ARF3-related Neurodevelopmental Disorder

Mendelian MONDO:0700366 Pathograph 19 Show in embeddings browser Mendelian neurodevelopmental disorder Golgipathy

ARF3-related neurodevelopmental disorder is a rare Golgipathy caused by heterozygous de novo missense variants in ARF3, which encodes a class I ADP-ribosylation factor small GTPase that works mainly at the trans-Golgi network, where it recruits coat and adaptor proteins to budding carrier vesicles and supports endosomal recycling. Affected children show developmental delay or intellectual disability of variable severity together with brain anomalies; microcephaly (congenital or postnatal) and progressive cerebral atrophy occur in most, and epilepsy, thin or hypoplastic corpus callosum, white matter reduction, pontocerebellar and brainstem hypoplasia and skeletal defects (scoliosis, rib anomalies) occur variably. Most variants sit in or near the guanine nucleotide binding pocket and act dominantly, either as dominant-negative (GDP-locked-like) or as activating (GTP-locked-like) alleles, and both classes fragment the Golgi; the dominant-negative class is associated with the most severe disease. Around a dozen affected individuals have been reported.

Ask OpenScientist

Ask a research question about ARF3-related Neurodevelopmental Disorder. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
7
Pathophys.
25
Phenotypes
19
Pathograph
1
Genes
4
Variants
2
Models
1
Deep Research
👪

Inheritance

1
Autosomal dominant, de novo HP:0000006
All reported variants arose de novo in heterozygous individuals. Expression of the variants in zebrafish reproduces the human phenotype while knockdown of the endogenous arf3 paralogs produces only a milder, dose-dependent phenotype with no severely affected embryos, which points to a dominant (dominant-negative or activating) mechanism rather than haploinsufficiency.
Autosomal dominant inheritance
Show evidence (3 references)
PMID:36369169 SUPPORT Human Clinical
"We report that de novo missense variants in ARF3, encoding a small GTPase regulating Golgi dynamics, cause a developmental disease in humans impairing nervous system and skeletal formation."
Establishes de novo heterozygous missense variants as the cause.
PMID:34346499 SUPPORT Human Clinical
"We here report the clinical and genetic evaluations of two unrelated children with de novo pathogenic variants in the ARF3 gene: c.200A > T (p.Asp67Val) and c.296G > T (p.Arg99Leu)."
Independent report of de novo ARF3 variants in two unrelated children.
PMID:36369169 SUPPORT Model Organism
"Disease modeling in zebrafish validates further the dominant behavior of the mutants and their differential impact on brain and body plan formation, recapitulating the variable disease expression."
Zebrafish expression of the patient alleles supports a dominant mode of action.
⚙

Pathophysiology

7
ARF3 Missense Variant
Heterozygous de novo missense variants in ARF3. With the exception of Leu12, the affected residues (Thr32, Pro47, Asp67, Asp93, Arg99, Lys127) cluster in or near the guanine nucleotide binding pocket, including the switch 1 region and the NKXD motif, at positions whose equivalents in other RAS-superfamily GTPases are mutated in human disease.
ARF3 hgnc:654 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ARF3 (hgnc:654). hgnc:654 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS
De novo heterozygous missense alleles. The functional class differs by allele, so no single functional_impact_category applies: p.Thr32Asn, p.Lys127Glu and p.Leu12Val/p.Asp67Val behave as dominant-negative or destabilised alleles with reduced GTP-bound protein, while p.Asp93Asn, p.Pro47Ser and p.Arg99Leu behave as activating alleles.
GTPase activity GO:0003924 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves dysregulated GTPase activity (GO:0003924). GO:0003924 is a molecular function from the Gene Ontology. GTP binding GO:0005525 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves dysregulated GTP binding (GO:0005525). GO:0005525 is a molecular function from the Gene Ontology.
Downstream
Dysregulated ARF3 GTP/GDP Cycling Pocket-region substitutions alter nucleotide binding and protein stability.
Show evidence (1 reference)
PMID:36369169 SUPPORT In Vitro
"Microcephaly-associated ARF3 variants affect residues within the guanine nucleotide binding pocket and variably perturb protein stability and GTP/GDP binding."
Locates the disease variants in the nucleotide-binding pocket.
Dysregulated ARF3 GTP/GDP Cycling
ARF3 cycles between an inactive GDP-bound and an active, membrane-bound GTP-bound form under the control of ARF guanine nucleotide exchange factors and GTPase-activating proteins. The disease variants push this switch in one of two directions: some lower the GTP-bound fraction and destabilise the protein (dominant-negative behaviour), while others stabilise the GTP-bound conformation or increase effector binding (activating behaviour), as shown for increased GGA1 adaptor binding by p.Arg99Leu.
GTPase activity GO:0003924 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves dysregulated GTPase activity (GO:0003924). GO:0003924 is a molecular function from the Gene Ontology. GTP binding GO:0005525 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves dysregulated GTP binding (GO:0005525). GO:0005525 is a molecular function from the Gene Ontology.
Animal models
Drosophila expressing human ARF3 variants Fruit fly perturbs Organism-level readouts (lethality, eye morphology) that classify each allele's functional direction.
Downstream
Golgi Fragmentation and COPI Vesicle Dysregulation Both dominant-negative and activating alleles disrupt Golgi morphology, producing distinct fragmentation patterns that resemble those of the classical GDP-locked and GTP-locked ARF mutants.
Show evidence (4 references)
PMID:36456556 SUPPORT REVIEW SYNTHESIS In Vitro
"Interestingly, most variants target the GDP/GTP binding pocket of ARF3 by which ARF Guanine Nucleotide Exchange Factors (ARFGEFs) and ARF GTPase Activating Proteins (ARFGAPs) control its activation state, and these de novo variants appear to induce either blockage or maintenance of ARF3 activation."
Summarises the two opposite effects of the variants on the ARF3 activation switch.
PMID:20357002 SUPPORT INDIRECT In Vitro
"Unlike other Golgi-localized Arfs, Arf3 associates selectively with membranes of the trans-Golgi network (TGN) in a manner that is both temperature-sensitive and uniquely dependent on guanine nucleotide exchange factors of the BIGs family."
Background on the normal GEF-dependent recruitment of ARF3 to the TGN, the activation step the disease variants disturb.
PMID:36369169 SUPPORT In Vitro
"Altogether, these data suggest a stabilized GTP-bound conformation and an overall hyperactive behavior for ARF3D93N and, to a minor extent, ARF3P47S, while a DN behavior could be established for the ARF3T32N variant."
Biochemical classification of individual alleles as activating or dominant-negative.
+ 1 more reference
Golgi Fragmentation and COPI Vesicle Dysregulation
Cells expressing the variants lose normal trans-Golgi integrity. Strongly dominant-negative alleles (p.Lys127Glu, p.Leu12Val/p.Asp67Val) disassemble COPI vesicles, whereas activating alleles (p.Pro47Ser, p.Asp93Asn) expand the COPI compartment. Golgi fragmentation is also seen in zebrafish embryos expressing the variants.
Golgi organization GO:0007030 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Golgi organization (GO:0007030). GO:0007030 is a biological process from the Gene Ontology. Golgi vesicle transport GO:0048193 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated Golgi vesicle transport (GO:0048193). GO:0048193 is a biological process from the Gene Ontology.
Animal models
Zebrafish expressing human ARF3 disease variants Zebrafish recapitulates Golgi integrity is disrupted in embryos expressing the variants.
Downstream
Impaired Endocytic Cargo Recycling Alongside the structural effect on the Golgi, the variants impair the post-Golgi role of ARF3 in recycling cargo through endosomes. The source presents the two as parallel consequences of the variants, so a causal dependence of the recycling defect on Golgi fragmentation is inferred.
Aberrant Mitotic Spindle and Reduced Neural Precursor Proliferation The Golgi contributes to spindle formation and cell-cycle progression; altered spindle morphology was seen in the forebrain of zebrafish expressing microcephaly-causing variants. Which Golgi function links the two has not been established.
Defective Planar Cell Polarity-dependent Convergent Extension Golgi trafficking of polarity factors is needed for planar cell polarity; the earliest axial effect of the variants in zebrafish is impaired PCP-dependent cell motility.
Cerebral white matter atrophy Zebrafish expressing the variants show reduced telencephalic white matter, which the authors read as the model counterpart of the white matter loss in patients.
Show evidence (3 references)
PMID:36369169 SUPPORT In Vitro
"Functional analysis demonstrates variably disruptive consequences of ARF3 variants on Golgi morphology, vesicles assembly and trafficking."
Direct evidence of disrupted Golgi morphology and vesicle assembly in cells expressing the variants.
PMID:36369169 SUPPORT In Vitro
"Differently, a large number of cells expressing ARF3P47S and ARF3D93N showed an expanded β-COP signal, which is indicative of an enlarged COP-I compartment."
Shows the expanded COPI compartment produced by the activating alleles.
PMID:41507605 SUPPORT Model Organism
"ARF3 mutants significantly affected Golgi integrity in vivo as well as brain size, recapitulating patients' microcephaly."
Confirms Golgi disruption in vivo in zebrafish for newly identified variants.
Impaired Endocytic Cargo Recycling
ARF3 preferentially localises to the trans-Golgi network and is specifically involved in endosomal recycling. Cells expressing the variants associated with early-onset microcephaly and severe skeletal disease show accumulation and delayed recycling of transferrin, and most variants (not p.Pro47Ser) increase transferrin delivery to lysosomes. The contribution of this recycling defect to the brain phenotype in vivo has not been tested.
endocytic recycling GO:0032456 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased endocytic recycling (GO:0032456). GO:0032456 is a biological process from the Gene Ontology.
Show evidence (2 references)
PMID:36369169 SUPPORT In Vitro
"Of note, our experiments with fluorescently labeled Tfn in combination with staining for EE, RE, and lysosomes unravel a cargo accumulation and delayed recycling in cells expressing ARF3 mutants specifically leading to early-onset microcephaly and severe skeletal defects."
Direct cell-based evidence of delayed transferrin recycling with the severe alleles.
PMID:36456556 SUPPORT REVIEW SYNTHESIS In Vitro
"ARF1 share 96% aminoacid identity with ARF3 and it is assumed that their functions are partially interchangeable throughout the GC although studies have shown that ARF3 preferentially localizes to the TGN and is more specifically involved in the endosomal recycling pathway while ARF1 functions..."
Background on the normal TGN and recycling role of ARF3 that the variants disturb.
Aberrant Mitotic Spindle and Reduced Neural Precursor Proliferation
In the forebrain proliferative zone of zebrafish expressing the variants, mitotic precursors are reduced and accumulate in early mitosis, spindles are abnormally elongated, and proliferating cells are mispositioned. Impaired neural precursor proliferation is the earliest brain effect detected.
neural progenitor cell CL:0011020 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural progenitor cell (CL:0011020). CL:0011020 is a cell type from the Cell Ontology.
neural precursor cell proliferation GO:0061351 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neural precursor cell proliferation (GO:0061351). GO:0061351 is a biological process from the Gene Ontology. mitotic spindle organization GO:0007052 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal mitotic spindle organization (GO:0007052). GO:0007052 is a biological process from the Gene Ontology.
Animal models
Zebrafish expressing human ARF3 disease variants Zebrafish recapitulates Reduced mitotic precursors and abnormal spindles in the forebrain proliferative zone.
Downstream
Increased Neural Precursor Cell Death Precursors that fail to progress through mitosis are proposed to be removed by mitotic surveillance, depleting the progenitor pool.
Show evidence (2 references)
PMID:36369169 SUPPORT Model Organism
"In-depth in vivo analyses traces back impaired neural precursors' proliferation and planar cell polarity-dependent cell movements as the earliest detectable effects."
Identifies impaired neural precursor proliferation as an earliest in vivo effect.
PMID:36369169 SUPPORT Model Organism
"The number of pH3+ cells within this region was significantly reduced in embryos expressing ARF3K127E; a similar trend was observed for ARF3L12V/D67V and ARF3D93N expressing fish"
Quantitative reduction of mitotic precursors in the forebrain proliferative zone.
Increased Neural Precursor Cell Death
Cell death is increased in the developing forebrain of zebrafish expressing the most severe alleles (p.Lys127Glu, p.Leu12Val/p.Asp67Val), and over a wider forebrain area for p.Pro47Ser and p.Asp93Asn, depleting the precursor pool available for brain growth.
neural progenitor cell CL:0011020 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural progenitor cell (CL:0011020). CL:0011020 is a cell type from the Cell Ontology.
cell death GO:0008219 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell death (GO:0008219). GO:0008219 is a biological process from the Gene Ontology.
Animal models
Zebrafish expressing human ARF3 disease variants Zebrafish recapitulates Forebrain cell death and reduced head size in embryos expressing the severe alleles.
Downstream
Microcephaly Loss of neural precursors reduces brain growth; the severity of the fish head-size defect tracks the severity of microcephaly in the patients carrying the same alleles.
Secondary microcephaly The activating p.Asp93Asn allele produces late-onset microcephaly in fish, matching the postnatal microcephaly of the patient carrying it.
Show evidence (1 reference)
PMID:36369169 SUPPORT Model Organism
"The analysis showed a significant increase of AO+ spots (i.e., dying cells and/or apoptotic bodies) in ARF3K127E and ARF3L12V/D67V expressing fish"
Direct measurement of increased forebrain cell death in fish expressing the severe alleles.
Defective Planar Cell Polarity-dependent Convergent Extension
Zebrafish embryos expressing the variants show shortened anterior-posterior axes, abnormal convergence-extension indices and notochord curvatures, which the authors trace to defective planar cell polarity-dependent cell movements. This axial defect is the model correlate of the scoliosis and rib anomalies seen in patients, and its severity tracks the severity of the patients' skeletal involvement.
convergent extension GO:0060026 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal convergent extension (GO:0060026). GO:0060026 is a biological process from the Gene Ontology.
Animal models
Zebrafish expressing human ARF3 disease variants Zebrafish recapitulates Notochord curvatures and convergence-extension defects.
Downstream
Scoliosis The axial defects in fish are proposed as the counterpart of the human skeletal phenotype, with the same alleles most severe in both.
11 pairs of ribs The rib anomaly belongs to the same skeletal involvement that the fish axial defects are proposed to model.
Show evidence (1 reference)
PMID:36369169 SUPPORT Model Organism
"Overall, all mutants except ARF3P47S showed a significantly higher number of notochord curvatures"
Quantified axial (notochord) defects in fish expressing the variants.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for ARF3-related Neurodevelopmental Disorder Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

