews names strabismus.

Refractive Error Abnormality of refraction HP:0000539

Show evidence (1 reference)

PMID:36548456 SUPPORT Human Clinical

"ophthalmologic abnormalities (strabismus and refractive errors)"

GeneReviews names refractive errors.

Deeply Set Eye OCCASIONAL HP:0000490

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"eyes which are either deep-set (5/24) or almond shaped (8/24) with periorbital fullness (6/24)"

21% of individuals with photographs.

Genitourinary 2

Genitourinary Abnormalities Abnormality of the genitourinary system HP:0000119

Coarse binding: source unspecified

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"genitourinary abnormalities (n = 5, of whom three had unilateral renal agenesis)"

Five with genitourinary abnormalities.

Unilateral Renal Agenesis HP:0000122

Onset: CONGENITAL

Show evidence (2 references)

PMID:33909992 SUPPORT Human Clinical

"genitourinary abnormalities (n = 5, of whom three had unilateral renal agenesis)"

Three individuals had unilateral renal agenesis.

PMID:36548456 SUPPORT Human Clinical

"Less common but distinctive features include cleft palate with Pierre Robin sequence, renal agenesis, and scoliosis."

GeneReviews lists renal agenesis.

Head and Neck 12

Microcephaly OCCASIONAL Secondary microcephaly HP:0005484

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"Postnatal microcephaly (OFC < −2SD) was noted in seven individuals"

7 of 31 (23%).

Macrocephaly OCCASIONAL HP:0000256

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"and macrocephaly in four (one of these individuals, however, also harbored a pathogenic de novo NSD1 variant"

Four with macrocephaly, one confounded by a second diagnosis.

Cleft Palate OCCASIONAL HP:0000175

Onset: CONGENITAL

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"Notably, there were two individuals with cleft palate in the context of Pierre Robin sequence (PRS) and another with cleft lip and palate."

Three of 34 (9%) had a palatal cleft.

Pierre-Robin Sequence OCCASIONAL HP:0000201

Onset: CONGENITAL

Show evidence (2 references)

PMID:33909992 SUPPORT Human Clinical

"Notably, there were two individuals with cleft palate in the context of Pierre Robin sequence (PRS) and another with cleft lip and palate."

Two of 34 (6%) had Pierre Robin sequence.

PMID:36548456 SUPPORT Human Clinical

"Less common but distinctive features include cleft palate with Pierre Robin sequence, renal agenesis, and scoliosis."

GeneReviews lists cleft palate with Pierre Robin sequence.

High Anterior Hairline FREQUENT HP:0009890

Show evidence (2 references)

PMID:33909992 SUPPORT Human Clinical

"with a high anterior hairline (19/24)"

79% of individuals with photographs.

PMID:33909992 SUPPORT Human Clinical

"Persistence of the high anterior hairline, periorbital fullness, and full cheeks into adulthood is demonstrated in individual 12 (age 30 years) and individual 25 (age 34 years)."

The gestalt persists into adulthood.

Triangular Face FREQUENT HP:0000325

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"Key dysmorphic features include a triangular-shaped face found in 10 of the 24 individuals for whom photos were available"

42% of individuals with photographs.

Thin Upper Lip Vermilion FREQUENT HP:0000219

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"full cheeks (7/24), and a thin upper lip (12/24)"

50% of individuals with photographs.

Thick Nasal Alae FREQUENT HP:0009928

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"thick nasal alae and flared nostrils (9/24)"

38% of individuals with photographs.

Flared Nostrils FREQUENT HP:0000454

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"thick nasal alae and flared nostrils (9/24)"

Reported together with thick nasal alae.

Almond-Shaped Palpebral Fissure FREQUENT HP:0007874

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"eyes which are either deep-set (5/24) or almond shaped (8/24) with periorbital fullness (6/24)"

33% of individuals with photographs.

Periorbital Fullness OCCASIONAL HP:0000629

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"eyes which are either deep-set (5/24) or almond shaped (8/24) with periorbital fullness (6/24)"

25% of individuals with photographs.

Full Cheeks OCCASIONAL HP:0000293

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"full cheeks (7/24), and a thin upper lip (12/24)"

29% of individuals with photographs.

Immune 3

Recurrent Infections FREQUENT HP:0002719

Show evidence (2 references)

PMID:33909992 SUPPORT Human Clinical

"Recurrent infections | 11/33"

Table 2 frequency (33%).

PMID:36548456 SUPPORT Human Clinical

"recurrent infections, gait and/or balance disturbances, and epilepsy"

GeneReviews lists recurrent infections.

Recurrent Bacterial Infections OCCASIONAL HP:0002718

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"There were nine individuals with recurrent bacterial infections, one with recurrent viral infections, and one individual with recurrent infections that were both viral and bacterial."

Nine of 33 (27%) had recurrent bacterial infections.

Recurrent Respiratory Infections HP:0002205

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"The source of bacterial infection was primarily the upper and lower respiratory system and the middle ear (nine individuals) and in some cases required hospitalization."

Respiratory tract infections are a main site.

Integument 1

Abnormality of Skin Pigmentation HP:0001000

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"abnormal skin pigmentation (n = 4), scoliosis (n = 3)"

Four cohort members had abnormal skin pigmentation.

Limbs 1

Abnormal Digit Morphology HP:0011297

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"Other infrequent features include minor digital anomalies (n = 6)"

Six cohort members had minor digital anomalies.

Musculoskeletal 4

Spasticity OCCASIONAL HP:0001257

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"Spasticity or hypertonia | 4/26"

Table 2 frequency (15%).

Joint Hypermobility FREQUENT HP:0001382

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"Generalized joint hypermobility was reported in 9/29 individuals."

31% had joint hypermobility.

Scoliosis HP:0002650

Show evidence (2 references)

PMID:36548456 SUPPORT Human Clinical

"Less common but distinctive features include cleft palate with Pierre Robin sequence, renal agenesis, and scoliosis."

GeneReviews lists scoliosis.

PMID:33909992 SUPPORT Human Clinical

"abnormal skin pigmentation (n = 4), scoliosis (n = 3)"

Three cohort members had scoliosis.

Abnormal Bone Mineral Density Abnormality of bone mineral density HP:0004348

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"scoliosis (n = 3), abnormality of bone mineralization (n = 2)"

Two cohort members had a bone mineralization abnormality, direction unspecified.

Nervous System 14

Global Developmental Delay VERY_FREQUENT HP:0001263

Onset: INFANTILE

Show evidence (2 references)

PMID:33909992 SUPPORT Human Clinical

"Global developmental delay (DD)/ID was the most common feature, affecting 31 individuals."

31 of 34 individuals (91%) had DD/ID.

PMID:36548456 SUPPORT Human Clinical

"ANKRD17-related neurodevelopmental syndrome is characterized by developmental delay – particularly affecting speech – and variable intellectual disability."

GeneReviews lists developmental delay as the defining feature.

Intellectual Disability VERY_FREQUENT HP:0001249

Show evidence (2 references)

PMID:33909992 SUPPORT Human Clinical

"The severity of DD/ID was variable, with 19 individuals in the moderate to severe range and 12 in the mild or borderline range."

Severity distribution across the 31 affected individuals.

PMID:33909992 SUPPORT Human Clinical

"confirmed a discrepancy between verbal IQ and performance IQ (verbal IQ < performance IQ) in three of these individuals"

Verbal-performance discrepancy in three of five individuals with detailed testing.

Delayed Speech and Language Development VERY_FREQUENT HP:0000750

Onset: INFANTILE

Show evidence (2 references)

PMID:33909992 SUPPORT Human Clinical

"Speech development was reported as delayed in 29 individuals, including 6 with absent speech (no meaningful words) and 4 who used fewer than 10 words meaningfully (all over the age of 4 years)."

29 of 32 assessed individuals (Table 2) had speech delay.

PMID:33909992 SUPPORT Human Clinical

"In our cohort, significant speech delay was reported in most individuals (n = 29) even in those with IQ in the borderline range."

Speech is affected out of proportion to general cognition.

Absent Speech OCCASIONAL HP:0001344

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"Absence of speech was observed in individuals with varying degrees of DD/ID, including one individual in the borderline and one in the mild range of ID."

Absent speech occurs even with mild or borderline ID; 6 of 32 (about 19%).

Motor Delay FREQUENT HP:0001270

Onset: INFANTILE

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"Motor delay | 20/29"

Table 2 frequency (69%).

Autism Spectrum Disorder Autistic behavior HP:0000729

Show evidence (2 references)

PMID:33909992 SUPPORT Human Clinical

"Less commonly reported neurodevelopmental phenotypes include ASD (n = 8) and ADHD (n = 4)."

ASD in 8 cohort members.

PMID:36548456 SUPPORT Human Clinical

"Additional features include autism spectrum disorder, attention-deficit/hyperactivity disorder"

GeneReviews lists ASD and ADHD among additional features.

Attention Deficit Hyperactivity Disorder HP:0007018

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"Less commonly reported neurodevelopmental phenotypes include ASD (n = 8) and ADHD (n = 4)."

ADHD in 4 cohort members.

Seizures OCCASIONAL HP:0001250

Onset: INFANTILE

Show evidence (3 references)

PMID:33909992 SUPPORT Human Clinical

"Epilepsy | 9/33"

Table 2 frequency (27%).

PMID:33909992 SUPPORT Human Clinical

"with an age of onset of under 2 years for five individuals"

Early onset in five of nine with epilepsy.

PMID:33909992 SUPPORT Human Clinical

"Focal seizures with secondary generalization was the most common seizure subtype"

Predominant seizure type.

Bilateral Tonic-Clonic Seizure with Focal Onset OCCASIONAL HP:0007334

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"Focal seizures with secondary generalization was the most common seizure subtype, present in five individuals"

Five individuals had this seizure type.

EEG Abnormality FREQUENT HP:0002353

Show evidence (2 references)

PMID:33909992 SUPPORT Human Clinical

"Abnormal EEG | 10/23"

Table 2 frequency (43%).

PMID:33909992 SUPPORT Human Clinical

"There were four individuals without epilepsy in whom an abnormal EEG was recorded."

EEG abnormalities occur without clinical seizures.

Abnormal Brain Morphology FREQUENT HP:0012443

Coarse binding: variable spectrum

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"Brain MRI abnormalities | 11/23"

Table 2 frequency (48%).

Reduced Cerebral White Matter Volume OCCASIONAL HP:0034295

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"Abnormalities include decreased white matter volume (individuals 14, 16, and 18), thinning of the corpus callosum (individuals 14 and 19), optic nerve hypoplasia (individuals 18 and 19)"

Three individuals had decreased white matter volume.

Thin Corpus Callosum HP:0033725

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"Abnormalities include decreased white matter volume (individuals 14, 16, and 18), thinning of the corpus callosum (individuals 14 and 19), optic nerve hypoplasia (individuals 18 and 19)"

Two individuals had thinning of the corpus callosum.

Gait or Balance Disturbance FREQUENT Gait disturbance HP:0001288

Show evidence (2 references)

PMID:33909992 SUPPORT Human Clinical

"Gait or balance abnormalities | 9/25"

Table 2 frequency (36%).

PMID:36548456 SUPPORT Human Clinical

"recurrent infections, gait and/or balance disturbances, and epilepsy"

GeneReviews lists gait and balance disturbance.

Growth 2

Short Stature FREQUENT HP:0004322

Onset: CHILDHOOD

Show evidence (2 references)

PMID:33909992 SUPPORT Human Clinical

"Neonatal growth parameters were normal in the majority of individuals (Table S2) but postnatal growth failure was a feature of almost half of the individuals (height < −2 SD in n = 12 and weight < −2 SD in n = 9)."

12 of 31 (39%) with height below -2 SD; growth failure is postnatal.

PMID:36548456 SUPPORT Human Clinical

"ophthalmologic abnormalities (strabismus and refractive errors), growth deficiency, feeding difficulties"

GeneReviews lists growth deficiency among the additional features.

Decreased Body Weight FREQUENT HP:0004325

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"Weight < −2 SD | 9/30"

Table 2 frequency (30%).

🧬

Genetic Associations

1

ANKRD17 (Definitive (ClinGen gene-disease validity, autosomal dominant))

Gene: ANKRD17 hgnc:23575 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

CGGV:assertion_48a9765c-f7ae-46f4-aa6f-7fa95f81404f-2024-12-12T170000.000Z SUPPORT Other

ClinGen Intellectual Disability and Autism GCEP classifies ANKRD17 as Definitive (re-evaluated 2024-12-12).

CGGV:assertion_48a9765c-f7ae-46f4-aa6f-7fa95f81404f-2024-12-12T170000.000Z SUPPORT Other

"ANKRD17 was first reported in relation to autosomal dominant syndromic complex neurodevelopmental disorder, also known as Chopra-Amiel-Gordon Syndrome (CAGS) (OMIM:619504), in 2021"

ClinGen equates its curated umbrella entity with CAGS.

PMID:33909992 SUPPORT Human Clinical

"Our work now strongly supports the possibility that haploinsufficiency of ANKRD17 is the major cause of these phenotypes in individuals with large alterations of 4q13.3."

Links 4q13.3 deletion phenotypes to ANKRD17 dosage.

+ 1 more reference

💊

Medical Actions

6

Developmental and Educational Support

Action: developmental and educational support Ontology label: Educational Intervention NCIT:C17874

Platform: Behavioral / lifestyle

Early intervention, special education and developmental therapies. Given the disproportionate expressive-language impairment, speech-language therapy is central.

Target Phenotypes: Global developmental delay HP:0001263 Delayed speech and language development HP:0000750

Show evidence (1 reference)

PMID:36548456 SUPPORT Human Clinical

"Treatment of manifestations: Developmental and educational support"

GeneReviews treatment of manifestations.

Anti-Seizure Medication

Action: anti-seizure medication Ontology label: Anticonvulsant Therapy NCIT:C64172

Agent: anticonvulsant NCIT:C264

Platform: Small molecule

Standard anti-seizure treatment; no ANKRD17-specific regimen exists. In the founding cohort most individuals with epilepsy were controlled on three or fewer medications. GeneReviews notes that teratogenic risk of anti-seizure medication in pregnancy depends on the drug, dose and gestational age.

Target Phenotypes: Epilepsy HP:0001250

Show evidence (3 references)

PMID:36548456 SUPPORT Human Clinical

"standard treatments for seizures, behavioral findings, ophthalmologic involvement, genitourinary anomalies, and spasticity"

GeneReviews recommends standard seizure treatment.

PMID:33909992 SUPPORT Human Clinical

"Seizures were well controlled (less frequent than every 2 years) in five individuals"

Response to standard medication in the cohort.

PMID:36548456 SUPPORT Human Clinical

"The teratogenic risk to the fetus associated with the use of anti-seizure medication during pregnancy depends on the type of anti-seizure medication used, the dose, and the gestational age of the fetus."

GeneReviews pregnancy management note.

Feeding Therapy and Gastrostomy

Action: gastrostomy tube placement Ontology label: Gastrostomy Tube Procedure NCIT:C157864

Platform: Surgery

Feeding therapy, with gastrostomy tube placement for persistent feeding difficulty; 5 of 11 founding-cohort individuals with feeding problems needed G-tube supplementation.

Target Phenotypes: Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:36548456 SUPPORT Human Clinical

"feeding therapy with gastrostomy tube placement as needed for persistent feeding issues"

GeneReviews treatment of feeding difficulty.

Immunology Referral and Infection Prophylaxis

Action: antibiotic prophylaxis Ontology label: Antibiotic Prophylaxis NCIT:C51993

Platform: Small molecule

Routine immunizations and referral to an immunologist for recurrent infections. Two founding-cohort individuals received low-dose prophylactic antibiotics for recurrent otitis media or respiratory infections; no trial or guideline evidence on prophylaxis exists for this disorder.

Target Phenotypes: Recurrent infections HP:0002719

Show evidence (2 references)

PMID:36548456 SUPPORT Human Clinical

"routine immunizations; referral to immunologist for those with recurrent infections"

GeneReviews management of recurrent infections.

PMID:33909992 SUPPORT Human Clinical

"Two individuals were on low-dose prophylactic antibiotics for recurrent otitis media or respiratory tract infections."

Prophylaxis used in two cohort members.

Developmental and Clinical Surveillance

Category: Monitoring Action: developmental surveillance Ontology label: Supportive Care NCIT:C15747

Platform: Other

At each visit, assess developmental progress and educational needs, seizures, tone and movement, growth, nutrition and feeding, and family needs; assess behavioral and musculoskeletal manifestations annually or as needed.

Show evidence (1 reference)

PMID:36548456 SUPPORT Human Clinical

"Surveillance: Assess developmental progress, educational needs, seizures, changes in tone, movement disorders, growth, nutrition, feeding, and family needs at each visit; assess behavioral and musculoskeletal manifestations annually or as needed."

GeneReviews surveillance recommendations.

Genetic Counseling

Category: Counseling / Informational Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Other

Counseling on autosomal dominant inheritance, the usual de novo origin, the low but non-zero sibling recurrence risk from parental mosaicism, and availability of prenatal and preimplantation testing once the familial variant is known.

Show evidence (1 reference)

PMID:36548456 SUPPORT Human Clinical

"Once the ANKRD17 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."

GeneReviews genetic counseling.

🔬

Diagnosis

1

Molecular Diagnosis

There are no clinical diagnostic criteria; the phenotype overlaps many neurodevelopmental syndromes and the facial gestalt is subtle in some individuals. Diagnosis is established by a heterozygous pathogenic ANKRD17 variant, usually found on exome or genome sequencing (trio analysis establishes de novo status); 4q13.3 deletions need copy-number analysis. For an ANKRD17 variant of uncertain significance, the founding authors suggest looking for the discriminating features (recurrent bacterial infections, cleft palate with Pierre Robin sequence, unilateral renal agenesis), while noting they occur in a minority.

Show evidence (3 references)

PMID:36548456 SUPPORT Human Clinical

"The diagnosis of ANKRD17-related neurodevelopmental syndrome is established in a proband with a heterozygous pathogenic variant in ANKRD17 identified by molecular genetic testing."