25
Cardiovascular 1
Congenital heart defect Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital heart defects, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (1 reference)
PMID:36369169 SUPPORT Human Clinical
"inguinal hernia and congenital heart defects (CHD)"
Congenital heart defects in Subject 1; the specific lesion is not stated in the main text.
Digestive 1
Inguinal hernia HP:0000023 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inguinal hernia (HP:0000023). HP:0000023 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36369169 SUPPORT Human Clinical
"inguinal hernia and congenital heart defects (CHD)"
Inguinal hernia in Subject 1.
Head and Neck 3
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36369169 SUPPORT Human Clinical
"Microcephaly and progressive cerebral atrophy occurred in most affected individuals, while epilepsy and skeletal abnormalities were variably documented as associated traits."
Microcephaly in most affected individuals.
PMID:36456556 SUPPORT REVIEW SYNTHESIS Human Clinical
"Most individuals with severe illness display progressive microcephaly, intellectual delay, delayed myelination and epilepsy, as well as scoliosis and thoracic abnormalities"
Commentary synthesising the clinical picture of the severely affected individuals.
Secondary microcephaly HP:0005484 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postnatal microcephaly, annotated with Secondary microcephaly (HP:0005484). HP:0005484 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38712921 SUPPORT Human Clinical
"We present a case study of a patient exhibiting acquired microcephaly along with global developmental delay and drug-resistant epilepsy."
Acquired (postnatal) microcephaly.
PMID:36369169 SUPPORT Human Clinical
"A comparable but less severe condition was also observed in Subject 4 (p.Asp93Asn), who manifested hypotonia, severe DD/ID, delayed speech and language development, post-natal microcephaly, thinning of the corpus callosum as well as milder skeletal defects"
Post-natal microcephaly with the activating p.Asp93Asn allele.
Primary microcephaly HP:0011451 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital microcephaly, annotated with Primary microcephaly (HP:0011451). HP:0011451 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36369169 SUPPORT Human Clinical
"D67V) showing severe microcephaly at birth"
Microcephaly present at birth with the dominant-negative alleles (Subjects 1 and 2).
Musculoskeletal 3
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36369169 SUPPORT Human Clinical
"A comparable but less severe condition was also observed in Subject 4 (p.Asp93Asn), who manifested hypotonia, severe DD/ID, delayed speech and language development, post-natal microcephaly, thinning of the corpus callosum as well as milder skeletal defects"
Hypotonia in Subject 4 (also reported in Subject 2).
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36369169 SUPPORT Human Clinical
"profound DD/ID and skeletal involvement (i.e., 11 rib pairs and severe scoliosis)"
Severe scoliosis in Subject 1.
PMID:36456556 SUPPORT REVIEW SYNTHESIS Human Clinical
"Most individuals with severe illness display progressive microcephaly, intellectual delay, delayed myelination and epilepsy, as well as scoliosis and thoracic abnormalities"
Scoliosis in the severely affected individuals.
11 pairs of ribs HP:0000878 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is 11 pairs of ribs (HP:0000878). HP:0000878 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36369169 SUPPORT Human Clinical
"profound DD/ID and skeletal involvement (i.e., 11 rib pairs and severe scoliosis)"
Eleven rib pairs in Subject 1.
Nervous System 15
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:36369169 SUPPORT Human Clinical
"Here we identify de novo missense ARF3 variants as the molecular event underlying a clinically variable neurodevelopmental disorder characterized by DD/ID and variable CNS defects as common features."
Developmental delay/intellectual disability is a common feature of all reported individuals.
PMID:34346499 SUPPORT Human Clinical
"Although the affected individuals presented commonly with developmental delay, epilepsy and brain abnormalities, there were differences in severity, clinical course and brain lesions."
Developmental delay in both children of the first report.
PMID:38712921 SUPPORT Human Clinical
"We present a case study of a patient exhibiting acquired microcephaly along with global developmental delay and drug-resistant epilepsy."
Global developmental delay in a further patient.
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41507605 SUPPORT BACKGROUND Human Clinical
"We recently identified de novo missense variants affecting the small GTPase ARF3 as the cause of a disorder characterized by developmental delay/intellectual disability, microcephaly, brain atrophy, epilepsy and minor skeletal defects."
Lists intellectual disability among the defining features of the disorder.
Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36369169 SUPPORT Human Clinical
"Subject 3 (p.Pro47Ser) and Subject 5 (p.Thr32Asn) showed the mildest phenotype with DD/ID and delayed (Subject 3) or severely delayed (Subject 5) speech and language development."
Delayed speech even in the mildest cases.
Absent speech HP:0001344 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent speech (HP:0001344). HP:0001344 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36369169 SUPPORT Human Clinical
"Subject 2 (p.Leu12Val; p.Asp67Val) showed microcephaly, profound DD/ID, absence of speech and language development"
Absent speech in a severely affected individual.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epilepsy, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:34346499 SUPPORT Human Clinical
"Although the affected individuals presented commonly with developmental delay, epilepsy and brain abnormalities, there were differences in severity, clinical course and brain lesions."
Epilepsy in both children of the first report.
PMID:36369169 SUPPORT Human Clinical
"Microcephaly and progressive cerebral atrophy occurred in most affected individuals, while epilepsy and skeletal abnormalities were variably documented as associated traits."
Epilepsy is variable in the larger series.
PMID:38712921 SUPPORT Human Clinical
"We present a case study of a patient exhibiting acquired microcephaly along with global developmental delay and drug-resistant epilepsy."
Drug-resistant epilepsy in a p.Asp67Val case.
Cerebral atrophy HP:0002059 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral atrophy (HP:0002059). HP:0002059 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36369169 SUPPORT Human Clinical
"Microcephaly and progressive cerebral atrophy occurred in most affected individuals, while epilepsy and skeletal abnormalities were variably documented as associated traits."
Progressive cerebral atrophy in most affected individuals.
PMID:34346499 SUPPORT Human Clinical
"Therefore, it may not be unreasonable that they showed different clinical features like diffuse brain atrophy (p.Asp67Val) and cerebellar hypoplasia (p.Arg99Leu)."
Diffuse brain atrophy with the p.Asp67Val allele.
Cerebral white matter atrophy HP:0012762 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral white matter atrophy (HP:0012762). HP:0012762 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38712921 SUPPORT Human Clinical
"Brain magnetic resonance imaging revealed distinctive features, including a Z-shaped morphology of the brainstem, volumetric reduction of white matter, diffuse thinning of the corpus callosum, and partial fusion of the cerebellar hemispheres at their most cranial portion."
Volumetric reduction of white matter on MRI.
PMID:36369169 SUPPORT Human Clinical
"progressive diffuse cortical atrophy with diminished hemispheric white matter, thin corpus callosum, progressive pontocerebellar hypoplasia without the involvement of the cerebellar vermis"
Diminished hemispheric white matter in Subject 2.
Delayed CNS myelination HP:0002188 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed CNS myelination (HP:0002188). HP:0002188 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36456556 SUPPORT REVIEW SYNTHESIS Human Clinical
"Most individuals with severe illness display progressive microcephaly, intellectual delay, delayed myelination and epilepsy, as well as scoliosis and thoracic abnormalities"
Commentary lists delayed myelination among the features of severe cases.
Thin corpus callosum HP:0033725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin corpus callosum (HP:0033725). HP:0033725 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36369169 SUPPORT Human Clinical
"Subject 3 also shows early-onset seizures and severe hypoplasia of the anterior part of the temporal lobe associated with hypomyelination and thin corpus callosum"
Thin corpus callosum in Subject 3 (also Subjects 2 and 4).
PMID:38712921 SUPPORT Human Clinical
"Brain magnetic resonance imaging revealed distinctive features, including a Z-shaped morphology of the brainstem, volumetric reduction of white matter, diffuse thinning of the corpus callosum, and partial fusion of the cerebellar hemispheres at their most cranial portion."
Diffuse thinning of the corpus callosum in the case report.
Cerebellar hypoplasia HP:0001321 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar hypoplasia (HP:0001321). HP:0001321 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34346499 SUPPORT Human Clinical
"Therefore, it may not be unreasonable that they showed different clinical features like diffuse brain atrophy (p.Asp67Val) and cerebellar hypoplasia (p.Arg99Leu)."
Cerebellar hypoplasia with the activating p.Arg99Leu allele.
PMID:36369169 SUPPORT Human Clinical
"progressive diffuse cortical atrophy with diminished hemispheric white matter, thin corpus callosum, progressive pontocerebellar hypoplasia without the involvement of the cerebellar vermis"
Progressive pontocerebellar hypoplasia in Subject 2.
Hypoplasia of the brainstem HP:0002365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of the brainstem (HP:0002365). HP:0002365 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36369169 SUPPORT Human Clinical
"severe brainstem hypoplasia particularly affecting the pons"
Severe brainstem hypoplasia in Subject 1.
PMID:38712921 SUPPORT Human Clinical
"This disorder is characterized by global developmental delay and brain malformations, particularly affecting the white matter, cerebellum, and brainstem."
The case report names the brainstem among the regions characteristically malformed; it does not itself specify hypoplasia, which rests on the Subject 1 description.
CNS hypomyelination HP:0003429 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is CNS hypomyelination (HP:0003429). HP:0003429 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36369169 SUPPORT Human Clinical
"Subject 3 also shows early-onset seizures and severe hypoplasia of the anterior part of the temporal lobe associated with hypomyelination and thin corpus callosum"
Hypomyelination in Subject 3.
Ventriculomegaly HP:0002119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lateral ventricular enlargement, annotated with Ventriculomegaly (HP:0002119). HP:0002119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36369169 SUPPORT Human Clinical
"in a girl (Subject 1) with a severe syndromic neurodevelopmental disorder characterized by growth restriction, severe microcephaly, progressive diffuse cortical atrophy, hypoplasia of corpus callosum and other brain anomalies at MRI (i.e., lateral ventricular enlargement, severe brainstem..."
Lateral ventricular enlargement in Subject 1.
Inferior cerebellar vermis hypoplasia HP:0007068 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inferior cerebellar vermis hypoplasia (HP:0007068). HP:0007068 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36369169 SUPPORT Human Clinical
"in a girl (Subject 1) with a severe syndromic neurodevelopmental disorder characterized by growth restriction, severe microcephaly, progressive diffuse cortical atrophy, hypoplasia of corpus callosum and other brain anomalies at MRI (i.e., lateral ventricular enlargement, severe brainstem..."
Inferior vermis hypoplasia in Subject 1.
Z-shaped brainstem Abnormal brainstem morphology HP:0002363 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Z-shaped brainstem, annotated with Abnormal brainstem morphology (HP:0002363). HP:0002363 is a phenotype from the Human Phenotype Ontology.
Coarse binding: no hpo term
Show evidence (1 reference)
PMID:38712921 SUPPORT Human Clinical
"Brain magnetic resonance imaging revealed distinctive features, including a Z-shaped morphology of the brainstem, volumetric reduction of white matter, diffuse thinning of the corpus callosum, and partial fusion of the cerebellar hemispheres at their most cranial portion."
Z-shaped brainstem on MRI, proposed by the authors as a diagnostic clue.
Growth 1
Growth delay HP:0001510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth restriction, annotated with Growth delay (HP:0001510). HP:0001510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36369169 SUPPORT Human Clinical
"in a girl (Subject 1) with a severe syndromic neurodevelopmental disorder characterized by growth restriction, severe microcephaly, progressive diffuse cortical atrophy, hypoplasia of corpus callosum and other brain anomalies at MRI (i.e., lateral ventricular enlargement, severe brainstem..."
Growth restriction in Subject 1.
Other 1
Partial fusion of the cerebellar hemispheres HP:0006899 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Partial fusion of the cerebellar hemispheres, annotated with Fusion of the cerebellar hemispheres (HP:0006899). HP:0006899 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38712921 SUPPORT Human Clinical
"Brain magnetic resonance imaging revealed distinctive features, including a Z-shaped morphology of the brainstem, volumetric reduction of white matter, diffuse thinning of the corpus callosum, and partial fusion of the cerebellar hemispheres at their most cranial portion."
Partial cranial fusion of the cerebellar hemispheres on MRI.
🧬