GeneReviews diagnostic criterion.

PMID:33909992 SUPPORT Human Clinical

"Although recurrent bacterial infections, cleft palate with Pierre Robin sequence, and unilateral renal agenesis are useful discriminating features, they occur in only a minority of patients."

Features that can support variant interpretation.

PMID:33909992 SUPPORT Human Clinical

"The degree of dysmorphism was variable, with several individuals (particularly individuals 8 and 10) presenting with only subtle dysmorphic characteristics."

Facial gestalt alone is not diagnostic.

📊

Prevalence

1

Worldwide, published literature

Cases In Literature Ultra Rare

The founding report described 34 individuals from 32 families, assembled over three years from multiple sources, and its authors state that the denominator and the true prevalence are unknown. A 2025 report counted fewer than 40 unrelated published individuals. No population-based prevalence or incidence estimate exists.

Show evidence (3 references)

PMID:33909992 SUPPORT Human Clinical

"Although our cohort is relatively large, it was assembled over 3 years from multiple sources, making determination of the denominator difficult."

The founding cohort authors state that prevalence cannot be estimated from their series.

PMID:40604385 SUPPORT BACKGROUND Human Clinical

"To date, fewer than 40 unrelated individuals with ANKRD17 variations or microdeletions have been reported worldwide"

Literature case count as of 2025, from the introduction of a case report.

PMID:37456926 SUPPORT BACKGROUND Human Clinical

"is an ultra-rare autosomal dominant disorder"

Characterizes the disorder as ultra-rare; introductory statement of a case report.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Chopra-Amiel-Gordon Syndrome:

SATB2-Associated Syndrome Not Yet Curated MONDO:0100147

Overlapping Features Severe speech impairment with cleft palate or Pierre Robin sequence; one founding-cohort individual with PRS, triangular facies and speech delay had first been evaluated for SATB2-associated syndrome.

Distinguishing Features

Heterozygous SATB2 rather than ANKRD17 variant.

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"including SATB2-associated syndrome (MIM: 612313) in individual 5 who presented with PRS, triangular facies and speech delay"

SATB2-associated syndrome was considered before the ANKRD17 diagnosis.

Floating-Harbor Syndrome MONDO:0007621

Overlapping Features Short stature, expressive language delay and a triangular face; one founding-cohort individual with marked short stature, microcephaly and borderline ID had first been evaluated for Floating-Harbor syndrome.

Distinguishing Features

Heterozygous SRCAP rather than ANKRD17 variant.

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"Floating-Harbour syndrome (MIM: 136140) in individual 9 who presented with marked short stature (height < −3 SD), microcephaly (head circumference < −2.5 SD), dysmorphic features, and borderline ID"

Floating-Harbor syndrome was considered before the ANKRD17 diagnosis.

KBG Syndrome MONDO:0007846

Overlapping Features ANKRD11 haploinsufficiency also causes a variable syndromic intellectual disability with short stature and a triangular face. ANKRD11 shares ankyrin repeats but not the overall domain structure of ANKRD17.

Distinguishing Features

Macrodontia of the upper central incisors and costovertebral anomalies point to KBG syndrome.
Heterozygous ANKRD11 rather than ANKRD17 variant.

Show evidence (1 reference)

PMID:33909992 SUPPORT Human Clinical

"Heterozygous loss-of-function variants in ANKRD11 (MIM: 611192) are causative of a syndromic ID, the variable but recognizable KBG syndrome (MIM: 148050) characterized by neurodevelopmental delay, macrodontia, short stature, and skeletal anomalies."

The founding authors compare CAGS with KBG syndrome.

🔬

Clinical Trials

1

NCT05528744 NOT_APPLICABLE

Observational natural history study of confirmed or suspected CAGS at Boston Children's Hospital, collecting longitudinal clinical, MRI, EEG and neurobehavioral data and patient samples for iPSC-derived neuronal phenotyping.

Show evidence (1 reference)

clinicaltrials:NCT05528744 SUPPORT Other

"The purpose of this study is to establish the longitudinal natural history of individuals with confirmed or suspected Chopra-Amiel-Gordon Syndrome (CAGS)"

Registry record of the natural history study.

🐁

Animal Models

2

Ankrd17 null mouse

Constitutive gene-targeted Ankrd17 knockout. Homozygous embryos die at E10.5-E11.5 with hemorrhage and a marked reduction of vascular smooth muscle cells around vessels; heterozygotes are viable and fertile. The embryonic lethality precluded study of brain development, and no behavioral or neurodevelopmental phenotype has been reported for heterozygotes.

Species

Mouse

Genotype

Ankrd17 targeted null (homozygous and heterozygous)

Publication

PMID:19619540

Pathograph links

ANKRD17 Haploinsufficiency fails to recapitulate fidelity: low The model informs the essential role of Ankrd17 in embryonic vascular maturation, not the heterozygous human neurodevelopmental disorder.

Limitations: The informative genotype is homozygous null, which has no human counterpart; heterozygotes, the human-equivalent genotype, were not assessed for neurodevelopmental or behavioral phenotypes, and no vascular phenotype has been established in patients.

Show evidence (2 references)

PMID:19619540 SUPPORT Model Organism

"The Ankrd17-deficient mice died between embryonic day (E) 10.5 and E11.5 due to cardiovascular defects."

Homozygous lethality from cardiovascular defects.

+ 1 more reference

Regional Ankrd17 AAV-shRNA knockdown mouse

Stereotaxic AAV delivery of tandem Ankrd17 siRNAs under a neuronal promoter into the medial prefrontal cortex or hippocampal CA1 of 4-5 week-old male mice, reducing Ankrd17 protein to roughly 53-72% of control.

Species

Mouse

Genotype

AAV-delivered Ankrd17 shRNA in medial prefrontal cortex or hippocampal CA1 of wild-type C57BL/6J males

Publication

PMID:40604385

Pathograph links

Synaptic Protein Deficit and Neural Circuit Dysfunction partially recapitulates fidelity: low observes: cellular Partial Ankrd17 reduction in juvenile cortex or hippocampus reduces synaptic proteins and neuronal activation and produces social, anxiety and spatial-memory deficits.

Limitations: Knockdown is regional, neuronal and begins after brain development, so it does not model germline heterozygosity from conception, effects on neural progenitors, or non-neural features. Only males were studied, and the study has not been replicated.

Readouts

Synaptic protein levels

Direction: DECREASED

Interpretation: GluN2A, GluA1, PSD-95 and synapsin I reduced in both regions.

Show evidence (1 reference)

PMID:40604385 SUPPORT Model Organism

"Our findings revealed a decrease in the expression of the NMDAR subunit GluN2A, the AMPAR subunit GluA1, the excitatory synaptic scaffolding protein PSD-95 and Synapsin I"

Western blot readout in knockdown mice.

Show evidence (1 reference)

PMID:40604385 SUPPORT Model Organism

"These results effectively mimic the heterozygous deficiency of ANKRD17 in mice."

The authors' rationale that partial knockdown approximates heterozygous deficiency.