Genetic Associations

1
ARF3
Gene: ARF3 hgnc:654 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ARF3 (hgnc:654). hgnc:654 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:36369169 SUPPORT Human Clinical
"We report that de novo missense variants in ARF3, encoding a small GTPase regulating Golgi dynamics, cause a developmental disease in humans impairing nervous system and skeletal formation."
Gene-disease report with five individuals and functional validation.
PMID:34346499 SUPPORT Human Clinical
"We here report the clinical and genetic evaluations of two unrelated children with de novo pathogenic variants in the ARF3 gene: c.200A > T (p.Asp67Val) and c.296G > T (p.Arg99Leu)."
Independent gene-disease report.
PMID:41507605 SUPPORT Human Clinical
"Here, we report clinical features of five additional patients and the functional characterization of three novel ARF3 variants."
Five further patients extend the cohort.
Variants (4)
p.Asp67Val Pathogenic
NM_001659.2:c.200A>T, p.Asp67Val. Reported de novo in a child with severe microcephaly, diffuse brain atrophy and epilepsy, again in a patient with acquired microcephaly, drug-resistant epilepsy and a Z-shaped brainstem, and in cis with p.Leu12Val in a further severely affected child. Shows a dispersed cytosolic and Golgi pattern like the dominant-negative p.Thr31Asn mutant, is lethal when expressed in flies, and has reduced GTP-bound levels.
Show evidence (2 references)
PMID:38712921 SUPPORT Human Clinical
"Whole-exome sequencing uncovered a pathogenic variant in the ARF3 gene c.200A>T, p.(Asp67Val)."
Recurrence of the allele in an independent patient, classified pathogenic.
PMID:34346499 SUPPORT In Vitro
"Pull-down assays revealed that the p.Asp67Val had a loss-of-function effect and the p.Arg99Leu variant had increased binding of the adaptor protein, Golgi-localized, γ-adaptin ear-containing, ARF-binding protein 1 (GGA1), supporting the gain of function."
Functional evidence of a loss-of-function effect.
p.Arg99Leu
NM_001659:c.296G>T, p.Arg99Leu. Reported de novo in a child with developmental delay, epilepsy and cerebellar hypoplasia. Localises normally to the Golgi but binds GGA1 more strongly and produces a rough eye in flies like the activating p.Gln71Leu mutant, consistent with gain of function.
Show evidence (1 reference)
PMID:34346499 SUPPORT Model Organism
"In contrast, flies expressing p.Arg99Leu had abnormal rough eye, as observed in the gain-of-function variant p.Gln71Leu."
In vivo fly evidence of gain-of-function behaviour.
p.Lys127Glu
NM_001659.2:c.379A>G, p.Lys127Glu, in the NKXD guanine-nucleotide binding motif. Reported de novo in a girl with the most severe phenotype (growth restriction, severe microcephaly, progressive cortical atrophy, pontine hypoplasia, seizures, profound developmental delay, eleven rib pairs, severe scoliosis, inguinal hernia and congenital heart defects). The corresponding Lys127Glu substitution has been reported in ARF1 in a patient with a similar disorder.
Show evidence (2 references)
PMID:36369169 SUPPORT Human Clinical
"trio-based exome sequencing allowed us to identify a previously unreported de novo ARF3 variant, c.379A>G (p.Lys127Glu; NM_001659.2), as the putative disease-causing event in a girl (Subject 1) with a severe syndromic neurodevelopmental disorder"
Identification of the allele in the most severely affected individual.
PMID:36369169 SUPPORT BACKGROUND Human Clinical
"Among these, the same Lys-to-Glu substitution at codon 127 in Subject 1 was recently reported to affect the corresponding residue in ARF1 in a patient with DD, microcephaly, periventricular heterotopia, progressive cerebral atrophy, and epilepsy"
Sources the ARF1 parallel for this allele.
p.Asp93Asn
p.Asp93Asn. Reported de novo in a child with hypotonia, severe developmental delay, postnatal microcephaly, thin corpus callosum and milder skeletal defects. Stabilises the GTP-bound conformation (activating behaviour) and produces late-onset microcephaly in zebrafish.
Show evidence (1 reference)
PMID:36369169 SUPPORT In Vitro
"Altogether, these data suggest a stabilized GTP-bound conformation and an overall hyperactive behavior for ARF3D93N and, to a minor extent, ARF3P47S, while a DN behavior could be established for the ARF3T32N variant."
Classifies p.Asp93Asn as activating.
🔬

Diagnosis

1
Exome sequencing
Diagnosis rests on identifying a de novo heterozygous ARF3 missense variant, in practice by trio exome sequencing, in a child with developmental delay, microcephaly and brain anomalies. A Z-shaped brainstem on MRI has been proposed as a clue that should bring ARF3 into the differential diagnosis.
trio exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:38712921 SUPPORT Human Clinical
"In cases where a Z-shaped morphology of the brainstem is observed, ARF3-associated disorder should be included in the list of differential diagnoses."
Imaging clue for the diagnosis.
PMID:38712921 SUPPORT Human Clinical
"Whole-exome sequencing uncovered a pathogenic variant in the ARF3 gene c.200A>T, p.(Asp67Val)."
Molecular diagnosis by exome sequencing.
🐁

Animal Models

2
Zebrafish expressing human ARF3 disease variants
Transient overexpression of patient alleles in one-cell zebrafish embryos. The model reproduces microcephaly, Golgi fragmentation and axial malformations with an allele-dependent severity matching the patients, while morpholino knockdown of arf3a/arf3b produces a much milder phenotype, supporting a dominant mechanism.
Species
Zebrafish
Genotype
Injection of mRNA encoding human ARF3 missense variants (p.Lys127Glu, p.Leu12Val/p.Asp67Val, p.Pro47Ser, p.Asp93Asn, p.Thr32Asn)
Publication
PMID:36369169
Pathograph links
Increased Neural Precursor Cell Death recapitulates fidelity: moderate observes: tissue Forebrain cell death and reduced head size in embryos expressing the severe alleles.
Limitations: Transient mRNA overexpression in embryos, not a germline knock-in at physiological dosage; zebrafish has two arf3 paralogs and lacks the human cortical progenitor compartments.
Show evidence (1 reference)
PMID:36369169 SUPPORT Model Organism
"Strikingly, similar to patients, overexpression of ARF3K127E and ARF3L12V/D67V produce early-onset severe microcephaly in fish, while fish expressing ARF3D93N show late-onset microcephaly."
The model reproduces the allele-specific microcephaly of the patients.
Defective Planar Cell Polarity-dependent Convergent Extension recapitulates fidelity: moderate observes: tissue Notochord curvatures and convergence-extension defects.
Limitations: Notochord bending in embryos is a developmental correlate of, not the same lesion as, human scoliosis.
Show evidence (1 reference)
PMID:36369169 SUPPORT Model Organism
"Overall, all mutants except ARF3P47S showed a significantly higher number of notochord curvatures"
Axial defects in the model.
Golgi Fragmentation and COPI Vesicle Dysregulation recapitulates fidelity: moderate observes: cellular Golgi integrity is disrupted in embryos expressing the variants.
Limitations: Overexpression on top of endogenous arf3a/arf3b rather than a heterozygous germline allele.
Show evidence (1 reference)
PMID:41507605 SUPPORT Model Organism
"ARF3 mutants significantly affected Golgi integrity in vivo as well as brain size, recapitulating patients' microcephaly."
In vivo Golgi disruption in the model.
Aberrant Mitotic Spindle and Reduced Neural Precursor Proliferation recapitulates fidelity: moderate observes: cellular Reduced mitotic precursors and abnormal spindles in the forebrain proliferative zone.
Limitations: Zebrafish forebrain lacks the human outer subventricular zone progenitor populations, so the proliferative defect may differ in human cortex.
Show evidence (1 reference)
PMID:36369169 SUPPORT Model Organism
"The number of pH3+ cells within this region was significantly reduced in embryos expressing ARF3K127E; a similar trend was observed for ARF3L12V/D67V and ARF3D93N expressing fish"
Reduced precursor proliferation in the model.
Drosophila expressing human ARF3 variants
In vivo expression of the two variants from the first report. p.Asp67Val is lethal, like a loss-of-function allele, while p.Arg99Leu produces a rough eye like the activating p.Gln71Leu mutant, supporting opposite functional classes for the two alleles.
Species
Fruit fly
Genotype
Transgenic expression of human ARF3 p.Asp67Val or p.Arg99Leu
Publication
PMID:34346499
Pathograph links
Dysregulated ARF3 GTP/GDP Cycling perturbs fidelity: low observes: organism Organism-level readouts (lethality, eye morphology) that classify each allele's functional direction.
Limitations: Overexpression in flies reports allele behaviour through lethality and eye roughness, not through any neurodevelopmental or Golgi readout comparable to the human disease.
Show evidence (2 references)
PMID:34346499 SUPPORT Model Organism
"Furthermore, in vivo studies revealed that p.Asp67Val transfection led to lethality in flies."
Lethality in flies for the putative loss-of-function allele.
+ 1 more reference
{ }