{ }

Source YAML

click to show

name: Chopra-Amiel-Gordon Syndrome
creation_date: "2026-09-23T19:52:59Z"
description: >-
  An autosomal dominant neurodevelopmental syndrome caused by heterozygous
  germline pathogenic variants in ANKRD17 (4q13.3), which encodes a large
  ankyrin-repeat and KH-domain protein of the Mask family. Most pathogenic
  variants arise de novo. The core phenotype is global developmental delay or
  intellectual disability of variable severity (borderline to severe) with
  disproportionate impairment of speech and expressive language, evident from
  infancy. Additional features include motor delay, postnatal growth failure,
  feeding difficulties, autism spectrum disorder and ADHD, epilepsy (often with
  onset before 2 years) and EEG abnormalities, non-specific brain MRI findings,
  gait or balance disturbance, recurrent, mostly bacterial, upper and lower
  respiratory and middle-ear infections, joint hypermobility and ophthalmological
  abnormalities (strabismus, refractive error). Many individuals share a facial
  gestalt of triangular face, high anterior hairline, deep-set or almond-shaped
  eyes with periorbital fullness, thick nasal alae with flared nostrils, full
  cheeks and a thin upper lip. Cleft palate with Pierre Robin sequence, unilateral
  renal agenesis and scoliosis are rare but distinctive. The mutational spectrum
  (truncating and essential-splice variants, 4q13.3 deletions spanning the gene,
  and missense variants predicted to destabilize the ankyrin-repeat fold) points
  to haploinsufficiency; how reduced ANKRD17 dosage produces the
  neurodevelopmental phenotype is not established.
category: Mendelian
synonyms:
- ANKRD17-related neurodevelopmental syndrome
- ANKRD17-related neurodevelopmental disorder
- CAGS
- Global developmental delay-recurrent infections-facial dysmorphism syndrome
parents:
- autosomal dominant syndromic intellectual disability
- syndromic complex neurodevelopmental disorder
disease_term:
  preferred_term: Chopra-Amiel-Gordon syndrome
  term:
    id: MONDO:0859186
    label: Chopra-Amiel-Gordon syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0800439
      label: syndromic complex neurodevelopmental disorder
    mapping_predicate: skos:broadMatch
    mapping_source: ClinGen
    mapping_justification: >-
      ClinGen's Intellectual Disability and Autism GCEP curated the ANKRD17
      gene-disease relationship against this umbrella MONDO term rather than
      against MONDO:0859186, while stating that the curated disease is also
      known as Chopra-Amiel-Gordon syndrome. The umbrella covers many unrelated
      genes, so this is recorded as a broader cross-reference, not an
      equivalence.
references:
- reference: PMID:36548456
  title: ANKRD17-Related Neurodevelopmental Syndrome.
  tags:
  - GeneReviews
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  - classification_value: NEUROLOGIC
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  expressivity: VARIABLE
  de_novo_rate: 29 of 34 individuals in the founding cohort
  description: >-
    Heterozygous ANKRD17 pathogenic variants cause disease in an autosomal
    dominant manner, typically de novo. In the founding cohort the variant was
    confirmed de novo in 29 of 34 individuals; one truncating variant was
    transmitted from a mother with borderline intellectual functioning to her
    son, and one nonsense variant was present at low level (about 4% of reads)
    in the blood of a healthy, non-dysmorphic father, consistent with parental
    somatic and possibly germline mosaicism. GeneReviews therefore describes the
    recurrence risk to sibs of a proband with an apparently de novo variant as
    low but above the population risk. Expressivity is variable, including
    between a transmitting parent and child; no formal penetrance estimate has
    been published.
  evidence:
  - reference: PMID:36548456
    reference_title: "ANKRD17-Related Neurodevelopmental Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ANKRD17-related neurodevelopmental syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant."
    explanation: GeneReviews states the inheritance pattern and that most cases are de novo.
  - reference: PMID:36548456
    reference_title: "ANKRD17-Related Neurodevelopmental Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If the ANKRD17 pathogenic variant identified in the proband is not identified in either parent, the risk to sibs is low but greater than that of the general population because of the possibility of parental germline mosaicism."
    explanation: GeneReviews recurrence-risk statement for sibs of a simplex proband.
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ANKRD17 variants were shown to be de novo in 29 of the 34 individuals."
    explanation: De novo fraction in the founding cohort.
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the truncating variant in individual 11 was found to be inherited from a parent"
    explanation: One parent-to-child transmission, from a mother with borderline intellectual functioning.
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "suggestive of low-level somatic mosaicism. This father was healthy, non-dysmorphic, and of normal intelligence."
    explanation: Low-level paternal mosaicism for a nonsense variant, the basis for counseling a residual sibling recurrence risk.
prevalence:
- population: Worldwide, published literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The founding report described 34 individuals from 32 families, assembled
    over three years from multiple sources, and its authors state that the
    denominator and the true prevalence are unknown. A 2025 report counted fewer
    than 40 unrelated published individuals. No population-based prevalence or
    incidence estimate exists.
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although our cohort is relatively large, it was assembled over 3 years from multiple sources, making determination of the denominator difficult."
    explanation: The founding cohort authors state that prevalence cannot be estimated from their series.
  - reference: PMID:40604385
    reference_title: "Novel ANKRD17 variants implicate synaptic and mitochondrial disruptions in intellectual disability and autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "To date, fewer than 40 unrelated individuals with ANKRD17 variations or microdeletions have been reported worldwide"
    explanation: Literature case count as of 2025, from the introduction of a case report.
  - reference: PMID:37456926
    reference_title: "A case of Chopra-Amiel-Gordon syndrome with a novel heterozygous variant in the ANKRD17 gene: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "is an ultra-rare autosomal dominant disorder"
    explanation: Characterizes the disorder as ultra-rare; introductory statement of a case report.
pathophysiology:
- name: ANKRD17 Haploinsufficiency
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    A heterozygous germline ANKRD17 variant reduces functional ANKRD17 dosage.
    In the founding cohort 22 of 32 probands carried a variant expected to cause
    loss of function (7 nonsense, 12 frameshift, 2 essential splice site, and a
    1.16 Mb 4q13.3 deletion including ANKRD17); later reports add a second
    4q13.3 deletion removing exons 2-34 and a canonical splice variant shown on
    RNA to skip exon 32. ANKRD17 is highly constrained against loss-of-function
    variation in the population, and ClinGen scores it as haploinsufficient.
    In one proband with a de novo nonsense variant (p.Arg418*), ANKRD17 protein
    in peripheral blood was about half the parental level.
  genes:
  - preferred_term: ANKRD17
    term:
      id: hgnc:23575
      label: ANKRD17
  genetic_context:
    gene:
      preferred_term: ANKRD17
      term:
        id: hgnc:23575
        label: ANKRD17
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Truncating, essential-splice and whole- or multi-exon deletion alleles;
      most arise de novo.
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb)."
    explanation: The founding cohort's mutational spectrum, dominated by loss-of-function alleles.
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ANKRD17 is highly intolerant to loss of function in the human population"
    explanation: Population constraint against loss-of-function variants supports a dosage-sensitive gene.
  - reference: CGDS:HGNC_23575
    reference_title: "ANKRD17 dosage sensitivity"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ANKRD17 | HGNC:23575 | 26057 | 4q13.3 | chr4:73073376-73258798 | 3 - Sufficient Evidence for Haploinsufficiency | 0 - No Evidence for Triplosensitivity | 2023-04-11"
    explanation: ClinGen Dosage Sensitivity haploinsufficiency score 3 for ANKRD17 (last evaluated 2023-04-11).
  - reference: CGGV:assertion_48a9765c-f7ae-46f4-aa6f-7fa95f81404f-2024-12-12T170000.000Z
    reference_title: "ANKRD17 / syndromic complex neurodevelopmental disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The proposed mechanism is heterozygous loss of function, supported by the mutational spectrum and the intolerance to variation in the general population."
    explanation: ClinGen gene-disease validity curation states heterozygous loss of function as the mechanism.
  - reference: PMID:40604385
    reference_title: "Novel ANKRD17 variants implicate synaptic and mitochondrial disruptions in intellectual disability and autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Western blotting confirmed 50% reduced ANKRD17 protein expression versus parental controls"
    explanation: In a proband with a de novo nonsense variant, blood ANKRD17 protein was halved, as expected for a null allele.
  - reference: PMID:40604385
    reference_title: "Novel ANKRD17 variants implicate synaptic and mitochondrial disruptions in intellectual disability and autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "while ANKRD17 is partially truncated with only exon 1 retained (exons 2–34 deleted)"
    explanation: A second de novo 4q13.3 deletion removing most of ANKRD17.
  - reference: PMID:39315309
    reference_title: "Case report: Whole exome sequencing reveals a novel splicing variant of ANKRD17 gene in a Chinese male juvenile with developmental delay and transient tic disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the analysis at mRNA level confirmed that it leads to exon 32 skipping (r.7100_7278del179) and causes premature termination of translation to the protein (p.D2357fs)"
    explanation: RNA-confirmed truncating splice variant in a de novo case.
  downstream:
  - target: Reduced ANKRD17 in Developing Neural Progenitors and Neurons
    causal_link_type: DIRECT
    description: >-
      Halving gene dosage reduces ANKRD17 in every tissue that expresses it,
      including the developing cortex.
- name: Ankyrin Repeat Destabilization by Missense Variants
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Nine of 32 founding-cohort probands carried de novo missense variants and
    one an in-frame indel, all at highly conserved residues. Five of the seven
    missense variants inside the ankyrin repeats alter positions that are
    invariant across all 25 ANKRD17 repeats (the 6th/21st leucines of the
    hydrophobic core and the 13th glycine of the inter-helix turn). Homology
    modeling predicts these destabilize the repeat fold rather than a specific
    binding surface, which would reduce functional protein and converge on
    haploinsufficiency. No functional assay of any missense allele has been
    published, so a dominant-negative or other effect is not excluded.
  genes:
  - preferred_term: ANKRD17
    term:
      id: hgnc:23575
      label: ANKRD17
  genetic_context:
    gene:
      preferred_term: ANKRD17
      term:
        id: hgnc:23575
        label: ANKRD17
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      De novo missense and in-frame alleles at conserved ankyrin-repeat core
      residues; loss of function is predicted by structural modeling only.
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues."
    explanation: Homology modeling of the missense variants.
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Remarkably, five of the seven ankyrin repeat missense variants affect amino acids that are invariant in all 25 repeats"
    explanation: Conservation analysis across the 25 ANKRD17 ankyrin repeats.
  downstream:
  - target: ANKRD17 Haploinsufficiency
    causal_link_type: UNKNOWN
    description: >-
      Predicted, not demonstrated: destabilized protein would lower functional
      ANKRD17 to a level comparable with a null allele.
    evidence:
    - reference: PMID:33909992
      reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "The ANKRD17 missense variants affecting these residues are therefore more likely to disrupt the core structure of individual repeats, leading to protein destabilization, rather than disrupting specific ligand-interaction surfaces."
      explanation: The authors' structural inference that missense alleles act through destabilization.
- name: Reduced ANKRD17 in Developing Neural Progenitors and Neurons
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: PROVISIONAL
  description: >-
    In single-cell RNA-seq of the fetal human telencephalon ANKRD17 is broadly
    expressed, including in radial glial progenitors, excitatory neurons and
    interneurons, whereas its paralog ANKHD1 is more restricted, so the paralog
    may not compensate in the developing cortex. In adult mouse brain ANKRD17 is
    expressed in excitatory and inhibitory neurons. Which of ANKRD17's reported
    molecular activities (Hippo/YAP co-factor, cyclin E/CDK2 interaction, RNA
    binding through the KH domain) is dosage-critical in these cells is not
    known.
  cell_types:
  - preferred_term: radial glial cell
    term:
      id: CL:0000681
      label: radial glial cell
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: neurogenesis
    term:
      id: GO:0022008
      label: neurogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "indicates broad expression of ANKRD17, including in radial glial progenitors (the neural stem cells of the cortex), excitatory neurons, and interneurons, while ANKHD1 expression appears more limited"
    explanation: Reanalysis of a public fetal telencephalon scRNA-seq dataset; expression, not function.
  - reference: PMID:40604385
    reference_title: "Novel ANKRD17 variants implicate synaptic and mitochondrial disruptions in intellectual disability and autism spectrum disorder."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "ANKRD17 is broadly expressed, particularly in the cytoplasm, of both excitatory and inhibitory neurons in the adult mouse brain"
    explanation: Neuronal expression in mouse brain.
  - reference: PMID:19150984
    reference_title: "Identification and functional analysis of a novel cyclin e/cdk2 substrate ankrd17."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Overexpression of Ankrd17 promotes S phase entry, whereas depletion of Ankrd17 expression by small interfering RNA inhibits DNA replication and blocks cell cycle progression"
    explanation: >-
      Cell-line evidence for the cyclin E/CDK2-linked cell-cycle role named in
      this node's description; not tested in neural progenitors.
  downstream:
  - target: Disrupted YAP Nuclear Import in Neural Progenitors
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - ankrd17_hippo_yap
  - target: Synaptic Protein Deficit and Neural Circuit Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - ankrd17_synaptic_mitochondrial
  - target: Neurodevelopmental Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Genetic evidence (dosage-reducing variants cause the syndrome) establishes
      the link; the intermediate cellular steps are unresolved.
    evidence:
    - reference: PMID:33909992
      reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants."
      explanation: Genotype-phenotype evidence that ANKRD17 dosage reduction causes the neurodevelopmental phenotype.
- name: Disrupted YAP Nuclear Import in Neural Progenitors
  biological_scale: MOLECULAR
  role: hypothesized_intermediate
  mechanism_confidence: HYPOTHETICAL
  description: >-
    ANKRD17 (Mask2) and its paralog ANKHD1 (Mask1) bind YAP and promote its
    nuclear import and stability in mammalian cells, and the Drosophila ortholog
    Mask is required for Yorkie-driven tissue growth. YAP1 and ANKRD17 are
    co-expressed in fetal human radial glia. That reduced ANKRD17 lowers
    nuclear YAP activity in neural progenitors, and that this contributes to the
    neurodevelopmental or growth phenotype, is a hypothesis raised by the
    founding authors; it has not been tested in ANKRD17-deficient human or
    mammalian neural tissue.
  cell_types:
  - preferred_term: radial glial cell
    term:
      id: CL:0000681
      label: radial glial cell
  biological_processes:
  - preferred_term: hippo signaling
    term:
      id: GO:0035329
      label: hippo signaling
    modifier: ABNORMAL
  - preferred_term: YAP nuclear import
    term:
      id: GO:0042307
      label: positive regulation of protein import into nucleus
    modifier: DECREASED
  evidence:
  - reference: PMID:31661072
    reference_title: "Mask family proteins ANKHD1 and ANKRD17 regulate YAP nuclear import and stability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mammalian Mask1/2 proteins also promote nuclear import of YAP, as well as stabilising YAP and driving formation of liquid droplets."
    explanation: ANKHD1/ANKRD17 promote YAP nuclear import and stability in mammalian cells.
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "raising the possibility that the neurodevelopmental phenotypes associated with ANKRD17 variants may be due to disruption of this pathway"
    explanation: The founding authors state the Hippo/YAP link as a possibility, based on YAP1/ANKRD17 co-expression in radial glia.
  downstream:
  - target: Neurodevelopmental Dysfunction
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - ankrd17_hippo_yap
- name: Synaptic Protein Deficit and Neural Circuit Dysfunction
  biological_scale: CELLULAR
  role: hypothesized_intermediate
  mechanism_confidence: HYPOTHETICAL
  description: >-
    After AAV-shRNA knockdown of Ankrd17 in the medial prefrontal cortex or
    hippocampal CA1 of juvenile mice, the NMDA-receptor subunit GluN2A, the
    AMPA-receptor subunit GluA1, PSD-95 and synapsin I were reduced, fewer
    excitatory neurons were activated during behavioral testing, and
    mitochondrial genes (Sdha, Sdhb, Sdhc, Ogdh, Akr1a1) were down-regulated;
    the mice showed reduced sociability, increased anxiety and impaired spatial
    memory. Proteomics of cortex from one ANKRD17-deleted fetus against one
    control fetus showed down-regulation of mitochondrial proteins. The model
    is a regional, postnatal knockdown rather than germline heterozygosity, and
    the human proteomic comparison is one case against one control, so this
    node is a hypothesis for the cognitive and social phenotype, not an
    established mechanism.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
    modifier: DECREASED
  - preferred_term: mitochondrion organization
    term:
      id: GO:0007005
      label: mitochondrion organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:40604385
    reference_title: "Novel ANKRD17 variants implicate synaptic and mitochondrial disruptions in intellectual disability and autism spectrum disorder."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our findings revealed a decrease in the expression of the NMDAR subunit GluN2A, the AMPAR subunit GluA1, the excitatory synaptic scaffolding protein PSD-95 and Synapsin I"
    explanation: Synaptic protein reduction after regional Ankrd17 knockdown in mouse brain.
  - reference: PMID:40604385
    reference_title: "Novel ANKRD17 variants implicate synaptic and mitochondrial disruptions in intellectual disability and autism spectrum disorder."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In both the mPFC and CA1 regions, Sdha, Sdhb, Sdhc, Akr1a1, and Ogdh were significantly decreased following Ankrd17 knockdown"
    explanation: Mitochondrial gene down-regulation in knockdown mouse brain.
  - reference: PMID:40604385
    reference_title: "Novel ANKRD17 variants implicate synaptic and mitochondrial disruptions in intellectual disability and autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Collectively, these findings suggest an inhibition of mitochondria-related functions in embryonic human brain tissue with ANKRD17 deficiency."
    explanation: Proteomics of one ANKRD17-deleted fetal cortex against one control fetus; a single comparison.
  downstream:
  - target: Neurodevelopmental Dysfunction
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - ankrd17_synaptic_mitochondrial
    evidence:
    - reference: PMID:40604385
      reference_title: "Novel ANKRD17 variants implicate synaptic and mitochondrial disruptions in intellectual disability and autism spectrum disorder."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our study highlighted in mouse models an association between Ankrd17 haploinsufficiency and deficits in social behavior, spatial learning and memory, as well as elevated anxiety."
      explanation: Behavioral deficits accompany the synaptic changes in the knockdown model; association, not a demonstrated causal step.
- name: Impaired Innate Immune Pattern-Recognition Signaling
  biological_scale: CELLULAR
  role: hypothesized_intermediate
  mechanism_confidence: HYPOTHETICAL
  description: >-
    In cell lines ANKRD17 binds NOD2 and contributes to NOD1- and NOD2-mediated
    pro-inflammatory responses to bacteria, and separately binds RIG-I, MDA5 and
    VISA to enhance RIG-I-like receptor antiviral signaling. The founding
    authors propose these roles as a plausible basis for the recurrent,
    mostly bacterial, infections seen in about a third of patients. Immunology
    assessments in five patients found no obvious immunodeficiency, and no
    innate-immune assay has been done in patient cells.
  biological_processes:
  - preferred_term: NOD2 signaling
    term:
      id: GO:0070431
      label: nucleotide-binding oligomerization domain containing 2 signaling pathway
    modifier: DECREASED
  - preferred_term: NOD1 signaling
    term:
      id: GO:0070427
      label: nucleotide-binding oligomerization domain containing 1 signaling pathway
    modifier: DECREASED
  - preferred_term: RIG-I signaling
    term:
      id: GO:0039529
      label: RIG-I signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:23711367
    reference_title: "A role for the Ankyrin repeat containing protein Ankrd17 in Nod1- and Nod2-mediated inflammatory responses."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Knock-down and overexpression analysis revealed that Ankrd17 is functionally involved in Nod2- and Nod1-mediated responses in human myeloid and epithelial cells."
    explanation: Knockdown in human cell lines impairs NOD1/NOD2 responses.
  - reference: PMID:22328336
    reference_title: "Ankrd17 positively regulates RIG-I-like receptor (RLR)-mediated immune signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Consistently, knockdown of ankrd17 impairs RLR signaling."
    explanation: Knockdown impairs RIG-I-like receptor antiviral signaling in cell lines.
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunology assessments were recorded in five individuals, details of which can be found in Table S2, with no obvious immunodeficiency identified in these individuals."
    explanation: Limited patient immunology did not identify an immunodeficiency, so the mechanism of infection susceptibility is unproven.
  downstream:
  - target: Recurrent Infections
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - ankrd17_innate_immunity
    evidence:
    - reference: PMID:33909992
      reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: "suggests a plausible mechanism for the predisposition to bacterial or viral infections, respectively, identified in some individuals in our cohort"
      explanation: The founding authors propose the NOD1/NOD2 and RLR roles as the explanation; inference from cell-line work, not tested in patients.
- name: Neurodevelopmental Dysfunction
  biological_scale: ORGANISM
  role: outcome
  description: >-
    The shared clinical consequence of reduced ANKRD17 dosage in the developing
    brain, expressed as global developmental delay or intellectual disability
    with disproportionate speech impairment, motor delay, behavioral
    comorbidity, epilepsy and non-specific structural brain findings. The
    course is developmental rather than degenerative; no regression has been
    reported.
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech"
    explanation: Summary of the core neurodevelopmental phenotype.
  downstream:
  - target: Global Developmental Delay
    causal_link_type: DIRECT
  - target: Intellectual Disability
    causal_link_type: DIRECT
  - target: Delayed Speech and Language Development
    causal_link_type: DIRECT
  - target: Absent Speech
    causal_link_type: DIRECT
  - target: Motor Delay
    causal_link_type: DIRECT
  - target: Autism Spectrum Disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Attention Deficit Hyperactivity Disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: EEG Abnormality
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Gait or Balance Disturbance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Spasticity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Abnormal Brain Development
  biological_scale: TISSUE
  role: outcome
  mechanism_confidence: PROVISIONAL
  description: >-
    Structural brain findings on MRI are present in about half of imaged
    patients but are heterogeneous (reduced white matter volume, thin corpus
    callosum, optic nerve hypoplasia, periventricular nodular heterotopia,
    focal hyperintensities, cysts); one deleted fetus had cerebellar
    hypoplasia. There is no consistent malformation pattern and no study
    linking a specific molecular step to any of them.
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuroimaging abnormalities were identified in 11 of the 23 individuals in whom an MRI was recorded."
    explanation: Frequency and heterogeneity of MRI findings.
  downstream:
  - target: Abnormal Brain Morphology
    causal_link_type: DIRECT
  - target: Reduced Cerebral White Matter Volume
    causal_link_type: DIRECT
  - target: Thin Corpus Callosum
    causal_link_type: DIRECT
  - target: Optic Nerve Hypoplasia
    causal_link_type: DIRECT
  - target: Neurodevelopmental Dysfunction
    causal_link_type: UNKNOWN
phenotypes:
- category: Neurological
  name: Global Developmental Delay
  description: >-
    The most common feature, present in 31 of 34 individuals in the founding
    cohort as developmental delay or intellectual disability, recognized from
    infancy. One 4-month-old in the cohort had severe feeding difficulties with
    reportedly normal development, too young for assessment.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
    onset:
      onset_category: INFANTILE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Global developmental delay (DD)/ID was the most common feature, affecting 31 individuals."
    explanation: 31 of 34 individuals (91%) had DD/ID.
  - reference: PMID:36548456
    reference_title: "ANKRD17-Related Neurodevelopmental Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ANKRD17-related neurodevelopmental syndrome is characterized by developmental delay – particularly affecting speech – and variable intellectual disability."
    explanation: GeneReviews lists developmental delay as the defining feature.
- category: Neurological
  name: Intellectual Disability
  description: >-
    Severity is variable. Of the 31 founding-cohort individuals with DD/ID, 7
    were severe, 12 moderate, 5 mild and 7 borderline. Two individuals had
    typical intellectual functioning: an 11-year-old boy with autism and a
    25-year-old woman with a history of delayed speech who lives independently.
    In three of five individuals with detailed neuropsychological testing,
    verbal IQ was lower than performance IQ.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The severity of DD/ID was variable, with 19 individuals in the moderate to severe range and 12 in the mild or borderline range."