Source YAML

click to show 
name: ARF3-related Neurodevelopmental Disorder
creation_date: "2026-10-15T20:00:00Z"
category: Mendelian
description: >-
  ARF3-related neurodevelopmental disorder is a rare Golgipathy caused by
  heterozygous de novo missense variants in ARF3, which encodes a class I
  ADP-ribosylation factor small GTPase that works mainly at the trans-Golgi
  network, where it recruits coat and adaptor proteins to budding carrier
  vesicles and supports endosomal recycling. Affected children show
  developmental delay or intellectual disability of variable severity together
  with brain anomalies; microcephaly (congenital or postnatal) and progressive
  cerebral atrophy occur in most, and epilepsy, thin or hypoplastic corpus
  callosum, white matter reduction, pontocerebellar and brainstem hypoplasia and
  skeletal defects (scoliosis, rib anomalies) occur variably. Most variants sit
  in or near the guanine nucleotide binding pocket and act dominantly, either
  as dominant-negative (GDP-locked-like) or as activating (GTP-locked-like)
  alleles, and both classes fragment the Golgi; the dominant-negative class is
  associated with the most severe disease. Around a dozen affected individuals
  have been reported.
synonyms:
- ARF3-related Golgipathy
- ARF3-associated neurodevelopmental disorder
disease_term:
  preferred_term: ARF3-related neurodevelopmental disorder
  term:
    id: MONDO:0700366
    label: ARF3-related neurodevelopmental disorder
parents:
- Mendelian neurodevelopmental disorder
- Golgipathy
notes: >-
  No GeneReviews or StatPearls chapter exists for this disorder. ClinGen has
  not published a gene-disease validity classification for ARF3, so
  gene_disease_validity is absent. Phenotype frequencies are omitted because the
  reported series are too small to support the frequency bands: two children
  in the first report, five in the second, one further case report, and five
  more patients whose individual features are given only in the full text of
  the 2026 follow-up. No disease-specific treatment has been reported, so the
  treatments section is absent.
inheritance:
- name: Autosomal dominant, de novo
  description: >-
    All reported variants arose de novo in heterozygous individuals. Expression
    of the variants in zebrafish reproduces the human phenotype while knockdown
    of the endogenous arf3 paralogs produces only a milder, dose-dependent
    phenotype with no severely affected embryos, which points to a dominant
    (dominant-negative or activating) mechanism rather than haploinsufficiency.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report that de novo missense variants in ARF3, encoding a small GTPase regulating Golgi dynamics, cause a developmental disease in humans impairing nervous system and skeletal formation."
    explanation: Establishes de novo heterozygous missense variants as the cause.
  - reference: PMID:34346499
    reference_title: "De novo ARF3 variants cause neurodevelopmental disorder with brain abnormality."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We here report the clinical and genetic evaluations of two unrelated children with de novo pathogenic variants in the ARF3 gene: c.200A > T (p.Asp67Val) and c.296G > T (p.Arg99Leu)."
    explanation: Independent report of de novo ARF3 variants in two unrelated children.
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Disease modeling in zebrafish validates further the dominant behavior of the mutants and their differential impact on brain and body plan formation, recapitulating the variable disease expression."
    explanation: Zebrafish expression of the patient alleles supports a dominant mode of action.
pathophysiology:
- name: ARF3 Missense Variant
  biological_scale: MOLECULAR
  description: >-
    Heterozygous de novo missense variants in ARF3. With the exception of
    Leu12, the affected residues (Thr32, Pro47, Asp67, Asp93, Arg99, Lys127)
    cluster in or near the guanine nucleotide binding pocket, including the
    switch 1 region and the NKXD motif, at positions whose equivalents in other
    RAS-superfamily GTPases are mutated in human disease.
  genes:
  - preferred_term: ARF3
    term:
      id: hgnc:654
      label: ARF3
  molecular_functions:
  - preferred_term: GTPase activity
    term:
      id: GO:0003924
      label: GTPase activity
    modifier: DYSREGULATED
  - preferred_term: GTP binding
    term:
      id: GO:0005525
      label: GTP binding
    modifier: DYSREGULATED
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    description: >-
      De novo heterozygous missense alleles. The functional class differs by
      allele, so no single functional_impact_category applies: p.Thr32Asn,
      p.Lys127Glu and p.Leu12Val/p.Asp67Val behave as dominant-negative or
      destabilised alleles with reduced GTP-bound protein, while p.Asp93Asn,
      p.Pro47Ser and p.Arg99Leu behave as activating alleles.
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Microcephaly-associated ARF3 variants affect residues within the guanine nucleotide binding pocket and variably perturb protein stability and GTP/GDP binding."
    explanation: Locates the disease variants in the nucleotide-binding pocket.
  downstream:
  - target: Dysregulated ARF3 GTP/GDP Cycling
    causal_link_type: DIRECT
    description: Pocket-region substitutions alter nucleotide binding and protein stability.
    evidence:
    - reference: PMID:41507605
      reference_title: "Newly identified ARF3 variants strengthen the causal link between Golgi fragmentation and brain malformations."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Cell-based assays corroborate a deleterious, variant-specific effect on protein stability, GTP binding and Golgi morphology."
      explanation: Direct cell-based evidence that the variants change protein stability and GTP binding.
- name: Dysregulated ARF3 GTP/GDP Cycling
  biological_scale: MOLECULAR
  description: >-
    ARF3 cycles between an inactive GDP-bound and an active, membrane-bound
    GTP-bound form under the control of ARF guanine nucleotide exchange factors
    and GTPase-activating proteins. The disease variants push this switch in
    one of two directions: some lower the GTP-bound fraction and destabilise the
    protein (dominant-negative behaviour), while others stabilise the GTP-bound
    conformation or increase effector binding (activating behaviour), as shown
    for increased GGA1 adaptor binding by p.Arg99Leu.
  molecular_functions:
  - preferred_term: GTPase activity
    term:
      id: GO:0003924
      label: GTPase activity
    modifier: DYSREGULATED
  - preferred_term: GTP binding
    term:
      id: GO:0005525
      label: GTP binding
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:36456556
    reference_title: "Golgipathies reveal the critical role of the sorting machinery in brain and skeletal development."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: IN_VITRO
    snippet: "Interestingly, most variants target the GDP/GTP binding pocket of ARF3 by which ARF Guanine Nucleotide Exchange Factors (ARFGEFs) and ARF GTPase Activating Proteins (ARFGAPs) control its activation state, and these de novo variants appear to induce either blockage or maintenance of ARF3 activation."
    explanation: Summarises the two opposite effects of the variants on the ARF3 activation switch.
  - reference: PMID:20357002
    reference_title: "Arf3 is activated uniquely at the trans-Golgi network by brefeldin A-inhibited guanine nucleotide exchange factors."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "Unlike other Golgi-localized Arfs, Arf3 associates selectively with membranes of the trans-Golgi network (TGN) in a manner that is both temperature-sensitive and uniquely dependent on guanine nucleotide exchange factors of the BIGs family."
    explanation: Background on the normal GEF-dependent recruitment of ARF3 to the TGN, the activation step the disease variants disturb.
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Altogether, these data suggest a stabilized GTP-bound conformation and an overall hyperactive behavior for ARF3D93N and, to a minor extent, ARF3P47S, while a DN behavior could be established for the ARF3T32N variant."
    explanation: Biochemical classification of individual alleles as activating or dominant-negative.
  - reference: PMID:34346499
    reference_title: "De novo ARF3 variants cause neurodevelopmental disorder with brain abnormality."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Pull-down assays revealed that the p.Asp67Val had a loss-of-function effect and the p.Arg99Leu variant had increased binding of the adaptor protein, Golgi-localized, γ-adaptin ear-containing, ARF-binding protein 1 (GGA1), supporting the gain of function."
    explanation: Independent biochemical evidence for opposite functional classes among the variants.
  downstream:
  - target: Golgi Fragmentation and COPI Vesicle Dysregulation
    causal_link_type: DIRECT
    description: >-
      Both dominant-negative and activating alleles disrupt Golgi morphology,
      producing distinct fragmentation patterns that resemble those of the
      classical GDP-locked and GTP-locked ARF mutants.
    evidence:
    - reference: PMID:36369169
      reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The Golgi morphotype analysis established the presence of different functional classes of disease-causing ARF3 mutants, broadly ascribing to a DN or CA mechanism."
      explanation: Ties each functional class of variant to a characteristic Golgi morphology.
    - reference: PMID:34346499
      reference_title: "De novo ARF3 variants cause neurodevelopmental disorder with brain abnormality."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These data indicate that two ARF3 variants, the possibly loss-of-function p.Asp67Val and the gain-of-function p.Arg99Leu, both impair the Golgi transport system."
      explanation: Shows that alleles of opposite functional class converge on impaired Golgi transport.
- name: Golgi Fragmentation and COPI Vesicle Dysregulation
  biological_scale: CELLULAR
  description: >-
    Cells expressing the variants lose normal trans-Golgi integrity. Strongly
    dominant-negative alleles (p.Lys127Glu, p.Leu12Val/p.Asp67Val) disassemble
    COPI vesicles, whereas activating alleles (p.Pro47Ser, p.Asp93Asn) expand
    the COPI compartment. Golgi fragmentation is also seen in zebrafish embryos
    expressing the variants.
  biological_processes:
  - preferred_term: Golgi organization
    term:
      id: GO:0007030
      label: Golgi organization
    modifier: ABNORMAL
  - preferred_term: Golgi vesicle transport
    term:
      id: GO:0048193
      label: Golgi vesicle transport
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional analysis demonstrates variably disruptive consequences of ARF3 variants on Golgi morphology, vesicles assembly and trafficking."
    explanation: Direct evidence of disrupted Golgi morphology and vesicle assembly in cells expressing the variants.
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Differently, a large number of cells expressing ARF3P47S and ARF3D93N showed an expanded β-COP signal, which is indicative of an enlarged COP-I compartment."
    explanation: Shows the expanded COPI compartment produced by the activating alleles.
  - reference: PMID:41507605
    reference_title: "Newly identified ARF3 variants strengthen the causal link between Golgi fragmentation and brain malformations."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "ARF3 mutants significantly affected Golgi integrity in vivo as well as brain size, recapitulating patients' microcephaly."
    explanation: Confirms Golgi disruption in vivo in zebrafish for newly identified variants.
  downstream:
  - target: Impaired Endocytic Cargo Recycling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Alongside the structural effect on the Golgi, the variants impair the
      post-Golgi role of ARF3 in recycling cargo through endosomes. The source
      presents the two as parallel consequences of the variants, so a causal
      dependence of the recycling defect on Golgi fragmentation is inferred.
    evidence:
    - reference: PMID:36456556
      reference_title: "Golgipathies reveal the critical role of the sorting machinery in brain and skeletal development."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: IN_VITRO
      snippet: "The expression of the variants disorganizes the structural morphology of the GC and the formation of COP-I vesicles at the cis face of the Golgi, but also impacts the post-Golgi function of ARF3 in cargo recycling through the endosomal compartments, judging by significant delays in transferrin recycling and accumulation of unrecycled transferrin in lysosomes."
      explanation: Links the Golgi disorganisation to the downstream endosomal recycling defect.
  - target: Aberrant Mitotic Spindle and Reduced Neural Precursor Proliferation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The Golgi contributes to spindle formation and cell-cycle progression;
      altered spindle morphology was seen in the forebrain of zebrafish
      expressing microcephaly-causing variants. Which Golgi function links the
      two has not been established.
    evidence:
    - reference: PMID:36369169
      reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "On the other hand, our live imaging of the developing fish forebrain determined the occurrence of altered spindle morphology in microcephaly-causing ARF3 mutants, which might ultimately underlie mitotic arrest and cell death."
      explanation: The authors propose the spindle defect as the route from mutant ARF3 to precursor loss; the intermediate step is not shown.
    - reference: PMID:36369169
      reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: BACKGROUND
      evidence_source: IN_VITRO
      snippet: "Last, given the importance of Golgi for the establishment and the dynamics of mitotic spindles in dividing precursors"
      explanation: The rationale linking Golgi integrity to spindle formation, as stated by the authors.
  - target: Defective Planar Cell Polarity-dependent Convergent Extension
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Golgi trafficking of polarity factors is needed for planar cell polarity;
      the earliest axial effect of the variants in zebrafish is impaired
      PCP-dependent cell motility.
    evidence:
    - reference: PMID:36369169
      reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Morphometric and live imaging analysis in early embryonic stages traced back the first assessable effect to defective PCP-mediated cell motility."
      explanation: Places the PCP defect as the earliest consequence of the variants in vivo; the Golgi-to-PCP link is inferred.
  - target: Cerebral white matter atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Zebrafish expressing the variants show reduced telencephalic white
      matter, which the authors read as the model counterpart of the white
      matter loss in patients.
    evidence:
    - reference: PMID:36369169
      reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Altogether, the morphometric parameters measured in vivo are consistent with the variable degree of impaired brain development as a distinctive feature of the disease and support the occurrence of telencephalic white matter defects as a common trait of this new Golgipathy."
      explanation: Fish morphometry links the variants to white matter defects; the cellular route from Golgi disruption is not resolved.
- name: Impaired Endocytic Cargo Recycling
  biological_scale: CELLULAR
  description: >-
    ARF3 preferentially localises to the trans-Golgi network and is
    specifically involved in endosomal recycling. Cells expressing the variants
    associated with early-onset microcephaly and severe skeletal disease show
    accumulation and delayed recycling of transferrin, and most variants (not
    p.Pro47Ser) increase transferrin delivery to lysosomes. The contribution of this recycling defect
    to the brain phenotype in vivo has not been tested.
  biological_processes:
  - preferred_term: endocytic recycling
    term:
      id: GO:0032456
      label: endocytic recycling
    modifier: DECREASED
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Of note, our experiments with fluorescently labeled Tfn in combination with staining for EE, RE, and lysosomes unravel a cargo accumulation and delayed recycling in cells expressing ARF3 mutants specifically leading to early-onset microcephaly and severe skeletal defects."
    explanation: Direct cell-based evidence of delayed transferrin recycling with the severe alleles.
  - reference: PMID:36456556
    reference_title: "Golgipathies reveal the critical role of the sorting machinery in brain and skeletal development."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: IN_VITRO
    snippet: "ARF1 share 96% aminoacid identity with ARF3 and it is assumed that their functions are partially interchangeable throughout the GC although studies have shown that ARF3 preferentially localizes to the TGN and is more specifically involved in the endosomal recycling pathway while ARF1 functions to both the cis and trans sides of the GC"
    explanation: Background on the normal TGN and recycling role of ARF3 that the variants disturb.
- name: Aberrant Mitotic Spindle and Reduced Neural Precursor Proliferation
  biological_scale: CELLULAR
  description: >-
    In the forebrain proliferative zone of zebrafish expressing the variants,
    mitotic precursors are reduced and accumulate in early mitosis, spindles
    are abnormally elongated, and proliferating cells are mispositioned.
    Impaired neural precursor proliferation is the earliest brain effect
    detected.
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: neural precursor cell proliferation
    term:
      id: GO:0061351
      label: neural precursor cell proliferation
    modifier: DECREASED
  - preferred_term: mitotic spindle organization
    term:
      id: GO:0007052
      label: mitotic spindle organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In-depth in vivo analyses traces back impaired neural precursors' proliferation and planar cell polarity-dependent cell movements as the earliest detectable effects."
    explanation: Identifies impaired neural precursor proliferation as an earliest in vivo effect.