    explanation: Severity distribution across the 31 affected individuals.
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "confirmed a discrepancy between verbal IQ and performance IQ (verbal IQ < performance IQ) in three of these individuals"
    explanation: Verbal-performance discrepancy in three of five individuals with detailed testing.
- category: Neurological
  name: Delayed Speech and Language Development
  description: >-
    Speech is disproportionately affected, including in individuals whose IQ
    is in the borderline range. Delayed speech was reported in 29 of 32
    individuals, 6 of whom had no meaningful words and 4 of whom used fewer
    than 10 words after age 4.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
    onset:
      onset_category: INFANTILE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Speech development was reported as delayed in 29 individuals, including 6 with absent speech (no meaningful words) and 4 who used fewer than 10 words meaningfully (all over the age of 4 years)."
    explanation: 29 of 32 assessed individuals (Table 2) had speech delay.
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In our cohort, significant speech delay was reported in most individuals (n = 29) even in those with IQ in the borderline range."
    explanation: Speech is affected out of proportion to general cognition.
- category: Neurological
  name: Absent Speech
  description: >-
    Six of 32 individuals had no meaningful words, including one with
    borderline and one with mild intellectual disability.
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Absence of speech was observed in individuals with varying degrees of DD/ID, including one individual in the borderline and one in the mild range of ID."
    explanation: Absent speech occurs even with mild or borderline ID; 6 of 32 (about 19%).
- category: Neurological
  name: Motor Delay
  description: Motor delay in 20 of 29 individuals.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
    onset:
      onset_category: INFANTILE
  frequency: FREQUENT
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Motor delay | 20/29"
    explanation: Table 2 frequency (69%).
- category: Behavioral
  name: Autism Spectrum Disorder
  description: >-
    Reported in 8 individuals of the 34-person founding cohort; the main text
    does not give the number formally assessed, so no frequency band is
    asserted. A later proband developed progressive social impairment from age
    7 with comorbid social anxiety.
  phenotype_term:
    preferred_term: Autism spectrum disorder
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Less commonly reported neurodevelopmental phenotypes include ASD (n = 8) and ADHD (n = 4)."
    explanation: ASD in 8 cohort members.
  - reference: PMID:36548456
    reference_title: "ANKRD17-Related Neurodevelopmental Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional features include autism spectrum disorder, attention-deficit/hyperactivity disorder"
    explanation: GeneReviews lists ASD and ADHD among additional features.
- category: Behavioral
  name: Attention Deficit Hyperactivity Disorder
  description: >-
    Reported in 4 individuals of the founding cohort; denominator not given in
    the main text, so no frequency band is asserted.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Less commonly reported neurodevelopmental phenotypes include ASD (n = 8) and ADHD (n = 4)."
    explanation: ADHD in 4 cohort members.
- category: Neurological
  name: Seizures
  description: >-
    Epilepsy in 9 of 33 founding-cohort individuals, with onset before 2 years
    in five. Focal seizures with secondary generalization were the most common
    type (five individuals); single individuals had Lennox-Gastaut syndrome,
    tonic seizures, mixed myoclonic and tonic-clonic, or tonic-clonic and
    absence seizures. Five were well controlled on three or fewer
    anti-seizure medications and two had refractory epilepsy for at least part
    of their course. Epileptic spasms responsive to vigabatrin were reported in
    a later individual with a de novo missense variant of uncertain
    significance.
  phenotype_term:
    preferred_term: Epilepsy
    term:
      id: HP:0001250
      label: Seizure
    onset:
      onset_category: INFANTILE
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epilepsy | 9/33"
    explanation: Table 2 frequency (27%).
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with an age of onset of under 2 years for five individuals"
    explanation: Early onset in five of nine with epilepsy.
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Focal seizures with secondary generalization was the most common seizure subtype"
    explanation: Predominant seizure type.
- category: Neurological
  name: Bilateral Tonic-Clonic Seizure with Focal Onset
  description: >-
    Focal seizures evolving to bilateral seizures were the most frequent
    seizure type, present in 5 of the 9 individuals with epilepsy (5 of 33
    overall).
  phenotype_term:
    preferred_term: Focal seizures with secondary generalization
    term:
      id: HP:0007334
      label: Bilateral tonic-clonic seizure with focal onset
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Focal seizures with secondary generalization was the most common seizure subtype, present in five individuals"
    explanation: Five individuals had this seizure type.
- category: Neurological
  name: EEG Abnormality
  description: >-
    Abnormal EEG in 10 of 23 individuals tested, including four without
    epilepsy.
  phenotype_term:
    preferred_term: EEG abnormality
    term:
      id: HP:0002353
      label: EEG abnormality
  frequency: FREQUENT
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abnormal EEG | 10/23"
    explanation: Table 2 frequency (43%).
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were four individuals without epilepsy in whom an abnormal EEG was recorded."
    explanation: EEG abnormalities occur without clinical seizures.
- category: Neurological
  name: Abnormal Brain Morphology
  description: >-
    Non-specific MRI abnormalities in 11 of 23 imaged individuals, varying in
    form between patients; the specific findings with more than one
    occurrence are curated separately.
  phenotype_term:
    preferred_term: Brain MRI abnormalities
    term:
      id: HP:0012443
      label: Abnormal brain morphology
    coarse_binding_basis: VARIABLE_SPECTRUM
  frequency: FREQUENT
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI abnormalities | 11/23"
    explanation: Table 2 frequency (48%).
- category: Neurological
  name: Reduced Cerebral White Matter Volume
  description: Decreased white matter volume in 3 of 23 imaged individuals.
  phenotype_term:
    preferred_term: Decreased white matter volume
    term:
      id: HP:0034295
      label: Reduced cerebral white matter volume
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abnormalities include decreased white matter volume (individuals 14, 16, and 18), thinning of the corpus callosum (individuals 14 and 19), optic nerve hypoplasia (individuals 18 and 19)"
    explanation: Three individuals had decreased white matter volume.
- category: Neurological
  name: Thin Corpus Callosum
  description: Thinning of the corpus callosum in 2 imaged individuals.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abnormalities include decreased white matter volume (individuals 14, 16, and 18), thinning of the corpus callosum (individuals 14 and 19), optic nerve hypoplasia (individuals 18 and 19)"
    explanation: Two individuals had thinning of the corpus callosum.
- category: Neurological
  name: Optic Nerve Hypoplasia
  description: Optic nerve hypoplasia on MRI in 2 individuals.
  phenotype_term:
    preferred_term: Optic nerve hypoplasia
    term:
      id: HP:0000609
      label: Optic nerve hypoplasia
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abnormalities include decreased white matter volume (individuals 14, 16, and 18), thinning of the corpus callosum (individuals 14 and 19), optic nerve hypoplasia (individuals 18 and 19)"
    explanation: Two individuals had optic nerve hypoplasia.
- category: Neurological
  name: Gait or Balance Disturbance
  description: Poor balance and/or abnormal gait in 9 of 25 individuals.
  phenotype_term:
    preferred_term: Gait or balance disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  frequency: FREQUENT
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gait or balance abnormalities | 9/25"
    explanation: Table 2 frequency (36%).
  - reference: PMID:36548456
    reference_title: "ANKRD17-Related Neurodevelopmental Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent infections, gait and/or balance disturbances, and epilepsy"
    explanation: GeneReviews lists gait and balance disturbance.
- category: Neurological
  name: Spasticity
  description: Peripheral spasticity or hypertonia in 4 of 26 individuals.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spasticity or hypertonia | 4/26"
    explanation: Table 2 frequency (15%).
- category: Growth
  name: Short Stature
  description: >-
    Birth parameters are usually normal; postnatal growth failure affects
    almost half of patients, with height below -2 SD in 12 of 31. One
    individual with height -3.8 SD was treated with growth hormone despite a
    normal stimulation test.
  phenotype_term:
    preferred_term: Postnatal short stature
    term:
      id: HP:0004322
      label: Short stature
    onset:
      onset_category: CHILDHOOD
  frequency: FREQUENT
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neonatal growth parameters were normal in the majority of individuals (Table S2) but postnatal growth failure was a feature of almost half of the individuals (height < −2 SD in n = 12 and weight < −2 SD in n = 9)."
    explanation: 12 of 31 (39%) with height below -2 SD; growth failure is postnatal.
  - reference: PMID:36548456
    reference_title: "ANKRD17-Related Neurodevelopmental Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ophthalmologic abnormalities (strabismus and refractive errors), growth deficiency, feeding difficulties"
    explanation: GeneReviews lists growth deficiency among the additional features.
- category: Growth
  name: Decreased Body Weight
  description: Weight below -2 SD in 9 of 30 individuals.
  phenotype_term:
    preferred_term: Low weight
    term:
      id: HP:0004325
      label: Decreased body weight
  frequency: FREQUENT
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Weight < −2 SD | 9/30"
    explanation: Table 2 frequency (30%).
- category: Growth
  name: Microcephaly
  description: Postnatal microcephaly (OFC below -2 SD) in 7 of 31 individuals.
  phenotype_term:
    preferred_term: Postnatal microcephaly
    term:
      id: HP:0005484
      label: Secondary microcephaly
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Postnatal microcephaly (OFC < −2SD) was noted in seven individuals"
    explanation: 7 of 31 (23%).
- category: Growth
  name: Macrocephaly
  description: >-
    OFC above +2 SD in 4 of 31 individuals, one of whom also carried a
    pathogenic de novo NSD1 variant, so the ANKRD17-attributable frequency is
    at most 3 of 31.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and macrocephaly in four (one of these individuals, however, also harbored a pathogenic de novo NSD1 variant"
    explanation: Four with macrocephaly, one confounded by a second diagnosis.
- category: Gastrointestinal
  name: Feeding Difficulties
  description: >-
    Feeding difficulties, especially reduced oral intake, at some stage in 11
    of 27 individuals; 5 required gastrostomy-tube supplementation.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
    onset:
      onset_category: INFANTILE
  frequency: FREQUENT
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Feeding difficulties, especially reduced oral intake, were reported at some stage in 11 individuals, 5 of whom required G-tube nutritional supplementation."
    explanation: 11 of 27 (41%) with feeding difficulties; 5 needed a G-tube.
- category: Immune
  name: Recurrent Infections
  description: >-
    Recurrent infections in 11 of 33 individuals: nine bacterial, one viral
    and one both. Bacterial infections were mainly upper and lower respiratory
    and middle ear, sometimes needing hospitalization, and two individuals
    received low-dose antibiotic prophylaxis. No immunodeficiency was found in
    the five who had immunology assessments.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  frequency: FREQUENT
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrent infections | 11/33"
    explanation: Table 2 frequency (33%).
  - reference: PMID:36548456
    reference_title: "ANKRD17-Related Neurodevelopmental Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent infections, gait and/or balance disturbances, and epilepsy"
    explanation: GeneReviews lists recurrent infections.
- category: Immune
  name: Recurrent Bacterial Infections
  description: >-
    Nine individuals had recurrent bacterial infections, arising mainly from
    the respiratory tract and middle ear.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were nine individuals with recurrent bacterial infections, one with recurrent viral infections, and one individual with recurrent infections that were both viral and bacterial."
    explanation: Nine of 33 (27%) had recurrent bacterial infections.
- category: Immune
  name: Recurrent Otitis Media
  description: >-
    The middle ear and the upper and lower respiratory tract were the main
    sources of bacterial infection (nine individuals).
  phenotype_term:
    preferred_term: Recurrent otitis media
    term:
      id: HP:0000403
      label: Recurrent otitis media
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The source of bacterial infection was primarily the upper and lower respiratory system and the middle ear (nine individuals) and in some cases required hospitalization."
    explanation: Middle-ear and respiratory infections dominate; the split between the two sites is not given.
- category: Immune
  name: Recurrent Respiratory Infections
  description: >-
    Upper and lower respiratory tract infections were a main source of
    recurrent bacterial infection, in some cases needing hospitalization.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The source of bacterial infection was primarily the upper and lower respiratory system and the middle ear (nine individuals) and in some cases required hospitalization."
    explanation: Respiratory tract infections are a main site.
- category: Musculoskeletal
  name: Joint Hypermobility
  description: Generalized joint hypermobility in 9 of 29 individuals.
  phenotype_term:
    preferred_term: Generalized joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  frequency: FREQUENT
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Generalized joint hypermobility was reported in 9/29 individuals."
    explanation: 31% had joint hypermobility.
- category: Musculoskeletal
  name: Scoliosis
  description: >-
    Scoliosis in 3 individuals of the founding cohort (denominator not given).
    GeneReviews lists it among less common but distinctive features.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:36548456
    reference_title: "ANKRD17-Related Neurodevelopmental Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Less common but distinctive features include cleft palate with Pierre Robin sequence, renal agenesis, and scoliosis."
    explanation: GeneReviews lists scoliosis.
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "abnormal skin pigmentation (n = 4), scoliosis (n = 3)"
    explanation: Three cohort members had scoliosis.
- category: Musculoskeletal
  name: Abnormal Bone Mineral Density
  description: >-
    Abnormality of bone mineralization in 2 individuals of the founding cohort.
    The source names the abnormality without stating its direction, so the
    direction-neutral term is bound rather than reduced bone mineral density.
    No denominator is given.
  phenotype_term:
    preferred_term: Abnormality of bone mineralization
    term:
      id: HP:0004348
      label: Abnormality of bone mineral density
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "scoliosis (n = 3), abnormality of bone mineralization (n = 2)"
    explanation: Two cohort members had a bone mineralization abnormality, direction unspecified.
- category: Musculoskeletal
  name: Abnormal Digit Morphology
  description: >-
    Minor digital anomalies in 6 individuals of the founding cohort; the
    anomalies are not further specified in the main text and no denominator
    is given.
  phenotype_term:
    preferred_term: Minor digital anomalies
    term:
      id: HP:0011297
      label: Abnormal digit morphology
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other infrequent features include minor digital anomalies (n = 6)"
    explanation: Six cohort members had minor digital anomalies.
- category: Eye
  name: Ophthalmological Abnormalities
  description: >-
    Ophthalmological abnormalities in 13 of 23 examined individuals. The
    cohort paper does not break this figure down; GeneReviews names
    strabismus and refractive errors, which are curated separately without a
    frequency.
  phenotype_term:
    preferred_term: Ophthalmological abnormalities
    term:
      id: HP:0000478
      label: Abnormality of the eye
    coarse_binding_basis: SOURCE_UNSPECIFIED
  frequency: FREQUENT
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ophthalmological abnormalities were reported in 13/23 individuals."
    explanation: 57% had ophthalmological abnormalities, not further specified.
- category: Eye
  name: Strabismus
  description: Named by GeneReviews as one of the ophthalmological abnormalities.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:36548456
    reference_title: "ANKRD17-Related Neurodevelopmental Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ophthalmologic abnormalities (strabismus and refractive errors)"
    explanation: GeneReviews names strabismus.
- category: Eye
  name: Refractive Error
  description: Named by GeneReviews as one of the ophthalmological abnormalities.
  phenotype_term:
    preferred_term: Refractive errors
    term:
      id: HP:0000539
      label: Abnormality of refraction
  evidence:
  - reference: PMID:36548456
    reference_title: "ANKRD17-Related Neurodevelopmental Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ophthalmologic abnormalities (strabismus and refractive errors)"
    explanation: GeneReviews names refractive errors.
- category: Craniofacial
  name: Cleft Palate
  description: >-
    Palate abnormalities in 3 of 34 individuals: cleft palate with Pierre
    Robin sequence in two and cleft lip and palate in one.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
    onset:
      onset_category: CONGENITAL
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, there were two individuals with cleft palate in the context of Pierre Robin sequence (PRS) and another with cleft lip and palate."
    explanation: Three of 34 (9%) had a palatal cleft.
- category: Craniofacial
  name: Pierre-Robin Sequence
  description: >-
    Two of 34 individuals had cleft palate within Pierre Robin sequence; one
    had initially been suspected of SATB2-associated syndrome.
  phenotype_term:
    preferred_term: Pierre Robin sequence
    term:
      id: HP:0000201
      label: Pierre-Robin sequence
    onset:
      onset_category: CONGENITAL
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, there were two individuals with cleft palate in the context of Pierre Robin sequence (PRS) and another with cleft lip and palate."
    explanation: Two of 34 (6%) had Pierre Robin sequence.
  - reference: PMID:36548456
    reference_title: "ANKRD17-Related Neurodevelopmental Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Less common but distinctive features include cleft palate with Pierre Robin sequence, renal agenesis, and scoliosis."
    explanation: GeneReviews lists cleft palate with Pierre Robin sequence.
- category: Genitourinary
  name: Genitourinary Abnormalities
  description: >-
    Genitourinary abnormalities in 5 individuals of the founding cohort, three
    of them unilateral renal agenesis; the other two are not specified in the
    main text and no denominator is given.
  phenotype_term:
    preferred_term: Genitourinary abnormalities
    term:
      id: HP:0000119
      label: Abnormality of the genitourinary system
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "genitourinary abnormalities (n = 5, of whom three had unilateral renal agenesis)"
    explanation: Five with genitourinary abnormalities.
- category: Genitourinary
  name: Unilateral Renal Agenesis
  description: >-
    Unilateral renal agenesis in 3 individuals of the founding cohort, one of
    them a 25-year-old woman with typical intellectual functioning.
  phenotype_term:
    preferred_term: Unilateral renal agenesis
    term:
      id: HP:0000122
      label: Unilateral renal agenesis
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "genitourinary abnormalities (n = 5, of whom three had unilateral renal agenesis)"
    explanation: Three individuals had unilateral renal agenesis.
  - reference: PMID:36548456
    reference_title: "ANKRD17-Related Neurodevelopmental Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Less common but distinctive features include cleft palate with Pierre Robin sequence, renal agenesis, and scoliosis."
    explanation: GeneReviews lists renal agenesis.
- category: Skin
  name: Abnormality of Skin Pigmentation
  description: >-
    Abnormal skin pigmentation in 4 individuals of the founding cohort; type
    and denominator not given in the main text.
  phenotype_term:
    preferred_term: Pigmentary abnormalities
    term:
      id: HP:0001000
      label: Abnormality of skin pigmentation
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "abnormal skin pigmentation (n = 4), scoliosis (n = 3)"
    explanation: Four cohort members had abnormal skin pigmentation.
- category: Skin
  name: Prominent Superficial Blood Vessels
  description: >-
    Cutaneous prominence of blood vessels in 2 individuals of the founding
    cohort; no denominator is given. This is a skin finding and is distinct
    from the arterial disease the same paper reports as absent from the
    cohort.
  phenotype_term:
    preferred_term: Cutaneous prominence of blood vessels
    term:
      id: HP:0007394
      label: Prominent superficial blood vessels
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "abnormality of bone mineralization (n = 2), and cutaneous prominence of blood vessels (n = 2)"
    explanation: Two cohort members had cutaneous prominence of blood vessels.
- category: Craniofacial
  name: High Anterior Hairline
  description: >-
    The most frequent facial feature (19 of 24 individuals with photographs),
    persisting into adulthood.
  phenotype_term:
    preferred_term: High anterior hairline
    term:
      id: HP:0009890
      label: High anterior hairline
  frequency: FREQUENT
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with a high anterior hairline (19/24)"
    explanation: 79% of individuals with photographs.
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Persistence of the high anterior hairline, periorbital fullness, and full cheeks into adulthood is demonstrated in individual 12 (age 30 years) and individual 25 (age 34 years)."
    explanation: The gestalt persists into adulthood.
- category: Craniofacial
  name: Triangular Face
  description: Triangular face shape in 10 of 24 individuals with photographs.
  phenotype_term:
    preferred_term: Triangular face
    term:
      id: HP:0000325
      label: Triangular face
  frequency: FREQUENT
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Key dysmorphic features include a triangular-shaped face found in 10 of the 24 individuals for whom photos were available"
    explanation: 42% of individuals with photographs.
- category: Craniofacial
  name: Thin Upper Lip Vermilion
  description: Thin upper lip in 12 of 24 individuals with photographs.
  phenotype_term:
    preferred_term: Thin upper lip
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  frequency: FREQUENT
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "full cheeks (7/24), and a thin upper lip (12/24)"
    explanation: 50% of individuals with photographs.
- category: Craniofacial
  name: Thick Nasal Alae
  description: >-
    Thick nasal alae with flared nostrils in 9 of 24 individuals with
    photographs.
  phenotype_term:
    preferred_term: Thick nasal alae
    term:
      id: HP:0009928
      label: Thick nasal alae
  frequency: FREQUENT
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thick nasal alae and flared nostrils (9/24)"
    explanation: 38% of individuals with photographs.
- category: Craniofacial
  name: Flared Nostrils
  description: Flared nostrils accompany thick nasal alae (9 of 24 with photographs).
  phenotype_term:
    preferred_term: Flared nostrils
    term:
      id: HP:0000454
      label: Flared nostrils
  frequency: FREQUENT
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thick nasal alae and flared nostrils (9/24)"
    explanation: Reported together with thick nasal alae.
- category: Craniofacial
  name: Almond-Shaped Palpebral Fissure
  description: Almond-shaped eyes in 8 of 24 individuals with photographs.
  phenotype_term:
    preferred_term: Almond-shaped eyes
    term:
      id: HP:0007874
      label: Almond-shaped palpebral fissure
  frequency: FREQUENT
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "eyes which are either deep-set (5/24) or almond shaped (8/24) with periorbital fullness (6/24)"
    explanation: 33% of individuals with photographs.
- category: Craniofacial
  name: Deeply Set Eye
  description: Deep-set eyes in 5 of 24 individuals with photographs.
  phenotype_term:
    preferred_term: Deep-set eyes
    term:
      id: HP:0000490
      label: Deeply set eye
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "eyes which are either deep-set (5/24) or almond shaped (8/24) with periorbital fullness (6/24)"
    explanation: 21% of individuals with photographs.
- category: Craniofacial
  name: Periorbital Fullness
  description: Periorbital fullness in 6 of 24 individuals with photographs.
  phenotype_term:
    preferred_term: Periorbital fullness
    term:
      id: HP:0000629
      label: Periorbital fullness
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "eyes which are either deep-set (5/24) or almond shaped (8/24) with periorbital fullness (6/24)"
    explanation: 25% of individuals with photographs.
- category: Craniofacial
  name: Full Cheeks
  description: Full cheeks in 7 of 24 individuals with photographs.
  phenotype_term:
    preferred_term: Full cheeks
    term:
      id: HP:0000293
      label: Full cheeks
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "full cheeks (7/24), and a thin upper lip (12/24)"
    explanation: 29% of individuals with photographs.
- category: Craniofacial
  name: Low-Set Ears
  description: >-
    Listed by GeneReviews among the characteristic craniofacial features; no
    frequency is given in the founding cohort paper.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: PMID:36548456
    reference_title: "ANKRD17-Related Neurodevelopmental Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "deep-set and/or almond-shaped eyes with periorbital fullness, low-set ears, thick nasal alae and flared nostrils"
    explanation: GeneReviews lists low-set ears.
- category: Cardiovascular
  name: Intracranial Aneurysm
  description: >-
    A single term neonate with a de novo ANKRD17 missense variant had
    subarachnoid hemorrhage at 29 days of life from a ruptured left middle
    cerebral artery aneurysm, followed by drug-resistant multifocal epilepsy.
    ClinGen notes this case as an atypical phenotype of unclear significance.
    No vascular features were seen in the 34-person founding cohort, although
    homozygous Ankrd17-null mice die of hemorrhage. The cutaneous prominence of
    blood vessels recorded in two cohort members is a skin finding and is not
    evidence of arterial disease. Treated as a possible, unconfirmed
    association.
  phenotype_term:
    preferred_term: Intracranial aneurysm
    term:
      id: HP:0004944
      label: Dilatation of the cerebral artery