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The number of pH3+ cells within this region was significantly reduced in embryos expressing ARF3K127E; a similar trend was observed for ARF3L12V/D67V and ARF3D93N expressing fish"
    explanation: Quantitative reduction of mitotic precursors in the forebrain proliferative zone.
  downstream:
  - target: Increased Neural Precursor Cell Death
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Precursors that fail to progress through mitosis are proposed to be
      removed by mitotic surveillance, depleting the progenitor pool.
    evidence:
    - reference: PMID:36369169
      reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "On the other hand, our live imaging of the developing fish forebrain determined the occurrence of altered spindle morphology in microcephaly-causing ARF3 mutants, which might ultimately underlie mitotic arrest and cell death."
      explanation: The authors' proposed causal step from spindle defect to cell death; stated as a possibility.
- name: Increased Neural Precursor Cell Death
  biological_scale: CELLULAR
  description: >-
    Cell death is increased in the developing forebrain of zebrafish
    expressing the most severe alleles (p.Lys127Glu, p.Leu12Val/p.Asp67Val),
    and over a wider forebrain area for p.Pro47Ser and p.Asp93Asn, depleting
    the precursor pool available for brain growth.
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: cell death
    term:
      id: GO:0008219
      label: cell death
    modifier: INCREASED
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The analysis showed a significant increase of AO+ spots (i.e., dying cells and/or apoptotic bodies) in ARF3K127E and ARF3L12V/D67V expressing fish"
    explanation: Direct measurement of increased forebrain cell death in fish expressing the severe alleles.
  downstream:
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Loss of neural precursors reduces brain growth; the severity of the fish
      head-size defect tracks the severity of microcephaly in the patients
      carrying the same alleles.
    evidence:
    - reference: PMID:36369169
      reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Strikingly, similar to patients, overexpression of ARF3K127E and ARF3L12V/D67V produce early-onset severe microcephaly in fish, while fish expressing ARF3D93N show late-onset microcephaly."
      explanation: The alleles that cause precursor death produce microcephaly in fish that matches the patients; the step from cell death to head size is inferred.
  - target: Secondary microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The activating p.Asp93Asn allele produces late-onset microcephaly in
      fish, matching the postnatal microcephaly of the patient carrying it.
    evidence:
    - reference: PMID:36369169
      reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Strikingly, similar to patients, overexpression of ARF3K127E and ARF3L12V/D67V produce early-onset severe microcephaly in fish, while fish expressing ARF3D93N show late-onset microcephaly."
      explanation: Allele-specific late-onset microcephaly in fish mirrors the patient; the intermediate steps are inferred.
- name: Defective Planar Cell Polarity-dependent Convergent Extension
  biological_scale: TISSUE
  description: >-
    Zebrafish embryos expressing the variants show shortened
    anterior-posterior axes, abnormal convergence-extension indices and
    notochord curvatures, which the authors trace to defective planar cell
    polarity-dependent cell movements. This axial defect is the model
    correlate of the scoliosis and rib anomalies seen in patients, and its
    severity tracks the severity of the patients' skeletal involvement.
  biological_processes:
  - preferred_term: convergent extension
    term:
      id: GO:0060026
      label: convergent extension
    modifier: ABNORMAL
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Overall, all mutants except ARF3P47S showed a significantly higher number of notochord curvatures"
    explanation: Quantified axial (notochord) defects in fish expressing the variants.
  downstream:
  - target: Scoliosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The axial defects in fish are proposed as the counterpart of the human
      skeletal phenotype, with the same alleles most severe in both.
    evidence:
    - reference: PMID:36369169
      reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Likewise in patients, similar defects are associated with DN and CA mutations, with p.K127E and p.L12V/D67V producing the most severe effects."
      explanation: Correlates allele severity of fish axial defects with patients' skeletal severity; the developmental route to human scoliosis is inferred.
  - target: 11 pairs of ribs
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The rib anomaly belongs to the same skeletal involvement that the fish
      axial defects are proposed to model.
    evidence:
    - reference: PMID:36369169
      reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Lastly, strengthening the causal association of the described ARF3 mutations to the observed skeletal traits, variable degrees of axial malformations have been highlighted in the generated fish models recapitulating the severity of the disease in humans."
      explanation: Fish axial malformations are presented as the model of the human skeletal traits, including the rib anomaly; the specific route is inferred.
phenotypes:
- category: Neurological
  name: Global developmental delay
  description: >-
    Developmental delay is the constant feature, ranging from mild to profound
    across the reported individuals.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we identify de novo missense ARF3 variants as the molecular event underlying a clinically variable neurodevelopmental disorder characterized by DD/ID and variable CNS defects as common features."
    explanation: Developmental delay/intellectual disability is a common feature of all reported individuals.
  - reference: PMID:34346499
    reference_title: "De novo ARF3 variants cause neurodevelopmental disorder with brain abnormality."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although the affected individuals presented commonly with developmental delay, epilepsy and brain abnormalities, there were differences in severity, clinical course and brain lesions."
    explanation: Developmental delay in both children of the first report.
  - reference: PMID:38712921
    reference_title: "Neurodevelopmental disorder associated with gene ARF3: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present a case study of a patient exhibiting acquired microcephaly along with global developmental delay and drug-resistant epilepsy."
    explanation: Global developmental delay in a further patient.
- category: Neurological
  name: Intellectual disability
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:41507605
    reference_title: "Newly identified ARF3 variants strengthen the causal link between Golgi fragmentation and brain malformations."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "We recently identified de novo missense variants affecting the small GTPase ARF3 as the cause of a disorder characterized by developmental delay/intellectual disability, microcephaly, brain atrophy, epilepsy and minor skeletal defects."
    explanation: Lists intellectual disability among the defining features of the disorder.
- category: Neurological
  name: Delayed speech and language development
  description: >-
    Speech is delayed in all reported individuals with a description of
    language, and absent in the most severely affected.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subject 3 (p.Pro47Ser) and Subject 5 (p.Thr32Asn) showed the mildest phenotype with DD/ID and delayed (Subject 3) or severely delayed (Subject 5) speech and language development."
    explanation: Delayed speech even in the mildest cases.
- category: Neurological
  name: Absent speech
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subject 2 (p.Leu12Val; p.Asp67Val) showed microcephaly, profound DD/ID, absence of speech and language development"
    explanation: Absent speech in a severely affected individual.
- category: Neurological
  name: Hypotonia
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A comparable but less severe condition was also observed in Subject 4 (p.Asp93Asn), who manifested hypotonia, severe DD/ID, delayed speech and language development, post-natal microcephaly, thinning of the corpus callosum as well as milder skeletal defects"
    explanation: Hypotonia in Subject 4 (also reported in Subject 2).
- category: Neurological
  name: Microcephaly
  description: >-
    Microcephaly occurs in most affected individuals. It is severe and present
    at birth with the dominant-negative alleles, and postnatal or acquired with
    milder alleles.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microcephaly and progressive cerebral atrophy occurred in most affected individuals, while epilepsy and skeletal abnormalities were variably documented as associated traits."
    explanation: Microcephaly in most affected individuals.
  - reference: PMID:36456556
    reference_title: "Golgipathies reveal the critical role of the sorting machinery in brain and skeletal development."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Most individuals with severe illness display progressive microcephaly, intellectual delay, delayed myelination and epilepsy, as well as scoliosis and thoracic abnormalities"
    explanation: Commentary synthesising the clinical picture of the severely affected individuals.
- category: Neurological
  name: Secondary microcephaly
  description: Postnatal or acquired microcephaly, reported with milder alleles and in the p.Asp67Val case report.
  phenotype_term:
    preferred_term: Postnatal microcephaly
    term:
      id: HP:0005484
      label: Secondary microcephaly
  evidence:
  - reference: PMID:38712921
    reference_title: "Neurodevelopmental disorder associated with gene ARF3: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present a case study of a patient exhibiting acquired microcephaly along with global developmental delay and drug-resistant epilepsy."
    explanation: Acquired (postnatal) microcephaly.
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A comparable but less severe condition was also observed in Subject 4 (p.Asp93Asn), who manifested hypotonia, severe DD/ID, delayed speech and language development, post-natal microcephaly, thinning of the corpus callosum as well as milder skeletal defects"
    explanation: Post-natal microcephaly with the activating p.Asp93Asn allele.
- category: Neurological
  name: Seizure
  description: >-
    Epilepsy occurs in a subset of patients, with early onset in some and
    drug resistance reported in one.
  phenotype_term:
    preferred_term: Epilepsy
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:34346499
    reference_title: "De novo ARF3 variants cause neurodevelopmental disorder with brain abnormality."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although the affected individuals presented commonly with developmental delay, epilepsy and brain abnormalities, there were differences in severity, clinical course and brain lesions."
    explanation: Epilepsy in both children of the first report.
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microcephaly and progressive cerebral atrophy occurred in most affected individuals, while epilepsy and skeletal abnormalities were variably documented as associated traits."
    explanation: Epilepsy is variable in the larger series.
  - reference: PMID:38712921
    reference_title: "Neurodevelopmental disorder associated with gene ARF3: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present a case study of a patient exhibiting acquired microcephaly along with global developmental delay and drug-resistant epilepsy."
    explanation: Drug-resistant epilepsy in a p.Asp67Val case.
- category: Neurological
  name: Cerebral atrophy
  description: Progressive diffuse cortical atrophy, most marked with the dominant-negative alleles.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microcephaly and progressive cerebral atrophy occurred in most affected individuals, while epilepsy and skeletal abnormalities were variably documented as associated traits."
    explanation: Progressive cerebral atrophy in most affected individuals.
  - reference: PMID:34346499
    reference_title: "De novo ARF3 variants cause neurodevelopmental disorder with brain abnormality."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, it may not be unreasonable that they showed different clinical features like diffuse brain atrophy (p.Asp67Val) and cerebellar hypoplasia (p.Arg99Leu)."
    explanation: Diffuse brain atrophy with the p.Asp67Val allele.
- category: Neurological
  name: Cerebral white matter atrophy
  description: Reduced hemispheric white matter volume.
  phenotype_term:
    preferred_term: Cerebral white matter atrophy
    term:
      id: HP:0012762
      label: Cerebral white matter atrophy
  evidence:
  - reference: PMID:38712921
    reference_title: "Neurodevelopmental disorder associated with gene ARF3: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain magnetic resonance imaging revealed distinctive features, including a Z-shaped morphology of the brainstem, volumetric reduction of white matter, diffuse thinning of the corpus callosum, and partial fusion of the cerebellar hemispheres at their most cranial portion."
    explanation: Volumetric reduction of white matter on MRI.
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive diffuse cortical atrophy with diminished hemispheric white matter, thin corpus callosum, progressive pontocerebellar hypoplasia without the involvement of the cerebellar vermis"
    explanation: Diminished hemispheric white matter in Subject 2.
- category: Neurological
  name: Delayed CNS myelination
  description: Delayed myelination; frank hypomyelination is recorded separately.
  phenotype_term:
    preferred_term: Delayed CNS myelination
    term:
      id: HP:0002188
      label: Delayed CNS myelination
  evidence:
  - reference: PMID:36456556
    reference_title: "Golgipathies reveal the critical role of the sorting machinery in brain and skeletal development."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Most individuals with severe illness display progressive microcephaly, intellectual delay, delayed myelination and epilepsy, as well as scoliosis and thoracic abnormalities"
    explanation: Commentary lists delayed myelination among the features of severe cases.
- category: Neurological
  name: Thin corpus callosum
  description: Thin or hypoplastic corpus callosum is reported in most imaged individuals.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subject 3 also shows early-onset seizures and severe hypoplasia of the anterior part of the temporal lobe associated with hypomyelination and thin corpus callosum"
    explanation: Thin corpus callosum in Subject 3 (also Subjects 2 and 4).
  - reference: PMID:38712921
    reference_title: "Neurodevelopmental disorder associated with gene ARF3: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain magnetic resonance imaging revealed distinctive features, including a Z-shaped morphology of the brainstem, volumetric reduction of white matter, diffuse thinning of the corpus callosum, and partial fusion of the cerebellar hemispheres at their most cranial portion."
    explanation: Diffuse thinning of the corpus callosum in the case report.
- category: Neurological
  name: Cerebellar hypoplasia
  phenotype_term:
    preferred_term: Cerebellar hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
  evidence:
  - reference: PMID:34346499
    reference_title: "De novo ARF3 variants cause neurodevelopmental disorder with brain abnormality."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, it may not be unreasonable that they showed different clinical features like diffuse brain atrophy (p.Asp67Val) and cerebellar hypoplasia (p.Arg99Leu)."
    explanation: Cerebellar hypoplasia with the activating p.Arg99Leu allele.
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive diffuse cortical atrophy with diminished hemispheric white matter, thin corpus callosum, progressive pontocerebellar hypoplasia without the involvement of the cerebellar vermis"
    explanation: Progressive pontocerebellar hypoplasia in Subject 2.
- category: Neurological
  name: Hypoplasia of the brainstem
  description: >-
    Brainstem involvement includes pontine hypoplasia and, in one case, a
    Z-shaped brainstem, which the case report proposes as a diagnostic clue.
  phenotype_term:
    preferred_term: Hypoplasia of the brainstem
    term:
      id: HP:0002365
      label: Hypoplasia of the brainstem
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe brainstem hypoplasia particularly affecting the pons"
    explanation: Severe brainstem hypoplasia in Subject 1.
  - reference: PMID:38712921
    reference_title: "Neurodevelopmental disorder associated with gene ARF3: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This disorder is characterized by global developmental delay and brain malformations, particularly affecting the white matter, cerebellum, and brainstem."
    explanation: The case report names the brainstem among the regions characteristically malformed; it does not itself specify hypoplasia, which rests on the Subject 1 description.
- category: Musculoskeletal
  name: Scoliosis
  description: >-
    Skeletal involvement is variable, most severe with the dominant-negative
    alleles, and includes scoliosis and thoracic or rib anomalies.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "profound DD/ID and skeletal involvement (i.e., 11 rib pairs and severe scoliosis)"
    explanation: Severe scoliosis in Subject 1.
  - reference: PMID:36456556
    reference_title: "Golgipathies reveal the critical role of the sorting machinery in brain and skeletal development."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Most individuals with severe illness display progressive microcephaly, intellectual delay, delayed myelination and epilepsy, as well as scoliosis and thoracic abnormalities"
    explanation: Scoliosis in the severely affected individuals.
- category: Musculoskeletal
  name: 11 pairs of ribs
  phenotype_term:
    preferred_term: 11 pairs of ribs
    term:
      id: HP:0000878
      label: 11 pairs of ribs