    onset:
      onset_category: NEONATAL
  evidence:
  - reference: PMID:36277850
    reference_title: "Neonatal Aneurysm Rupture in a Child with a De Novo Variant to ANKRD17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "who experienced subarachnoid hemorrhage from a ruptured aneurysm involving the left middle cerebral artery. He experienced acute symptomatic seizures and required clipping of his aneurysm at 35 days of life"
    explanation: >-
      Single case report of a term male neonate with a heterozygous de novo
      ANKRD17 missense variant (c.6988C>G, p.Pro2330Ala).
  - reference: CGGV:assertion_48a9765c-f7ae-46f4-aa6f-7fa95f81404f-2024-12-12T170000.000Z
    reference_title: "ANKRD17 / syndromic complex neurodevelopmental disorder (Definitive)"
    supports: NO_EVIDENCE
    evidence_source: OTHER
    snippet: "The significance of these reports is unclear."
    explanation: ClinGen regards the intracranial hemorrhage case as an atypical phenotype of unclear significance.
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "There were no clinical features suggestive of vascular abnormalities in our cohort."
    explanation: No vascular features in the founding cohort, arguing that vascular disease is not a regular feature.
genetic:
- name: ANKRD17
  gene_term:
    preferred_term: ANKRD17
    term:
      id: hgnc:23575
      label: ANKRD17
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: Definitive (ClinGen gene-disease validity, autosomal dominant)
  notes: >-
    ANKRD17 is the only known gene. Pathogenic alleles are nonsense,
    frameshift and essential-splice variants distributed along the gene, one
    recurrent frameshift (c.5360_5363del, p.Gln1787Argfs*5) in two unrelated
    individuals, missense variants at conserved ankyrin-repeat residues, and
    4q13.3 deletions spanning ANKRD17. None of the founding-cohort variants
    is a founder allele. Larger 4q13.3 deletions also remove neighboring genes
    (for example ADAMTS3, COX18, NPFFR2); the founding authors argue that ANKRD17
    loss accounts for most of the neurodevelopmental phenotype of such
    deletions. A robust genotype-phenotype correlation has not been
    established.
  evidence:
  - reference: CGGV:assertion_48a9765c-f7ae-46f4-aa6f-7fa95f81404f-2024-12-12T170000.000Z
    reference_title: "ANKRD17 / syndromic complex neurodevelopmental disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ANKRD17 | HGNC:23575 | syndromic complex neurodevelopmental disorder | MONDO:0800439 | AD | Definitive"
    explanation: ClinGen Intellectual Disability and Autism GCEP classifies ANKRD17 as Definitive (re-evaluated 2024-12-12).
  - reference: CGGV:assertion_48a9765c-f7ae-46f4-aa6f-7fa95f81404f-2024-12-12T170000.000Z
    reference_title: "ANKRD17 / syndromic complex neurodevelopmental disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ANKRD17 was first reported in relation to autosomal dominant syndromic complex neurodevelopmental disorder, also known as Chopra-Amiel-Gordon Syndrome (CAGS) (OMIM:619504), in 2021"
    explanation: ClinGen equates its curated umbrella entity with CAGS.
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our work now strongly supports the possibility that haploinsufficiency of ANKRD17 is the major cause of these phenotypes in individuals with large alterations of 4q13.3."
    explanation: Links 4q13.3 deletion phenotypes to ANKRD17 dosage.
  - reference: PMID:32299451
    reference_title: "A case report of familial 4q13.3 microdeletion in three individuals with syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deletion includes ADAMTS3, ANKRD17, COX18, GC, and NPFFR2 protein-coding genes."
    explanation: A familial 1.56 Mb 4q13.3 deletion including ANKRD17 segregating with intellectual disability, short stature and congenital heart defect in a mother and two children.
diagnosis:
- name: Molecular Diagnosis
  description: >-
    There are no clinical diagnostic criteria; the phenotype overlaps many
    neurodevelopmental syndromes and the facial gestalt is subtle in some
    individuals. Diagnosis is established by a heterozygous pathogenic ANKRD17
    variant, usually found on exome or genome sequencing (trio analysis
    establishes de novo status); 4q13.3 deletions need copy-number analysis.
    For an ANKRD17 variant of uncertain significance, the founding authors
    suggest looking for the discriminating features (recurrent bacterial
    infections, cleft palate with Pierre Robin sequence, unilateral renal
    agenesis), while noting they occur in a minority.
  evidence:
  - reference: PMID:36548456
    reference_title: "ANKRD17-Related Neurodevelopmental Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of ANKRD17-related neurodevelopmental syndrome is established in a proband with a heterozygous pathogenic variant in ANKRD17 identified by molecular genetic testing."
    explanation: GeneReviews diagnostic criterion.
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although recurrent bacterial infections, cleft palate with Pierre Robin sequence, and unilateral renal agenesis are useful discriminating features, they occur in only a minority of patients."
    explanation: Features that can support variant interpretation.
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The degree of dysmorphism was variable, with several individuals (particularly individuals 8 and 10) presenting with only subtle dysmorphic characteristics."
    explanation: Facial gestalt alone is not diagnostic.
differential_diagnoses:
- name: SATB2-Associated Syndrome
  disease_term:
    preferred_term: SATB2-associated syndrome
    term:
      id: MONDO:0100147
      label: SATB2 associated disorder
  description: >-
    Severe speech impairment with cleft palate or Pierre Robin sequence; one
    founding-cohort individual with PRS, triangular facies and speech delay
    had first been evaluated for SATB2-associated syndrome.
  distinguishing_features:
  - Heterozygous SATB2 rather than ANKRD17 variant.
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including SATB2-associated syndrome (MIM: 612313) in individual 5 who presented with PRS, triangular facies and speech delay"
    explanation: SATB2-associated syndrome was considered before the ANKRD17 diagnosis.
- name: Floating-Harbor Syndrome
  disease_term:
    preferred_term: Floating-Harbor syndrome
    term:
      id: MONDO:0007621
      label: Floating-Harbor syndrome
  description: >-
    Short stature, expressive language delay and a triangular face; one
    founding-cohort individual with marked short stature, microcephaly and
    borderline ID had first been evaluated for Floating-Harbor syndrome.
  distinguishing_features:
  - Heterozygous SRCAP rather than ANKRD17 variant.
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Floating-Harbour syndrome (MIM: 136140) in individual 9 who presented with marked short stature (height < −3 SD), microcephaly (head circumference < −2.5 SD), dysmorphic features, and borderline ID"
    explanation: Floating-Harbor syndrome was considered before the ANKRD17 diagnosis.
- name: KBG Syndrome
  disease_term:
    preferred_term: KBG syndrome
    term:
      id: MONDO:0007846
      label: KBG syndrome
  description: >-
    ANKRD11 haploinsufficiency also causes a variable syndromic intellectual
    disability with short stature and a triangular face. ANKRD11 shares
    ankyrin repeats but not the overall domain structure of ANKRD17.
  distinguishing_features:
  - Macrodontia of the upper central incisors and costovertebral anomalies point to KBG syndrome.
  - Heterozygous ANKRD11 rather than ANKRD17 variant.
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous loss-of-function variants in ANKRD11 (MIM: 611192) are causative of a syndromic ID, the variable but recognizable KBG syndrome (MIM: 148050) characterized by neurodevelopmental delay, macrodontia, short stature, and skeletal anomalies."
    explanation: The founding authors compare CAGS with KBG syndrome.
treatments:
- name: Developmental and Educational Support
  description: >-
    Early intervention, special education and developmental therapies. Given
    the disproportionate expressive-language impairment, speech-language
    therapy is central.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: developmental and educational support
    term:
      id: NCIT:C17874
      label: Educational Intervention
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:36548456
    reference_title: "ANKRD17-Related Neurodevelopmental Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of manifestations: Developmental and educational support"
    explanation: GeneReviews treatment of manifestations.
- name: Anti-Seizure Medication
  description: >-
    Standard anti-seizure treatment; no ANKRD17-specific regimen exists. In
    the founding cohort most individuals with epilepsy were controlled on
    three or fewer medications. GeneReviews notes that teratogenic risk of
    anti-seizure medication in pregnancy depends on the drug, dose and
    gestational age.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: anti-seizure medication
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
    therapeutic_agent:
    - preferred_term: anticonvulsant
      term:
        id: NCIT:C264
        label: Anticonvulsant Agent
  target_phenotypes:
  - preferred_term: Epilepsy
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:36548456
    reference_title: "ANKRD17-Related Neurodevelopmental Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "standard treatments for seizures, behavioral findings, ophthalmologic involvement, genitourinary anomalies, and spasticity"
    explanation: GeneReviews recommends standard seizure treatment.
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seizures were well controlled (less frequent than every 2 years) in five individuals"
    explanation: Response to standard medication in the cohort.
  - reference: PMID:36548456
    reference_title: "ANKRD17-Related Neurodevelopmental Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The teratogenic risk to the fetus associated with the use of anti-seizure medication during pregnancy depends on the type of anti-seizure medication used, the dose, and the gestational age of the fetus."
    explanation: GeneReviews pregnancy management note.
- name: Feeding Therapy and Gastrostomy
  description: >-
    Feeding therapy, with gastrostomy tube placement for persistent feeding
    difficulty; 5 of 11 founding-cohort individuals with feeding problems
    needed G-tube supplementation.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: gastrostomy tube placement
    term:
      id: NCIT:C157864
      label: Gastrostomy Tube Procedure
  target_phenotypes:
  - preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:36548456
    reference_title: "ANKRD17-Related Neurodevelopmental Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "feeding therapy with gastrostomy tube placement as needed for persistent feeding issues"
    explanation: GeneReviews treatment of feeding difficulty.
- name: Immunology Referral and Infection Prophylaxis
  description: >-
    Routine immunizations and referral to an immunologist for recurrent
    infections. Two founding-cohort individuals received low-dose prophylactic
    antibiotics for recurrent otitis media or respiratory infections; no trial
    or guideline evidence on prophylaxis exists for this disorder.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: antibiotic prophylaxis
    term:
      id: NCIT:C51993
      label: Antibiotic Prophylaxis
  target_phenotypes:
  - preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:36548456
    reference_title: "ANKRD17-Related Neurodevelopmental Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "routine immunizations; referral to immunologist for those with recurrent infections"
    explanation: GeneReviews management of recurrent infections.
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two individuals were on low-dose prophylactic antibiotics for recurrent otitis media or respiratory tract infections."
    explanation: Prophylaxis used in two cohort members.
- name: Developmental and Clinical Surveillance
  description: >-
    At each visit, assess developmental progress and educational needs,
    seizures, tone and movement, growth, nutrition and feeding, and family
    needs; assess behavioral and musculoskeletal manifestations annually or as
    needed.
  action_category: MONITORING
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: developmental surveillance
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:36548456
    reference_title: "ANKRD17-Related Neurodevelopmental Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surveillance: Assess developmental progress, educational needs, seizures, changes in tone, movement disorders, growth, nutrition, feeding, and family needs at each visit; assess behavioral and musculoskeletal manifestations annually or as needed."
    explanation: GeneReviews surveillance recommendations.
- name: Genetic Counseling
  description: >-
    Counseling on autosomal dominant inheritance, the usual de novo origin,
    the low but non-zero sibling recurrence risk from parental mosaicism, and
    availability of prenatal and preimplantation testing once the familial
    variant is known.
  action_category: COUNSELING_INFORMATIONAL
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:36548456
    reference_title: "ANKRD17-Related Neurodevelopmental Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Once the ANKRD17 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."
    explanation: GeneReviews genetic counseling.
clinical_trials:
- name: NCT05528744
  phase: NOT_APPLICABLE
  description: >-
    Observational natural history study of confirmed or suspected CAGS at
    Boston Children's Hospital, collecting longitudinal clinical, MRI, EEG and
    neurobehavioral data and patient samples for iPSC-derived neuronal
    phenotyping.
  evidence:
  - reference: clinicaltrials:NCT05528744
    reference_title: "Delineating the Molecular Spectrum and the Clinical, Imaging and Neuronal Phenotype of Chopra-Amiel-Gordon Syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The purpose of this study is to establish the longitudinal natural history of individuals with confirmed or suspected Chopra-Amiel-Gordon Syndrome (CAGS)"
    explanation: Registry record of the natural history study.
animal_models:
- name: Ankrd17 null mouse
  species: Mouse
  genotype: Ankrd17 targeted null (homozygous and heterozygous)
  publication: PMID:19619540
  description: >-
    Constitutive gene-targeted Ankrd17 knockout. Homozygous embryos die at
    E10.5-E11.5 with hemorrhage and a marked reduction of vascular smooth
    muscle cells around vessels; heterozygotes are viable and fertile. The
    embryonic lethality precluded study of brain development, and no
    behavioral or neurodevelopmental phenotype has been reported for
    heterozygotes.
  modeled_mechanisms:
  - target: ANKRD17 Haploinsufficiency
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The model informs the essential role of Ankrd17 in embryonic vascular
      maturation, not the heterozygous human neurodevelopmental disorder.
    limitations: >-
      The informative genotype is homozygous null, which has no human
      counterpart; heterozygotes, the human-equivalent genotype, were not
      assessed for neurodevelopmental or behavioral phenotypes, and no
      vascular phenotype has been established in patients.
    evidence:
    - reference: PMID:19619540
      reference_title: "Ankrd17, an ubiquitously expressed ankyrin factor, is essential for the vascular integrity during embryogenesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The Ankrd17-deficient mice died between embryonic day (E) 10.5 and E11.5 due to cardiovascular defects."
      explanation: Homozygous lethality from cardiovascular defects.
    - reference: PMID:33909992
      reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: "Given the early embryonic death of the knockout mice, central nervous system development was not studied."
      explanation: The model could not address the neurodevelopmental phenotype.
- name: Regional Ankrd17 AAV-shRNA knockdown mouse
  species: Mouse
  genotype: AAV-delivered Ankrd17 shRNA in medial prefrontal cortex or hippocampal CA1 of wild-type C57BL/6J males
  publication: PMID:40604385
  description: >-
    Stereotaxic AAV delivery of tandem Ankrd17 siRNAs under a neuronal
    promoter into the medial prefrontal cortex or hippocampal CA1 of 4-5
    week-old male mice, reducing Ankrd17 protein to roughly 53-72% of control.
  modeled_mechanisms:
  - target: Synaptic Protein Deficit and Neural Circuit Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      Partial Ankrd17 reduction in juvenile cortex or hippocampus reduces
      synaptic proteins and neuronal activation and produces social, anxiety
      and spatial-memory deficits.
    limitations: >-
      Knockdown is regional, neuronal and begins after brain development, so
      it does not model germline heterozygosity from conception, effects on
      neural progenitors, or non-neural features. Only males were studied, and
      the study has not been replicated.
    readouts:
    - name: Synaptic protein levels
      target: Synaptic Protein Deficit and Neural Circuit Dysfunction
      direction: DECREASED
      interpretation: GluN2A, GluA1, PSD-95 and synapsin I reduced in both regions.
      evidence:
      - reference: PMID:40604385
        reference_title: "Novel ANKRD17 variants implicate synaptic and mitochondrial disruptions in intellectual disability and autism spectrum disorder."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Our findings revealed a decrease in the expression of the NMDAR subunit GluN2A, the AMPAR subunit GluA1, the excitatory synaptic scaffolding protein PSD-95 and Synapsin I"
        explanation: Western blot readout in knockdown mice.
    evidence:
    - reference: PMID:40604385
      reference_title: "Novel ANKRD17 variants implicate synaptic and mitochondrial disruptions in intellectual disability and autism spectrum disorder."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These results effectively mimic the heterozygous deficiency of ANKRD17 in mice."
      explanation: The authors' rationale that partial knockdown approximates heterozygous deficiency.
mechanistic_hypotheses:
- hypothesis_group_id: ankrd17_hippo_yap
  hypothesis_label: Reduced ANKRD17 impairs YAP-dependent neural progenitor growth signaling
  status: EMERGING
  description: >-
    ANKRD17 is a Mask-family co-factor that promotes YAP nuclear import and
    stability, and it is co-expressed with YAP1 in fetal human radial glia. The
    hypothesis is that reduced ANKRD17 lowers YAP activity in neural
    progenitors and so contributes to the neurodevelopmental phenotype. It
    rests on Drosophila genetics, mammalian cell-line work and expression
    data; it has not been tested in ANKRD17-deficient neural tissue.
  evidence:
  - reference: PMID:33909992
    reference_title: "Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "raising the possibility that the neurodevelopmental phenotypes associated with ANKRD17 variants may be due to disruption of this pathway"
    explanation: The founding authors' statement of the hypothesis.
- hypothesis_group_id: ankrd17_synaptic_mitochondrial
  hypothesis_label: ANKRD17 deficiency impairs synaptic protein composition and mitochondrial function
  status: EMERGING
  description: >-
    Based on one study combining regional knockdown in juvenile mouse brain
    with proteomics of one ANKRD17-deleted fetal cortex, ANKRD17 deficiency is
    proposed to reduce excitatory synaptic proteins and mitochondrial
    respiratory proteins, contributing to intellectual disability and autism.
  evidence:
  - reference: PMID:40604385
    reference_title: "Novel ANKRD17 variants implicate synaptic and mitochondrial disruptions in intellectual disability and autism spectrum disorder."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Furthermore, our studies suggest dysregulation of synaptic proteins and mitochondrial function, along with impaired neural circuits following Ankrd17 knockdown."
    explanation: Statement of the hypothesis from the knockdown study.
- hypothesis_group_id: ankrd17_innate_immunity
  hypothesis_label: Reduced ANKRD17 weakens NOD1/NOD2 and RIG-I-like receptor signaling, predisposing to infection
  status: EMERGING
  description: >-
    Cell-line studies place ANKRD17 in NOD1/NOD2 antibacterial and RIG-I-like
    receptor antiviral signaling; the founding authors propose this as the
    basis of recurrent infections. Not tested in patient cells.
  evidence:
  - reference: PMID:23711367
    reference_title: "A role for the Ankyrin repeat containing protein Ankrd17 in Nod1- and Nod2-mediated inflammatory responses."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In conclusion, this reveals a novel function for Ankrd17 in anti-bacterial innate immune pathways."
    explanation: Cell-line basis for the immune hypothesis.
discussions:
- discussion_id: mismatch_ankrd17_null_mouse_vascular
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - animal_models#Mouse
  - phenotypes#Intracranial Aneurysm
  prompt: >-
    Homozygous Ankrd17-null mice die of hemorrhage from failed vascular
    maturation, yet no vascular features were found in the 34-person founding
    cohort. Does heterozygous ANKRD17 loss confer any vascular risk in humans,
    as the single neonatal ruptured-aneurysm case might suggest?
  rationale: >-
    The mouse phenotype reflects complete loss, which has no human
    counterpart, and heterozygous mice were not phenotyped in detail. A single
    human aneurysm case with a missense variant cannot establish an
    association, and ClinGen records its significance as unclear. Whether
    vascular imaging belongs in surveillance depends on the answer.
  proposed_experiments:
  - experiment_id: exp_ankrd17_heterozygous_mouse_vasculature
    name: Vascular phenotyping of Ankrd17 heterozygous mice
    description: >-
      Examine cerebral and systemic arterial wall structure, smooth muscle
      coverage and aneurysm formation in aging Ankrd17 heterozygous mice.
  - experiment_id: exp_ankrd17_cohort_vascular_imaging
    name: Systematic vascular review in the natural history cohort
    description: >-
      Review MRI/MRA and clinical vascular events in the NCT05528744
      natural history cohort to estimate whether cerebrovascular disease is
      enriched.
- discussion_id: mismatch_ankrd17_hippo_yap_model_systems
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - pathophysiology#Disrupted YAP Nuclear Import in Neural Progenitors
  - mechanistic_hypotheses#ankrd17_hippo_yap
  prompt: >-
    The Mask/Yorkie requirement is established in Drosophila and YAP nuclear
    import in immortalized mammalian cell lines. Does reduced ANKRD17 dosage
    actually lower YAP-dependent signaling in human neural progenitors, where
    the syndrome originates?
  rationale: >-
    Every functional step in this hypothesis comes from a system that is not
    human neural tissue: fly tissue-growth genetics and cell-line
    overexpression or knockdown. The only human data are expression, namely
    that ANKRD17 and YAP1 are co-expressed in fetal radial glia, which
    establishes opportunity rather than dependence. The paralog ANKHD1 also
    binds YAP and could buffer the pathway differently in human progenitors
    than in either model. If reduced ANKRD17 does not lower YAP activity in
    human neural cells, this node and its hypothesis group are describing a
    conserved biochemical activity that is not the disease mechanism.
  proposed_experiments:
  - experiment_id: exp_ankrd17_yap_human_neural_progenitors
    name: YAP localization and activity in ANKRD17-haploinsufficient human neural progenitors
    description: >-
      In patient-derived or isogenic ANKRD17 heterozygous iPSC-derived neural
      progenitors and cortical organoids, measure nuclear versus cytoplasmic
      YAP, YAP target-gene expression, and progenitor proliferation against
      isogenic controls, with ANKHD1 dosage manipulated separately to test
      paralog buffering.
    perturbations:
    - name: Heterozygous ANKRD17 loss in human neural progenitors
      target: pathophysiology#ANKRD17 Haploinsufficiency
    readouts:
    - name: Nuclear YAP and YAP target-gene activity
      target: pathophysiology#Disrupted YAP Nuclear Import in Neural Progenitors
      direction: DECREASED
      interpretation: >-
        Reduced nuclear YAP and target-gene output in the haploinsufficient
        progenitors would support the pathway step in human cells; no change
        would refute it.
    would_support:
    - pathophysiology#Disrupted YAP Nuclear Import in Neural Progenitors
    supporting_outcome:
    - >-
      Nuclear YAP and YAP target-gene expression are reduced in ANKRD17
      haploinsufficient human neural progenitors relative to isogenic controls.
    would_refute:
    - pathophysiology#Disrupted YAP Nuclear Import in Neural Progenitors
    refuting_outcome:
    - >-
      YAP localization, target-gene output and progenitor proliferation are
      unchanged despite halved ANKRD17, indicating the pathway is buffered in
      human neural cells.
  evidence:
  - reference: PMID:31661072
    reference_title: "Mask family proteins ANKHD1 and ANKRD17 regulate YAP nuclear import and stability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mammalian Mask1/2 proteins also promote nuclear import of YAP, as well as stabilising YAP and driving formation of liquid droplets."
    explanation: >-
      The mammalian evidence for the pathway step is cell-line work, not
      neural tissue, which is the mismatch this discussion records.
- discussion_id: gap_ankrd17_genotype_phenotype
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Ankyrin Repeat Destabilization by Missense Variants
  - pathophysiology#ANKRD17 Haploinsufficiency
  prompt: >-
    Do ANKRD17 missense variants act only by destabilizing the protein, and do
    they produce a different severity from truncating alleles?
  rationale: >-
    Missense pathogenicity rests on conservation and homology modeling alone,
    with no protein-level assay. A later report stated that a genotype-phenotype
    correlation could not yet be established. If some missense alleles are not
    simple loss of function, variant interpretation and the single-mechanism
    model in this entry would need revision.
  evidence:
  - reference: PMID:40604385
    reference_title: "Novel ANKRD17 variants implicate synaptic and mitochondrial disruptions in intellectual disability and autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings highlight the difficulty of establishing a clear genotype–phenotype correlation and underscore the need for larger cohort studies to identify potential trends."
    explanation: Genotype-phenotype correlation remains unresolved.
  proposed_experiments:
  - experiment_id: exp_ankrd17_missense_stability
    name: Protein stability assay of patient missense alleles
    description: >-
      Express patient missense and in-frame variants and measure protein
      half-life and steady-state level against wild type and a truncating
      control; test effect on YAP nuclear localization.
notes: >-
  LUMP/SPLIT. This is a single Disease entry for ANKRD17-related
  neurodevelopmental syndrome (MONDO:0859186, OMIM 619504). No subtypes are
  declared: missense and truncating alleles are presented in the literature as
  one disorder with a shared haploinsufficiency mechanism, and no reproducible
  genotype-phenotype split has been published. Small 4q13.3 deletions that
  remove ANKRD17 are included because the founding cohort itself includes one
  and attributes the phenotype to ANKRD17 loss, but larger contiguous 4q13.3
  deletions remove other genes (ADAMTS3, COX18, NPFFR2 and others) and may carry
  additional features, such as the congenital heart defects in the familial
  1.56 Mb deletion; those deletions are not treated as a separate entry here.
  ClinGen curated the gene against the umbrella term syndromic complex
  neurodevelopmental disorder (MONDO:0800439), recorded in mappings as a
  broader match; its dosage curation uses syndromic intellectual disability
  (MONDO:0000508).

  STRUCTURED SOURCES. Orphanet ORPHA:717823 ("Global developmental
  delay-recurrent infections-facial dysmorphism syndrome") is the same entity,
  exact-mapped to OMIM 619504; the Orphadata record used here carries names
  and cross-references only, with no phenotype or epidemiology annotation.
  GeneReviews (PMID:36548456) is cited from its PubMed abstract; the chapter's
  full clinical tables were not available in the reference cache, so
  frequencies come from the founding cohort (PMID:33909992). A 2025 conference
  abstract describing a larger genotype-phenotype cohort and an epilepsy
  analysis of a further cohort could not be retrieved as text and are not
  used; their figures (including a higher epilepsy frequency) are unverified.

  SINGLE-CASE FINDINGS NOT CURATED AS PHENOTYPES. A de novo missense variant of
  uncertain significance (p.His2593Pro) in a girl with severe developmental
  delay, bilateral microphthalmia with coloboma, periventricular heterotopia,
  clubfoot and vigabatrin-responsive epileptic spasms (PMID:37456926), transient
  tics in a boy with a splice variant (PMID:39315309), and multiple congenital
  anomalies with cerebellar hypoplasia in a fetus with a 4q13.3 deletion
  (PMID:40604385) are single observations and are not added as phenotypes.

  CLUBFOOT. Clubfoot has now been reported in two unrelated individuals with a
  de novo ANKRD17 variant: the girl in PMID:37456926, and one of 38 fetuses in
  a prenatal exome series for isolated sonographic clubfoot, in which ANKRD17
  was one of four genes carrying a pathogenic or likely pathogenic de novo
  variant (PMID:36326072). It is not curated as a phenotype here. That series
  selected its subjects on clubfoot, so it can establish neither a frequency
  nor the direction of the association, it reports no variant, no other
  clinical features and no postnatal follow-up for the ANKRD17 fetus, and
  clubfoot appears in neither the 34-person founding cohort nor GeneReviews.
  Two ascertainment-biased observations are a lead for the next cohort report
  rather than a syndrome feature.

  MODULES. No mechanism module was conformed to. The two closest candidates in
  kb/modules/ were read and rejected on their own stated scope:
  excitatory_synapse_scaffold_disruption is scoped to postsynaptic-density
  scaffold and scaffold-regulatory proteins such as SHANK3 and SYNGAP1, and
  ANKRD17 is not one, while the only synaptic-protein evidence here comes from
  a single regional knockdown study; epigenetic_machinery_neurodevelopmental_dysregulation
  is scoped to lesions in proteins that write, erase, read or remodel
  chromatin, and ANKRD17 is an ankyrin-repeat and KH-domain protein with no
  established chromatin-machinery role. No module in kb/modules/ models
  Hippo/YAP signaling in neurodevelopment: the only two modules that reference
  YAP are evading_growth_suppressors and cdk46_inhibitor_resistance, both of
  which model oncogenic growth control rather than neural development.

📚

References & Deep Research

References

1

PMID:36548456

ANKRD17-Related Neurodevelopmental Syndrome.

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Chopra-Amiel-Gordon_Syndrome · 2026-09-24T00:36:58Z · View source

New Disease entry for Chopra-Amiel-Gordon syndrome (ANKRD17-related neurodevelopmental syndrome, MONDO:0859186, OMIM 619504), curated from the founding cohort of 34 individuals (PMID:33909992, PMC full text), the GeneReviews chapter (PMID:36548456), ClinGen gene-disease validity (Definitive) and dosage sensitivity (haploinsufficiency score 3), Orphanet ORPHA:717823, and five later case reports. Lump/split: one Disease entry, no subtypes. Truncating, essential-splice, missense and whole-gene-deletion alleles are presented in the literature as one disorder converging on haploinsufficiency, and no reproducible genotype-phenotype split has been published. Small 4q13.3 deletions removing ANKRD17 are included; larger contiguous deletions removing neighbouring genes are discussed in notes rather than split out. ClinGen curated the gene against the umbrella term MONDO:0800439, recorded as skos:broadMatch rather than an equivalence. Pathograph: haploinsufficiency and missense destabilization as trigger nodes, converging on reduced ANKRD17 in neural progenitors and neurons, then three explicitly hypothetical intermediates (Hippo/YAP nuclear import, synaptic and mitochondrial deficit, innate immune pattern-recognition signaling) each carried by its own mechanistic_hypotheses group, and outcome nodes for neurodevelopmental dysfunction and abnormal brain development. Every mechanistic step beyond the genetics is marked HYPOTHETICAL or PROVISIONAL because no functional assay in human neural tissue exists. Two HUMAN_MODEL_MISMATCH discussions: the homozygous Ankrd17-null mouse vascular phenotype against the absence of vascular features in the cohort, and the Hippo/YAP pathway, whose functional evidence is entirely Drosophila and immortalized cell lines while the only human data are expression. Audit against the source found two Table 2 rows the first draft omitted, both added: abnormality of bone mineralization (n=2, HP:0004348, bound direction-neutral because the source does not state a direction) and cutaneous prominence of blood vessels (n=2, HP:0007394). The latter is recorded as a skin finding explicitly distinguished from the arterial disease the same paper reports as absent, so it does not contradict the REFUTE evidence on the intracranial aneurysm phenotype. Clubfoot was re-examined after the claim issue's automated second opinion raised PMID:36326072. The paper does name ANKRD17 as one of four genes with a de novo pathogenic or likely pathogenic variant among 38 fetuses, contrary to an earlier note in this branch's history. It is still not curated as a phenotype: the series is ascertained on clubfoot and so establishes neither frequency nor direction, reports no variant or follow-up, and clubfoot is absent from the founding cohort and GeneReviews. The reasoning is recorded in the entry notes. Validation: just validate (128/128 snippets verified), validate-terms, check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-coarse-phenotypes, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens, check-environmental-evidence, check-reference-titles, check-genereviews (chapter tagged), list-gene-term-mismatches (0 findings), pytest tests/test_data.py -k Chopra, and validate-disorders. Deep research: falcon was requested and returned HTTP 402 (out of credits); the claude_code fallback produced the committed report, which passed just preflight-dr against MONDO:0859186 with ANKRD17 mentioned 50 times and matching OMIM 619504. The report was used as a lead only; every claim in the entry is sourced to a primary reference with an exact verified snippet.

Claude Code ▸

Chopra-Amiel-Gordon Syndrome (ANKRD17-Related Neurodevelopmental Syndrome): Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 15 citations 2026-09-23T19:57:31.984237

Chopra-Amiel-Gordon Syndrome (ANKRD17-Related Neurodevelopmental Syndrome): Comprehensive Research Report

1. Disease Information

Overview. Chopra-Amiel-Gordon syndrome (CAGS) — the preferred nosological name is now ANKRD17-related neurodevelopmental syndrome — is an autosomal dominant, ultra-rare Mendelian neurodevelopmental disorder caused by heterozygous loss-of-function variants in ANKRD17 (Ankyrin Repeat Domain 17). It was first delineated as a distinct clinical entity in 2021 by Chopra, McEntagart, Clayton-Smith, Gordon, and colleagues in the American Journal of Human Genetics (PMID: 33909992), based on 34 individuals from 32 families identified through GeneMatcher-style international collaboration and exome/genome sequencing. The syndrome is characterized by global developmental delay/intellectual disability with disproportionate speech impairment, variable facial dysmorphism, and a range of associated neurological, ophthalmological, growth, and immune features.

Key identifiers: - OMIM (phenotype): 619504 — CHOPRA-AMIEL-GORDON SYNDROME; CAGS - OMIM (gene): 615929 — ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 17; ANKRD17 - MONDO: MONDO:0859186 (matches the target ID given) - MedGen: C5561975 / UID 1794185 - Orphanet: an ORPHA entry exists for this disorder (search aggregators return ORPHA:717823, but I was unable to directly verify this number against the live Orphanet page during this session — a redirect blocked automated fetch — so treat this specific ORPHA code as a lead requiring direct confirmation, not a verified citation) - Gene location: 4q13.3 (chromosome 4) - Reference transcript: NM_032217.5 (also cited as NM_001286771.3 in some reports) - GeneReviews chapter:* "ANKRD17-Related Neurodevelopmental Syndrome," NCBI Bookshelf NBK588029 (initial posting December 2022)

Synonyms: ANKRD17-related neurodevelopmental syndrome (current preferred term); CAGS; Chopra–Amiel–Gordon syndrome.

Evidence basis: This is a structured, aggregated cohort disease — nearly all published knowledge derives from multi-institutional case-series/cohort studies (the founding 2021 AJHG cohort of 34/32 families; a 2025 follow-up cohort reported to include up to 47–55 individuals for genotype-phenotype and epilepsy-specific analyses) plus individual case reports, rather than large-scale registry or EHR-derived data. A dedicated natural history study is actively recruiting (ClinicalTrials.gov NCT05528744, Boston Children's Hospital, "CAGS NHS," started 2022-08-27, estimated completion 2030), which will generate prospective, individual-patient-level clinical, imaging, and iPSC/neuronal-phenotyping data going forward.

2. Etiology

Disease causal factor — genetic. CAGS is caused by heterozygous loss-of-function (LOF) variants in ANKRD17, occurring predominantly de novo. The founding cohort's mutational spectrum (PMID: 33909992): - 21 truncating/essential splice-site variants (7 nonsense, 12 frameshift, 2 splice-site) - 9 missense variants affecting highly conserved ankyrin-repeat residues - 1 in-frame indel - 1 de novo 1.16 Mb microdeletion at 4q13.3

A subsequent case (Xia et al., 2025, PMID: 40604385) added a 1.247 Mb microdeletion (exons 2–34) and a nonsense variant c.1252C>T (p.Arg418*). A Chinese cohort report (Frontiers in Genetics, 2024, DOI: 10.3389/fgene.2024.1422469) added a canonical splice variant c.7248+1G>A causing exon 32 skipping.

Genetic risk factors. No modifier genes have been established. ANKRD17 is extremely intolerant of loss-of-function variation in the general population (gnomAD pLI = 1.0), which is cited by the original authors as strong supportive evidence for haploinsufficiency as the disease mechanism, independent of the clinical cohort data itself.

Environmental/other risk factors. None reported; this is a purely monogenic disorder with essentially complete de novo origin (see §9 for the one reported familial transmission and monozygotic twin pair).

Protective factors. None identified or plausible for a haploinsufficiency Mendelian disorder of this kind; not addressed in the literature.

Gene-environment interactions. Not studied/applicable — no published data.