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "profound DD/ID and skeletal involvement (i.e., 11 rib pairs and severe scoliosis)"
    explanation: Eleven rib pairs in Subject 1.
- category: Neurological
  name: Primary microcephaly
  description: Severe microcephaly present at birth with the dominant-negative alleles.
  phenotype_term:
    preferred_term: Congenital microcephaly
    term:
      id: HP:0011451
      label: Primary microcephaly
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "D67V) showing severe microcephaly at birth"
    explanation: Microcephaly present at birth with the dominant-negative alleles (Subjects 1 and 2).
- category: Neurological
  name: CNS hypomyelination
  phenotype_term:
    preferred_term: CNS hypomyelination
    term:
      id: HP:0003429
      label: CNS hypomyelination
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subject 3 also shows early-onset seizures and severe hypoplasia of the anterior part of the temporal lobe associated with hypomyelination and thin corpus callosum"
    explanation: Hypomyelination in Subject 3.
- category: Neurological
  name: Ventriculomegaly
  phenotype_term:
    preferred_term: Lateral ventricular enlargement
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in a girl (Subject 1) with a severe syndromic neurodevelopmental disorder characterized by growth restriction, severe microcephaly, progressive diffuse cortical atrophy, hypoplasia of corpus callosum and other brain anomalies at MRI (i.e., lateral ventricular enlargement, severe brainstem hypoplasia particularly affecting the pons, cerebellar inferior vermis hypoplasia)"
    explanation: Lateral ventricular enlargement in Subject 1.
- category: Neurological
  name: Inferior cerebellar vermis hypoplasia
  phenotype_term:
    preferred_term: Inferior cerebellar vermis hypoplasia
    term:
      id: HP:0007068
      label: Inferior cerebellar vermis hypoplasia
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in a girl (Subject 1) with a severe syndromic neurodevelopmental disorder characterized by growth restriction, severe microcephaly, progressive diffuse cortical atrophy, hypoplasia of corpus callosum and other brain anomalies at MRI (i.e., lateral ventricular enlargement, severe brainstem hypoplasia particularly affecting the pons, cerebellar inferior vermis hypoplasia)"
    explanation: Inferior vermis hypoplasia in Subject 1.
- category: Neurological
  name: Z-shaped brainstem
  description: Z-shaped brainstem on MRI, reported in one p.Asp67Val patient; no more specific HPO term exists for this shape.
  phenotype_term:
    preferred_term: Z-shaped brainstem
    term:
      id: HP:0002363
      label: Abnormal brainstem morphology
    coarse_binding_basis: NO_HPO_TERM
  evidence:
  - reference: PMID:38712921
    reference_title: "Neurodevelopmental disorder associated with gene ARF3: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain magnetic resonance imaging revealed distinctive features, including a Z-shaped morphology of the brainstem, volumetric reduction of white matter, diffuse thinning of the corpus callosum, and partial fusion of the cerebellar hemispheres at their most cranial portion."
    explanation: Z-shaped brainstem on MRI, proposed by the authors as a diagnostic clue.
- category: Neurological
  name: Partial fusion of the cerebellar hemispheres
  description: >-
    Partial fusion of the cerebellar hemispheres at their most cranial portion,
    reported in one p.Asp67Val patient.
  phenotype_term:
    preferred_term: Partial fusion of the cerebellar hemispheres
    term:
      id: HP:0006899
      label: Fusion of the cerebellar hemispheres
  evidence:
  - reference: PMID:38712921
    reference_title: "Neurodevelopmental disorder associated with gene ARF3: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain magnetic resonance imaging revealed distinctive features, including a Z-shaped morphology of the brainstem, volumetric reduction of white matter, diffuse thinning of the corpus callosum, and partial fusion of the cerebellar hemispheres at their most cranial portion."
    explanation: Partial cranial fusion of the cerebellar hemispheres on MRI.
- category: Growth
  name: Growth delay
  phenotype_term:
    preferred_term: Growth restriction
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in a girl (Subject 1) with a severe syndromic neurodevelopmental disorder characterized by growth restriction, severe microcephaly, progressive diffuse cortical atrophy, hypoplasia of corpus callosum and other brain anomalies at MRI (i.e., lateral ventricular enlargement, severe brainstem hypoplasia particularly affecting the pons, cerebellar inferior vermis hypoplasia)"
    explanation: Growth restriction in Subject 1.
- category: Cardiovascular
  name: Congenital heart defect
  description: Reported in one individual (Subject 1, p.Lys127Glu); the lesion type is not given in the main text.
  phenotype_term:
    preferred_term: Congenital heart defects
    term:
      id: HP:0001627
      label: Abnormal heart morphology
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "inguinal hernia and congenital heart defects (CHD)"
    explanation: Congenital heart defects in Subject 1; the specific lesion is not stated in the main text.
- category: Gastrointestinal
  name: Inguinal hernia
  phenotype_term:
    preferred_term: Inguinal hernia
    term:
      id: HP:0000023
      label: Inguinal hernia
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "inguinal hernia and congenital heart defects (CHD)"
    explanation: Inguinal hernia in Subject 1.
genetic:
- name: ARF3
  gene_term:
    preferred_term: ARF3
    term:
      id: hgnc:654
      label: ARF3
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    ARF3 (12q13.12) encodes ADP-ribosylation factor 3, a class I ARF small
    GTPase that shares 96% amino-acid identity with ARF1. All reported
    disease variants are de novo heterozygous missense changes. Variants
    reported to date include p.Leu12Val with p.Asp67Val in cis, p.Thr32Asn,
    p.Pro47Ser, p.Asp67Val, p.Asp93Asn, p.Arg99Leu and p.Lys127Glu (on
    NM_001659), with further variants in the 2026 follow-up series. Variant
    records below cover the alleles with a published per-allele clinical or
    functional description that can be quoted; p.Thr32Asn, p.Pro47Ser and the
    p.Leu12Val/p.Asp67Val haplotype are characterised in the pathophysiology
    node's genetic_context instead. ARF1, its closest paralog, causes a
    clinically similar disorder. A heterozygous ARF3 nonsense allele
    (p.Arg99*) inherited from a clinically unaffected parent has been reported
    as a secondary finding in a child with Bosch-Boonstra-Schaaf optic atrophy
    syndrome (PMID:42606787); a single carrier does not establish whether ARF3
    haploinsufficiency is tolerated.
  evidence:
  - reference: PMID:36369169
    reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report that de novo missense variants in ARF3, encoding a small GTPase regulating Golgi dynamics, cause a developmental disease in humans impairing nervous system and skeletal formation."
    explanation: Gene-disease report with five individuals and functional validation.
  - reference: PMID:34346499
    reference_title: "De novo ARF3 variants cause neurodevelopmental disorder with brain abnormality."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We here report the clinical and genetic evaluations of two unrelated children with de novo pathogenic variants in the ARF3 gene: c.200A > T (p.Asp67Val) and c.296G > T (p.Arg99Leu)."
    explanation: Independent gene-disease report.
  - reference: PMID:41507605
    reference_title: "Newly identified ARF3 variants strengthen the causal link between Golgi fragmentation and brain malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report clinical features of five additional patients and the functional characterization of three novel ARF3 variants."
    explanation: Five further patients extend the cohort.
  variants:
  - name: p.Asp67Val
    description: >-
      NM_001659.2:c.200A>T, p.Asp67Val. Reported de novo in a child with
      severe microcephaly, diffuse brain atrophy and epilepsy, again in a
      patient with acquired microcephaly, drug-resistant epilepsy and a
      Z-shaped brainstem, and in cis with p.Leu12Val in a further severely
      affected child. Shows a dispersed cytosolic and Golgi pattern like the
      dominant-negative p.Thr31Asn mutant, is lethal when expressed in flies,
      and has reduced GTP-bound levels.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:38712921
      reference_title: "Neurodevelopmental disorder associated with gene ARF3: A case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Whole-exome sequencing uncovered a pathogenic variant in the ARF3 gene c.200A>T, p.(Asp67Val)."
      explanation: Recurrence of the allele in an independent patient, classified pathogenic.
    - reference: PMID:34346499
      reference_title: "De novo ARF3 variants cause neurodevelopmental disorder with brain abnormality."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Pull-down assays revealed that the p.Asp67Val had a loss-of-function effect and the p.Arg99Leu variant had increased binding of the adaptor protein, Golgi-localized, γ-adaptin ear-containing, ARF-binding protein 1 (GGA1), supporting the gain of function."
      explanation: Functional evidence of a loss-of-function effect.
  - name: p.Arg99Leu
    description: >-
      NM_001659:c.296G>T, p.Arg99Leu. Reported de novo in a child with
      developmental delay, epilepsy and cerebellar hypoplasia. Localises
      normally to the Golgi but binds GGA1 more strongly and produces a rough
      eye in flies like the activating p.Gln71Leu mutant, consistent with gain
      of function.
    evidence:
    - reference: PMID:34346499
      reference_title: "De novo ARF3 variants cause neurodevelopmental disorder with brain abnormality."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In contrast, flies expressing p.Arg99Leu had abnormal rough eye, as observed in the gain-of-function variant p.Gln71Leu."
      explanation: In vivo fly evidence of gain-of-function behaviour.
  - name: p.Lys127Glu
    description: >-
      NM_001659.2:c.379A>G, p.Lys127Glu, in the NKXD guanine-nucleotide binding
      motif. Reported de novo in a girl with the most severe phenotype
      (growth restriction, severe microcephaly, progressive cortical atrophy,
      pontine hypoplasia, seizures, profound developmental delay, eleven rib
      pairs, severe scoliosis, inguinal hernia and congenital heart defects).
      The corresponding Lys127Glu substitution has been reported in ARF1 in a
      patient with a similar disorder.
    evidence:
    - reference: PMID:36369169
      reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "trio-based exome sequencing allowed us to identify a previously unreported de novo ARF3 variant, c.379A>G (p.Lys127Glu; NM_001659.2), as the putative disease-causing event in a girl (Subject 1) with a severe syndromic neurodevelopmental disorder"
      explanation: Identification of the allele in the most severely affected individual.
    - reference: PMID:36369169
      reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
      supports: SUPPORT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: "Among these, the same Lys-to-Glu substitution at codon 127 in Subject 1 was recently reported to affect the corresponding residue in ARF1 in a patient with DD, microcephaly, periventricular heterotopia, progressive cerebral atrophy, and epilepsy"
      explanation: Sources the ARF1 parallel for this allele.
  - name: p.Asp93Asn
    description: >-
      p.Asp93Asn. Reported de novo in a child with hypotonia, severe
      developmental delay, postnatal microcephaly, thin corpus callosum and
      milder skeletal defects. Stabilises the GTP-bound conformation
      (activating behaviour) and produces late-onset microcephaly in zebrafish.
    evidence:
    - reference: PMID:36369169
      reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Altogether, these data suggest a stabilized GTP-bound conformation and an overall hyperactive behavior for ARF3D93N and, to a minor extent, ARF3P47S, while a DN behavior could be established for the ARF3T32N variant."
      explanation: Classifies p.Asp93Asn as activating.
diagnosis:
- name: Exome sequencing
  description: >-
    Diagnosis rests on identifying a de novo heterozygous ARF3 missense
    variant, in practice by trio exome sequencing, in a child with
    developmental delay, microcephaly and brain anomalies. A Z-shaped
    brainstem on MRI has been proposed as a clue that should bring ARF3 into
    the differential diagnosis.
  diagnosis_term:
    preferred_term: trio exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:38712921
    reference_title: "Neurodevelopmental disorder associated with gene ARF3: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In cases where a Z-shaped morphology of the brainstem is observed, ARF3-associated disorder should be included in the list of differential diagnoses."
    explanation: Imaging clue for the diagnosis.
  - reference: PMID:38712921
    reference_title: "Neurodevelopmental disorder associated with gene ARF3: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing uncovered a pathogenic variant in the ARF3 gene c.200A>T, p.(Asp67Val)."
    explanation: Molecular diagnosis by exome sequencing.
animal_models:
- name: Zebrafish expressing human ARF3 disease variants
  species: Zebrafish
  genotype: Injection of mRNA encoding human ARF3 missense variants (p.Lys127Glu, p.Leu12Val/p.Asp67Val, p.Pro47Ser, p.Asp93Asn, p.Thr32Asn)
  description: >-
    Transient overexpression of patient alleles in one-cell zebrafish embryos.
    The model reproduces microcephaly, Golgi fragmentation and axial
    malformations with an allele-dependent severity matching the patients,
    while morpholino knockdown of arf3a/arf3b produces a much milder
    phenotype, supporting a dominant mechanism.
  publication: PMID:36369169
  modeled_mechanisms:
  - target: Increased Neural Precursor Cell Death
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Forebrain cell death and reduced head size in embryos expressing the severe alleles.
    limitations: >-
      Transient mRNA overexpression in embryos, not a germline knock-in at
      physiological dosage; zebrafish has two arf3 paralogs and lacks the
      human cortical progenitor compartments.
    evidence:
    - reference: PMID:36369169
      reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Strikingly, similar to patients, overexpression of ARF3K127E and ARF3L12V/D67V produce early-onset severe microcephaly in fish, while fish expressing ARF3D93N show late-onset microcephaly."
      explanation: The model reproduces the allele-specific microcephaly of the patients.
  - target: Defective Planar Cell Polarity-dependent Convergent Extension
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Notochord curvatures and convergence-extension defects.
    limitations: >-
      Notochord bending in embryos is a developmental correlate of, not the
      same lesion as, human scoliosis.
    evidence:
    - reference: PMID:36369169
      reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Overall, all mutants except ARF3P47S showed a significantly higher number of notochord curvatures"
      explanation: Axial defects in the model.
  - target: Golgi Fragmentation and COPI Vesicle Dysregulation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Golgi integrity is disrupted in embryos expressing the variants.
    limitations: >-
      Overexpression on top of endogenous arf3a/arf3b rather than a
      heterozygous germline allele.
    evidence:
    - reference: PMID:41507605
      reference_title: "Newly identified ARF3 variants strengthen the causal link between Golgi fragmentation and brain malformations."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "ARF3 mutants significantly affected Golgi integrity in vivo as well as brain size, recapitulating patients' microcephaly."
      explanation: In vivo Golgi disruption in the model.
  - target: Aberrant Mitotic Spindle and Reduced Neural Precursor Proliferation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Reduced mitotic precursors and abnormal spindles in the forebrain proliferative zone.
    limitations: >-
      Zebrafish forebrain lacks the human outer subventricular zone progenitor
      populations, so the proliferative defect may differ in human cortex.
    evidence:
    - reference: PMID:36369169
      reference_title: "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The number of pH3+ cells within this region was significantly reduced in embryos expressing ARF3K127E; a similar trend was observed for ARF3L12V/D67V and ARF3D93N expressing fish"
      explanation: Reduced precursor proliferation in the model.
- name: Drosophila expressing human ARF3 variants
  species: Fruit fly
  genotype: Transgenic expression of human ARF3 p.Asp67Val or p.Arg99Leu
  description: >-
    In vivo expression of the two variants from the first report. p.Asp67Val
    is lethal, like a loss-of-function allele, while p.Arg99Leu produces a
    rough eye like the activating p.Gln71Leu mutant, supporting opposite
    functional classes for the two alleles.
  publication: PMID:34346499
  modeled_mechanisms:
  - target: Dysregulated ARF3 GTP/GDP Cycling
    relationship: PERTURBS
    fidelity: LOW
    model_scale: ORGANISM
    description: Organism-level readouts (lethality, eye morphology) that classify each allele's functional direction.
    limitations: >-
      Overexpression in flies reports allele behaviour through lethality and
      eye roughness, not through any neurodevelopmental or Golgi readout
      comparable to the human disease.
    evidence:
    - reference: PMID:34346499
      reference_title: "De novo ARF3 variants cause neurodevelopmental disorder with brain abnormality."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Furthermore, in vivo studies revealed that p.Asp67Val transfection led to lethality in flies."
      explanation: Lethality in flies for the putative loss-of-function allele.
    - reference: PMID:34346499
      reference_title: "De novo ARF3 variants cause neurodevelopmental disorder with brain abnormality."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In contrast, flies expressing p.Arg99Leu had abnormal rough eye, as observed in the gain-of-function variant p.Gln71Leu."
      explanation: Gain-of-function-like phenotype for p.Arg99Leu.
📚

References & Deep Research

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: ARF3-related_Neurodevelopmental_Disorder · 2026-10-15T20:45:23Z · View source

New entry for ARF3-related neurodevelopmental disorder (MONDO:0700366), claimed in issue 14421. Deep research: falcon was requested by default but was unavailable (deep-research-client providers --check: 'falcon: UNREACHABLE - 503 Failed to authenticate -- the provider reported a temporary server-side failure'); the --fallback flag does not fire for this retryable 503 class, so OpenScientist was run by hand (research/ARF3-related_Neurodevelopmental_Disorder-deep-research-openscientist.md). Its reference validation was clean (8/8 resolved) and preflight-dr passed (ARF3 mentioned 48 times). The report gives ARF3 as HGNC:653, which resolves to no term; the entry binds hgnc:654, verified as ARF3 against the HGNC build. Of the report's citations, PMID:20357002 (BIG-dependent TGN recruitment of Arf3) was added as evidence; PMID:42606787 (inherited ARF3 p.Arg99* in an unaffected parent) is mentioned in the genetic notes only, because a single carrier does not establish whether haploinsufficiency is tolerated; PMID:37185208 (ARF1 differential) and PMID:37102998 (ARF nanodomains) were not needed for any claim. Core sources were found by direct PubMed search: Sakamoto 2021 (PMID:34346499), Fasano 2022 (PMID:36369169, full text), the 2024 case report (PMID:38712921), Muto 2026 (PMID:41507605) and the El Ghouzzi and Boncompain 2022 commentary (PMID:36456556). No GeneReviews/StatPearls chapter (check-genereviews NO_CHAPTER) and no ClinGen classification. Pathophysiology is built as a chain from the variant through GTP/GDP cycling, Golgi/COPI disruption, endocytic recycling, spindle/precursor proliferation and cell death, and PCP-dependent axial defects; edges to phenotypes are model-organism and marked INDIRECT. Phenotype frequencies omitted because the cohorts are too small. Validation: just validate (schema, terms, references) passed; count-verified-snippets 82/82; validate-disorders passed; check-entity-refs, check-causal-targets, check-duplicate-keys, check-coarse-phenotypes, check-reference-titles and the snippet baselines clean. An independent pre-PR review (fresh-context subagent) found no blocking issues; applied: Golgi-to-recycling edge downgraded to indirect, spindle edge given its own quote, unsourced cell-death-to-developmental-delay edge removed, PCP node rebound from Wnt/PCP signalling to GO:0060026 convergent extension, cell death rebound to GO:0008219, lysosomal-overload and morpholino wording corrected, eight single-patient or imaging phenotypes added from Fasano 2022 and the case report, two zebrafish model links added. PR review round 1 (PR 14423): inferior vermis hypoplasia rebound from the HP:0006817 grouping term to HP:0007068; duplicate Subject 3 item removed from Delayed CNS myelination; partial cerebellar hemisphere fusion added (HP:0006899); Drosophila model record added from PMID:34346499; PMID:42606787 cited in the genetic notes; GTPase activity and GTP binding bound on the ARF3 Missense Variant node to clear the newly-ungrounded-genes CI gate. After the round: count-verified-snippets 84/84, check_gene_activity_grounding --against-ref origin/main OK.

OpenScientist ▸
ARF3-related Neurodevelopmental Disorder — Comprehensive Disease Characteristics Report
openscientist-autonomous 8 citations 2026-10-15T16:42:18.746312

ARF3-related Neurodevelopmental Disorder — Comprehensive Disease Characteristics Report

Disease: ARF3-related Neurodevelopmental Disorder MONDO ID: MONDO:0700366 Category: Mendelian (autosomal dominant, de novo) Report compiled: 2026-10-15 | Based on all available primary literature (5 clinical/functional reports, <10 patients, 2021–2026)

Summary

ARF3-related neurodevelopmental disorder is an ultrarare, autosomal-dominant "Golgipathy" caused by de novo heterozygous missense variants in ARF3 (ADP-ribosylation factor 3), a class I small GTPase that governs vesicle trafficking and membrane dynamics at the trans-Golgi network (TGN). Fewer than ~10 patients have been reported worldwide since the first description in 2021. The core clinical phenotype comprises global developmental delay/intellectual disability, progressive (often acquired) microcephaly, epilepsy (frequently drug-resistant), and brain atrophy, accompanied by distinctive neuroimaging — reduced cerebral white matter, thin corpus callosum, cerebellar anomalies, and a characteristic Z-shaped brainstem — plus minor skeletal defects (PMID: 34346499; PMID: 36369169; PMID: 38712921; PMID: 41507605).

Mechanistically, pathogenic variants cluster in or near the guanine-nucleotide-binding pocket of ARF3 and disrupt the GTP/GDP cycle in a variant-specific manner. Some variants (e.g., p.Asp67Val) behave as loss-of-function/dominant-negative alleles and produce the most severe phenotype, whereas others (e.g., p.Arg99Leu) show gain-of-function behavior (increased GGA1 adaptor binding). The downstream consequence is Golgi fragmentation and trafficking failure, which in the developing brain impairs neural precursor proliferation and planar-cell-polarity (PCP)-dependent cell movements, yielding microcephaly and cortical/cerebellar/brainstem malformation. Convergent evidence from human genetics, in vitro assays, and in vivo zebrafish and Drosophila models supports this unified model (PMID: 34346499; PMID: 36369169; PMID: 41507605).

There is no disease-modifying therapy. Management is entirely supportive and symptomatic (antiseizure medications, developmental/rehabilitative therapies, and management of feeding, visual, and orthopedic complications). All reported cases are de novo with no familial recurrence, no founder effect, and no identified sex, ethnic, or geographic predilection. Notably, a truncating/haploinsufficiency allele (p.Arg99*) inherited from an unaffected parent was judged non-causative, arguing against simple haploinsufficiency and supporting a dominant-negative/gain-of-function disease mechanism (PMID: 42606787).

Key Findings

Finding 1 — De novo dominant ARF3 missense variants cause a neurodevelopmental Golgipathy

Three independent reports establish causation across the full available literature. Sakamoto et al. 2021 described two unrelated children with de novo c.200A>T (p.Asp67Val) and c.296G>T (p.Arg99Leu), noting that "In this family, ARF3 mainly works at the trans-Golgi network (TGN), and no ARF3-related phenotypes have yet been described in humans. We here report the clinical and genetic evaluations of two unrelated children with de novo pathogenic variants in the ARF3 gene: c.200A > T (p.Asp67Val) and c.296G > T (p.Arg99Leu)" (PMID: 34346499). Fasano/Muto et al. 2022 confirmed dominant missense causation of a disorder "encoding a small GTPase regulating Golgi dynamics, cause a developmental disease in humans impairing nervous system and skeletal formation" (PMID: 36369169). Muto/Lauri et al. 2026 added five more patients and three novel variants, describing "a disorder characterized by developmental delay/intellectual disability, microcephaly, brain atrophy, epilepsy and minor skeletal defects" (PMID: 41507605). Inheritance is autosomal dominant, de novo.

Finding 2 — Core clinical phenotype: DD/ID, microcephaly, epilepsy, brain atrophy with Z-shaped brainstem

Across the ~9 reported patients, the recurrent features are global developmental delay/intellectual disability, microcephaly (often acquired/progressive), epilepsy (frequently drug-resistant), brain atrophy, and minor skeletal defects (PMID: 41507605). MRI shows a distinctive signature: "a Z-shaped morphology of the brainstem, volumetric reduction of white matter, diffuse thinning of the corpus callosum, and partial fusion of the cerebellar hemispheres" (PMID: 38712921). Severity is variable: "the affected individuals presented commonly with developmental delay, epilepsy and brain abnormalities, there were differences in severity, clinical course and brain lesions" (PMID: 34346499).

Finding 3 — Mechanism: variant-specific Golgi fragmentation via dominant-negative and gain-of-function effects

Functional assays show variants cluster in/near the guanine-nucleotide-binding pocket and perturb the GTP/GDP cycle. Pull-down assays revealed that "the p.Asp67Val had a loss-of-function effect and the p.Arg99Leu variant had increased binding of the adaptor protein, Golgi-localized, γ-adaptin ear-containing, ARF-binding protein 1 (GGA1), supporting the gain of function" (PMID: 34346499). Variants "affect residues within the guanine nucleotide binding pocket and variably perturb protein stability and GTP/GDP binding. Functional analysis demonstrates variably disruptive consequences of ARF3 variants on Golgi morphology, vesicles assembly and trafficking" (PMID: 36369169). The earliest developmental effects are "impaired neural precursors' proliferation and planar cell polarity-dependent cell movements" (PMID: 36369169).

Finding 4 — Model organisms recapitulate the disorder; dominant-negative = severe

Zebrafish reproduce the Golgi and microcephaly phenotypes: "Zebrafish models confirm the dominant behavior of the tested variants and their variable impact on development. ARF3 mutants significantly affected Golgi integrity in vivo as well as brain size, recapitulating patients' microcephaly" (PMID: 41507605). Drosophila show variant-specific toxicity: "in vivo studies revealed that p.Asp67Val transfection led to lethality in flies. In contrast, flies expressing p.Arg99Leu had abnormal rough eye" (PMID: 34346499). Variants with dominant-negative behavior are linked "to a markedly severe phenotype" (PMID: 41507605), establishing a genotype–severity correlation.

Finding 5 — Identifiers and variant spectrum; haploinsufficiency is not disease-causing

Causal gene ARF3 (HGNC:653; NCBI Gene 377; Ensembl ENSG00000134287; OMIM 103190; UniProt P61204; locus 12q13.12) encodes a 181-aa N-myristoylated class I ARF small GTPase. Reported de novo pathogenic/likely-pathogenic missense variants (all germline, all absent from gnomAD) include the recurrent, dominant-negative, most-severe c.200A>T p.(Asp67Val); the gain-of-function c.296G>T p.(Arg99Leu); and additional pocket-residue substitutions in the 2022 and 2026 cohorts. Critically, a nonsense allele "NM_001659.3:c.295C>T, p.Arg99*... was inherited from the clinically unaffected father, indicating it is unlikely to be the primary causative variant"* (PMID: 42606787) — arguing against simple haploinsufficiency and supporting a dominant-negative/gain-of-function mechanism.

Finding 6 — Epidemiology, prognosis, and management

ARF3-related NDD is ultrarare: "The neurodevelopmental disorder associated with the ARF3 gene is exceptionally rare, with only two previously documented cases in the literature" (PMID: 38712921). No prevalence/incidence estimates exist; no sex, ethnic, or geographic predilection; all cases de novo. Onset is congenital/early-infantile; course is chronic and lifelong, exemplified by "a patient exhibiting acquired microcephaly along with global developmental delay and drug-resistant epilepsy" (PMID: 38712921). No disease-modifying therapy exists; care is supportive.

Finding 7 — Anatomy affected and differential diagnosis within ARF-family Golgipathies

The primary affected organ is the brain, with characteristic "Z-shaped morphology of the brainstem, volumetric reduction of white matter, diffuse thinning of the corpus callosum, and partial fusion of the cerebellar hemispheres" (PMID: 38712921), plus secondary skeletal involvement — the disease "impairing nervous system and skeletal formation" (PMID: 36369169). Differential diagnosis includes other Golgipathies/ARF-pathway disorders: ARF1-related NDD with periventricular nodular heterotopia and microcephaly ([PMID: 37185208]) and ARFGEF2 (BIG2)-related recessive periventricular heterotopia/microcephaly.

Finding 8 — Unified synthesis

Across all primary literature, ARF3-related NDD is consistently an autosomal-dominant, de novo missense Golgipathy. The findings "document a key role of ARF3 in Golgi function and demonstrate its pleiotropic impact on development" (PMID: 36369169) and "underscore the specific vulnerability of the nervous system to ARF and Golgi dysfunction" (PMID: 41507605).

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

  1. A de novo missense mutation in ARF3 alters a residue in/near the guanine-nucleotide-binding pocket → leads to an ARF3 GTPase with abnormal GTP/GDP cycling and/or reduced stability (PMID: 36369169). (demonstrated in vitro)
  2. The altered nucleotide cycle results in variant-specific dysfunction that branches:
  3. Branch A — Dominant-negative / loss-of-function (e.g., p.Asp67Val): mutant is abnormally dispersed in cytosol and disperses the Golgi (mimicking the classic DN p.Thr31Asn) → poisons the endogenous ARF3 pathway (PMID: 34346499).
  4. Branch B — Gain-of-function (e.g., p.Arg99Leu): increased GGA1 adaptor binding → aberrant trafficking activity (PMID: 34346499).
  5. Both branches lead to Golgi fragmentation and disrupted vesicle assembly/trafficking at the TGN (PMID: 36369169). (demonstrated in vitro/in vivo)
  6. Trafficking failure results in impaired neural precursor proliferation and defective PCP-dependent cell movements — the earliest detectable effects (PMID: 36369169). (demonstrated in vivo)
  7. These defects lead to reduced brain growth → microcephaly, brain atrophy, white-matter hypoplasia, thin corpus callosum, cerebellar/brainstem (Z-shaped) malformation (PMID: 38712921).
  8. Structural brain defects result in developmental delay/intellectual disability and epilepsy (PMID: 41507605).

Inferred genotype–severity relationship: dominant-negative variants predict the most severe phenotype (PMID: 41507605).

 De novo ARF3 missense variant
 (nucleotide-binding pocket: Asp67, Arg99, Lys38, Thr32-region)
 │
 ▼
 Abnormal GTP/GDP cycling + reduced protein stability
 │
┌────────┴─────────┐
▼                  ▼
 Branch A: DN/LoF     Branch B: GoF
 (e.g. p.Asp67Val)    (e.g. p.Arg99Leu)
 cytosolic + Golgi    ↑GGA1 adaptor
 dispersion           binding
└────────┬─────────┘
 ▼
GOLGI FRAGMENTATION
   (disrupted vesicle assembly/trafficking at TGN)
 │
 ▼
 Impaired neural precursor proliferation
 + defective planar-cell-polarity movements   ← earliest detectable effect
 │
 ▼
 Microcephaly • brain atrophy • white-matter hypoplasia
 thin corpus callosum • cerebellar fusion • Z-shaped brainstem
 │
 ▼
 Developmental delay / intellectual disability • epilepsy
 (+ minor skeletal defects)

 Severity:  Dominant-negative  >>  Gain-of-function

Ontology mapping. GO biological process: GO:0048193 (Golgi vesicle transport), GO:0006886 (intracellular protein transport), GO:0061351 (neural precursor cell proliferation), GO:0001736 (establishment of planar polarity); GO cellular component: GO:0005802 (trans-Golgi network), GO:0005794 (Golgi apparatus), GO:0000139 (Golgi membrane); Cell Ontology: CL:0000031/CL:0000681 (neuroblast/radial glial cell), CL:0000540 (neuron); UBERON: UBERON:0000955 (brain), UBERON:0002316 (white matter), UBERON:0002336 (corpus callosum), UBERON:0002037 (cerebellum), UBERON:0002298 (brainstem).

Section-by-Section Disease Characteristics

1. Disease Information

Dominantly inherited, de novo Golgipathy from ARF3 missense variants; presents in infancy with DD/ID, microcephaly, epilepsy, brain atrophy, and minor skeletal defects. Identifiers: MONDO:0700366; gene ARF3 HGNC:653 / NCBI 377 / Ensembl ENSG00000134287 / OMIM *103190 / UniProt P61204 / 12q13.12. Synonyms: ARF3-related Golgipathy; ARF3 neurodevelopmental disorder with brain abnormality; ADP-ribosylation factor 3-related disorder. No dedicated Orphanet/ICD/MeSH code identified (data not available). Source = individual-patient reports (not EHR/registry).

2. Etiology

Purely genetic — heterozygous de novo ARF3 missense variants in/near the nucleotide-binding pocket. No susceptibility loci, modifier genes, environmental/lifestyle/infectious factors, protective alleles, or gene–environment interactions identified. A truncating allele (p.Arg99*) inherited from an unaffected parent is non-causative (PMID: 42606787).

3. Phenotypes

Phenotype HPO term Frequency (qualitative) Onset / course
Global developmental delay HP:0001263 Universal (~100%) Infantile, chronic
Intellectual disability HP:0001249 Very frequent Childhood, stable
Microcephaly (often acquired) HP:0000252 / HP:0005484 Frequent Postnatal, progressive
Epilepsy (often drug-resistant) HP:0001250 / HP:0032794 Frequent Infancy–childhood
Cerebral atrophy HP:0002059 / HP:0012444 Frequent Progressive
White-matter hypoplasia HP:0012762 Frequent Early
Thin corpus callosum HP:0033725 Frequent Congenital
Z-shaped brainstem HP:0002363 Distinctive marker Congenital
Cerebellar hypoplasia/fusion HP:0001321 / HP:0007360 Reported Congenital
Hypotonia HP:0001252 Reported Infantile
Minor skeletal defects HP:0000924 Variable subset Congenital

Severity is variable and variant-dependent. QoL impact is severe and lifelong; no formal QoL instrument data exist.

4. Genetic/Molecular Information

Variant (cDNA / protein) Type Mechanism Note
c.200A>T, p.(Asp67Val) Missense LoF / dominant-negative Recurrent; most severe; lethal in flies
c.296G>T, p.(Arg99Leu) Missense Gain-of-function (↑GGA1) Rough-eye in flies
p.(Arg99Cys/His), other pocket residues Missense Variable GTP/GDP binding & stability 2022/2026 cohorts
c.295C>T, p.(Arg99*) Nonsense Truncating/LoF Not causative (inherited, unaffected father)

All pathogenic alleles germline, de novo, absent from gnomAD; ACMG classification pathogenic/likely pathogenic (PS2, PM1, PM2, PS3). No modifier genes, epigenetic mechanisms, or chromosomal abnormalities implicated.

5. Environmental Information

Not applicable (monogenic de novo disorder). No toxins, radiation, lifestyle factors, or infectious agents implicated.

6. Mechanism / Pathophysiology

See Mechanistic Model above. Upstream: variant → GTPase nucleotide-cycling defect. Downstream: Golgi fragmentation → trafficking failure → impaired neural progenitor proliferation/PCP → brain malformation → clinical disease. No metabolic, immune, or infectious involvement. No patient-tissue omics/CRISPR-screen data reported yet (gap).

7. Anatomical Structures Affected

Primary organ: brain/CNS (UBERON:0000955). Sites (bilateral/midline): cerebral white matter (UBERON:0002316), corpus callosum (UBERON:0002336, thinned), cerebellum (UBERON:0002037, partial fusion), brainstem (UBERON:0002298, Z-shaped). Secondary: skeletal system (minor defects). Subcellular lesion: Golgi/TGN (GO:0005794/GO:0005802). Cell level: neural progenitor/radial glial cells.

8. Temporal Development

Onset congenital/early-infantile; insidious neurodevelopmental presentation; epilepsy onset infancy–childhood. Course chronic/lifelong; microcephaly and brain atrophy often progressive. No remission. Critical period = fetal/early-postnatal neurogenesis (neural precursor proliferation window).

9. Inheritance and Population

Autosomal dominant, de novo. Penetrance presumed complete for pathogenic missense; variable expressivity (variant-dependent). No anticipation; germline mosaicism possible (small residual recurrence risk); no founder effect; consanguinity not relevant; carrier frequency ~0. Ultrarare (<10 patients worldwide); no prevalence/incidence estimate; no sex/ethnic/geographic predilection; pediatric age distribution; cases reported across several countries.

10. Diagnostics

Definitive diagnosis = trio WES/WGS detecting a de novo ARF3 missense variant; ARF3 may appear on ID/epilepsy/microcephaly NGS panels; single-gene/Sanger used for confirmation and segregation. CMA, karyotype, FISH, mtDNA, repeat-expansion testing typically non-contributory (exclude differentials). Brain MRI is key (Z-shaped brainstem, white-matter/cerebellar signature). EEG for epilepsy. No specific biomarker; metabolic/CDG screen normal. Differential diagnosis: ARF1-related NDD, ARFGEF2-related heterotopia, CDGs, other microcephaly–malformation syndromes. No newborn/carrier screening applicable; inherited truncating ARF3 alleles can be benign incidental findings (PMID: 42606787).

11. Outcome/Prognosis

No systematic survival/mortality data; severe cases (drug-resistant epilepsy, profound disability) carry attendant risks. High lifelong morbidity (ID, motor impairment, epilepsy; care dependence). Key prognostic factor = variant class (dominant-negative = markedly more severe). Limited recovery potential; structural brain changes largely fixed; supportive therapy improves function but is not curative.

12. Treatment

No disease-modifying therapy. Supportive/multidisciplinary care (NCIT:C15226): antiseizure medications (NCIT:C264) for often-refractory epilepsy; physical (NCIT:C15534), occupational (NCIT:C15230), and speech (NCIT:C15351) therapy; early intervention/special education; management of feeding, vision, and orthopedic issues. No gene/cell/RNA/targeted/immunotherapy approved or in trials; no ARF3-specific NCT trials; no pharmacogenomic guidance. Personalized care currently limited to variant-class-based prognostic counseling.

13. Prevention

No primary prevention (de novo). Secondary: early surveillance, EEG/MRI, early seizure control and intervention therapy. Tertiary: prevent epilepsy/aspiration/contracture complications. Genetic counseling: ~1% recurrence risk for parents (germline mosaicism); 50% transmission risk from an affected individual; prenatal/PGT feasible if familial variant known. No population/newborn/carrier screening; public-health/environmental interventions not applicable.

14. Other Species / Natural Disease

ARF3 is highly conserved. Orthologs: mouse Arf3 (NCBI Gene 11842; NCBI:txid10090), zebrafish arf3a/arf3b (NCBI:txid7955), Drosophila Arf79F (NCBI:txid7227). No naturally occurring ARF3 disease in animals (not in OMIA); no veterinary relevance or zoonotic potential. Strong conservation of the ARF/Golgi machinery underlies faithful disease modeling.

15. Model Organisms

Model System Key findings PMID
Zebrafish mutant-ARF3 mRNA overexpression Dominant behavior; impaired Golgi integrity in vivo; reduced brain size (recapitulates microcephaly); variant-specific 36369169; 41507605
Drosophila variant expression p.Asp67Val lethal (DN); p.Arg99Leu rough-eye (GoF, like p.Gln71Leu) 34346499
Cellular/in vitro localization, pull-down, GTP/GDP & GGA1 binding, stability Variant functional classification (DN vs GoF) 34346499; 36369169

Strengths: recapitulate Golgi fragmentation and microcephaly; reproduce variant-specific severity. Limitations: overexpression (not knock-in) designs; cognition/epilepsy not directly modeled; no mouse/iPSC/organoid model exists (gap). Resources: ZFIN, FlyBase (Arf79F), MGI (Arf3).

Evidence Base

PMID Title (abbrev.) Evidence type Contribution
34346499 De novo ARF3 variants cause neurodevelopmental disorder with brain abnormality human / in vitro / model First 2 patients; TGN role; DN (p.Asp67Val) vs GoF (p.Arg99Leu) via pull-down and fly models
36369169 Dominant ARF3 variants disrupt Golgi integrity... recapitulated in zebrafish human / in vitro / model Dominant causation; pocket localization; Golgi/trafficking assays; zebrafish microcephaly; neural precursor/PCP mechanism
41507605 Newly identified ARF3 variants strengthen... Golgi fragmentation and brain malformations human / in vitro / model +5 patients, 3 novel variants; zebrafish confirm dominant behavior; DN = severe
38712921 Neurodevelopmental disorder associated with gene ARF3: a case report human Distinctive Z-shaped brainstem MRI; ultrarare status; acquired microcephaly + drug-resistant epilepsy
42606787 De novo NR2F1 variant... (segregation analysis) human Inherited ARF3 p.Arg99* truncating allele is non-causative — argues against haploinsufficiency
37185208 ARF1 de novo variants / periventricular nodular heterotopia human Differential diagnosis; supports shared ARF-family Golgipathy class

Background ARF/Golgi cell-biology support (ARF3 is uniquely activated at the TGN; ARF1/ARF3 occupy distinct TGN nanodomains): PMID: 20357002, PMID: 37102998.

Supported vs Refuted Hypotheses

  • Supported: (i) de novo dominant ARF3 missense variants cause a neurodevelopmental Golgipathy; (ii) mechanism = Golgi fragmentation/trafficking failure impairing neural precursor proliferation and PCP movements; (iii) dominant-negative variants cause the most severe phenotype; (iv) zebrafish/Drosophila recapitulate core features.
  • Refuted / not supported: simple haploinsufficiency as the disease mechanism (an inherited truncating allele is non-causative, PMID: 42606787); any environmental/infectious etiology; existence of any disease-modifying therapy.

Limitations and Knowledge Gaps

  1. Very small sample (<10 patients) limits confidence in genotype–phenotype correlations, penetrance, expressivity, and the full phenotypic range; milder presentations are likely under-ascertained.
  2. No epidemiological estimates (prevalence, incidence, sex ratio) are possible.
  3. No mammalian (mouse) knock-in or iPSC/organoid model exists; current models rely on overexpression in zebrafish/Drosophila and do not directly model cognition or epilepsy.
  4. No biomarkers (biochemical, proteomic, metabolomic) and no formal diagnostic criteria are defined; diagnosis is molecular + radiological.
  5. Mechanistic resolution of how Golgi fragmentation specifically causes PCP and proliferation defects, and why the nervous system is selectively vulnerable, is incomplete.
  6. No therapeutics; whether DN and GoF variants respond to different (mechanism-matched) interventions is untested.
  7. Ontology/clinical coding (ICD, Orphanet, MeSH) for this disorder is not firmly established in the reviewed sources.

Proposed Follow-up Experiments / Actions

  1. Establish an international patient registry and GeneMatcher-driven cohort expansion to refine phenotype, natural history, penetrance, and genotype–phenotype correlations.
  2. Generate endogenous-level mouse knock-in and human iPSC-derived cerebral organoid models of DN (p.Asp67Val) and GoF (p.Arg99Leu) variants to model neurogenesis, microcephaly, and epilepsy, and to serve as preclinical therapeutic platforms.
  3. Mechanism-resolved cell biology: quantitative live-imaging of Golgi dynamics, vesicle trafficking, and PCP cell movements in patient-derived neural precursors; map the ARF3–GGA1/adaptor interactome by proteomics.
  4. Systematic variant functional classification: a standardized assay panel (stability, GTP/GDP binding, Golgi morphology, GGA1 binding) to triage future VUS and build a DN-vs-GoF classifier to inform prognosis.
  5. Single-cell / spatial transcriptomics of model brain to define which neural cell types and developmental windows are most vulnerable (CL/UBERON annotation).
  6. Therapeutic exploration: test whether modulating ARF GTPase cycling or Golgi-stress responses rescues model phenotypes; for GoF alleles, evaluate allele-selective knockdown (ASO/siRNA).
  7. Formalize ontology mapping (confirm/obtain ICD-11, Orphanet, MeSH codes) and complete HPO annotation with frequency data for knowledge-base integration.

Report based on 5 primary clinical/functional publications plus supporting ARF-biology literature (2021–2026). All mechanistic and clinical claims are attributed to the cited PMIDs; evidence types (human clinical, in vitro, model organism) are indicated throughout.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 8
Resolved 8
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 8
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 37
Resolved 36
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 21
Terms named correctly 17
Terms named as a different term 0
Terms whose name is worth a second look 4

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:

  • CL:0000681 (1 mention) - the report calls it "neuroblast/radial glial cell"; CL calls it radial glial cell
  • HP:0012762 (1 mention) - the report calls it "White-matter hypoplasia"; HP calls it Cerebral white matter atrophy
  • HP:0002363 (1 mention) - the report calls it "Z-shaped brainstem"; HP calls it Abnormal brainstem morphology, and lists "Abnormal shape of brainstem" among its other names
  • HP:0000924 (1 mention) - the report calls it "Minor skeletal defects"; HP calls it Abnormality of the skeletal system, and lists "Skeletal anomalies" among its other names

36 of 37 terms resolved to a current term; the rest could not be looked up either way.