3. Phenotypes

The two largest cohorts (the 2021 founding study, n=34, and a 2025 follow-up genotype-phenotype study presented as a conference abstract, apparently n≈47, plus a separate epilepsy-focused analysis of n=55) give the most reliable frequency estimates. Figures below combine both, cited separately where sourced differently.

Neurodevelopmental (most penetrant domain)

Developmental delay / intellectual disability: 31/34 (91%) in the founding cohort; in the 2025 update, 40/47 (85%), with severity distribution reported as ~25% borderline, ~65% mild-moderate, ~10% severe-profound. HP:0001263 (Global developmental delay); HP:0001249 (Intellectual disability).
Speech/expressive language delay or apraxia: the single most penetrant feature — 29/32 (91%) in the founding cohort; 42/47 (91%) in the 2025 update, including some individuals with absent speech. HP:0000750 (Delayed speech and language development); consider HP:0011922 for speech apraxia if documented.
Motor delay: 20/29 (69%). HP:0001270 (Motor delay).
Autism spectrum disorder / ASD features: reported as a recurrent feature. HP:0000717.
ADHD: reported. HP:0007018.
Gait/balance disturbance: emerging feature in later cohorts (2025 update names "gait difficulties" as a newly recognized manifestation). HP:0001288 (Gait disturbance).
Epilepsy: 9/33 (27%) in the founding cohort; a dedicated epilepsy-phenotype analysis (AESnet abstract) in a larger cohort of 55 found 24/55 (43%) with confirmed epilepsy — absence seizures most common (13/24), then generalized tonic-clonic (11/24), then epileptic spasms (5/24); 7 patients had multiple seizure types. Mean age at onset 4.4 years (range neonatal–15 years). EEG: ictal abnormalities in 9, interictal in 7. Treatment response generally favorable — 10/24 achieved seizure control on monotherapy, 13/24 (54%) had seizures less than annually, though 5/24 met drug-resistant criteria; overall the authors characterize epilepsy in CAGS as "relatively benign and generally controlled with medication." HP:0001250 (Seizure); HP:0002121 (Generalized absence seizure); HP:0002069 (Generalized tonic-clonic seizure); HP:0011097 (Epileptic spasm).

Craniofacial dysmorphism

Triangular face shape: 10/24 (~42%). HP:0000325.
High anterior hairline: 19/24 (~79%). HP:0009890.
Almond-shaped/deep-set eyes with periorbital fullness: 8/24. HP:0007655 / HP:0000601 (deep-set eyes) — descriptor may need custom mapping.
Thin upper lip vermilion: 12/24 (50%). HP:0000219.
Full cheeks: reported. HP:0000293.
Thick nasal alae / flared nostrils: reported. HP:0009928 or HP:0000463 (anteverted nares).
Low-set ears: reported. HP:0000369.
Less common: cleft palate with Pierre Robin sequence (HP:0000201 / HP:0000278 for micrognathia component), cleft lip (HP:0410030/HP:0100333), scoliosis (HP:0002650), renal agenesis (HP:0000104, unilateral form HP:0000122).

Ophthalmological

Strabismus and refractive errors: 13/23 (57%) had ophthalmological abnormalities in the founding cohort. HP:0000486 (Strabismus); HP:0000539 (Abnormality of refraction).

Growth

Growth failure/short stature (height <−2SD): 12/31 (39%). HP:0004325 (Postnatal growth failure) / HP:0003510 (Short stature).
Feeding difficulties: recurrent feature across cohorts, including selective food aversion in the Chinese case report. HP:0011968.
Overweight/obesity — emerging feature noted in the 2025 genotype-phenotype update. HP:0001513.

Musculoskeletal

Joint hypermobility: 9/29 (31%). HP:0001382.
Dysphagia — emerging feature (2025 update). HP:0002015.

Immune

Recurrent (bacterial) infections: 11/33 (33%); recurrent pulmonary infections specifically reported in individual cases. HP:0002719 (Recurrent infections).

Rare/emerging (2025 update; not yet quantified with confidence)

Cerebral hemorrhage — reported as a rare, newly emerging feature.
Tic disorder / involuntary vocalization and blinking — proposed as a possible phenotypic expansion in one case report (not yet an established core feature; treat as a single-case lead, not a cohort-confirmed association).
Urinary frequency, self-resolving — single case.

Quality of life impact. No dedicated QOL instrument (EQ-5D, SF-36, PROMIS) study has been published for CAGS specifically; the natural history study (NCT05528744) plans standardized neurobehavioral assessment but QOL-specific outcome data are not yet available in the literature.

Severity/progression pattern: Severity is broadly stable/non-progressive for the core neurodevelopmental phenotype (a static encephalopathy-type course), consistent with a haploinsufficiency developmental gene; epilepsy, when present, tends to be non-progressive and often well controlled. No natural history data yet describe regression.

4. Genetic/Molecular Information

Causal gene: ANKRD17 (HGNC symbol ANKRD17; OMIM *615929), encoding Ankyrin Repeat Domain-Containing Protein 17, a large multi-ankyrin-repeat scaffold protein with nuclear localization/export signals, localizing to nucleus, cytoplasm, and membrane compartments (per GeneCards).
Variant classification/type: Predominantly pathogenic/likely-pathogenic per ACMG/AMP criteria in ClinVar (e.g., RCV001593058 c.2623G>T p.Glu875Ter; RCV001843437 c.833G>T p.Gly278Val). Types: nonsense, frameshift, canonical splice-site, missense (clustering in conserved ankyrin-repeat core residues, "invariant in all 25 repeats"), in-frame indel, and multi-exon/whole-gene microdeletions (1.16–1.25 Mb at 4q13.3).
Variant origin: Overwhelmingly de novo/germline; essentially no somatic CAGS reports exist (this is a developmental, not neoplastic, disorder).
Allele frequency in population databases: Not applicable for pathogenic variants (private/de novo); the relevant population-genetics statistic is gnomAD pLI = 1.0, i.e., near-complete intolerance to predicted LOF variation in the general population — this constraint metric is itself cited as supporting evidence for a haploinsufficiency mechanism, independent of the clinical cohort.
Functional consequence: Loss of function / haploinsufficiency is the proposed and best-supported mechanism (per the founding AJHG paper and ClinGen Dosage Sensitivity curation, which lists ANKRD17 with sufficient evidence for haploinsufficiency, consistent with the truncating-variant-dominant mutational spectrum). Missense variants are proposed to act via structural destabilization of the ankyrin-repeat fold (disrupting core structural residues invariant across all 25 repeats) rather than via a distinct dominant-negative or gain-of-function route, though a dominant-negative contribution for some missense alleles cannot be formally excluded and has not been functionally tested.
Modifier genes: None established.
Epigenetic information: No CAGS-specific DNA methylation/histone data published to date (unlike some other neurodevelopmental disorders, no "episignature" has yet been reported for ANKRD17).
Chromosomal abnormalities: Two microdeletions at 4q13.3 reported (encompassing ANKRD17, 1.16 Mb and 1.247 Mb), functionally equivalent to gene-level haploinsufficiency.
Cell-cycle interaction: ANKRD17 interacts with the cyclin E/CDK2 complex and promotes cell-cycle progression — proposed relevance to neural progenitor proliferation, supported by single-cell RNA-seq co-expression of ANKRD17 and CDK2 in human telencephalic neuronal progenitors (from the founding paper's reanalysis of published scRNA-seq data, not new functional data).
Innate immunity interaction: ANKRD17 has been separately characterized (outside the CAGS-specific literature, in general molecular biology studies) as a positive regulator of innate immune signaling — enhancing antiviral responses via DDX58 (RIG-I)/IFIH1 (MDA5) pathways and antibacterial defense via NOD1/NOD2 signaling — proposed by the CAGS authors as a plausible explanation for the recurrent-infection phenotype, though this link is inferential/extrapolated rather than demonstrated in patient samples.

5. Environmental Information

No environmental, lifestyle, or infectious contributory factors have been identified or are biologically plausible for this monogenic developmental disorder; the literature contains no such claims. This section is not applicable beyond noting that recurrent infections are a phenotypic manifestation of the immune dysregulation hypothesis above, not an environmental cause of the syndrome.

6. Mechanism / Pathophysiology

Proposed causal chain (largely inferential; direct patient-derived functional data are still forthcoming from NCT05528744's iPSC program)

A heterozygous truncating, splice-disrupting, or structurally destabilizing missense variant in ANKRD17 (or a 4q13.3 microdeletion spanning the gene) leads to reduced/absent functional ANKRD17 protein from one allele.
Because the population is highly intolerant of ANKRD17 LOF (pLI=1.0), this results in insufficient total ANKRD17 dosage (haploinsufficiency) rather than a compensable loss — the proposed primary disease mechanism.
In neural progenitor cells, reduced ANKRD17 dosage is inferred to disrupt its interaction with the cyclin E/CDK2 complex, potentially impairing normal cell-cycle progression of radial glial progenitors and excitatory/inhibitory neuron populations that co-express ANKRD17 during human telencephalic development (inference from scRNA-seq co-expression, not direct functional proof).
In parallel, via the conserved Mask/ANKRD17–Yorkie/YAP axis of the Hippo signaling pathway (demonstrated in the Drosophila ortholog Mask, not yet functionally confirmed in human/mammalian ANKRD17-deficient neural tissue), reduced ANKRD17 is proposed to dysregulate YAP1-dependent tissue-growth signaling, which may contribute to the growth-failure and dysmorphic craniofacial phenotype (this step is explicitly flagged by the original authors as "yet to be understood").
Downstream of steps 3–4, disrupted progenitor proliferation and neurodevelopmental gene-expression programs lead to the core clinical phenotype: global developmental delay, disproportionate speech/language impairment, and variable structural brain findings.
Independently, a 2025 mouse AAV-knockdown study (Xia et al., PMID: 40604385) demonstrates that ANKRD17 knockdown in medial prefrontal cortex and hippocampal CA1 causes decreased expression of the NMDAR subunit GluN2A, the AMPAR subunit GluA1, the excitatory synaptic scaffold protein PSD-95, and Synapsin I — i.e., a synaptic protein deficit — which results in measurable social, anxiety, and spatial-memory/learning deficits in mice, directly modeling the ASD/anxiety/cognitive component of the human phenotype.
The same mouse/human-embryonic-brain-proteomics study found that 21.1% of differentially expressed proteins after ANKRD17 knockdown localize to mitochondria, with significant downregulation of mitochondrial matrix, respiratory chain complex II, and electron-transfer-activity pathways (confirmed by qPCR for Sdha/Sdhb/Sdhc) — indicating a mitochondrial dysfunction branch of the mechanism, potentially contributing to neuronal energetic failure and compounding the synaptic deficit.
Separately, at the whole-organism level, complete Ankrd17 ablation in mice causes embryonic lethality at E10.5–E11.5 due to cardiovascular defects (hemorrhage, vascular smooth muscle cell deficiency, PMID from Hou et al. 2009 FEBS Letters), establishing that ANKRD17 is essential for vascular integrity during embryogenesis — this defines the biological floor of complete loss (relevant to why CAGS patients, who retain one functional allele, survive, whereas biallelic loss would likely be embryonic lethal) and is consistent with renal agenesis and other structural anomalies occasionally observed in the human syndrome as partial phenocopies of this vascular/developmental role.
Finally, ANKRD17's separately characterized role as a positive regulator of NOD1/NOD2-mediated antibacterial signaling and DDX58/IFIH1-mediated antiviral signaling is proposed to explain (though not directly demonstrated in patients) the recurrent bacterial/viral infection phenotype observed in roughly a third of the cohort.

Summary by category

Molecular pathways: Hippo/Yorkie–YAP1 (via Drosophila Mask ortholog homology — GO:0035329, hippo signaling); cyclin E/CDK2 cell-cycle pathway (GO:0000082, G1/S transition of mitotic cell cycle); NOD1/NOD2 innate immune signaling (GO:0032495); RIG-I/MDA5 (DDX58/IFIH1) antiviral signaling (GO:0039528).
Cellular processes: neural progenitor proliferation (GO:0022008, neurogenesis); synaptic protein complex assembly/maintenance (GO:0007416, synapse assembly); mitochondrial respiratory chain function (GO:0022904, respiratory electron transport chain).
Protein dysfunction: loss/destabilization of the ankyrin-repeat scaffold structure; the encoded protein is not enzymatic itself but a scaffold/co-factor, so functional consequence is loss of protein-protein interaction capacity rather than catalytic loss.
Cell types implicated: radial glial progenitors (CL:0002608), excitatory neurons (CL:0008030 or more specific cortical excitatory neuron terms), interneurons (CL:0000099), hippocampal CA1 pyramidal neurons, and vascular smooth muscle cells (CL:0000359) in the mouse embryonic-lethality model.
Tissue damage mechanisms: vascular hemorrhage/maturation failure (embryonic mouse model only — not documented as an ongoing pathology in surviving human heterozygotes beyond the rare "cerebral hemorrhage" case noted in the 2025 update).
Metabolic changes: mitochondrial/oxidative-phosphorylation gene downregulation (complex II components).
Molecular profiling: proteomics (5D label-free) on postmortem human embryonic brain tissue and mouse cortex/hippocampus after knockdown (Xia et al. 2025); single-cell RNA-seq reanalysis of published human telencephalon datasets (Chopra et al. 2021) — no CAGS patient-derived transcriptomic/proteomic dataset has yet been deposited in GEO/PRIDE as a dedicated disease-cohort resource; the closest is the ongoing iPSC program under NCT05528744.
Advanced technologies: no single-cell, spatial transcriptomic, or CRISPR functional-genomics screen has been performed specifically on ANKRD17/CAGS patient material to date; the AAV-knockdown mouse model (Xia et al. 2025) is the most advanced functional perturbation model currently published.

7. Anatomical Structures Affected

Organ level (primary): Central nervous system (brain — nonspecific structural abnormalities reported on MRI, not yet systematically characterized; a dedicated imaging arm is part of NCT05528744); craniofacial skeleton/soft tissue.
Secondary/associated: Eyes (strabismus, refractive error); ears (low-set position); kidneys (rare renal agenesis); skeletal system (scoliosis, joint hypermobility); immune system (recurrent infection susceptibility); cardiovascular system (implicated in the mouse null model but not established as an ongoing human phenotype); growth/endocrine axis (short stature, feeding difficulty, and — per the 2025 update — obesity/overweight).
Body systems: Nervous system, craniofacial/skeletal system, ophthalmological system, immune system, growth/endocrine system, and (in the null-mouse model only) cardiovascular system.
Tissue/cell level: cortical excitatory and inhibitory neurons, radial glial neural progenitors, hippocampal CA1 neurons, medial prefrontal cortex neurons (mouse knockdown model), vascular smooth muscle (mouse null model).
Subcellular level: synapse (postsynaptic density — PSD-95/GluN2A/GluA1 reduction); mitochondria (respiratory chain complex II downregulation); nucleus/cytoplasm/membrane (ANKRD17's own subcellular localization per GeneCards/UniProt).
Suggested ontology terms: UBERON:0000955 (brain); UBERON:0002037 (cerebellum, relevant to the cerebellar hypoplasia noted in the 2025 fetal case); UBERON:0001954 (Ammon's horn/CA1); UBERON:0002316 (prefrontal cortex region approximation); CL:0002608 (radial glial cell); CL:0000359 (vascular smooth muscle cell); GO:0005739 (mitochondrion, cellular component); GO:0045211 (postsynaptic membrane).
Lateralization: Not applicable/no pattern reported — this is a systemic developmental disorder without lateralized organ involvement.

8. Temporal Development

Onset: Prenatal/congenital in the broadest sense (germline de novo mutation present from conception), but clinically apparent from infancy/early childhood as developmental delay becomes evident; one severe prenatal-onset case (fetus with multiple congenital anomalies including cerebellar hypoplasia and growth retardation) has been reported (Xia et al. 2025), indicating the phenotypic range extends to prenatally lethal/severe presentations.
Onset pattern: Insidious/developmental rather than acute — a static developmental encephalopathy pattern is most consistent with the described natural history, though epilepsy onset can occur any time from the neonatal period to age 15 (mean 4.4 years).
Progression: No evidence of a degenerative/progressive course for the core neurodevelopmental phenotype; described features are stable developmental differences rather than regression. Epilepsy, when present, is generally non-progressive and often becomes well controlled with monotherapy over time.
Disease course pattern: Chronic, lifelong, non-remitting developmental disability of variable severity (borderline to severe-profound); epilepsy course is described as "relatively benign."
Critical periods: Neurodevelopmental vulnerability is inferred to center on early corticogenesis (based on ANKRD17/CDK2/YAP1 co-expression in radial glial progenitors during human telencephalic development), but no clinical intervention-timing data yet exist.
Age range reported in the literature: founding cohort spanned 4 months to 34 years, indicating the phenotype is recognizable and has been documented from infancy through adulthood.

9. Inheritance and Population

Epidemiology: CAGS is an ultra-rare disorder; fewer than 40 individuals were reported in the literature by 2023, with more recent aggregate cohorts (2025 conference presentations) citing up to ~47–55 characterized individuals and lay/registry sources suggesting >100 total diagnoses worldwide by 2025 as awareness and diagnostic sequencing access have increased. No formal population-based prevalence or incidence estimate (cases per 100,000) has been published; this is consistent with a condition still being ascertained primarily through clinical exome/genome sequencing in developmental-delay cohorts rather than through population screening.
Inheritance pattern: Autosomal dominant (AD).
De novo rate: The overwhelming majority of cases are de novo. The founding cohort documented one familial transmission (an affected mother and her affected son) and one pair of monozygotic female twins, demonstrating that germline/gonadal transmission and full penetrance in an identical genetic background are both possible, though rare in the reported cohort.
Penetrance: Appears to be high/complete for the core developmental-delay/speech phenotype based on reported cases (no confirmed non-penetrant carriers have been described in the literature to date, though ascertainment bias toward symptomatic probands limits this conclusion).
Expressivity: Markedly variable — severity ranges from borderline/mild intellectual disability to severe-profound disability, and dysmorphic/systemic features (epilepsy, infections, growth, ophthalmological, skeletal) are present in only a subset of cases, indicating substantial variable expressivity even among carriers of similar (truncating) variant types.
Genetic anticipation: Not applicable/not reported — this is not a repeat-expansion disorder.
Germline mosaicism: GeneReviews explicitly notes that if the proband's variant is not found in either parent's blood, sibling recurrence risk remains slightly elevated above general population risk due to the possibility of parental germline mosaicism — standard AD de novo genetic-counseling guidance.
Founder effects: None reported; variants identified to date are private (unique per family) rather than recurrent founder alleles.
Consanguinity: Not implicated (AD, predominantly de novo mechanism).
Carrier frequency: Not applicable in the traditional sense for an AD de novo disorder (there is no "carrier" state distinct from being affected, given the described high penetrance).
Genotype-phenotype correlation (2025 update): A statistically significant difference in mean phenotype/hemi-severity score (HSS) was found across four variant classes (splice-site, other LOF, missense, multi-gene deletion); missense variants trended toward greater severity, reaching statistical significance specifically against splice-site variants. Within missense variants, those affecting the C-terminus or invariant ankyrin-repeat residues trended toward greater severity than other missense variants. No sex-based difference in severity was found.
Population demographics: No ethnic, geographic, or ancestry-specific enrichment has been reported; cases have been described from North America, Europe, and East Asia (e.g., the Georgian case report, PMID: 37456926, and the Chinese case report, DOI: 10.3389/fgene.2024.1422469), consistent with a pan-ethnic de novo disorder.
Sex ratio: Founding cohort was 19 females:15 males; the 2025 genotype-phenotype study found no severity difference by sex — overall the disorder appears to affect both sexes roughly equally, consistent with autosomal (not X-linked) inheritance.

10. Diagnostics

Primary diagnostic modality: Molecular genetic testing — exome sequencing (ES) or genome sequencing (GS), typically as a trio (proband + parents) to establish de novo status, is the standard diagnostic approach given the lack of a single characteristic "gestalt" sufficient for clinical diagnosis alone and the private nature of each variant. Chromosomal microarray (CMA) can detect the rarer 4q13.3 microdeletion cases. Single-gene sequencing of ANKRD17 is possible once suspected but is not typically the first-tier test given the nonspecific overlapping phenotype.
Clinical/laboratory tests: No specific biomarker, enzyme assay, or metabolic screening test exists; this is not a biochemically detectable disorder.
Imaging: Brain MRI is recommended as part of the diagnostic workup given nonspecific structural brain abnormalities reported in some patients (formal MRI phenotyping is a stated objective of the ongoing NCT05528744 natural history study, but a systematized neuroimaging phenotype has not yet been published in detail).
Electrophysiology: EEG indicated for patients with seizures; ictal abnormalities were found in 9/24 and interictal in 7/24 of the epilepsy sub-cohort.
Genetic testing hierarchy: ES/GS trio-based analysis (first-tier for undiagnosed developmental delay in current practice generally, applicable here); CMA for deletion detection; targeted single-gene ANKRD17 sequencing once a phenotype-driven suspicion exists (e.g., via the GeneReviews chapter's suggested clinical criteria).
Standardized diagnostic criteria: No formal consensus clinical diagnostic criteria (akin to DSM/ICD operational criteria) have been published; diagnosis is molecular, confirmed by identification of a heterozygous pathogenic/likely pathogenic ANKRD17 variant in the context of a compatible phenotype.
Differential diagnosis: Given the phenotypic overlap with numerous other neurodevelopmental syndromes, GeneReviews lists differential considerations including Down syndrome, Pierre Robin sequence (isolated), and other genetically distinct developmental-delay/dysmorphism syndromes; broadly, CAGS sits within the large differential of "exome-first" neurodevelopmental disorders and is distinguished definitively only by molecular confirmation.
Screening: No population or newborn screening program exists or is applicable (private de novo variants, no biochemical screening analyte).

11. Outcome / Prognosis

Survival/mortality: No formal survival statistics (5-year/10-year survival, standardized mortality ratio) have been published; the disorder as characterized in living cohorts is not associated with premature mortality in the literature to date, though the reported prenatal/fetal case with multiple severe congenital anomalies (Xia et al. 2025) illustrates that the severe end of the phenotypic spectrum can be life-limiting in utero.
Morbidity/function: Variable, ranging from borderline learning difficulties to severe-profound intellectual disability with need for lifelong multidisciplinary care; gait/balance disturbance and dysphagia (2025 update) suggest functional mobility and feeding-related morbidity in a subset.
Quality of life measures: No published disease-specific or generic (EQ-5D/SF-36/PROMIS) QOL data yet.
Complications: Recurrent bacterial/viral infections in roughly a third of patients; rare renal agenesis; rare cerebral hemorrhage (2025 update, not yet quantified); epilepsy (managed medically in the majority).
Recovery potential: As a static developmental disorder, "recovery" in the traditional sense is not expected; developmental therapies aim to maximize functional trajectory rather than reverse an underlying degenerative process.
Prognostic factors: The 2025 genotype-phenotype analysis suggests variant type (missense, especially C-terminal or invariant-repeat-residue missense) trends toward a more severe phenotype than truncating/splice-site variants, offering an early basis for genotype-informed prognostic counseling, though this remains a trend rather than a validated predictive model.
Prognostic biomarkers: None established.

12. Treatment

There is no disease-modifying or curative therapy; management is entirely supportive/symptomatic and multidisciplinary, consistent with GeneReviews guidance.

Pharmacotherapy: Anti-seizure medications for the subset with epilepsy — the epilepsy phenotype study found the majority achieve control with monotherapy (10/24), and seizures are generally infrequent (54% experience seizures less than annually), with only ~21% (5/24) meeting drug-resistant epilepsy criteria. No CAGS-specific pharmacogenomic guidance exists. Suggested NCIT term: NCIT:C15986 (Pharmacotherapy) as the general action term, with specific anti-seizure agents added as therapeutic_agent per individual case reports (agent-level detail not systematically reported in aggregate).
Advanced therapeutics: No gene therapy, cell therapy, RNA-based therapy, targeted therapy, or immunotherapy has been developed or trialed for CAGS; given the haploinsufficiency mechanism, an allele-restoring approach (e.g., AAV-mediated gene supplementation) is theoretically conceivable but has not been reported even preclinically for this specific gene/disorder.
Surgical/interventional: Cleft palate repair for the subset with Pierre Robin sequence/cleft palate (NCIT:C15329, Surgical Procedure category); management of renal agenesis as clinically indicated in rare cases.
Supportive/rehabilitative care (core of management): Physical therapy (NCIT:C15302), occupational therapy (NCIT:C121351), and speech-language therapy (NCIT:C159273) are central given the disproportionate speech impairment and motor/gait involvement; nutritional/feeding support (NCIT:C15447, Dietary Intervention) for feeding difficulties; ophthalmological monitoring and correction (glasses/strabismus surgery) for refractive error and strabismus; genetic counseling (NCIT:C15240) for families.
Experimental/clinical trials: No therapeutic clinical trials exist. The only registered study is the observational natural history study NCT05528744 (Boston Children's Hospital, "Delineating the Molecular Spectrum and the Clinical, Imaging and Neuronal Phenotype of Chopra-Amiel-Gordon Syndrome"), which is a registry/biosample (including iPSC generation) study, not an interventional trial — important to distinguish when curating clinical_trials entries (phase would be NOT_APPLICABLE, an observational study).
Surveillance (per GeneReviews): At each visit — assessment of developmental progress, educational needs, seizure activity, tone/movement changes, growth, nutrition/feeding status, and family psychosocial needs; annual or as-needed assessment of behavioral and musculoskeletal manifestations (e.g., scoliosis, joint hypermobility).
Treatment algorithms/combination therapy/personalized medicine: None established beyond general developmental-disorder multidisciplinary care pathways; the emerging genotype-severity correlation (missense vs. truncating) could eventually inform anticipatory/personalized surveillance intensity, but this is not yet formalized into any published algorithm.

13. Prevention

As a predominantly de novo monogenic disorder, primary prevention in the population-health sense is not applicable.

Primary prevention: Not applicable (de novo mutation, not preventable by lifestyle/exposure modification).
Secondary prevention: Prenatal diagnosis is possible once a familial variant is known (relevant for the rare familial transmission case and for recurrence-risk counseling after germline mosaicism); no population-based screening program exists given the ultra-rare, non-recurrent (private-variant) nature of the disorder.
Genetic counseling: Central prevention/planning tool — recurrence risk to siblings of a proband with an apparently de novo variant is low but slightly above general-population risk (germline mosaicism); risk to offspring of an affected individual is 50% (autosomal dominant), as demonstrated by the one reported affected mother-son transmission.
Screening/risk stratification: Not applicable at a population level; clinically, ES/GS-based diagnosis in children presenting with developmental delay and the described dysmorphism functions as the practical "detection" pathway.
Prophylaxis: No specific prophylactic medications indicated; management of recurrent infection susceptibility follows general pediatric infectious-disease supportive care rather than a CAGS-specific prophylactic regimen (not described in the literature).

14. Other Species / Natural Disease

Taxonomy of model/comparative species used: Mouse (Mus musculus, NCBITaxon:10090); Drosophila melanogaster (NCBITaxon:7227, ortholog studies of Mask); human (NCBITaxon:9606).
Orthologous gene: Ankrd17 (mouse, MGI ortholog); Mask (Drosophila ortholog — "Multiple Ankyrin repeats Single KH domain").
Natural disease in other species: No naturally occurring veterinary/companion-animal disease attributable to spontaneous ANKRD17 loss-of-function has been reported (unlike many single-gene disorders with recognized breed-specific veterinary counterparts in OMIA); all animal data derive from engineered (knockout/knockdown) models rather than naturally occurring disease.
Comparative biology: The vascular-integrity role of ANKRD17 (embryonic lethality with hemorrhage in complete mouse knockout) and the Hippo-pathway growth-regulatory role of Drosophila Mask indicate deep evolutionary conservation of ANKRD17/Mask function in tissue growth and vascular development across bilaterians, providing mechanistic continuity between invertebrate growth-control biology and the human neurodevelopmental phenotype (though the human disorder is a heterozygous partial-loss state, not the complete loss modeled in these systems).
Zoonotic potential/transmission: Not applicable — this is a non-infectious, non-transmissible genetic disorder.

15. Model Organisms

Model	Type	Key findings	Citation
Complete Ankrd17 knockout mouse	Genetic (constitutive KO)	Embryonic lethal E10.5–E11.5; severe hemorrhage; drastically reduced vascular smooth muscle cells surrounding vessels; incomplete vascular maturation	Hou et al., FEBS Lett 2009
AAV-mediated Ankrd17 knockdown mouse (mPFC and hippocampal CA1)	Induced/regional knockdown (haploinsufficiency-mimicking)	Reduced GluN2A (NMDAR subunit), GluA1 (AMPAR subunit), PSD-95, Synapsin I in cortex/hippocampus; behavioral deficits in three-chamber social test, open-field (anxiety), Y-maze (spatial learning/memory); mitochondrial respiratory chain complex II gene downregulation (Sdha/Sdhb/Sdhc) confirmed by qPCR; proteomics (5D label-free) on mouse tissue and postmortem human embryonic brain showing 21.1% of differentially expressed proteins mitochondrially localized	Xia et al., J Neurodev Disord 2025 (PMID: 40604385)
Drosophila Mask (ortholog) mutant/RNAi	Genetic (invertebrate)	Mask functions as a co-factor of Yorkie in the Hippo pathway; required for tissue growth, specifically eye and wing growth in loss-of-function studies (cited by Chopra et al. 2021 as supportive homology evidence, not newly generated data in that paper)	Cited in Chopra et al., AJHG 2021 (original Mask functional studies predate the CAGS description)
Human patient iPSC-derived neurons	Planned/in-progress human cellular model	Patient-specific iPSC lines and isogenic controls for neuronal reprogramming and phenotyping — explicitly planned to "bridge the knowledge gap on the biological underpinnings of the disorder"	NCT05528744 (Boston Children's Hospital natural history study, ongoing)

Model limitations: No published model to date fully recapitulates the heterozygous, partial-loss-of-function human genotype in a way that captures the full spectrum of human craniofacial dysmorphism, speech-specific impairment, or immune phenotype; the complete-knockout mouse models total absence (embryonic lethal, not directly comparable to the surviving heterozygous human state), while the AAV-knockdown model targets only two adult brain regions rather than the developmental, whole-organism haploinsufficiency state present from conception in patients. No zebrafish model of ANKRD17 loss was identified in the literature search performed for this report — this appears to be a genuine gap rather than an omission (worth noting explicitly per the reporting instructions for unavailable information).

Summary of Ontology Term Suggestions

MONDO: MONDO:0859186 (as given/confirmed)
OMIM: 619504 (phenotype), *615929 (gene)
HGNC: ANKRD17 (verify exact HGNC ID via direct HGNC lookup before binding — not independently confirmed in this session)
Key HP terms: HP:0001263, HP:0001249, HP:0000750, HP:0001270, HP:0000717, HP:0007018, HP:0001288, HP:0001250, HP:0002121, HP:0002069, HP:0011097, HP:0000325, HP:0009890, HP:0000219, HP:0000486, HP:0000539, HP:0004325, HP:0003510, HP:0011968, HP:0001382, HP:0002719, HP:0002650, HP:0000104, HP:0001513, HP:0002015
GO terms (biological process): GO:0035329 (hippo signaling), GO:0000082 (G1/S transition of mitotic cell cycle), GO:0032495 (NOD1/NOD2 response), GO:0022008 (neurogenesis), GO:0007416 (synapse assembly), GO:0022904 (respiratory electron transport chain)
CL terms: CL:0002608 (radial glial cell), CL:0000359 (vascular smooth muscle cell), CL:0000099 (interneuron)
UBERON terms: UBERON:0000955 (brain), UBERON:0002037 (cerebellum), UBERON:0001954 (Ammon's horn)
NCIT treatment terms: NCIT:C15986 (Pharmacotherapy), NCIT:C15302 (Physical Therapy), NCIT:C121351 (Occupational Therapy), NCIT:C159273 (Speech Therapy), NCIT:C15329 (Surgical Procedure), NCIT:C15447 (Dietary Intervention), NCIT:C15240 (Genetic Counseling)

All ontology term suggestions above are model-generated leads only — per this repository's Ontology Term Contract, each must be independently looked up (via runoak/OAK or the relevant cache/<prefix>/terms.csv) at the moment it is written into KB YAML; none should be bound from this report without a fresh verification step.

Key Sources

Flagged gaps/uncertainties for curator follow-up: (1) exact Orphanet ORPHA code unverified directly; (2) no zebrafish model found; (3) no episignature/epigenetic study published; (4) no dedicated QOL instrument data; (5) full GeneReviews percentage table (Table 2) could not be directly fetched (blocked by bot verification) — the frequencies cited above were cross-validated from the primary AJHG paper and the 2025 follow-up abstract instead.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	7
Resolved	7
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	7
On topic	6
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	66
Resolved	63
Unresolved (possible confabulation)	0
Obsolete	2
Unverifiable	1
Terms whose name was checked	39
Terms named correctly	25
Terms named as a different term	6
Terms whose name is worth a second look	8

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0859186 (3 mentions) - the report calls it "matches the target ID given"; MONDO calls it Chopra-Amiel-Gordon syndrome
HP:0004325 (2 mentions) - the report calls it "Postnatal growth failure"; HP calls it Decreased body weight
GO:0032495 (2 mentions) - the report calls it "NOD1/NOD2 response"; GO calls it response to muramyl dipeptide
CL:0002608 (3 mentions) - the report calls it "Cell types implicated: radial glial progenitors", "radial glial cell"; CL calls it hippocampal neuron**
UBERON:0002037 (2 mentions) - the report calls it "cerebellum, relevant to the cerebellar hypoplasia noted in the 2025 fetal case", "cerebellum"; UBERON calls it cerebellum
UBERON:0002316 (1 mention) - the report calls it "prefrontal cortex region approximation"; UBERON calls it white matter

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0039528 (GO_0039528) (1 mention) - replaced by GO:0002753
CL:0008030 (obsolete excitatory neuron) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0002121 (2 mentions) - the report calls it "Generalized absence seizure"; HP calls it Generalized non-motor (absence) seizure
HP:0002069 (2 mentions) - the report calls it "Generalized tonic-clonic seizure"; HP calls it Bilateral tonic-clonic seizure
HP:0000601 (1 mention) - the report calls it "deep-set eyes"; HP calls it Hypotelorism, and lists "Closely spaced eyes" among its other names
HP:0003510 (2 mentions) - the report calls it "Short stature"; HP calls it Severe short stature
CL:0000359 (3 mentions) - the report calls it "vascular smooth muscle cell"; CL calls it vascular associated smooth muscle cell, and lists "vascular smooth muscle cell" among its other names
UBERON:0001954 (2 mentions) - the report calls it "Ammon's horn/CA1", "Ammon's horn"; UBERON calls it Ammon's horn
GO:0005739 (1 mention) - the report calls it "mitochondrion, cellular component"; GO calls it mitochondrion
NCIT:C159273 (2 mentions) - the report calls it "Speech Therapy"; NCIT calls it Speech Language Therapy

Terms named inconsistently

The report gives these identifiers more than one name of its own:

CL:0002608 - called "Cell types implicated:** radial glial progenitors", "radial glial cell"
UBERON:0002037 - called "cerebellum, relevant to the cerebellar hypoplasia noted in the 2025 fetal case", "cerebellum"
UBERON:0001954 - called "Ammon's horn/CA1", "Ammon's horn"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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References & Deep Research

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Deep Research

Chopra-Amiel-Gordon Syndrome (ANKRD17-Related Neurodevelopmental Syndrome): Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

Neurodevelopmental (most penetrant domain)

Craniofacial dysmorphism

Ophthalmological

Growth

Musculoskeletal

Immune

Rare/emerging (2025 update; not yet quantified with confidence)

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Proposed causal chain (largely inferential; direct patient-derived functional data are still forthcoming from NCT05528744's iPSC program)

Summary by category

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Ontology Term Suggestions

Key Sources

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver