Perisylvian Polymicrogyria with Cerebellar Hypoplasia and Arthrogryposis

Mendelian MONDO:0014679 Pathograph 20 Show in embeddings browser PI4KA-related disorder Malformation of cortical development

Perisylvian polymicrogyria with cerebellar hypoplasia and arthrogryposis (PMGYCHA) is the severe, prenatal-onset end of the PI4KA-related disorder spectrum. It is caused by biallelic variants in PI4KA, which encodes phosphatidylinositol 4-kinase IIIalpha — the kinase that performs the first committed step of plasma membrane phosphoinositide metabolism, converting phosphatidylinositol to PI(4)P. PI4KIIIalpha does not act alone: it works as a heterotetramer with TTC7A/B and FAM126A/B, recruited to the plasma membrane by palmitoylated EFR3A/B, and disease variants act either by damaging catalysis directly or by disturbing assembly of that complex. Because PI(4)P is the precursor of PI(4,5)P2 and PI(3,4,5)P3, its depletion degrades membrane identity and signalling across many tissues, and the phenotype tracks which organ-specific arm of the complex a particular allele impairs. The entity named here was delineated in a family in which three fetuses had perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis, and it sits at the lethal end of a spectrum whose milder presentations include hypomyelinating leukodystrophy, multiple intestinal atresia with inflammatory bowel disease, combined immunodeficiency, and adolescent- or adult-onset spastic paraplegia.

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Mappings
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Inheritance
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Pathophys.
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Phenotypes
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Gaps
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Pathograph
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Genes
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Medical Actions
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Differentials
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Models
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References
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Deep Research
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Mappings

MONDO
MONDO:0014679 polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis
skos:exactMatch MONDO
MONDO:1040012 PI4KA-related disorder Not Yet Curated
skos:broadMatch MONDO
MONDO:1040012 is the whole PI4KA allelic spectrum — the same gene also produces hypomyelinating leukodystrophy, multiple intestinal atresia with inflammatory bowel disease, combined immunodeficiency, and late-onset hereditary spastic paraplegia, and GeneReviews treats all of these as one "PI4KA-related disorder". This entry is scoped to the prenatal-onset brain-malformation presentation (MONDO:0014679), so the broader term is a broadMatch and must not retire it from the curation queue.
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Inheritance

1
Autosomal recessive HP:0000007
Biallelic PI4KA variants are required. In the family that delineated this entity the two variants were in trans — a paternally transmitted nonsense allele and a maternally transmitted catalytic-domain missense allele — and segregated with the phenotype. Across the wider PI4KA cohorts no affected individual carries two complete loss-of-function alleles, consistent with complete loss of PI4KIIIalpha activity being incompatible with development.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:25855803 SUPPORT Human Clinical
"In these regions, the only plausibly pathogenic mutations were compound heterozygous variants in PI4KA, which Sanger sequencing confirmed segregated consistent with autosomal recessive inheritance."
Documents biallelic segregation in the family in which this entity was defined.
PMID:35951779 SUPPORT Human Clinical
"GENETIC COUNSELING: PI4KA-related disorder is inherited in an autosomal recessive manner."
GeneReviews states the recessive inheritance pattern for the disorder as a whole.
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Discussions and Knowledge Gaps

1
Why do fetuses with biallelic PI4KA variants develop arthrogryposis, and is it secondary to the brain malformation or an independent consequence of PI(4)P depletion in muscle or motor neurons?
KNOWLEDGE GAP pi4ka_arthrogryposis_mechanism_unknown
Attached to
phenotypes#Arthrogryposis multiplex congenita pathophysiology#Depletion of the Plasma Membrane PI(4)P Pool
Arthrogryposis is one of the three features this entity is named for, but no mechanism has been proposed for it. The obvious explanation is fetal akinesia secondary to the cortical and cerebellar malformation, which is how arthrogryposis arises in many CNS malformation syndromes. That is an inference from the general pathophysiology of fetal akinesia, not something demonstrated for PI4KA: no motor neuron or neuromuscular junction phenotype has been reported in PI4KA patients or in any PI4KA model, and PI(4)P and PI(4,5)P2 have direct roles in ion channel regulation and vesicle release that could plausibly act at the neuromuscular junction independently of the brain lesion. One informative observation does exist and narrows the gap rather than leaving it untouched: fetal skeletal muscle histology in the index family is reported as normal, which argues against a primary myopathy and favours fetal akinesia secondary to neurologic dysfunction. That result is in the full text of the 2015 index report and is recorded here as prose without an evidence item because it cannot currently be quoted - references_cache holds only the abstract of PMID:25855803 (content_type abstract_only; a re-fetch on 2026-09-04 returned the abstract again) and DOI:10.1093/hmg/ddv117 is content_type unavailable. Should the full text become retrievable, this belongs in the entry as a REFUTE item against a primary-myopathy mechanism. What is still open is motor output rather than muscle structure: no electrophysiology and no neuromuscular junction assessment has been reported in an affected fetus. The entry therefore records no causal edge into the arthrogryposis phenotype, and this gap is the reason.
Proposed experiments
Motor neuron and neuromuscular junction assessment in PI4KA fetuses
pi4ka_fetal_motor_unit_assessment
Muscle structure has already been examined in the index family and was normal, so this experiment targets what that observation does not settle. Where a further affected pregnancy is examined, obtain spinal cord histology alongside the brain, count anterior horn motor neurons, and assess neuromuscular junction architecture by alpha-bungarotoxin and neurofilament or synaptic-vesicle staining, testing whether the motor unit is intrinsically abnormal or is structurally intact and merely receiving no descending drive. Repeat muscle histology serves only as an internal control on the earlier normal result.
Would support
phenotypes#Arthrogryposis multiplex congenita
Supporting outcome
  • Motor neuron number or neuromuscular junction architecture is abnormal, indicating a peripheral mechanism additional to fetal akinesia from the brain lesion
Refuting outcome
  • Motor neurons and junctions are structurally normal alongside the already-normal muscle, consistent with arthrogryposis being purely secondary to the CNS malformation
Conditional or hypomorphic Pi4ka allele with fetal movement phenotyping
pi4ka_hypomorph_mouse_movement
Build a hypomorphic or conditional Pi4ka allele that survives gestation (the complete null does not), then phenotype fetal movement by ultrasound and score joint contractures at birth, comparing a CNS-restricted deletion against a muscle- or motor-neuron-restricted deletion to separate the two candidate origins.
Would support
phenotypes#Arthrogryposis multiplex congenita
Supporting outcome
  • Contractures follow CNS-restricted deletion, establishing arthrogryposis as secondary to the brain malformation
Refuting outcome
  • Contractures require peripheral deletion, establishing an independent neuromuscular mechanism
Show evidence (2 references)
PMID:34415310 SUPPORT Human Clinical
"This disorder comprises perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis, and was identified in a small nuclear family with three female foetuses"
Documents arthrogryposis as a defining feature while showing the entity rests on a single family of three fetuses, which is why no neuromuscular data exist.
PMID:34415310 SUPPORT Model Organism
"Accordingly, germline Pi4ka loss of function variants that abolish PI4KIIIα activity are incompatible with embryonic development."
Explains why no mouse model has been available to address the question.
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Pathophysiology

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Biallelic PI4KA Loss-of-Function
PI4KA encodes phosphatidylinositol 4-kinase IIIalpha, the kinase responsible for the predominant plasma membrane pool of PI(4)P. In the family defining this entity the paternal allele is a nonsense variant (p.Arg796Ter) and the maternal allele a missense substitution at a conserved catalytic-domain residue (p.Asp1854Asn); expression studies confirmed that residue is required for kinase activity. Notably, no reported patient carries two complete loss-of-function alleles — total abolition of PI4KIIIalpha activity is incompatible with embryonic development — so the disease-causing genotypes are hypomorphic in aggregate.
PI4KA hgnc:8983 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves decreased PI4KA (hgnc:8983). hgnc:8983 is a gene from the HUGO Gene Nomenclature Committee. ↓ DECREASED
Genetic context variant_origin: GERMLINE zygosity: COMPOUND_HETEROZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
Compound heterozygosity for a nonsense allele and a catalytic-domain missense allele, in trans.
phosphatidylinositol 4-kinase IIIalpha activity GO:0004430 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased phosphatidylinositol 4-kinase IIIalpha activity, annotated with 1-phosphatidylinositol 4-kinase activity (GO:0004430). GO:0004430 is a molecular function from the Gene Ontology. ↓ DECREASED
Animal models
Pi4ka null mouse Mus musculus fails to recapitulate The complete null is embryonic lethal and therefore cannot reproduce the human disease, which depends on residual PI4KIIIalpha activity.
Downstream
Impaired Function of the PI4KIIIalpha-TTC7-FAM126-EFR3 Complex Variants act either by damaging catalysis directly or by perturbing the protein-protein interfaces that assemble and position the holoenzyme.
Show evidence (4 references)
PMID:25855803 SUPPORT Human Clinical
"The paternally transmitted variant predicted a premature stop mutation (c.2386C>T; p.R796X), whereas the maternally transmitted variant predicted a missense substitution (c.5560G>A; p.D1854N) at a conserved residue within the catalytic domain."
Defines the two causal alleles in the family that delineated this entity.
PMID:25855803 SUPPORT In Vitro
"Functional studies using expressed wild-type or mutant PI4KA enzyme confirmed the importance of p.D1854 for kinase activity."
Functional confirmation that the missense allele damages catalysis.
PMID:34415310 SUPPORT In Vitro
"The Asp1854Asn substitution affects the catalytic domain in line with its reduced PI4KIIIα enzymatic activity, impacting both PI4KIIIα-TTC7A and PI4KIIIα-TTC7B complexes."
Independent enzymatic confirmation for the specific allele carried by this entity's index family.
+ 1 more reference
Impaired Function of the PI4KIIIalpha-TTC7-FAM126-EFR3 Complex
PI4KIIIalpha generates PI(4)P only as part of a heterotetramer with TTC7A/B and FAM126A/B, which homodimerizes and is delivered to the plasma membrane by the palmitoylated protein EFR3A/B. Structural work shows the EFR3A C-terminus binding both TTC7B and FAM126A, and that disrupting those interfaces reduces PI4KA recruitment to the membrane — so the complex is the functional unit, not the kinase alone. This architecture also explains why variants in the partner genes phenocopy parts of the PI4KA spectrum: FAM126A variants cause hypomyelinating leukodystrophy and TTC7A variants cause intestinal atresia with immunodeficiency.
plasma membrane GO:0005886 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves plasma membrane (GO:0005886). GO:0005886 is a cellular component from the Gene Ontology.
Downstream
Depletion of the Plasma Membrane PI(4)P Pool A complex that cannot assemble or cannot reach the plasma membrane cannot make PI(4)P where it is needed.
Show evidence (3 references)
PMID:34415310 SUPPORT Other
"PI4KIIIα's role in PI4P generation requires its assembly into a heterotetrameric complex with EFR3, TTC7 and FAM126."
States the requirement for complex assembly.
PMID:39705356 SUPPORT In Vitro
"Fundamental to PI4KA activity is its targeted recruitment to the plasma membrane by the lipidated proteins EFR3A and EFR3B."
Establishes EFR3-mediated membrane recruitment as a requirement for activity.
PMID:39705356 SUPPORT In Vitro
"Multiple posttranslational modifications and disease linked mutations map to this site, providing insight into how PI4KA membrane recruitment can be regulated and disrupted in human disease."
Connects the structural interface to human disease-causing variants.
Depletion of the Plasma Membrane PI(4)P Pool
PI(4)P generated by PI4KIIIalpha is the entry point to plasma membrane phosphoinositide metabolism and the precursor of PI(4,5)P2 and PI(3,4,5)P3, which control membrane identity, ion channel behaviour, trafficking and signalling. In patients, PI4KA protein and PI(4)P are both measurably reduced in fibroblasts, and phosphoinositide species are reduced in peripheral blood mononuclear cells — so the biochemical lesion is demonstrated in patient material, not only inferred from the genotype.
plasma membrane PI(4)P synthesis GO:0046854 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased plasma membrane PI(4)P synthesis, annotated with phosphatidylinositol phosphate biosynthetic process (GO:0046854). GO:0046854 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Pi4ka knockdown zebrafish Danio rerio partially recapitulates Dose reduction rather than abolition of Pi4ka produces developmental defects including brain abnormalities, matching the partial-loss mechanism of the human disease.
Downstream
Impaired Neuronal Migration in the Developing Cerebral Cortex Phosphoinositide signalling is required for the cortical development program whose failure produces polymicrogyria.
Cerebellar hypoplasia The cerebellum is affected alongside the cortex in the same fetuses. No cerebellum-specific mechanism has been demonstrated, so this edge is drawn from the depleted PI(4)P pool directly to the phenotype rather than through a dedicated cerebellar-development node the literature would not support.
Abnormal dentate nucleus morphology The dentate nuclei are dysplastic in the same fetuses. As with the cerebellar hypoplasia edge above, no dentate-specific mechanism has been demonstrated, so the edge runs from the depleted PI(4)P pool straight to the phenotype rather than through a cerebellar-development node the literature would not support.
Impaired Myelination PI4KIIIalpha drives phosphatidylserine transport from the endoplasmic reticulum to the plasma membrane, and phosphatidylserine is a major myelin lipid, so loss of the enzyme disturbs the membrane lipidome from which myelin is built.
Show evidence (3 references)
PMID:34415322 SUPPORT Human Clinical
"PI4KA and PI(4)P levels were significantly diminished in the fibroblasts of five patients."
Direct measurement of reduced PI(4)P in patient cells.
PMID:34415322 SUPPORT Human Clinical
"Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells."
Independent assay confirming reduced kinase activity in two patient cell types.
PMID:34415322 SUPPORT Human Clinical
"Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients' fibroblasts."
Shows the protein itself, not only its product, is reduced in patient cells.
Impaired Neuronal Migration in the Developing Cerebral Cortex
Polymicrogyria is a malformation of cortical development attributed to impaired neuronal migration, producing an excessively folded cortex with too many small gyri and abnormal lamination. In this disorder the migration defect is regional rather than global, concentrating around the sylvian fissures — the perisylvian cortex is among the last regions to complete migration and organization, and is the region most often affected in polymicrogyria of any cause.
migrating cortical neuron CL:0010012 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves migrating cortical neuron, annotated with cerebral cortex neuron (CL:0010012). CL:0010012 is a cell type from the Cell Ontology.
neuron migration GO:0001764 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neuron migration (GO:0001764). GO:0001764 is a biological process from the Gene Ontology. ↓ DECREASED cerebral cortex development GO:0021987 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cerebral cortex development (GO:0021987). GO:0021987 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Perisylvian polymicrogyria The failed migration program is what the polymicrogyric cortex records.
Show evidence (1 reference)
PMID:25855803 SUPPORT Human Clinical
"In this study, exome sequencing in a family where three fetuses had all been diagnosed with PMG and cerebellar hypoplasia allowed us to identify regions of the genome for which both chromosomes were shared identical-by-descent, reducing the search space for causative variants to 8.6% of the genome."
Documents the polymicrogyria phenotype in the three affected fetuses of the index family.
Impaired Myelination
In patients who survive to be imaged, the dominant white matter finding is hypomyelination — a failure to deposit myelin rather than to maintain it — with white matter atrophy and a thin corpus callosum. The same lesion arises from variants in FAM126A, the PI4KIIIalpha complex partner, which cause hypomyelination and congenital cataracts, so this arm of the phenotype is a property of the complex rather than of PI4KA specifically. One patient in an independent PI4KA cohort had bilateral perisylvian polymicrogyria alongside this myelination phenotype, which is what links this node to the present entity rather than only to the milder end of the spectrum.
oligodendrocyte CL:0000128 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves oligodendrocyte (CL:0000128). CL:0000128 is a cell type from the Cell Ontology.
myelination GO:0042552 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased myelination (GO:0042552). GO:0042552 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Schwann-cell-specific Pi4ka conditional knockout mouse Mus musculus partially recapitulates Reproduces the failure to build normal myelin, and the lipid deficit proposed to cause it, in an animal that survives.
Downstream
Thin corpus callosum The thin corpus callosum is reported as part of the same white matter picture as the hypomyelination, in the same patients.
CNS hypomyelination Failure of myelin deposition is what the hypomyelinating MRI pattern shows.
Show evidence (2 references)
PMID:34415310 SUPPORT Human Clinical
"Here we show that biallelic PI4KA sequence alterations in humans are associated with neurological disease, in particular hypomyelinating leukodystrophy."
Establishes hypomyelinating leukodystrophy as the predominant neurological finding in the PI4KA cohort.
PMID:34415322 SUPPORT Human Clinical
"Patients 1 and 2 exhibited diffuse hypomyelination, global white matter atrophy with posterior predominance, a thin corpus callosum and colpocephaly."
Patient-level description of the hypomyelination and associated white matter findings.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Perisylvian Polymicrogyria with Cerebellar Hypoplasia and Arthrogryposis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

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Blood 1
Leukopenia Decreased total leukocyte count HP:0001882 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukopenia, annotated with Decreased total leukocyte count (HP:0001882). HP:0001882 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35951779 SUPPORT Human Clinical
"CLINICAL CHARACTERISTICS: PI4KA-related disorder is a clinically variable disorder characterized primarily by neurologic dysfunction (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus), gastrointestinal manifestations (multiple intestinal atresia,..."
GeneReviews lists leukopenia as part of the combined immunodeficiency.
Digestive 3
Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
4 of 8 developmental-encephalopathy patients in the PMID:34415322 cohort, 2 of whom needed nasogastric feeding in the first weeks of life. No FrequencyEnum band is asserted, for the same denominator reason as the other phenotypes here. This phenotype is the target of the gastrostomy treatment, which previously had nothing in the entry to point at.
Show evidence (2 references)
PMID:34415322 SUPPORT Human Clinical
"Four patients had feeding difficulties in early childhood, and two required nasogastric tube feeding during the first weeks of life."
Quantifies feeding difficulty and tube feeding in the cohort.
PMID:35951779 SUPPORT Human Clinical
"speech-language therapy for speech impairment and/or dysphagia"
GeneReviews management names dysphagia as a manifestation requiring speech-language therapy.
Multiple intestinal atresia Multiple small bowel atresias HP:0004797 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Multiple small bowel atresias (HP:0004797). HP:0004797 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34415310 SUPPORT Human Clinical
"In addition, affected individuals may present with inflammatory bowel disease, multiple intestinal atresia and combined immunodeficiency."
Documents multiple intestinal atresia in the PI4KA cohort.
Inflammatory bowel disease Inflammation of the large intestine HP:0002037 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inflammatory bowel disease, annotated with Inflammation of the large intestine (HP:0002037). HP:0002037 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34415310 SUPPORT Human Clinical
"Five patients with hypomyelinating leukodystrophy were additionally identified, two of whom also had IBD."
Documents IBD in two of five patients with the hypomyelinating presentation.
Eye 1
Nystagmus HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34415310 SUPPORT Human Clinical
"The affected individuals from Families 5–7 all presented with nystagmus, ataxia and lower limb spasticity, and magnetic resonance neuroimaging revealed hypomyelinating leukodystrophy reminiscent of Pelizaeus–Merzbacher-like disease (Fig."
Documents nystagmus in three families.
Head and Neck 1
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.
4 of 10 patients in the PMID:34415322 cohort had a head circumference below -2 SD at last examination, with normal cranial circumference at birth in all; the PMID:34415310 Family 3 child, homozygous for p.(Asp1854Asn) — the maternally transmitted missense allele of the PMID:25855803 index family — was -10 SD. No FrequencyEnum band is asserted. HP:0005484 (Secondary microcephaly) is deliberately not used: it fits the PMID:34415322 cohort, whose head circumference was normal at birth, but the timing is not stated for the -10 SD child, so the more specific term would be narrower than the claim. No incoming causal edge is drawn: no source in this entry attributes the microcephaly to a specific curated node.
Show evidence (2 references)
PMID:34415322 SUPPORT Human Clinical
"four (Patients 2, 3, 6 and 8) had a head circumference less than two standard deviations (SD) below the mean"
Reports head circumference below -2 SD in four patients at last examination.
PMID:34415310 SUPPORT Human Clinical
"This 13-year-old is severely microcephalic (−10 standard deviations) and presented from Day 1 of life with treatment-resistant seizures."
Documents severe microcephaly in the child homozygous for the index family's missense allele.
Immune 1
Combined immunodeficiency HP:0005387 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Combined immunodeficiency (HP:0005387). HP:0005387 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34415310 SUPPORT Human Clinical
"In addition, affected individuals may present with inflammatory bowel disease, multiple intestinal atresia and combined immunodeficiency."
Documents combined immunodeficiency in the PI4KA cohort.
PMID:34415310 SUPPORT Human Clinical
"No putative pathogenic variants in TTC7A or other genes associated with primary immunodeficiency were identified."
Excludes TTC7A as the cause of the immunodeficiency in that patient, attributing it to PI4KA.
Limbs 1
Overlapping fingers HP:0010557 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Overlapping fingers (HP:0010557). HP:0010557 is a phenotype from the Human Phenotype Ontology.
Left with no incoming causal edge, for the same reason as the arthrogryposis phenotype it accompanies: the mechanism that produces the fetal contracture complex in this disorder is not established, and is recorded as a KNOWLEDGE_GAP in `discussions` rather than papered over with a plausible edge.
Show evidence (1 reference)
PMID:34415322 SUPPORT Human Clinical
"Previously, mutations in PI4KA were reported in three foetuses from a single family who showed bilateral polymicrogyria with hypoplasia/dysplasia of the cerebellum, olivary and dentate nucleus abnormalities, joint contractures and overlapping fingers."
Records overlapping fingers in the three affected fetuses of the index family.
Musculoskeletal 3
Arthrogryposis multiplex congenita HP:0002804 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arthrogryposis multiplex congenita (HP:0002804). HP:0002804 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34415310 SUPPORT Human Clinical
"This disorder comprises perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis, and was identified in a small nuclear family with three female foetuses"
Names arthrogryposis as a defining component of this entity.
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.
Axial hypotonia in 7 of 8 developmental-encephalopathy patients in the PMID:34415322 cohort, with severe global hypotonia in the eighth, plus central hypotonia in the PMID:34415310 Family 3 child homozygous for the p.Asp1854Asn allele of the index family. No FrequencyEnum band is asserted: the denominator is one referred series covering the wider PI4KA spectrum, not this entity. HP:0008936 (Axial hypotonia) is deliberately not used, because it would be narrower than the claim, which includes the globally hypotonic patient. No incoming causal edge is drawn: no source attributes the hypotonia to a specific curated node.
Show evidence (1 reference)
PMID:34415322 SUPPORT Human Clinical
"Axial hypotonia with limb spasticity and pyramidal signs were present in all patients except Patient 2, in whom severe global hypotonia predominated and a neurophysiological study performed at 11 months of age showed axonal sensory neuropathy."
Reports axial hypotonia in all but one patient and severe global hypotonia in that one.
Limb spasticity Lower limb spasticity HP:0002061 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lower limb spasticity (HP:0002061). HP:0002061 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34415310 SUPPORT Human Clinical
"The affected individuals from Families 5–7 all presented with nystagmus, ataxia and lower limb spasticity, and magnetic resonance neuroimaging revealed hypomyelinating leukodystrophy reminiscent of Pelizaeus–Merzbacher-like disease (Fig."
Documents lower limb spasticity with nystagmus and ataxia in three families.
Nervous System 9
Perisylvian polymicrogyria HP:0012650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Perisylvian polymicrogyria (HP:0012650). HP:0012650 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34415310 SUPPORT Human Clinical
"This disorder comprises perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis, and was identified in a small nuclear family with three female foetuses"
Names perisylvian polymicrogyria as a defining component of this entity.
PMID:35951779 SUPPORT Human Clinical
"Brain MRI findings can include hypomyelinating leukodystrophy, cerebellar hypoplasia/atrophy, thin or dysplastic corpus callosum, and/or perisylvian polymicrogyria."
GeneReviews lists perisylvian polymicrogyria among the recognized brain MRI findings.
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 (1 reference)
PMID:25855803 SUPPORT Human Clinical
"In this study, exome sequencing in a family where three fetuses had all been diagnosed with PMG and cerebellar hypoplasia allowed us to identify regions of the genome for which both chromosomes were shared identical-by-descent, reducing the search space for causative variants to 8.6% of the genome."
Records cerebellar hypoplasia in all three affected fetuses of the index family.
Abnormal dentate nucleus morphology HP:0100321 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysplastic dentate nuclei, annotated with Abnormal dentate nucleus morphology (HP:0100321). HP:0100321 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34415322 SUPPORT Human Clinical
"Previously, mutations in PI4KA were reported in three foetuses from a single family who showed bilateral polymicrogyria with hypoplasia/dysplasia of the cerebellum, olivary and dentate nucleus abnormalities, joint contractures and overlapping fingers."
A later cohort paper's summary of the index family, recording dentate and olivary nucleus abnormalities in the three affected fetuses.
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:34415322 SUPPORT Human Clinical
"Group 1 patients showed a pattern of marked, diffuse supratentorial and infratentorial hypomyelination associated with white matter atrophy and a thin corpus callosum (Patients 1–4), incomplete/delayed myelination (Patients 5–7) and bilateral perisylvian polymicrogyria (Patient 8)."
Documents hypomyelination in the cohort including the patient with perisylvian polymicrogyria.
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 (1 reference)
PMID:35951779 SUPPORT Human Clinical
"Brain MRI findings can include hypomyelinating leukodystrophy, cerebellar hypoplasia/atrophy, thin or dysplastic corpus callosum, and/or perisylvian polymicrogyria."
GeneReviews lists thin or dysplastic corpus callosum among the MRI findings.
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.
No FrequencyEnum band is asserted. All eight patients of the developmental-encephalopathy group in the PMID:34415322 cohort had global developmental delay in the first 12 months, but that group is a referred series spanning the wider PI4KA spectrum, not an ascertained sample of this entity, and the three index fetuses of PMID:25855803 were terminated before development could be assessed.
Show evidence (1 reference)
PMID:35951779 SUPPORT Human Clinical
"CLINICAL CHARACTERISTICS: PI4KA-related disorder is a clinically variable disorder characterized primarily by neurologic dysfunction (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus), gastrointestinal manifestations (multiple intestinal atresia,..."
GeneReviews clinical characteristics list developmental delay and intellectual disability.
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.
Moderate-to-severe in 7 of the 8 developmental-encephalopathy patients of the PMID:34415322 cohort and mild in 1. No FrequencyEnum band is asserted: that cohort is a referred series spanning the wider PI4KA spectrum rather than an ascertained sample of this entity. No incoming causal edge is drawn: no source in this entry attributes the intellectual disability to a specific one of the curated brain lesions rather than to their combination.
Show evidence (2 references)
PMID:34415322 SUPPORT Human Clinical
"At the last examination (3–19 years of age), all of the patients presented moderate-to-severe intellectual disability, except for Patient 5, in whom intellectual disability was mild."
Reports the severity distribution of intellectual disability across the cohort at last examination.
PMID:35951779 SUPPORT Human Clinical
"CLINICAL CHARACTERISTICS: PI4KA-related disorder is a clinically variable disorder characterized primarily by neurologic dysfunction (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus), gastrointestinal manifestations (multiple intestinal atresia,..."
GeneReviews lists intellectual disability among the core neurologic features.
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
No incoming causal edge from the polymicrogyria node is drawn. A polymicrogyric cortex is a recognized epileptogenic lesion in general, but none of the sources cited in this entry makes that attribution for these patients, and the one description of seizure triggers in the PMID:34415322 cohort ties them to fever and infection rather than to the malformation. The earlier wording of this description asserted the link without a citation and has been removed.
Show evidence (1 reference)
PMID:35951779 SUPPORT Human Clinical
"CLINICAL CHARACTERISTICS: PI4KA-related disorder is a clinically variable disorder characterized primarily by neurologic dysfunction (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus), gastrointestinal manifestations (multiple intestinal atresia,..."
GeneReviews lists seizures among the neurologic features.
Ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34415310 SUPPORT Human Clinical
"The affected individuals from Families 5–7 all presented with nystagmus, ataxia and lower limb spasticity, and magnetic resonance neuroimaging revealed hypomyelinating leukodystrophy reminiscent of Pelizaeus–Merzbacher-like disease (Fig."
Documents ataxia in three families.
🧬

Genetic Associations

1
PI4KA
Gene: PI4KA hgnc:8983 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PI4KA (hgnc:8983). hgnc:8983 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal recessive
Show evidence (3 references)
PMID:34415322 SUPPORT Human Clinical
"Accordingly, the pLI value of PI4KA was 0.00031, and the pRec value was 1, indicating that biallelic deleterious variants in this gene are pathogenic."
Population constraint metrics supporting a recessive disease mechanism.
PMID:34415322 SUPPORT Human Clinical
"Interestingly, 7 of 13 conserved missense/in-frame variants were clustered near the active site of PI4KA in the catalytic and ‘cradle’ domains (Fig."
Documents the clustering of disease variants around the active site.
PMID:34415322 SUPPORT Human Clinical
"Patients 4 and 9 shared one of the truncating variants (p.Thr2053SerfsTer4) but displayed discordant phenotypes."
Documents the discordant phenotypes seen in patients sharing one allele, the basis for the genotype-phenotype note.
💊

Medical Actions

5
Multidisciplinary supportive care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Behavioral / lifestyle
There is no disease-modifying therapy. GeneReviews recommends individualized care by a multidisciplinary team, with annual neurologic, developmental and gastrointestinal assessment, audiology and ophthalmology review through childhood, and monitoring for infection susceptibility.
Show evidence (2 references)
PMID:35951779 SUPPORT Human Clinical
"MANAGEMENT: Treatment: Individualized care by a multidisciplinary team; physical therapy, occupational therapy, mobility aids, and medical management as needed for limb spasticity and motor issues; speech-language therapy for speech impairment and/or dysphagia; communication aids as needed;..."
The GeneReviews management statement for the disorder.
PMID:35951779 SUPPORT Human Clinical
"Surveillance: Neurologic, developmental, and gastrointestinal assessments annually or as needed; consider complete blood count and inflammatory markers annually or as indicated by symptomatology; endoscopy as needed; monitor for increased susceptibility to infection; annual audiology and..."
The GeneReviews surveillance schedule this treatment's description states.
Physical and occupational therapy for spasticity
Action: Physical TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Physical Therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. NCIT:C15302
Platform: Behavioral / lifestyle
Physical therapy, occupational therapy and mobility aids for limb spasticity and motor impairment, the mainstay of management for surviving patients.
Mechanism Target:
Limb spasticity — Directed at the motor consequence rather than at the underlying lipid kinase defect.
Show evidence (1 reference)
PMID:35951779 SUPPORT Human Clinical
"physical therapy, occupational therapy, mobility aids, and medical management as needed for limb spasticity and motor issues"
States that physical and occupational therapy are directed at limb spasticity.
Show evidence (1 reference)
PMID:35951779 SUPPORT Human Clinical
"physical therapy, occupational therapy, mobility aids, and medical management as needed for limb spasticity and motor issues"
GeneReviews recommendation for motor management.
Anti-seizure medication
Action: Anticonvulsant TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Anticonvulsant Therapy (NCIT:C64172). NCIT:C64172 is a clinical intervention from the NCI Thesaurus. NCIT:C64172
Agent: anticonvulsant agent NCIT:C264 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses anticonvulsant agent (NCIT:C264). NCIT:C264 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Standard anti-seizure medication as needed; no agent is specific to this disorder and no PI4KA-specific efficacy data exist.
Mechanism Target:
Seizures — Symptomatic seizure control.
Show evidence (1 reference)
PMID:35951779 SUPPORT Human Clinical
"anti-seizure medication as needed for seizures"
States the indication for anti-seizure medication.
Show evidence (1 reference)
PMID:35951779 SUPPORT Human Clinical
"anti-seizure medication as needed for seizures"
GeneReviews recommendation for seizure management.
Gastrostomy for feeding difficulty
Action: GastrostomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Gastrostomy (NCIT:C52006). NCIT:C52006 is a clinical intervention from the NCI Thesaurus. NCIT:C52006
Platform: Surgery
Gastrostomy as needed for feeding problems and dysphagia, which are common in the severe neurological presentations.
Mechanism Target:
Feeding difficulties — Bypasses the oral route rather than correcting the neurological cause of the dysphagia.
Show evidence (1 reference)
PMID:35951779 SUPPORT Human Clinical
"gastrostomy as needed for feeding issues"
Names feeding difficulty as the indication the gastrostomy addresses.
Show evidence (1 reference)
PMID:35951779 SUPPORT Human Clinical
"gastrostomy as needed for feeding issues"
States the indication for gastrostomy.
Genetic counselling and reproductive options
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Behavioral / lifestyle
Autosomal recessive inheritance carries a 25% recurrence risk per pregnancy. Once the familial variants are known, carrier testing for at-risk relatives and prenatal or preimplantation genetic testing become available — directly relevant here, since the entity was defined in a family that lost three consecutive pregnancies.
Show evidence (2 references)
PMID:35951779 SUPPORT Human Clinical
"Once the PI4KA pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible."
States the reproductive options that follow molecular diagnosis.
PMID:35951779 SUPPORT Human Clinical
"If both parents are known to be heterozygous for a PI4KA pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants."
States the recurrence risk that counselling conveys.
🔬

Diagnosis

3
Fetal or postnatal brain imaging
Prenatal ultrasound or MRI showing polymicrogyria with cerebellar hypoplasia, or postnatal MRI showing hypomyelination, cerebellar hypoplasia or atrophy, a thin or dysplastic corpus callosum, and perisylvian polymicrogyria, raises the possibility of PI4KA-related disease.
Show evidence (1 reference)
PMID:35951779 SUPPORT Human Clinical
"Brain MRI findings can include hypomyelinating leukodystrophy, cerebellar hypoplasia/atrophy, thin or dysplastic corpus callosum, and/or perisylvian polymicrogyria."
GeneReviews lists the recognized neuroimaging findings.
PI4KA molecular genetic testing
The diagnosis is established by identifying biallelic pathogenic PI4KA variants. Because the phenotype overlaps TTC7A- and FAM126A-related disease, a gene panel or exome/genome approach is more useful than single-gene testing.
Show evidence (1 reference)
PMID:35951779 SUPPORT Human Clinical
"DIAGNOSIS/TESTING: The diagnosis of PI4KA-related disorder is established in a proband with characteristic features and biallelic PI4KA pathogenic variants identified by molecular genetic testing."
States the molecular diagnostic criterion.
PI4KA and PI(4)P assay in patient fibroblasts
Western blot and immunofluorescence for PI4KA, immunofluorescence against the PI(4)P head group, and targeted phosphoinositide lipidomics on fibroblasts or PBMCs all show reduced values in patients. These are research assays, but the authors propose them as candidate diagnostic and prognostic biomarkers.
Show evidence (1 reference)
PMID:34415322 SUPPORT Human Clinical
"PIP levels were reduced in the PBMCs of four patients, and specifically PI(4)P was diminished as shown in fibroblasts of five patients, suggesting that their use as biomarkers for diagnosis and prognosis may be indicated."
Proposes the phosphoinositide measurements as diagnostic and prognostic biomarkers.
📊

Prevalence

1
Worldwide
Unknown Ultra Rare
No population-based estimate exists. This specific prenatal-onset presentation was reported in one family with three affected fetuses (PMID:25855803); a second family carrying the same p.Asp1854Asn allele was subsequently reported (PMID:34415310), and one of ten patients in an independent PI4KA cohort had bilateral perisylvian polymicrogyria (PMID:34415322). The wider PI4KA-related disorder had roughly two dozen published patients as of the 2021-2022 reports. No numerator/denominator for a population rate is available, so no numeric rate is asserted here.
Show evidence (1 reference)
PMID:34415310 SUPPORT Human Clinical
"This disorder comprises perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis, and was identified in a small nuclear family with three female foetuses"
Records that the entity rests on a single small family of three affected fetuses, the basis for treating it as ultra-rare.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Perisylvian Polymicrogyria with Cerebellar Hypoplasia and Arthrogryposis:

Other phosphoinositide-pathway polymicrogyria
Overlapping Features Variants in PIK3CA, PIK3R2, AKT3 and FIG4 — all in phosphoinositide metabolism or its downstream signalling — also cause polymicrogyria, with or without megalencephaly and capillary malformation. Megalencephaly and the mosaic, somatic pattern of the PIK3CA/AKT3 disorders are the main discriminators from the recessive, non-overgrowth PI4KA phenotype.
Show evidence (1 reference)
PMID:34415322 SUPPORT Human Clinical
"For instance, variants in the PIK3CA, PIK3R2, AKT3, and FIG4 genes have been linked to the development of polymicrogyria, which can be associated or not with megalencephaly and capillary malformation,5,9–12 and PI4K2A variants have been associated with intellectual disability and epilepsy."
Lists the other phosphoinositide-pathway genes that cause polymicrogyria.
🐁

Animal Models

3
Pi4ka null mouse KNOCKOUT
Germline Pi4ka loss-of-function in the mouse abolishes PI4KIIIalpha activity and is incompatible with embryonic development. This is a negative result with real explanatory force: it is why every reported human patient carries at least one hypomorphic allele, and it means the complete null cannot be used to model this disease.
Species
Mus musculus
Genotype
Pi4ka germline loss-of-function
Genes
PI4KA hgnc:8983 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns PI4KA (hgnc:8983). hgnc:8983 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:34415310
Pathograph links
Biallelic PI4KA Loss-of-Function fails to recapitulate fidelity: low The complete null is embryonic lethal and therefore cannot reproduce the human disease, which depends on residual PI4KIIIalpha activity.
Limitations: Because homozygous null embryos do not develop, the model yields no information about cortical migration, cerebellar development or arthrogryposis. Modelling this disorder requires a hypomorphic or conditional allele. Conditional Pi4ka alleles do exist and have been used tissue-specifically — the Schwann-cell-specific deletion curated below is one — but no conditional allele directed at the developing CNS, and no knock-in of a patient missense variant such as p.Asp1854Asn, has been reported.
Show evidence (1 reference)
PMID:34415310 SUPPORT Model Organism
"Accordingly, germline Pi4ka loss of function variants that abolish PI4KIIIα activity are incompatible with embryonic development."
Documents that the complete murine null does not survive to model the human phenotype.
Show evidence (1 reference)
PMID:34415310 SUPPORT Model Organism
"Accordingly, germline Pi4ka loss of function variants that abolish PI4KIIIα activity are incompatible with embryonic development."
Establishes the embryonic lethality that constrains modelling of this disorder.
Schwann-cell-specific Pi4ka conditional knockout mouse KNOCKOUT
Deleting Pi4ka only in Schwann cells escapes the embryonic lethality of the germline null and produces a viable animal with a myelination phenotype: sciatic nerves show substantially reduced myelin thickness, impaired nerve conduction and motor deficits, with phosphatidylserine and phosphatidylethanolamine disproportionately depleted from the myelin lipid content. This is the model that grounds the phosphatidylserine arm of the myelination mechanism in vivo.
Species
Mus musculus
Genotype
Pi4ka conditional deletion restricted to Schwann cells
Genes
PI4KA hgnc:8983 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns PI4KA (hgnc:8983). hgnc:8983 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:29874576
Pathograph links
Impaired Myelination partially recapitulates fidelity: moderate Reproduces the failure to build normal myelin, and the lipid deficit proposed to cause it, in an animal that survives.
Limitations: The deletion is restricted to Schwann cells, so the lesion is in the peripheral nervous system while the human disease is dominated by central hypomyelination in oligodendrocytes; peripheral neuropathy was found in only one of the reported PI4KA patients. It is also a complete deletion within that lineage rather than the partial loss the human hypomorphic genotypes produce, and it says nothing about cortical migration, cerebellar development or arthrogryposis.
Readouts
Sciatic nerve myelin thickness and nerve conduction
Direction: DECREASED
Interpretation: Loss of PI4KA in a myelinating cell is by itself sufficient to produce thin myelin with a functional deficit.
Show evidence (1 reference)
PMID:29874576 SUPPORT Model Organism
"sciatic nerves of mice lacking phosphatidylinositol 4-kinase alpha (PI4KA) in Schwann cells (SCs) show substantially reduced myelin thickness with grave consequences on nerve conductivity and motor functions"
Reports the myelin thickness and nerve conduction measurements in the conditional knockout.
Myelin phosphatidylserine content in mutant nerve
Direction: DECREASED
Interpretation: Identifies the specific lipid deficit that links PI(4)P depletion to defective myelin.
Show evidence (1 reference)
PMID:29874576 SUPPORT Model Organism
"PI4KA inactivation disproportionally reduced phosphatidylserine, phosphatidylethanolamine, and sphingomyelin content in mutant nerves, with similar changes observed in SCs treated with a PI4KA inhibitor."
Quantifies the phosphatidylserine and phosphatidylethanolamine deficit in mutant nerve.
Show evidence (1 reference)
PMID:34415310 SUPPORT Model Organism
"Mice with a Schwann cell-specific Pi4ka deletion display neuropathy motor symptoms and severe myelination defects, with significantly reduced myelin thickness and lipid content most severely affecting phosphatidylserine and phosphatidylethanolamine, two major myelin components."
The PI4KA patient cohort paper cites this model as the in vivo support for the myelination mechanism it proposes.
Show evidence (1 reference)
PMID:29874576 SUPPORT Model Organism
"sciatic nerves of mice lacking phosphatidylinositol 4-kinase alpha (PI4KA) in Schwann cells (SCs) show substantially reduced myelin thickness with grave consequences on nerve conductivity and motor functions"
Establishes that the conditional knockout is viable and has a myelination phenotype, which is what makes it usable where the germline null is not.
Pi4ka knockdown zebrafish KNOCKDOWN
Knockdown rather than knockout, which is what makes it usable: partial reduction of Pi4ka in zebrafish produces multiple developmental defects including brain abnormalities, mirroring the hypomorphic human genotypes.
Species
Danio rerio
Genotype
Pi4ka morpholino knockdown
Genes
PI4KA hgnc:8983 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns PI4KA (hgnc:8983). hgnc:8983 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:34415322
Pathograph links
Depletion of the Plasma Membrane PI(4)P Pool partially recapitulates fidelity: moderate Dose reduction rather than abolition of Pi4ka produces developmental defects including brain abnormalities, matching the partial-loss mechanism of the human disease.
Limitations: Morpholino knockdown is transient and carries well-known off-target and toxicity risks; the reported phenotype is described at the level of gross developmental defects, with the most prominent being loss of pectoral fins rather than a cortical malformation, and teleosts have no gyrencephalic cortex in which polymicrogyria could be modelled at all.
Readouts
Gross developmental defects after Pi4ka knockdown
Direction: ALTERED
Interpretation: Partial Pi4ka reduction is sufficient to derange development, supporting dose-dependence of the human phenotype.
Show evidence (1 reference)
PMID:34415322 SUPPORT Model Organism
"downregulation of Pi4ka expression in zebrafish leads to multiple developmental defects affecting the brain, heart, trunk and most prominently the loss of pectoral fins, while the Pi4ka orthologue knockout is lethal in flies, mice and yeast."
Reports the knockdown phenotype and contrasts it with the lethality of complete knockout.
Show evidence (1 reference)
PMID:34415322 SUPPORT Model Organism
"Animal models in which PI4KA homologues are inactivated show profound abnormalities: downregulation of Pi4ka expression in zebrafish leads to multiple developmental defects affecting the brain, heart, trunk and most prominently the loss of pectoral fins, while the Pi4ka orthologue knockout is..."
Supports treating the zebrafish knockdown as informative for partial PI4KA loss.
{ }

Source YAML

click to show 
name: Perisylvian Polymicrogyria with Cerebellar Hypoplasia and Arthrogryposis
creation_date: "2026-09-03T00:00:00Z"
category: Mendelian
description: >
  Perisylvian polymicrogyria with cerebellar hypoplasia and arthrogryposis
  (PMGYCHA) is the severe, prenatal-onset end of the PI4KA-related disorder
  spectrum. It is caused by biallelic variants in PI4KA, which encodes
  phosphatidylinositol 4-kinase IIIalpha — the kinase that performs the first
  committed step of plasma membrane phosphoinositide metabolism, converting
  phosphatidylinositol to PI(4)P. PI4KIIIalpha does not act alone: it works as a
  heterotetramer with TTC7A/B and FAM126A/B, recruited to the plasma membrane by
  palmitoylated EFR3A/B, and disease variants act either by damaging catalysis
  directly or by disturbing assembly of that complex. Because PI(4)P is the
  precursor of PI(4,5)P2 and PI(3,4,5)P3, its depletion degrades membrane
  identity and signalling across many tissues, and the phenotype tracks which
  organ-specific arm of the complex a particular allele impairs. The entity
  named here was delineated in a family in which three fetuses had perisylvian
  polymicrogyria, cerebellar hypoplasia and arthrogryposis, and it sits at the
  lethal end of a spectrum whose milder presentations include hypomyelinating
  leukodystrophy, multiple intestinal atresia with inflammatory bowel disease,
  combined immunodeficiency, and adolescent- or adult-onset spastic paraplegia.
disease_term:
  preferred_term: Perisylvian polymicrogyria with cerebellar hypoplasia and arthrogryposis
  term:
    id: MONDO:0014679
    label: polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0014679
      label: polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
  - term:
      id: MONDO:1040012
      label: PI4KA-related disorder
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >
      MONDO:1040012 is the whole PI4KA allelic spectrum — the same gene also
      produces hypomyelinating leukodystrophy, multiple intestinal atresia with
      inflammatory bowel disease, combined immunodeficiency, and late-onset
      hereditary spastic paraplegia, and GeneReviews treats all of these as one
      "PI4KA-related disorder". This entry is scoped to the prenatal-onset
      brain-malformation presentation (MONDO:0014679), so the broader term is a
      broadMatch and must not retire it from the curation queue.
parents:
- PI4KA-related disorder
- Malformation of cortical development
synonyms:
- PMGYCHA
- Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis
- PI4KA-related perisylvian polymicrogyria
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    Biallelic PI4KA variants are required. In the family that delineated this
    entity the two variants were in trans — a paternally transmitted nonsense
    allele and a maternally transmitted catalytic-domain missense allele — and
    segregated with the phenotype. Across the wider PI4KA cohorts no affected
    individual carries two complete loss-of-function alleles, consistent with
    complete loss of PI4KIIIalpha activity being incompatible with development.
  evidence:
  - reference: PMID:25855803
    reference_title: "Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In these regions, the only plausibly pathogenic mutations were compound heterozygous variants in PI4KA, which Sanger sequencing confirmed segregated consistent with autosomal recessive inheritance."
    explanation: Documents biallelic segregation in the family in which this entity was defined.
  - reference: PMID:35951779
    reference_title: PI4KA-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GENETIC COUNSELING: PI4KA-related disorder is inherited in an autosomal recessive manner."
    explanation: GeneReviews states the recessive inheritance pattern for the disorder as a whole.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: ULTRA_RARE
  notes: >
    No population-based estimate exists. This specific prenatal-onset
    presentation was reported in one family with three affected fetuses
    (PMID:25855803); a second family carrying the same p.Asp1854Asn allele was
    subsequently reported (PMID:34415310), and one of ten patients in an
    independent PI4KA cohort had bilateral perisylvian polymicrogyria
    (PMID:34415322). The wider PI4KA-related disorder had roughly two dozen
    published patients as of the 2021-2022 reports. No numerator/denominator for
    a population rate is available, so no numeric rate is asserted here.
  evidence:
  - reference: PMID:34415310
    reference_title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This disorder comprises perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis, and was identified in a small nuclear family with three female foetuses"
    explanation: Records that the entity rests on a single small family of three affected fetuses, the basis for treating it as ultra-rare.
pathophysiology:
- name: Biallelic PI4KA Loss-of-Function
  biological_scale: MOLECULAR
  description: >
    PI4KA encodes phosphatidylinositol 4-kinase IIIalpha, the kinase responsible
    for the predominant plasma membrane pool of PI(4)P. In the family defining
    this entity the paternal allele is a nonsense variant (p.Arg796Ter) and the
    maternal allele a missense substitution at a conserved catalytic-domain
    residue (p.Asp1854Asn); expression studies confirmed that residue is required
    for kinase activity. Notably, no reported patient carries two complete
    loss-of-function alleles — total abolition of PI4KIIIalpha activity is
    incompatible with embryonic development — so the disease-causing genotypes
    are hypomorphic in aggregate.
  genetic_context:
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    zygosity: COMPOUND_HETEROZYGOUS
    description: >-
      Compound heterozygosity for a nonsense allele and a catalytic-domain
      missense allele, in trans.
  gene:
    preferred_term: PI4KA
    modifier: DECREASED
    term:
      id: hgnc:8983
      label: PI4KA
  molecular_functions:
  - preferred_term: phosphatidylinositol 4-kinase IIIalpha activity
    modifier: DECREASED
    term:
      id: GO:0004430
      label: 1-phosphatidylinositol 4-kinase activity
  downstream:
  - target: Impaired Function of the PI4KIIIalpha-TTC7-FAM126-EFR3 Complex
    description: >
      Variants act either by damaging catalysis directly or by perturbing the
      protein-protein interfaces that assemble and position the holoenzyme.
    evidence:
    - reference: PMID:34415310
      reference_title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Our cellular, biochemical and structural modelling studies indicate that PI4KA-associated phenotypical outcomes probably stem from impairment of PI4KIIIα-TTC7-FAM126's organ-specific functions, due to defective catalytic activity or altered intra-complex functional interactions."
      explanation: States the two mechanisms by which PI4KA variants disable the holoenzyme.
  evidence:
  - reference: PMID:25855803
    reference_title: "Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The paternally transmitted variant predicted a premature stop mutation (c.2386C>T; p.R796X), whereas the maternally transmitted variant predicted a missense substitution (c.5560G>A; p.D1854N) at a conserved residue within the catalytic domain."
    explanation: Defines the two causal alleles in the family that delineated this entity.
  - reference: PMID:25855803
    reference_title: "Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional studies using expressed wild-type or mutant PI4KA enzyme confirmed the importance of p.D1854 for kinase activity."
    explanation: Functional confirmation that the missense allele damages catalysis.
  - reference: PMID:34415310
    reference_title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The Asp1854Asn substitution affects the catalytic domain in line with its reduced PI4KIIIα enzymatic activity, impacting both PI4KIIIα-TTC7A and PI4KIIIα-TTC7B complexes."
    explanation: Independent enzymatic confirmation for the specific allele carried by this entity's index family.
  - reference: PMID:34415322
    reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients harbouring one loss-of-function variant were compound heterozygotes with a missense or in-frame variant, with no patients harbouring two loss-of-function variants."
    explanation: Establishes that biallelic complete loss of function is not observed, supporting the hypomorphic-genotype claim.
- name: Impaired Function of the PI4KIIIalpha-TTC7-FAM126-EFR3 Complex
  biological_scale: MOLECULAR
  description: >
    PI4KIIIalpha generates PI(4)P only as part of a heterotetramer with TTC7A/B
    and FAM126A/B, which homodimerizes and is delivered to the plasma membrane by
    the palmitoylated protein EFR3A/B. Structural work shows the EFR3A C-terminus
    binding both TTC7B and FAM126A, and that disrupting those interfaces reduces
    PI4KA recruitment to the membrane — so the complex is the functional unit,
    not the kinase alone. This architecture also explains why variants in the
    partner genes phenocopy parts of the PI4KA spectrum: FAM126A variants cause
    hypomyelinating leukodystrophy and TTC7A variants cause intestinal atresia
    with immunodeficiency.
  cellular_components:
  - preferred_term: plasma membrane
    term:
      id: GO:0005886
      label: plasma membrane
  downstream:
  - target: Depletion of the Plasma Membrane PI(4)P Pool
    description: >
      A complex that cannot assemble or cannot reach the plasma membrane cannot
      make PI(4)P where it is needed.
    evidence:
    - reference: PMID:39705356
      reference_title: Molecular basis for plasma membrane recruitment of PI4KA by EFR3.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Complex disrupting mutations in TTC7B, FAM126A, and EFR3 decrease PI4KA recruitment to the plasma membrane."
      explanation: Shows directly that damaging the complex interfaces reduces the kinase's delivery to its site of action.
  evidence:
  - reference: PMID:34415310
    reference_title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PI4KIIIα's role in PI4P generation requires its assembly into a heterotetrameric complex with EFR3, TTC7 and FAM126."
    explanation: States the requirement for complex assembly.
  - reference: PMID:39705356
    reference_title: Molecular basis for plasma membrane recruitment of PI4KA by EFR3.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Fundamental to PI4KA activity is its targeted recruitment to the plasma membrane by the lipidated proteins EFR3A and EFR3B."
    explanation: Establishes EFR3-mediated membrane recruitment as a requirement for activity.
  - reference: PMID:39705356
    reference_title: Molecular basis for plasma membrane recruitment of PI4KA by EFR3.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Multiple posttranslational modifications and disease linked mutations map to this site, providing insight into how PI4KA membrane recruitment can be regulated and disrupted in human disease."
    explanation: Connects the structural interface to human disease-causing variants.
- name: Depletion of the Plasma Membrane PI(4)P Pool
  biological_scale: CELLULAR
  description: >
    PI(4)P generated by PI4KIIIalpha is the entry point to plasma membrane
    phosphoinositide metabolism and the precursor of PI(4,5)P2 and PI(3,4,5)P3,
    which control membrane identity, ion channel behaviour, trafficking and
    signalling. In patients, PI4KA protein and PI(4)P are both measurably reduced
    in fibroblasts, and phosphoinositide species are reduced in peripheral blood
    mononuclear cells — so the biochemical lesion is demonstrated in patient
    material, not only inferred from the genotype.
  biological_processes:
  - preferred_term: plasma membrane PI(4)P synthesis
    modifier: DECREASED
    term:
      id: GO:0046854
      label: phosphatidylinositol phosphate biosynthetic process
  downstream:
  - target: Impaired Neuronal Migration in the Developing Cerebral Cortex
    description: >
      Phosphoinositide signalling is required for the cortical development
      program whose failure produces polymicrogyria.
    evidence:
    - reference: PMID:25855803
      reference_title: "Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our results emphasize the importance of phosphoinositide signalling in early brain development."
      explanation: The authors' own conclusion linking the phosphoinositide lesion to the brain malformation.
  - target: Cerebellar hypoplasia
    description: >
      The cerebellum is affected alongside the cortex in the same fetuses. No
      cerebellum-specific mechanism has been demonstrated, so this edge is drawn
      from the depleted PI(4)P pool directly to the phenotype rather than through
      a dedicated cerebellar-development node the literature would not support.
    evidence:
    - reference: PMID:25855803
      reference_title: "Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our results emphasize the importance of phosphoinositide signalling in early brain development."
      explanation: >
        The authors attribute the whole malformation, cerebellar hypoplasia
        included, to the phosphoinositide lesion. The step from a general
        early-brain-development requirement to the cerebellar phenotype
        specifically is an inference; no cerebellum-specific experiment is
        reported.
      directness: INDIRECT
  - target: Abnormal dentate nucleus morphology
    description: >
      The dentate nuclei are dysplastic in the same fetuses. As with the
      cerebellar hypoplasia edge above, no dentate-specific mechanism has been
      demonstrated, so the edge runs from the depleted PI(4)P pool straight to
      the phenotype rather than through a cerebellar-development node the
      literature would not support.
    evidence:
    - reference: PMID:34415322
      reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Previously, mutations in PI4KA were reported in three foetuses from a single family who showed bilateral polymicrogyria with hypoplasia/dysplasia of the cerebellum, olivary and dentate nucleus abnormalities, joint contractures and overlapping fingers."
      explanation: >-
        Records the dentate nucleus abnormality in the affected fetuses. The
        step from the phosphoinositide lesion to this specific cerebellar
        nucleus is an inference; no dentate-specific experiment is reported.
      directness: INDIRECT
  - target: Impaired Myelination
    description: >
      PI4KIIIalpha drives phosphatidylserine transport from the endoplasmic
      reticulum to the plasma membrane, and phosphatidylserine is a major myelin
      lipid, so loss of the enzyme disturbs the membrane lipidome from which
      myelin is built.
    evidence:
    - reference: PMID:34415310
      reference_title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "PI4KIIIα has been described as a major factor driving phosphatidylserine transport from the endoplasmic reticulum to the plasma membrane"
      explanation: States the phosphatidylserine-transport role of PI4KIIIalpha that the node description asserts.
    - reference: PMID:29874576
      reference_title: Schwann-Cell-Specific Deletion of Phosphatidylinositol 4-Kinase Alpha Causes Aberrant Myelination.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "PI4KA inactivation disproportionally reduced phosphatidylserine, phosphatidylethanolamine, and sphingomyelin content in mutant nerves, with similar changes observed in SCs treated with a PI4KA inhibitor."
      explanation: Shows in vivo that losing PI4KA depletes phosphatidylserine in myelinating nerve, closing the step from PI(4)P depletion to a myelin lipid deficit.
    - reference: PMID:34415322
      reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "PI4KA malfunction may lead to disturbances in the brain cell membrane lipidome, resulting in aberrant myelination."
      explanation: >
        States the proposed route from PI(4)P depletion to abnormal myelination.
        The authors frame it as a mechanism the data are consistent with rather
        than one they demonstrate, so the edge is indirect.
      directness: INDIRECT
  evidence:
  - reference: PMID:34415322
    reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PI4KA and PI(4)P levels were significantly diminished in the fibroblasts of five patients."
    explanation: Direct measurement of reduced PI(4)P in patient cells.
  - reference: PMID:34415322
    reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells."
    explanation: Independent assay confirming reduced kinase activity in two patient cell types.
  - reference: PMID:34415322
    reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients' fibroblasts."
    explanation: Shows the protein itself, not only its product, is reduced in patient cells.
- name: Impaired Neuronal Migration in the Developing Cerebral Cortex
  biological_scale: CELLULAR
  description: >
    Polymicrogyria is a malformation of cortical development attributed to
    impaired neuronal migration, producing an excessively folded cortex with too
    many small gyri and abnormal lamination. In this disorder the migration
    defect is regional rather than global, concentrating around the sylvian
    fissures — the perisylvian cortex is among the last regions to complete
    migration and organization, and is the region most often affected in
    polymicrogyria of any cause.
  cell_types:
  - preferred_term: migrating cortical neuron
    term:
      id: CL:0010012
      label: cerebral cortex neuron
  biological_processes:
  - preferred_term: neuron migration
    modifier: DECREASED
    term:
      id: GO:0001764
      label: neuron migration
  - preferred_term: cerebral cortex development
    modifier: ABNORMAL
    term:
      id: GO:0021987
      label: cerebral cortex development
  downstream:
  - target: Perisylvian polymicrogyria
    description: >
      The failed migration program is what the polymicrogyric cortex records.
    evidence:
    - reference: PMID:25855803
      reference_title: "Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Polymicrogyria (PMG) is a structural brain abnormality involving the cerebral cortex that results from impaired neuronal migration and although several genes have been implicated, many cases remain unsolved."
      explanation: States that polymicrogyria results from impaired neuronal migration.
  evidence:
  - reference: PMID:25855803
    reference_title: "Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, exome sequencing in a family where three fetuses had all been diagnosed with PMG and cerebellar hypoplasia allowed us to identify regions of the genome for which both chromosomes were shared identical-by-descent, reducing the search space for causative variants to 8.6% of the genome."
    explanation: Documents the polymicrogyria phenotype in the three affected fetuses of the index family.
- name: Impaired Myelination
  biological_scale: TISSUE
  description: >
    In patients who survive to be imaged, the dominant white matter finding is
    hypomyelination — a failure to deposit myelin rather than to maintain it —
    with white matter atrophy and a thin corpus callosum. The same lesion arises
    from variants in FAM126A, the PI4KIIIalpha complex partner, which cause
    hypomyelination and congenital cataracts, so this arm of the phenotype is a
    property of the complex rather than of PI4KA specifically. One patient in an
    independent PI4KA cohort had bilateral perisylvian polymicrogyria alongside
    this myelination phenotype, which is what links this node to the present
    entity rather than only to the milder end of the spectrum.
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  biological_processes:
  - preferred_term: myelination
    modifier: DECREASED
    term:
      id: GO:0042552
      label: myelination
  downstream:
  - target: Thin corpus callosum
    description: >
      The thin corpus callosum is reported as part of the same white matter
      picture as the hypomyelination, in the same patients.
    evidence:
    - reference: PMID:34415322
      reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Group 1 patients showed a pattern of marked, diffuse supratentorial and infratentorial hypomyelination associated with white matter atrophy and a thin corpus callosum (Patients 1–4), incomplete/delayed myelination (Patients 5–7) and bilateral perisylvian polymicrogyria (Patient 8)."
      explanation: >
        Reports the thin corpus callosum as associated with the hypomyelination
        and white matter atrophy in the same patients. The source states an
        association within one imaging pattern, not a demonstrated causal
        sequence, so this edge is indirect.
      directness: INDIRECT
  - target: CNS hypomyelination
    description: >
      Failure of myelin deposition is what the hypomyelinating MRI pattern shows.
    evidence:
    - reference: PMID:34415322
      reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Group 1 patients showed a pattern of marked, diffuse supratentorial and infratentorial hypomyelination associated with white matter atrophy and a thin corpus callosum (Patients 1–4), incomplete/delayed myelination (Patients 5–7) and bilateral perisylvian polymicrogyria (Patient 8)."
      explanation: Describes the hypomyelination pattern and places perisylvian polymicrogyria in the same patient group.
  evidence:
  - reference: PMID:34415310
    reference_title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we show that biallelic PI4KA sequence alterations in humans are associated with neurological disease, in particular hypomyelinating leukodystrophy."
    explanation: Establishes hypomyelinating leukodystrophy as the predominant neurological finding in the PI4KA cohort.
  - reference: PMID:34415322
    reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients 1 and 2 exhibited diffuse hypomyelination, global white matter atrophy with posterior predominance, a thin corpus callosum and colpocephaly."
    explanation: Patient-level description of the hypomyelination and associated white matter findings.
phenotypes:
- category: Neurologic
  name: Perisylvian polymicrogyria
  description: >
    Excessive, abnormally small cortical folding concentrated around the sylvian
    fissures — the defining brain malformation of this entity and the finding for
    which it is named.
  diagnostic: true
  phenotype_term:
    preferred_term: Perisylvian polymicrogyria
    term:
      id: HP:0012650
      label: Perisylvian polymicrogyria
  evidence:
  - reference: PMID:34415310
    reference_title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This disorder comprises perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis, and was identified in a small nuclear family with three female foetuses"
    explanation: Names perisylvian polymicrogyria as a defining component of this entity.
  - reference: PMID:35951779
    reference_title: PI4KA-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI findings can include hypomyelinating leukodystrophy, cerebellar hypoplasia/atrophy, thin or dysplastic corpus callosum, and/or perisylvian polymicrogyria."
    explanation: GeneReviews lists perisylvian polymicrogyria among the recognized brain MRI findings.
- category: Neurologic
  name: Cerebellar hypoplasia
  description: >
    Underdevelopment of the cerebellum, present in all three fetuses of the index
    family and part of the defining triad.
  diagnostic: true
  phenotype_term:
    preferred_term: Cerebellar hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
  evidence:
  - reference: PMID:25855803
    reference_title: "Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, exome sequencing in a family where three fetuses had all been diagnosed with PMG and cerebellar hypoplasia allowed us to identify regions of the genome for which both chromosomes were shared identical-by-descent, reducing the search space for causative variants to 8.6% of the genome."
    explanation: Records cerebellar hypoplasia in all three affected fetuses of the index family.
- category: Neurologic
  name: Abnormal dentate nucleus morphology
  description: >
    Dysplasia of the cerebellar dentate nuclei in the fetuses of the index
    family, reported alongside abnormalities of the olivary nuclei. The olivary
    finding is not separately curated: HPO has no morphology term for the
    inferior olivary nucleus. Searching the ontology for "olivary", "olive" and
    "inferior olivary" returns only Olivary degeneration (HP:0008303),
    Olivopontocerebellar atrophy, Olivopontocerebellar hypoplasia and Superior
    olive hypertrophy, none of which describes a dysplastic inferior olive in a
    fetus, so binding one would be a worse claim than leaving it in prose.
  phenotype_term:
    preferred_term: Dysplastic dentate nuclei
    term:
      id: HP:0100321
      label: Abnormal dentate nucleus morphology
  evidence:
  - reference: PMID:34415322
    reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously, mutations in PI4KA were reported in three foetuses from a single family who showed bilateral polymicrogyria with hypoplasia/dysplasia of the cerebellum, olivary and dentate nucleus abnormalities, joint contractures and overlapping fingers."
    explanation: >-
      A later cohort paper's summary of the index family, recording dentate and
      olivary nucleus abnormalities in the three affected fetuses.
- category: Musculoskeletal
  name: Arthrogryposis multiplex congenita
  description: >
    Multiple congenital joint contractures, the third component of the defining
    triad. Its mechanism in this disorder is not established — see the knowledge
    gap recorded in `discussions`.
  diagnostic: true
  phenotype_term:
    preferred_term: Arthrogryposis multiplex congenita
    term:
      id: HP:0002804
      label: Arthrogryposis multiplex congenita
  evidence:
  - reference: PMID:34415310
    reference_title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This disorder comprises perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis, and was identified in a small nuclear family with three female foetuses"
    explanation: Names arthrogryposis as a defining component of this entity.
- category: Musculoskeletal
  name: Overlapping fingers
  description: >
    Overlapping fingers in the fetuses of the index family, part of the fetal
    contracture complex alongside the arthrogryposis rather than a separate
    malformation.
  phenotype_term:
    preferred_term: Overlapping fingers
    term:
      id: HP:0010557
      label: Overlapping fingers
  notes: >
    Left with no incoming causal edge, for the same reason as the arthrogryposis
    phenotype it accompanies: the mechanism that produces the fetal contracture
    complex in this disorder is not established, and is recorded as a
    KNOWLEDGE_GAP in `discussions` rather than papered over with a plausible
    edge.
  evidence:
  - reference: PMID:34415322
    reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously, mutations in PI4KA were reported in three foetuses from a single family who showed bilateral polymicrogyria with hypoplasia/dysplasia of the cerebellum, olivary and dentate nucleus abnormalities, joint contractures and overlapping fingers."
    explanation: >-
      Records overlapping fingers in the three affected fetuses of the index
      family.
- category: Neurologic
  name: CNS hypomyelination
  description: >
    Diffuse supratentorial and infratentorial hypomyelination on MRI in patients
    who survive to be imaged, often with white matter atrophy. Not assessable in
    the terminated fetuses of the index family, but present in a PI4KA patient
    who also had bilateral perisylvian polymicrogyria.
  phenotype_term:
    preferred_term: CNS hypomyelination
    term:
      id: HP:0003429
      label: CNS hypomyelination
  evidence:
  - reference: PMID:34415322
    reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Group 1 patients showed a pattern of marked, diffuse supratentorial and infratentorial hypomyelination associated with white matter atrophy and a thin corpus callosum (Patients 1–4), incomplete/delayed myelination (Patients 5–7) and bilateral perisylvian polymicrogyria (Patient 8)."
    explanation: Documents hypomyelination in the cohort including the patient with perisylvian polymicrogyria.
- category: Neurologic
  name: Thin corpus callosum
  description: >
    A thin or dysplastic corpus callosum accompanies the white matter changes on
    MRI.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:35951779
    reference_title: PI4KA-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI findings can include hypomyelinating leukodystrophy, cerebellar hypoplasia/atrophy, thin or dysplastic corpus callosum, and/or perisylvian polymicrogyria."
    explanation: GeneReviews lists thin or dysplastic corpus callosum among the MRI findings.
- category: Neurologic
  name: Global developmental delay
  description: >
    Surviving patients present with global developmental delay in the first year
    of life; this and the intellectual disability it evolves into are the
    dominant clinical burden outside the neonatal period.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  notes: >
    No FrequencyEnum band is asserted. All eight patients of the
    developmental-encephalopathy group in the PMID:34415322 cohort had global
    developmental delay in the first 12 months, but that group is a referred
    series spanning the wider PI4KA spectrum, not an ascertained sample of this
    entity, and the three index fetuses of PMID:25855803 were terminated before
    development could be assessed.
  evidence:
  - reference: PMID:35951779
    reference_title: PI4KA-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CLINICAL CHARACTERISTICS: PI4KA-related disorder is a clinically variable disorder characterized primarily by neurologic dysfunction (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus), gastrointestinal manifestations (multiple intestinal atresia, inflammatory bowel disease), and combined immunodeficiency (leukopenia, variable immunoglobulin defects)."
    explanation: GeneReviews clinical characteristics list developmental delay and intellectual disability.
- category: Neurologic
  name: Intellectual disability
  description: >
    Intellectual disability follows the early developmental delay in surviving
    patients and is moderate to severe in most, mild in a minority. It is the
    feature that determines educational and communication needs, which is why it
    is curated separately from the developmental-delay phenotype it grows out of.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  notes: >
    Moderate-to-severe in 7 of the 8 developmental-encephalopathy patients of the
    PMID:34415322 cohort and mild in 1. No FrequencyEnum band is asserted: that
    cohort is a referred series spanning the wider PI4KA spectrum rather than an
    ascertained sample of this entity. No incoming causal edge is drawn: no
    source in this entry attributes the intellectual disability to a specific one
    of the curated brain lesions rather than to their combination.
  evidence:
  - reference: PMID:34415322
    reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the last examination (3–19 years of age), all of the patients presented moderate-to-severe intellectual disability, except for Patient 5, in whom intellectual disability was mild."
    explanation: Reports the severity distribution of intellectual disability across the cohort at last examination.
  - reference: PMID:35951779
    reference_title: PI4KA-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CLINICAL CHARACTERISTICS: PI4KA-related disorder is a clinically variable disorder characterized primarily by neurologic dysfunction (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus), gastrointestinal manifestations (multiple intestinal atresia, inflammatory bowel disease), and combined immunodeficiency (leukopenia, variable immunoglobulin defects)."
    explanation: GeneReviews lists intellectual disability among the core neurologic features.
- category: Neurologic
  name: Hypotonia
  description: >
    Hypotonia is the predominant early tone abnormality, axial in most patients
    and combined with limb spasticity and pyramidal signs, but global and severe
    in the one patient who also had an axonal sensory neuropathy. It is present
    from the neonatal period in the severe presentations.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  notes: >
    Axial hypotonia in 7 of 8 developmental-encephalopathy patients in the
    PMID:34415322 cohort, with severe global hypotonia in the eighth, plus
    central hypotonia in the PMID:34415310 Family 3 child homozygous for the
    p.Asp1854Asn allele of the index family. No FrequencyEnum band is asserted:
    the denominator is one referred series covering the wider PI4KA spectrum, not
    this entity. HP:0008936 (Axial hypotonia) is deliberately not used, because it
    would be narrower than the claim, which includes the globally hypotonic
    patient. No incoming causal edge is drawn: no source attributes the hypotonia
    to a specific curated node.
  evidence:
  - reference: PMID:34415322
    reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Axial hypotonia with limb spasticity and pyramidal signs were present in all patients except Patient 2, in whom severe global hypotonia predominated and a neurophysiological study performed at 11 months of age showed axonal sensory neuropathy."
    explanation: Reports axial hypotonia in all but one patient and severe global hypotonia in that one.
- category: Gastrointestinal
  name: Feeding difficulties
  description: >
    Feeding difficulties and dysphagia in early childhood, severe enough in some
    infants to require nasogastric tube feeding and, in the GeneReviews
    management recommendations, gastrostomy. Distinct from the structural
    intestinal disease (atresia, inflammatory bowel disease) curated separately.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  notes: >
    4 of 8 developmental-encephalopathy patients in the PMID:34415322 cohort, 2
    of whom needed nasogastric feeding in the first weeks of life. No
    FrequencyEnum band is asserted, for the same denominator reason as the other
    phenotypes here. This phenotype is the target of the gastrostomy treatment,
    which previously had nothing in the entry to point at.
  evidence:
  - reference: PMID:34415322
    reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four patients had feeding difficulties in early childhood, and two required nasogastric tube feeding during the first weeks of life."
    explanation: Quantifies feeding difficulty and tube feeding in the cohort.
  - reference: PMID:35951779
    reference_title: PI4KA-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "speech-language therapy for speech impairment and/or dysphagia"
    explanation: GeneReviews management names dysphagia as a manifestation requiring speech-language therapy.
- category: Neurologic
  name: Microcephaly
  description: >
    Head circumference is normal at birth and falls below the normal range
    afterwards in a substantial minority, and is extreme in one child homozygous
    for the p.Asp1854Asn allele that the index family carried.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  notes: >
    4 of 10 patients in the PMID:34415322 cohort had a head circumference below
    -2 SD at last examination, with normal cranial circumference at birth in all;
    the PMID:34415310 Family 3 child, homozygous for p.(Asp1854Asn) — the
    maternally transmitted missense allele of the PMID:25855803 index family — was
    -10 SD. No FrequencyEnum band is asserted. HP:0005484 (Secondary microcephaly)
    is deliberately not used: it fits the PMID:34415322 cohort, whose head
    circumference was normal at birth, but the timing is not stated for the
    -10 SD child, so the more specific term would be narrower than the claim. No
    incoming causal edge is drawn: no source in this entry attributes the
    microcephaly to a specific curated node.
  evidence:
  - reference: PMID:34415322
    reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "four (Patients 2, 3, 6 and 8) had a head circumference less than two standard deviations (SD) below the mean"
    explanation: Reports head circumference below -2 SD in four patients at last examination.
  - reference: PMID:34415310
    reference_title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This 13-year-old is severely microcephalic (−10 standard deviations) and presented from Day 1 of life with treatment-resistant seizures."
    explanation: Documents severe microcephaly in the child homozygous for the index family's missense allele.
- category: Neurologic
  name: Limb spasticity
  description: >
    Spasticity affecting the limbs, most prominent in the lower limbs; at the
    mild end of the spectrum it can be the only feature, presenting as
    adolescent- or adult-onset hereditary spastic paraplegia.
  phenotype_term:
    preferred_term: Lower limb spasticity
    term:
      id: HP:0002061
      label: Lower limb spasticity
  evidence:
  - reference: PMID:34415310
    reference_title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected individuals from Families 5–7 all presented with nystagmus, ataxia and lower limb spasticity, and magnetic resonance neuroimaging revealed hypomyelinating leukodystrophy reminiscent of Pelizaeus–Merzbacher-like disease (Fig."
    explanation: Documents lower limb spasticity with nystagmus and ataxia in three families.
- category: Neurologic
  name: Seizures
  description: >
    Seizures occur in surviving patients, often from the neonatal period, and can
    be treatment-resistant.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  notes: >
    No incoming causal edge from the polymicrogyria node is drawn. A
    polymicrogyric cortex is a recognized epileptogenic lesion in general, but
    none of the sources cited in this entry makes that attribution for these
    patients, and the one description of seizure triggers in the PMID:34415322
    cohort ties them to fever and infection rather than to the malformation. The
    earlier wording of this description asserted the link without a citation and
    has been removed.
  evidence:
  - reference: PMID:35951779
    reference_title: PI4KA-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CLINICAL CHARACTERISTICS: PI4KA-related disorder is a clinically variable disorder characterized primarily by neurologic dysfunction (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus), gastrointestinal manifestations (multiple intestinal atresia, inflammatory bowel disease), and combined immunodeficiency (leukopenia, variable immunoglobulin defects)."
    explanation: GeneReviews lists seizures among the neurologic features.
- category: Neurologic
  name: Nystagmus
  description: >
    Nystagmus, reported together with ataxia and spasticity in the hypomyelinating
    presentations.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:34415310
    reference_title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected individuals from Families 5–7 all presented with nystagmus, ataxia and lower limb spasticity, and magnetic resonance neuroimaging revealed hypomyelinating leukodystrophy reminiscent of Pelizaeus–Merzbacher-like disease (Fig."
    explanation: Documents nystagmus in three families.
- category: Neurologic
  name: Ataxia
  description: >
    Ataxia, consistent with the cerebellar involvement that is part of the
    defining triad.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:34415310
    reference_title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected individuals from Families 5–7 all presented with nystagmus, ataxia and lower limb spasticity, and magnetic resonance neuroimaging revealed hypomyelinating leukodystrophy reminiscent of Pelizaeus–Merzbacher-like disease (Fig."
    explanation: Documents ataxia in three families.
- category: Gastrointestinal
  name: Multiple intestinal atresia
  description: >
    Multiple congenital atresias of the small bowel. Until PI4KA was implicated,
    TTC7A — the gene encoding PI4KIIIalpha's binding partner — was the only known
    genetic cause of this finding, which is why the two disorders overlap.
  phenotype_term:
    preferred_term: Multiple small bowel atresias
    term:
      id: HP:0004797
      label: Multiple small bowel atresias
  evidence:
  - reference: PMID:34415310
    reference_title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, affected individuals may present with inflammatory bowel disease, multiple intestinal atresia and combined immunodeficiency."
    explanation: Documents multiple intestinal atresia in the PI4KA cohort.
- category: Gastrointestinal
  name: Inflammatory bowel disease
  description: >
    Early-onset inflammatory bowel disease, reported in a subset of patients
    including two of five with hypomyelinating leukodystrophy.
  phenotype_term:
    preferred_term: Inflammatory bowel disease
    term:
      id: HP:0002037
      label: Inflammation of the large intestine
  evidence:
  - reference: PMID:34415310
    reference_title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five patients with hypomyelinating leukodystrophy were additionally identified, two of whom also had IBD."
    explanation: Documents IBD in two of five patients with the hypomyelinating presentation.
- category: Immunologic
  name: Combined immunodeficiency
  description: >
    Combined immunodeficiency with leukopenia and variable immunoglobulin
    defects. In one Amish infant homozygous for p.Tyr1623Asp, multiple intestinal
    atresia with severe immunodeficiency caused death at three weeks, with no
    pathogenic TTC7A variant present.
  phenotype_term:
    preferred_term: Combined immunodeficiency
    term:
      id: HP:0005387
      label: Combined immunodeficiency
  evidence:
  - reference: PMID:34415310
    reference_title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, affected individuals may present with inflammatory bowel disease, multiple intestinal atresia and combined immunodeficiency."
    explanation: Documents combined immunodeficiency in the PI4KA cohort.
  - reference: PMID:34415310
    reference_title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No putative pathogenic variants in TTC7A or other genes associated with primary immunodeficiency were identified."
    explanation: Excludes TTC7A as the cause of the immunodeficiency in that patient, attributing it to PI4KA.
- category: Hematologic
  name: Leukopenia
  description: >
    Reduced total leukocyte count, part of the combined immunodeficiency
    phenotype.
  phenotype_term:
    preferred_term: Leukopenia
    term:
      id: HP:0001882
      label: Decreased total leukocyte count
  evidence:
  - reference: PMID:35951779
    reference_title: PI4KA-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CLINICAL CHARACTERISTICS: PI4KA-related disorder is a clinically variable disorder characterized primarily by neurologic dysfunction (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus), gastrointestinal manifestations (multiple intestinal atresia, inflammatory bowel disease), and combined immunodeficiency (leukopenia, variable immunoglobulin defects)."
    explanation: GeneReviews lists leukopenia as part of the combined immunodeficiency.
genetic:
- name: PI4KA
  gene_term:
    preferred_term: PI4KA
    term:
      id: hgnc:8983
      label: PI4KA
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:25855803
      reference_title: "Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In these regions, the only plausibly pathogenic mutations were compound heterozygous variants in PI4KA, which Sanger sequencing confirmed segregated consistent with autosomal recessive inheritance."
      explanation: Biallelic segregation in the index family.
  notes: >
    PI4KA at 22q11.21 encodes the 2102-residue phosphatidylinositol 4-kinase
    IIIalpha, organized into an alpha-solenoid domain, a dimerization domain, a
    "cradle" domain that contacts TTC7, and a C-terminal catalytic domain. The
    two alleles defining this entity are p.Arg796Ter (paternal, nonsense) and
    p.Asp1854Asn (maternal, catalytic domain); the latter recurs in an
    independent family and has been shown enzymatically to reduce activity of
    both the TTC7A- and the TTC7B-containing complex. Across the published
    cohorts, missense and in-frame variants cluster near the active site in the
    catalytic and cradle domains, and genotype does not cleanly predict which
    organ system dominates — two patients sharing one truncating allele had
    discordant phenotypes (severe infantile leukodystrophy versus spastic
    paraparesis with onset at 17), the difference tracking with the second
    allele. gnomAD constraint is consistent with a purely recessive mechanism
    (pLI 0.00031, pRec 1).
  evidence:
  - reference: PMID:34415322
    reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Accordingly, the pLI value of PI4KA was 0.00031, and the pRec value was 1, indicating that biallelic deleterious variants in this gene are pathogenic."
    explanation: Population constraint metrics supporting a recessive disease mechanism.
  - reference: PMID:34415322
    reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, 7 of 13 conserved missense/in-frame variants were clustered near the active site of PI4KA in the catalytic and ‘cradle’ domains (Fig."
    explanation: Documents the clustering of disease variants around the active site.
  - reference: PMID:34415322
    reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients 4 and 9 shared one of the truncating variants (p.Thr2053SerfsTer4) but displayed discordant phenotypes."
    explanation: Documents the discordant phenotypes seen in patients sharing one allele, the basis for the genotype-phenotype note.
diagnosis:
- name: Fetal or postnatal brain imaging
  description: >
    Prenatal ultrasound or MRI showing polymicrogyria with cerebellar hypoplasia,
    or postnatal MRI showing hypomyelination, cerebellar hypoplasia or atrophy, a
    thin or dysplastic corpus callosum, and perisylvian polymicrogyria, raises
    the possibility of PI4KA-related disease.
  evidence:
  - reference: PMID:35951779
    reference_title: PI4KA-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI findings can include hypomyelinating leukodystrophy, cerebellar hypoplasia/atrophy, thin or dysplastic corpus callosum, and/or perisylvian polymicrogyria."
    explanation: GeneReviews lists the recognized neuroimaging findings.
- name: PI4KA molecular genetic testing
  description: >
    The diagnosis is established by identifying biallelic pathogenic PI4KA
    variants. Because the phenotype overlaps TTC7A- and FAM126A-related disease,
    a gene panel or exome/genome approach is more useful than single-gene
    testing.
  evidence:
  - reference: PMID:35951779
    reference_title: PI4KA-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DIAGNOSIS/TESTING: The diagnosis of PI4KA-related disorder is established in a proband with characteristic features and biallelic PI4KA pathogenic variants identified by molecular genetic testing."
    explanation: States the molecular diagnostic criterion.
- name: PI4KA and PI(4)P assay in patient fibroblasts
  description: >
    Western blot and immunofluorescence for PI4KA, immunofluorescence against the
    PI(4)P head group, and targeted phosphoinositide lipidomics on fibroblasts or
    PBMCs all show reduced values in patients. These are research assays, but the
    authors propose them as candidate diagnostic and prognostic biomarkers.
  evidence:
  - reference: PMID:34415322
    reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PIP levels were reduced in the PBMCs of four patients, and specifically PI(4)P was diminished as shown in fibroblasts of five patients, suggesting that their use as biomarkers for diagnosis and prognosis may be indicated."
    explanation: Proposes the phosphoinositide measurements as diagnostic and prognostic biomarkers.
differential_diagnoses:
- name: TTC7A-related multiple intestinal atresia with combined immunodeficiency
  description: >
    TTC7A encodes PI4KIIIalpha's direct binding partner, and biallelic TTC7A
    variants produce the intestinal and immunological arm of the same phenotype —
    early-onset inflammatory bowel disease through multiple intestinal atresia
    with or without combined immunodeficiency. Distinguishing the two requires
    sequencing; in the Amish PI4KA family this was done explicitly, and no
    pathogenic TTC7A variant was found.
  evidence:
  - reference: PMID:34415310
    reference_title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The striking phenotypical overlap between TTC7A deficiency patients and the MIA and immunodeficiency affecting the Amish neonates indicates that the p.(Tyr1623Asp) substitution may specifically impair PI4KIIIα-TTC7A binding."
    explanation: States the phenotypic overlap with TTC7A deficiency and its structural explanation.
- name: FAM126A-related hypomyelination and congenital cataracts
  description: >
    FAM126A (hyccin) is the other regulatory subunit of the complex; its loss
    causes hypomyelination and congenital cataracts, whose proposed mechanism is
    defective PI(4)P production in oligodendrocytes. The white matter phenotype
    is essentially the same lesion reached through a different subunit, and the
    congenital cataracts are the discriminating feature.
  evidence:
  - reference: PMID:34415322
    reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is intriguing that pathogenic variants in FAM126A, a gene that encodes another partner of the PI4KA/TTC7/FAM126A protein complex, cause hypomyelinating leukodystrophy"
    explanation: >
      Identifies FAM126A, the other regulatory subunit of the PI4KIIIalpha
      complex, as a cause of hypomyelinating leukodystrophy. The continuation of
      the same sentence attributes that disorder to defective PI(4)P production
      in oligodendrocytes; it is not quoted here because the intervening
      bracketed OMIM reference makes the longer span unmatchable by the snippet
      validator.
- name: Other phosphoinositide-pathway polymicrogyria
  description: >
    Variants in PIK3CA, PIK3R2, AKT3 and FIG4 — all in phosphoinositide metabolism
    or its downstream signalling — also cause polymicrogyria, with or without
    megalencephaly and capillary malformation. Megalencephaly and the mosaic,
    somatic pattern of the PIK3CA/AKT3 disorders are the main discriminators from
    the recessive, non-overgrowth PI4KA phenotype.
  evidence:
  - reference: PMID:34415322
    reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For instance, variants in the PIK3CA, PIK3R2, AKT3, and FIG4 genes have been linked to the development of polymicrogyria, which can be associated or not with megalencephaly and capillary malformation,5,9–12 and PI4K2A variants have been associated with intellectual disability and epilepsy."
    explanation: Lists the other phosphoinositide-pathway genes that cause polymicrogyria.
treatments:
- name: Multidisciplinary supportive care
  description: >
    There is no disease-modifying therapy. GeneReviews recommends individualized
    care by a multidisciplinary team, with annual neurologic, developmental and
    gastrointestinal assessment, audiology and ophthalmology review through
    childhood, and monitoring for infection susceptibility.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:35951779
    reference_title: PI4KA-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MANAGEMENT: Treatment: Individualized care by a multidisciplinary team; physical therapy, occupational therapy, mobility aids, and medical management as needed for limb spasticity and motor issues; speech-language therapy for speech impairment and/or dysphagia; communication aids as needed; educational support for intellectual disability; anti-seizure medication as needed for seizures; gastrostomy as needed for feeding issues; treatments for multiple intestinal atresia and inflammatory bowel disease per surgeon and gastroenterologist; treatment of immunodeficiency per immunologist; standard treatment for hearing and vision issues."
    explanation: The GeneReviews management statement for the disorder.
  - reference: PMID:35951779
    reference_title: PI4KA-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surveillance: Neurologic, developmental, and gastrointestinal assessments annually or as needed; consider complete blood count and inflammatory markers annually or as indicated by symptomatology; endoscopy as needed; monitor for increased susceptibility to infection; annual audiology and ophthalmology evaluations throughout childhood."
    explanation: The GeneReviews surveillance schedule this treatment's description states.
- name: Physical and occupational therapy for spasticity
  description: >
    Physical therapy, occupational therapy and mobility aids for limb spasticity
    and motor impairment, the mainstay of management for surviving patients.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_mechanisms:
  - target: Limb spasticity
    description: >
      Directed at the motor consequence rather than at the underlying lipid
      kinase defect.
    evidence:
    - reference: PMID:35951779
      reference_title: PI4KA-Related Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "physical therapy, occupational therapy, mobility aids, and medical management as needed for limb spasticity and motor issues"
      explanation: States that physical and occupational therapy are directed at limb spasticity.
  evidence:
  - reference: PMID:35951779
    reference_title: PI4KA-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "physical therapy, occupational therapy, mobility aids, and medical management as needed for limb spasticity and motor issues"
    explanation: GeneReviews recommendation for motor management.
- name: Anti-seizure medication
  description: >
    Standard anti-seizure medication as needed; no agent is specific to this
    disorder and no PI4KA-specific efficacy data exist.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Anticonvulsant Therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
    therapeutic_agent:
    - preferred_term: anticonvulsant agent
      term:
        id: NCIT:C264
        label: Anticonvulsant Agent
  target_mechanisms:
  - target: Seizures
    description: >
      Symptomatic seizure control.
    evidence:
    - reference: PMID:35951779
      reference_title: PI4KA-Related Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "anti-seizure medication as needed for seizures"
      explanation: States the indication for anti-seizure medication.
  evidence:
  - reference: PMID:35951779
    reference_title: PI4KA-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "anti-seizure medication as needed for seizures"
    explanation: GeneReviews recommendation for seizure management.
- name: Gastrostomy for feeding difficulty
  description: >
    Gastrostomy as needed for feeding problems and dysphagia, which are common in
    the severe neurological presentations.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Gastrostomy
    term:
      id: NCIT:C52006
      label: Gastrostomy
  target_mechanisms:
  - target: Feeding difficulties
    description: >
      Bypasses the oral route rather than correcting the neurological cause of
      the dysphagia.
    evidence:
    - reference: PMID:35951779
      reference_title: PI4KA-Related Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "gastrostomy as needed for feeding issues"
      explanation: Names feeding difficulty as the indication the gastrostomy addresses.
  evidence:
  - reference: PMID:35951779
    reference_title: PI4KA-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gastrostomy as needed for feeding issues"
    explanation: States the indication for gastrostomy.
- name: Genetic counselling and reproductive options
  description: >
    Autosomal recessive inheritance carries a 25% recurrence risk per pregnancy.
    Once the familial variants are known, carrier testing for at-risk relatives
    and prenatal or preimplantation genetic testing become available — directly
    relevant here, since the entity was defined in a family that lost three
    consecutive pregnancies.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:35951779
    reference_title: PI4KA-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Once the PI4KA pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible."
    explanation: States the reproductive options that follow molecular diagnosis.
  - reference: PMID:35951779
    reference_title: PI4KA-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If both parents are known to be heterozygous for a PI4KA pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants."
    explanation: States the recurrence risk that counselling conveys.
animal_models:
- name: Pi4ka null mouse
  species: Mus musculus
  genotype: Pi4ka germline loss-of-function
  category: KNOCKOUT
  genes:
  - preferred_term: PI4KA
    term:
      id: hgnc:8983
      label: PI4KA
  publication: PMID:34415310
  description: >
    Germline Pi4ka loss-of-function in the mouse abolishes PI4KIIIalpha activity
    and is incompatible with embryonic development. This is a negative result
    with real explanatory force: it is why every reported human patient carries
    at least one hypomorphic allele, and it means the complete null cannot be
    used to model this disease.
  modeled_mechanisms:
  - target: Biallelic PI4KA Loss-of-Function
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >
      The complete null is embryonic lethal and therefore cannot reproduce the
      human disease, which depends on residual PI4KIIIalpha activity.
    limitations: >-
      Because homozygous null embryos do not develop, the model yields no
      information about cortical migration, cerebellar development or
      arthrogryposis. Modelling this disorder requires a hypomorphic or
      conditional allele. Conditional Pi4ka alleles do exist and have been used
      tissue-specifically — the Schwann-cell-specific deletion curated below is
      one — but no conditional allele directed at the developing CNS, and no
      knock-in of a patient missense variant such as p.Asp1854Asn, has been
      reported.
    evidence:
    - reference: PMID:34415310
      reference_title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Accordingly, germline Pi4ka loss of function variants that abolish PI4KIIIα activity are incompatible with embryonic development."
      explanation: Documents that the complete murine null does not survive to model the human phenotype.
  evidence:
  - reference: PMID:34415310
    reference_title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Accordingly, germline Pi4ka loss of function variants that abolish PI4KIIIα activity are incompatible with embryonic development."
    explanation: Establishes the embryonic lethality that constrains modelling of this disorder.
- name: Schwann-cell-specific Pi4ka conditional knockout mouse
  species: Mus musculus
  genotype: Pi4ka conditional deletion restricted to Schwann cells
  category: KNOCKOUT
  genes:
  - preferred_term: PI4KA
    term:
      id: hgnc:8983
      label: PI4KA
  publication: PMID:29874576
  description: >
    Deleting Pi4ka only in Schwann cells escapes the embryonic lethality of the
    germline null and produces a viable animal with a myelination phenotype:
    sciatic nerves show substantially reduced myelin thickness, impaired nerve
    conduction and motor deficits, with phosphatidylserine and
    phosphatidylethanolamine disproportionately depleted from the myelin lipid
    content. This is the model that grounds the phosphatidylserine arm of the
    myelination mechanism in vivo.
  modeled_mechanisms:
  - target: Impaired Myelination
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >
      Reproduces the failure to build normal myelin, and the lipid deficit
      proposed to cause it, in an animal that survives.
    limitations: >-
      The deletion is restricted to Schwann cells, so the lesion is in the
      peripheral nervous system while the human disease is dominated by central
      hypomyelination in oligodendrocytes; peripheral neuropathy was found in only
      one of the reported PI4KA patients. It is also a complete deletion within
      that lineage rather than the partial loss the human hypomorphic genotypes
      produce, and it says nothing about cortical migration, cerebellar
      development or arthrogryposis.
    readouts:
    - name: Sciatic nerve myelin thickness and nerve conduction
      target: Impaired Myelination
      direction: DECREASED
      interpretation: >
        Loss of PI4KA in a myelinating cell is by itself sufficient to produce
        thin myelin with a functional deficit.
      evidence:
      - reference: PMID:29874576
        reference_title: Schwann-Cell-Specific Deletion of Phosphatidylinositol 4-Kinase Alpha Causes Aberrant Myelination.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "sciatic nerves of mice lacking phosphatidylinositol 4-kinase alpha (PI4KA) in Schwann cells (SCs) show substantially reduced myelin thickness with grave consequences on nerve conductivity and motor functions"
        explanation: Reports the myelin thickness and nerve conduction measurements in the conditional knockout.
    - name: Myelin phosphatidylserine content in mutant nerve
      target: Impaired Myelination
      direction: DECREASED
      interpretation: >
        Identifies the specific lipid deficit that links PI(4)P depletion to
        defective myelin.
      evidence:
      - reference: PMID:29874576
        reference_title: Schwann-Cell-Specific Deletion of Phosphatidylinositol 4-Kinase Alpha Causes Aberrant Myelination.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "PI4KA inactivation disproportionally reduced phosphatidylserine, phosphatidylethanolamine, and sphingomyelin content in mutant nerves, with similar changes observed in SCs treated with a PI4KA inhibitor."
        explanation: Quantifies the phosphatidylserine and phosphatidylethanolamine deficit in mutant nerve.
    evidence:
    - reference: PMID:34415310
      reference_title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice with a Schwann cell-specific Pi4ka deletion display neuropathy motor symptoms and severe myelination defects, with significantly reduced myelin thickness and lipid content most severely affecting phosphatidylserine and phosphatidylethanolamine, two major myelin components."
      explanation: The PI4KA patient cohort paper cites this model as the in vivo support for the myelination mechanism it proposes.
  evidence:
  - reference: PMID:29874576
    reference_title: Schwann-Cell-Specific Deletion of Phosphatidylinositol 4-Kinase Alpha Causes Aberrant Myelination.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "sciatic nerves of mice lacking phosphatidylinositol 4-kinase alpha (PI4KA) in Schwann cells (SCs) show substantially reduced myelin thickness with grave consequences on nerve conductivity and motor functions"
    explanation: Establishes that the conditional knockout is viable and has a myelination phenotype, which is what makes it usable where the germline null is not.
- name: Pi4ka knockdown zebrafish
  species: Danio rerio
  genotype: Pi4ka morpholino knockdown
  category: KNOCKDOWN
  genes:
  - preferred_term: PI4KA
    term:
      id: hgnc:8983
      label: PI4KA
  publication: PMID:34415322
  description: >
    Knockdown rather than knockout, which is what makes it usable: partial
    reduction of Pi4ka in zebrafish produces multiple developmental defects
    including brain abnormalities, mirroring the hypomorphic human genotypes.
  modeled_mechanisms:
  - target: Depletion of the Plasma Membrane PI(4)P Pool
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >
      Dose reduction rather than abolition of Pi4ka produces developmental
      defects including brain abnormalities, matching the partial-loss mechanism
      of the human disease.
    limitations: >-
      Morpholino knockdown is transient and carries well-known off-target and
      toxicity risks; the reported phenotype is described at the level of gross
      developmental defects, with the most prominent being loss of pectoral fins
      rather than a cortical malformation, and teleosts have no gyrencephalic
      cortex in which polymicrogyria could be modelled at all.
    readouts:
    - name: Gross developmental defects after Pi4ka knockdown
      target: Depletion of the Plasma Membrane PI(4)P Pool
      direction: ALTERED
      interpretation: >
        Partial Pi4ka reduction is sufficient to derange development, supporting
        dose-dependence of the human phenotype.
      evidence:
      - reference: PMID:34415322
        reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "downregulation of Pi4ka expression in zebrafish leads to multiple developmental defects affecting the brain, heart, trunk and most prominently the loss of pectoral fins, while the Pi4ka orthologue knockout is lethal in flies, mice and yeast."
        explanation: Reports the knockdown phenotype and contrasts it with the lethality of complete knockout.
    evidence:
    - reference: PMID:34415322
      reference_title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Animal models in which PI4KA homologues are inactivated show profound abnormalities: downregulation of Pi4ka expression in zebrafish leads to multiple developmental defects affecting the brain, heart, trunk and most prominently the loss of pectoral fins, while the Pi4ka orthologue knockout is lethal in flies, mice and yeast."
      explanation: Supports treating the zebrafish knockdown as informative for partial PI4KA loss.
discussions:
- discussion_id: pi4ka_arthrogryposis_mechanism_unknown
  kind: KNOWLEDGE_GAP
  prompt: >
    Why do fetuses with biallelic PI4KA variants develop arthrogryposis, and is
    it secondary to the brain malformation or an independent consequence of
    PI(4)P depletion in muscle or motor neurons?
  rationale: >
    Arthrogryposis is one of the three features this entity is named for, but no
    mechanism has been proposed for it. The obvious explanation is fetal akinesia
    secondary to the cortical and cerebellar malformation, which is how
    arthrogryposis arises in many CNS malformation syndromes. That is an
    inference from the general pathophysiology of fetal akinesia, not something
    demonstrated for PI4KA: no motor neuron or neuromuscular junction phenotype
    has been reported in PI4KA patients or in any PI4KA model, and
    PI(4)P and PI(4,5)P2 have direct roles in ion channel regulation and vesicle
    release that could plausibly act at the neuromuscular junction independently
    of the brain lesion.

    One informative observation does exist and narrows the gap rather than
    leaving it untouched: fetal skeletal muscle histology in the index family is
    reported as normal, which argues against a primary myopathy and favours
    fetal akinesia secondary to neurologic dysfunction. That result is in the
    full text of the 2015 index report and is recorded here as prose without an
    evidence item because it cannot currently be quoted - references_cache holds
    only the abstract of PMID:25855803 (content_type abstract_only; a re-fetch on
    2026-09-04 returned the abstract again) and DOI:10.1093/hmg/ddv117 is
    content_type unavailable. Should the full text become retrievable, this
    belongs in the entry as a REFUTE item against a primary-myopathy mechanism.

    What is still open is motor output rather than muscle structure: no
    electrophysiology and no neuromuscular junction assessment has been reported
    in an affected fetus. The entry therefore records no causal edge into the
    arthrogryposis phenotype, and this gap is the reason.
  attaches_to:
  - phenotypes#Arthrogryposis multiplex congenita
  - pathophysiology#Depletion of the Plasma Membrane PI(4)P Pool
  proposed_experiments:
  - experiment_id: pi4ka_fetal_motor_unit_assessment
    name: Motor neuron and neuromuscular junction assessment in PI4KA fetuses
    description: >
      Muscle structure has already been examined in the index family and was
      normal, so this experiment targets what that observation does not settle.
      Where a further affected pregnancy is examined, obtain spinal cord
      histology alongside the brain, count anterior horn motor neurons, and
      assess neuromuscular junction architecture by alpha-bungarotoxin and
      neurofilament or synaptic-vesicle staining, testing whether the motor unit
      is intrinsically abnormal or is structurally intact and merely receiving no
      descending drive. Repeat muscle histology serves only as an internal
      control on the earlier normal result.
    would_support:
    - phenotypes#Arthrogryposis multiplex congenita
    supporting_outcome:
    - Motor neuron number or neuromuscular junction architecture is abnormal, indicating a peripheral mechanism additional to fetal akinesia from the brain lesion
    refuting_outcome:
    - Motor neurons and junctions are structurally normal alongside the already-normal muscle, consistent with arthrogryposis being purely secondary to the CNS malformation
  - experiment_id: pi4ka_hypomorph_mouse_movement
    name: Conditional or hypomorphic Pi4ka allele with fetal movement phenotyping
    description: >
      Build a hypomorphic or conditional Pi4ka allele that survives gestation
      (the complete null does not), then phenotype fetal movement by ultrasound
      and score joint contractures at birth, comparing a CNS-restricted deletion
      against a muscle- or motor-neuron-restricted deletion to separate the two
      candidate origins.
    would_support:
    - phenotypes#Arthrogryposis multiplex congenita
    supporting_outcome:
    - Contractures follow CNS-restricted deletion, establishing arthrogryposis as secondary to the brain malformation
    refuting_outcome:
    - Contractures require peripheral deletion, establishing an independent neuromuscular mechanism
  evidence:
  - reference: PMID:34415310
    reference_title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This disorder comprises perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis, and was identified in a small nuclear family with three female foetuses"
    explanation: Documents arthrogryposis as a defining feature while showing the entity rests on a single family of three fetuses, which is why no neuromuscular data exist.
  - reference: PMID:34415310
    reference_title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Accordingly, germline Pi4ka loss of function variants that abolish PI4KIIIα activity are incompatible with embryonic development."
    explanation: Explains why no mouse model has been available to address the question.
notes: >
  Scope and lump/split. MONDO carries both MONDO:0014679 (this prenatal-onset
  brain-malformation entity) and MONDO:1040012 (PI4KA-related disorder, the whole
  allelic spectrum), and GeneReviews describes the latter as one clinically
  variable disorder. This entry is anchored on MONDO:0014679 because that is what
  the curation queue held, and the pathograph is written around the brain
  malformation. Features from the wider spectrum — hypomyelination, intestinal
  atresia, inflammatory bowel disease, combined immunodeficiency, spastic
  paraplegia — are included because they arise from the same molecular lesion and
  because one reported patient had bilateral perisylvian polymicrogyria together
  with the hypomyelinating phenotype. The relationship to MONDO:1040012 is
  recorded as a broadMatch so the broader concept stays in the curation queue and
  can be curated separately, or this entry re-scoped, if the field settles on the
  spectrum name.

  Gene symbol. HGNC's approved symbol is PI4KA; much of the primary literature
  writes the protein as PI4KIIIalpha or PI4KIIIα, and both forms appear in quoted
  snippets.

  What is deliberately absent. No causal edge runs into the arthrogryposis
  phenotype — the mechanism is not established and the honest state is recorded
  as a KNOWLEDGE_GAP discussion rather than papered over with a plausible edge.
  No prevalence rate is asserted. No frequency bands are asserted on any
  phenotype: the entity rests on one family of three fetuses, and every
  supporting cohort (PMID:34415310, PMID:34415322) enrolled patients across the
  whole PI4KA spectrum, so their denominators are not this entity's patient
  count.

  Which features are in, and which index-family findings are missing. The rule
  applied is that a feature is curated when a cached reference states it in a
  quotable sentence. That is why several features of the wider PI4KA-related
  disorder that the index fetuses did not have - leukopenia, inflammatory bowel
  disease, multiple intestinal atresia, combined immunodeficiency - are present:
  GeneReviews and the two 2021 cohort papers state them directly, and they arise
  from the same molecular lesion. It is also why several findings that were
  present in every fetus of the index family are absent: bilateral talipes
  equinovarus, micrognathia and externally rotated hips, together with the
  variable dolichocephaly, ventriculomegaly, small pons, renal pelviectasis and
  borderline pulmonary hypoplasia, appear only in the full text of the 2015
  index report, which is not retrievable (PMID:25855803 is cached
  abstract_only, re-fetched 2026-09-04 with the same result, and
  DOI:10.1093/hmg/ddv117 is unavailable). Those are omissions of quotable
  source, not of judgement, and should be added when the full text can be
  fetched. The two index-family findings that a later cohort paper does restate
  in a quotable sentence - dentate and olivary nucleus abnormality, and
  overlapping fingers - are curated.
references:
- reference: PMID:25855803
  title: "Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis."
- reference: PMID:35951779
  title: PI4KA-Related Disorder.
  tags:
  - GeneReviews
- reference: PMID:34415310
  title: "Biallelic PI4KA variants cause neurological, intestinal and immunological disease."
- reference: PMID:34415322
  title: Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
- reference: PMID:29874576
  title: Schwann-Cell-Specific Deletion of Phosphatidylinositol 4-Kinase Alpha Causes Aberrant Myelination.
- reference: PMID:39705356
  title: Molecular basis for plasma membrane recruitment of PI4KA by EFR3.
📚

References & Deep Research

References

6
PMID:25855803
Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis.
No top-level findings curated for this source.
PMID:35951779
PI4KA-Related Disorder.
No top-level findings curated for this source.
PMID:34415310
Biallelic PI4KA variants cause neurological, intestinal and immunological disease.
No top-level findings curated for this source.
PMID:34415322
Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
No top-level findings curated for this source.
PMID:29874576
Schwann-Cell-Specific Deletion of Phosphatidylinositol 4-Kinase Alpha Causes Aberrant Myelination.
No top-level findings curated for this source.
PMID:39705356
Molecular basis for plasma membrane recruitment of PI4KA by EFR3.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (2)

Review round: correct the arthrogryposis knowledge-gap rationale and record the phenotype scoping rule · 2026-09-04T17:29:00Z · View source

Addressed the two blocking findings on PR #10900. Finding 1, inverted assertion: the pi4ka_arthrogryposis_mechanism_unknown rationale said no muscle histology or electrophysiology has ever been reported, and the adjacent clause said no muscle phenotype has been reported in PI4KA patients or any model. The deep-research artifact committed with this PR states three separate times, each citing Pagnamenta 2015 pages 2-4, that fetal muscle histology was normal and that this argues against a primary myopathy and favours fetal akinesia secondary to neurologic dysfunction. The rationale therefore asserted an untouched question where an informative negative result exists. The muscle clause was removed from the no-phenotype-reported sentence, and a paragraph now records the normal muscle histology and what it implies. It is recorded as prose without an evidence item because it cannot be quoted: references_cache/PMID_25855803.md is content_type abstract_only and a re-fetch on 2026-09-04 returned the abstract again with a byte-identical file, and DOI:10.1093/hmg/ddv117 is content_type unavailable. The rationale says so explicitly and flags that it belongs as a REFUTE item against a primary-myopathy mechanism once the full text is retrievable. Proposed experiment 1 was retargeted from muscle structure to motor unit assessment (anterior horn motor neuron counts, neuromuscular junction architecture) since muscle structure has already been looked at; its id, name, description and both outcome statements were rewritten, and repeat muscle histology is now framed as an internal control. Finding 2, phenotype scoping: the full text of the 2015 index report cannot be fetched, so the index-family findings the review named (bilateral talipes equinovarus, micrognathia, externally rotated hips, and the variable dolichocephaly, ventriculomegaly, small pons, renal pelviectasis, borderline pulmonary hypoplasia) still cannot be quoted. Resolution 2 was taken: a notes paragraph now states the rule that decided which features are in (a cached reference states it in a quotable sentence), explains why wider-spectrum features the index fetuses did not have are present, and lists the index-family findings that are absent and why. Two index-family findings turned out to be quotable after all, from PMID:34415322's summary of the earlier family, and were curated: Abnormal dentate nucleus morphology (HP:0100321) and Overlapping fingers (HP:0010557). The dentate phenotype is wired as a downstream target of the PI(4)P depletion node with directness INDIRECT, mirroring the existing cerebellar hypoplasia edge. Overlapping fingers is left unwired with a notes entry pointing at the same knowledge gap as the arthrogryposis phenotype. The olivary nucleus abnormality reported in the same sentence is not separately curated: HPO searches for olivary, olive and inferior olivary return only Olivary degeneration, Olivopontocerebellar atrophy, Olivopontocerebellar hypoplasia and Superior olive hypertrophy, none of which describes a dysplastic fetal inferior olive, and that search is recorded in the phenotype description. Non-blocking items taken: the GeneReviews surveillance sentence is now quoted on the Multidisciplinary supportive care treatment whose description asserted it, and PMID:39705356 was added to the top-level references block. Declined: pharmacologic spasticity management, because GeneReviews names no agent and no cached reference names baclofen, diazepam or botulinum toxin, so a therapeutic_agent binding would rest on the research report alone; and broadening the differential diagnoses, because none of the proposed additions is stated in a quotable sentence in any cached reference. Validation: just validate green including reference validation, validate-terms passed, count-verified-snippets 82/82, check-entity-refs, check-duplicate-keys, check-causal-targets, check-enum-values, check-qualifier-terms all clean, and whole-KB check-title-snippets, check-snippet-length, check-folded-hyphens and check-snippet-grading all report no new violations.

Review round 1: phenotypes, myelination mechanism, Schwann-cell model, pathograph, deep research · 2026-09-04T06:38:32Z · View source

Addressed the CHANGES_REQUESTED review on PR #10900. (1) Tagged the GeneReviews chapter PMID:35951779 with tags: [GeneReviews] in the top-level references list, and added PMID:34415322 and PMID:29874576 to that list. (2) Added research/Polymicrogyria_Perisylvian_With_Cerebellar_Hypoplasia_And_Arthrogryposis-deep-research-falcon.md, generated with 'just research-disorder falcon'; 4/4 references verified, 0 confabulation. (3) Added four phenotypes from already-cached sources: Hypotonia (HP:0001252 rather than the narrower HP:0008936, because one of the eight patients had global rather than axial hypotonia), Feeding difficulties (HP:0011968), Microcephaly (HP:0000252 rather than HP:0005484 Secondary microcephaly, because the timing is unstated for the -10 SD child), and Intellectual disability (HP:0001249) split out from the former combined 'Global developmental delay and intellectual disability' phenotype, which is now 'Global developmental delay'. Each carries a numerator/denominator in notes and no FrequencyEnum band, since the denominator is a referred series spanning the wider PI4KA spectrum. (4) The Gastrostomy treatment now has a target_mechanisms link to the new Feeding difficulties phenotype. (5) Cited the phosphatidylserine mechanism the 'Impaired Myelination' edge asserted without support, using the PMID:34415310 sentence naming PI4KIIIalpha as a driver of ER-to-plasma-membrane phosphatidylserine transport plus the in vivo lipid measurement from the primary Schwann-cell paper. (6) Added the Schwann-cell-specific conditional Pi4ka knockout mouse (PMID:29874576, newly fetched) as a third animal model, PARTIALLY_RECAPITULATES against Impaired Myelination with two readouts, and corrected the Pi4ka-null limitations text, which claimed no hypomorphic or conditional allele had been reported; conditional alleles do exist, so the absence claim is now narrowed to a CNS-directed conditional and to a patient-variant knock-in, both of which a PubMed search found no report of. (7) Pathograph: added edges from the PI(4)P depletion node to Cerebellar hypoplasia and from Impaired Myelination to Thin corpus callosum, both INDIRECT with the inference step stated. Declined the suggested polymicrogyria-to-Seizures edge: no cached source makes that attribution for these patients, and the Seizures description that asserted it without a citation was rewritten. Nodes/edges went from 28/12 to 32/15. Validation: just validate (78/78 snippets), validate-terms, check-entity-refs, check-duplicate-keys, check-causal-targets, check-enum-values, check-qualifier-terms all pass.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 16 citations 2026-09-03T23:31:48.778441

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Perisylvian Polymicrogyria with Cerebellar Hypoplasia and Arthrogryposis
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Perisylvian Polymicrogyria with Cerebellar Hypoplasia and Arthrogryposis covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Research report: Perisylvian polymicrogyria with cerebellar hypoplasia and arthrogryposis

Executive summary and evidence limits

This is an ultra-rare, congenital, autosomal-recessive PI4KA disorder defined by bilateral perisylvian polymicrogyria (PMG), cerebellar hypoplasia/dysplasia, and fetal arthrogryposis. The defining evidence is unusually narrow: the original 2015 report described three affected female fetuses from one family, all carrying the same compound-heterozygous PI4KA variants. Later studies established a broader and clinically heterogeneous PI4KA-related disorder spectrum, but most such patients do not necessarily have the complete named triad. Consequently, the original family’s 3/3 frequencies must not be interpreted as population penetrance estimates. (pagnamenta2015germlinerecessivemutations pages 1-2, pagnamenta2015germlinerecessivemutations pages 2-4, verdura2021biallelicpi4kavariants pages 1-2)

No disease-specific publication from 2023–2024 materially expanded the narrowly defined syndrome in the retrieved literature. The most important later evidence is the 2021 PI4KA cohort and a 2022 expert PI4KA-related-disorder review. No relevant disease-specific interventional trial was identified.

Domain Best-supported finding Evidence scope/strength Key identifiers or quantitative details
Entity and gene A severe congenital Mendelian disorder caused by biallelic PI4KA variants and defined by perisylvian polymicrogyria, cerebellar hypoplasia, and arthrogryposis. Curated disease–gene association plus primary human familial evidence. (pagnamenta2015germlinerecessivemutations pages 1-2, OpenTargets Search: perisylvian polymicrogyria with cerebellar hypoplasia and arthrogryposis-PI4KA) OMIM 616531; MONDO:0014679; PI4KA/ENSG00000241973; PMID 25855803.
Original cohort Three affected female fetuses occurred in one nonconsanguineous European-ancestry family; three additional early miscarriages were reported. Single-family case series; strong segregation but very small ascertainment base. (pagnamenta2015germlinerecessivemutations pages 2-4, pagnamenta2015germlinerecessivemutations pages 1-2) Pregnancy terminations at 34, 28, and 16 gestational weeks.
Causal variants All three fetuses were compound heterozygous for a paternal stop-gain and maternal catalytic-domain missense variant. Segregation confirmed by Sanger sequencing; missense effect supported experimentally. (pagnamenta2015germlinerecessivemutations pages 1-2, pagnamenta2015germlinerecessivemutations pages 4-6, pagnamenta2015germlinerecessivemutations pages 2-4) NM_058004.3:c.2386C>T, p.(Arg796Ter) and c.5560G>A, p.(Asp1854Asn); germline, autosomal recessive.
Cardinal brain phenotype Bilateral perisylvian polymicrogyria and cerebellar hypoplasia/dysplasia were present in all three reported fetuses. Prenatal MRI and fetal neuropathology; 3/3, but frequencies are family-specific rather than population estimates. (pagnamenta2015germlinerecessivemutations pages 2-4) PMG 3/3 (100%); cerebellar hypoplasia/dysplasia 3/3 (100%); abnormal vermis/dentate nuclei also described.
Cardinal musculoskeletal phenotype Congenital arthrogryposis/joint contractures with bilateral talipes equinovarus and externally rotated hips occurred in all three fetuses. Direct fetal examination/pathology; 3/3 in the original family. (pagnamenta2015germlinerecessivemutations pages 2-4) Arthrogryposis/contractures 3/3 (100%); bilateral talipes equinovarus 3/3 (100%); flexed knees and wrist contracture varied.
Other congenital findings Micrognathia was consistent; variable findings included dolichocephaly, ventriculomegaly, small pons, dysplastic olivary nuclei, renal pelviectasis, and mild/borderline pulmonary hypoplasia. Patient-level fetal observations; frequencies generally limited to the three-family cohort. (pagnamenta2015germlinerecessivemutations pages 2-4) Micrognathia 3/3 (100%); normal muscle histology argues against a primary myopathy in this family. (pagnamenta2015germlinerecessivemutations pages 2-4)
Inheritance and recurrence The disorder follows autosomal-recessive inheritance; heterozygous carriers are considered asymptomatic. Strong intrafamilial segregation and broader PI4KA disease curation. (baple2022pi4karelateddisorder pages 1-3, baple2022pi4karelateddisorder pages 11-14) If both parents are carriers: 25% affected, 50% carrier, 25% neither variant per pregnancy.
Biochemical mechanism PI4KA/PI4KIIIα generates plasma-membrane phosphatidylinositol-4-phosphate needed to sustain PI(4,5)P₂ and downstream membrane signaling. p.Asp1854Asn abolishes detectable catalytic activity in vitro. Direct COS-7 biochemical assay for p.Asp1854Asn; downstream developmental chain remains inferred. (pagnamenta2015germlinerecessivemutations pages 4-6, pagnamenta2015germlinerecessivemutations pages 7-8, pagnamenta2015germlinerecessivemutations pages 6-7) Mutant and wild-type protein abundance was comparable in the assay; activity of p.Asp1854Asn was indistinguishable from negative controls. p.Arg796Ter protein function was not directly tested.
Broader PI4KA spectrum Other biallelic PI4KA genotypes produce a continuum from severe developmental encephalopathy, hypomyelination, structural brain abnormalities, immune/GI disease, and contractures to pure hereditary spastic paraplegia. Ten-patient multicenter cohort plus later case reports; informative for gene-level disease but not equivalent to the narrowly defined 616531 phenotype. (verdura2021biallelicpi4kavariants pages 4-4, verdura2021biallelicpi4kavariants pages 7-9, verdura2021biallelicpi4kavariants pages 1-2) In the 2021 cohort, 10 unrelated patients were reported; one additional p.Asp1854Asn-homozygous patient had bilateral perisylvian PMG.
Diagnosis Diagnosis rests on compatible prenatal/postnatal neuroimaging and contractures plus identification of biallelic pathogenic/likely pathogenic PI4KA variants with parental segregation. Expert disease review supported by primary exome-sequencing discovery. (pagnamenta2015germlinerecessivemutations pages 1-2, baple2022pi4karelateddisorder pages 1-3) Fetal ultrasound/MRI; postnatal brain MRI when applicable; multigene panel, WES, or WGS with CNV analysis. PI4KAP1/PI4KAP2 pseudogenes require assay-specific validation. A VUS alone is not diagnostic.
Treatment and trials No disease-modifying therapy is established; management is manifestation-directed and multidisciplinary. No relevant interventional trial was identified in the retrieved ClinicalTrials.gov search. Expert management recommendations extrapolated from the broader PI4KA spectrum; no syndrome-specific treatment trial or response-rate evidence. (baple2022pi4karelateddisorder pages 1-3, baple2022pi4karelateddisorder pages 10-11) PT/OT, mobility and communication aids, standard antiseizure therapy, spasticity treatment, feeding support/gastrostomy, and indicated GI, immune, hearing, and vision care. Leflunomide remains investigational.
Epidemiology and prognosis gaps Population prevalence, incidence, penetrance, sex ratio, survival, life expectancy, quality-of-life scores, and prognostic biomarkers have not been established for the specific syndrome. Evidence is inadequate because the defining report comprised only three terminated pregnancies in one family. (pagnamenta2015germlinerecessivemutations pages 2-4, pagnamenta2015germlinerecessivemutations pages 1-2) The observed 3/3 phenotype frequencies must not be interpreted as general-population penetrance estimates; no live-born natural-history cohort exists for the narrowly defined disorder.

Table: Knowledge-base summary of the defining PI4KA-associated fetal syndrome, separating direct evidence from the original family from findings across the broader PI4KA-related disorder spectrum. It highlights quantitative observations and major diagnostic, therapeutic, epidemiologic, and prognostic gaps.

1. Disease information

Definition

Perisylvian polymicrogyria with cerebellar hypoplasia and arthrogryposis is a prenatal-onset malformation syndrome caused by biallelic pathogenic PI4KA variants. PMG is a malformation of cortical development characterized by excessive small gyri and abnormal cortical organization/lamination; in this syndrome it predominantly involves the cortex surrounding both Sylvian fissures. Cerebellar underdevelopment/dysplasia and congenital joint contractures complete the defining phenotype. (pagnamenta2015germlinerecessivemutations pages 1-2, pagnamenta2015germlinerecessivemutations pages 2-4)

Identifiers and synonyms

  • MONDO: MONDO:0014679.
  • OMIM phenotype: 616531.
  • Causal target: PI4KA, phosphatidylinositol 4-kinase alpha; Ensembl ENSG00000241973.
  • Common name: Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis.
  • Useful alternative: PI4KA-related perisylvian polymicrogyria with cerebellar hypoplasia and arthrogryposis.
  • Broader umbrella term: PI4KA-related disorder; this includes hypomyelinating leukodystrophy, gastrointestinal/immunologic disease, and hereditary spastic paraplegia and is not synonymous with the complete fetal triad. (baple2022pi4karelateddisorder pages 1-3, OpenTargets Search: perisylvian polymicrogyria with cerebellar hypoplasia and arthrogryposis-PI4KA, verdura2021biallelicpi4kavariants pages 1-2)
  • ICD-10/ICD-11 and MeSH: no unique disease-specific code or descriptor was established in the retrieved sources. Coding ordinarily requires broader congenital brain-malformation, arthrogryposis, and genetic-disease categories.
  • Orphanet: no confidently verified disease-specific identifier was recovered.

The evidence is aggregated disease-level literature derived from individual family/patient observations, not an EHR-derived cohort or population registry.

Foundational reference

Pagnamenta et al., Human Molecular Genetics, published online 8 April 2015, DOI: 10.1093/hmg/ddv117, PMID 25855803. Its abstract states: “exome sequencing in a family where three fetuses had all been diagnosed with PMG and cerebellar hypoplasia” identified compound-heterozygous PI4KA variants, and concludes that the findings “emphasize the importance of phosphoinositide signalling in early brain development.” (pagnamenta2015germlinerecessivemutations pages 1-2, OpenTargets Search: perisylvian polymicrogyria with cerebellar hypoplasia and arthrogryposis-PI4KA)

2. Etiology, risk, protection, and gene–environment interaction

Causal factor

The established initiating cause is germline biallelic PI4KA dysfunction. In the defining family, the paternal allele was NM_058004.3:c.2386C>T, p.(Arg796Ter), and the maternal allele was c.5560G>A, p.(Asp1854Asn). Both were present in all three affected fetuses and segregated under an autosomal-recessive model. (pagnamenta2015germlinerecessivemutations pages 1-2, pagnamenta2015germlinerecessivemutations pages 2-4)

Risk factors

  • Genetic: two pathogenic or likely pathogenic PI4KA alleles in trans are the principal risk factor. A prior affected pregnancy and parental carrier status create a 25% recurrence probability in each pregnancy.
  • Family history/consanguinity: the original parents were unrelated and of European ancestry; consanguinity is therefore not required. (pagnamenta2015germlinerecessivemutations pages 1-2, baple2022pi4karelateddisorder pages 11-14)
  • Environmental, lifestyle, occupational, infectious, age, or sex risks: none are established for the named syndrome. All three defining fetuses were female, but the sample is too small and family-specific to imply sex limitation. General reports that diet can modulate PI4KA expression or that PI4KA participates in hepatitis C biology do not demonstrate disease risk or G×E interaction. (pagnamenta2015germlinerecessivemutations pages 2-4, zhang2022asynonymousmutation pages 8-10)

Protective factors

No genetic protective alleles, modifier variants, diets, medications, or environmental exposures have been demonstrated. Heterozygous carriers are considered clinically unaffected, but carrier state should not be described as a “protective factor.” (baple2022pi4karelateddisorder pages 11-14)

Gene–environment interaction

No syndrome-specific G×E interaction has been demonstrated. The developmental phenotype appears primarily determined by severe inherited PI4KA dysfunction; variable residual enzyme activity and protein-complex interactions are more plausible modifiers than documented environmental exposures.

3. Phenotypes

Frequencies below refer only to the original three fetuses and are therefore observed family frequencies, not robust disease-wide estimates.

Phenotype Type, onset, observed frequency and course Suggested HPO term
Bilateral perisylvian PMG Congenital structural CNS malformation; 3/3; fixed developmental lesion Polymicrogyria, HP:0002126; bilateral perisylvian PMG where available
Cerebellar hypoplasia/dysplasia Congenital imaging/pathology sign; 3/3; fixed Cerebellar hypoplasia, HP:0001321
Arthrogryposis/joint contractures Congenital physical manifestation; 3/3 Arthrogryposis multiplex congenita, HP:0002804; congenital joint contracture
Bilateral talipes equinovarus Congenital limb deformity; 3/3 Talipes equinovarus, HP:0001762
Externally rotated hips Congenital postural/deformation finding; 3/3 Abnormality of the hip joint/position
Micrognathia Craniofacial sign; 3/3 Micrognathia, HP:0000347
Flexed knees Contracture; present in II-2 and II-3, 2/3 Knee flexion contracture
Wrist contracture Contracture; left wrist in II-3, 1/3 Wrist flexion contracture
Dolichocephaly Cranial shape; II-2 and II-3, 2/3 Dolichocephaly, HP:0000268
Small pons/brainstem abnormality Congenital neuropathologic sign; variably reported Pontine hypoplasia
Ventriculomegaly Prenatal imaging sign; variable Ventriculomegaly, HP:0002119
Dysplastic dentate nuclei Neuropathologic manifestation Abnormal cerebellar morphology
Dysplastic olivary nuclei Neuropathologic manifestation in II-3 Abnormality of the inferior olivary nucleus
Renal pelviectasis Congenital renal imaging finding; variable Pyelectasis/hydronephrosis
Mild/borderline lung hypoplasia Congenital secondary/deformation finding; variable Pulmonary hypoplasia, HP:0002089

Prenatal MRI showed bilateral perisylvian PMG and a small cerebellum; II-2 also had delayed sulcation. Neuropathology documented abnormal vermis, dentate nuclei, and, in II-3, olivary nuclei. Muscle histology was normal, favoring fetal akinesia secondary to neurologic dysfunction rather than a demonstrated primary myopathy. (pagnamenta2015germlinerecessivemutations pages 2-4)

The broader PI4KA spectrum can include developmental delay/intellectual disability, absent or poor speech, seizures, axial hypotonia, peripheral spasticity/hyperreflexia, ataxia, dystonia, nystagmus, feeding difficulty, hypomyelination, thin corpus callosum, cerebral/cerebellar atrophy, intestinal disease, and immune defects. These should be attached to the umbrella PI4KA-related disorder, not automatically asserted in every patient with the named fetal syndrome. (baple2022pi4karelateddisorder pages 1-3, zhang2022asynonymousmutation pages 1-2, verdura2021biallelicpi4kavariants pages 1-2)

Functional and quality-of-life impact

No EQ-5D, SF-36, PROMIS, caregiver-burden, or disease-specific quality-of-life study exists. The defining pregnancies were terminated at 34, 28, and 16 weeks, so live-born developmental function cannot be estimated from the original family. In surviving patients elsewhere in the PI4KA spectrum, severe motor, communication, feeding, seizure, and spasticity phenotypes can substantially impair independence, but that is gene-spectrum rather than triad-specific evidence. (pagnamenta2015germlinerecessivemutations pages 2-4, baple2022pi4karelateddisorder pages 1-3)

4. Genetic and molecular information

Causal gene

PI4KA encodes the approximately 240-kDa phosphatidylinositol 4-kinase IIIα (PI4KIIIα), highly expressed in brain and placenta and functioning with regulatory partners including TTC7A/TTC7B, FAM126/HYCC1, and EFR3 at membranes. (pagnamenta2015germlinerecessivemutations pages 6-7, zhang2022asynonymousmutation pages 2-4)

Defining variants

  1. c.2386C>T, p.(Arg796Ter) — paternal, exon 20 stop-gain, germline. It predicts premature truncation. The transcript was detectable in adult parental blood without substantial nonsense-mediated decay, but truncated-protein production, stability, localization, and catalytic function were not directly tested. (pagnamenta2015germlinerecessivemutations pages 4-6, pagnamenta2015germlinerecessivemutations pages 2-4)
  2. c.5560G>A, p.(Asp1854Asn) — maternal, exon 48 missense variant at a highly conserved catalytic-domain residue. Structural modeling places Asp1854 as important to ATP-binding-pocket folding. Expressed mutant protein had no measurable kinase activity despite abundance comparable with wild type. (pagnamenta2015germlinerecessivemutations pages 4-6, pagnamenta2015germlinerecessivemutations pages 7-8)

The original report predated current routine ACMG/AMP deposition practices in the evidence retrieved. The segregation, rarity, predicted truncation, conservation, and functional assay strongly support pathogenicity, but database-level ClinVar review status and current gnomAD counts should be checked directly before assigning a contemporary laboratory classification.

Additional molecular findings

Two later Turkish individuals were described as homozygous for p.Asp1854Asn; at least one had bilateral perisylvian PMG, strengthening recurrence of the cortical phenotype. A 2021 study of 10 unrelated patients found eight compound heterozygotes and two homozygotes and suggested that surviving patients often retain residual PI4KA function—no patient carried two unequivocal loss-of-function alleles. (baple2022pi4karelateddisorder pages 6-8, verdura2021biallelicpi4kavariants pages 4-4, verdura2021biallelicpi4kavariants pages 7-9)

No validated disease-specific modifier gene, methylation signature, epigenetic mechanism, recurrent chromosomal abnormality, somatic variant, or genetic anticipation is known. PI4KAP1 and PI4KAP2 are nearby pseudogenes that create an important technical testing hazard, not causal loci. (pagnamenta2015germlinerecessivemutations pages 8-9, baple2022pi4karelateddisorder pages 1-3)

5. Environmental information

No toxin, radiation, pollutant, medication, occupational exposure, smoking, alcohol, diet, exercise pattern, or pathogen has been shown to cause or modify this Mendelian syndrome. Prenatal infection and vascular disruption remain general differentials for PMG, but are not established etiologies in the genetically confirmed PI4KA family. Thus, environmental and infectious annotations should be entered as not demonstrated, not “absent by proof.”

6. Mechanism/pathophysiology

Ordered causal chain

  1. Biallelic germline PI4KA variants lead to severe reduction of functional PI4KIIIα; catalytic inactivity is demonstrated for p.Asp1854Asn, whereas the protein-level consequence of p.Arg796Ter is inferred.
  2. Reduced PI4KIIIα activity leads to deficient conversion of phosphatidylinositol to phosphatidylinositol-4-phosphate [PI(4)P] at the plasma membrane; this step is established PI4KA biochemistry but was not measured in the original fetal tissue.
  3. Reduced PI(4)P leads to impaired maintenance of plasma-membrane PI(4,5)P₂ and altered membrane trafficking/signaling; inferred for the defining fetuses.
  4. Altered phosphoinositide pools lead to disturbed PLC–IP3–Ca²⁺ and PI3K–AKT–mTOR-linked signaling and membrane organization during neurodevelopment; biologically plausible but not directly demonstrated in fetal cortex. (pagnamenta2015germlinerecessivemutations pages 4-6, pagnamenta2015germlinerecessivemutations pages 6-7)
  5. Developmental signaling/membrane defects lead to abnormal cortical organization/migration and cerebellar/brainstem morphogenesis; inferred from phenotype and broader patient-cell evidence.
  6. Abnormal cerebral, cerebellar, and motor-system development branches into:
  7. cortical disorganization → bilateral perisylvian PMG;
  8. hindbrain developmental impairment → vermian/cerebellar hypoplasia and dysplastic dentate/olivary nuclei;
  9. reduced fetal motor output → fetal akinesia, joint contractures, talipes, and arthrogryposis; this last link is inferred, supported by normal fetal muscle histology. (pagnamenta2015germlinerecessivemutations pages 2-4)

Direct versus inferred evidence

Direct human biochemical evidence: HA-tagged wild-type and p.Asp1854Asn PI4KA were expressed in COS-7 cells, immunoprecipitated, and tested with ATP and phosphatidylinositol in an ADP-GLO assay. Mutant activity was indistinguishable from negative controls while Western blotting showed comparable protein recovery. (pagnamenta2015germlinerecessivemutations pages 4-6, pagnamenta2015germlinerecessivemutations pages 7-8)

Direct broader-spectrum cellular evidence: fibroblasts and peripheral-blood mononuclear cells from patients with other biallelic PI4KA genotypes showed reduced protein, reduced PI4KA activity, and altered PI/PIP/PIP₂ measurements. (verdura2021biallelicpi4kavariants pages 7-9, verdura2021biallelicpi4kavariants pages 1-2)

Not demonstrated: fetal single-cell or spatial transcriptomics, proteomics, metabolomics, lipidomics of affected brain, CRISPR screens, immune activation, oxidative injury, apoptosis, autophagy, or a disease-specific epigenetic signature.

Suggested mechanistic ontology annotations

  • GO biological process: phosphatidylinositol phosphorylation; phosphoinositide-mediated signaling; regulation of plasma-membrane organization; nervous-system development; cerebral-cortex development; cerebellum development; neuron migration; myelination—the latter is broader-spectrum evidence.
  • GO molecular function: phosphatidylinositol 4-kinase activity (GO:0004430); ATP binding.
  • GO cellular component: plasma membrane (GO:0005886); PI4KIIIα membrane-associated complex.
  • Candidate cell types (CL): neural progenitor cell, radial glial cell, migrating neuron, cortical neuron, cerebellar granule-neuron precursor, Purkinje cell, oligodendrocyte, skeletal-muscle cell. The first five are mechanistically plausible targets; direct cell-type-specific fetal data are unavailable.
  • Chemical entities: phosphatidylinositol, PI(4)P, PI(4,5)P₂, ATP, ADP, and Ca²⁺; CHEBI identifiers should be validated against the release used by the knowledge base.

7. Anatomical structures affected

Organ/system level

The primary system is the central nervous system, particularly bilateral perisylvian cerebral cortex, cerebellum/vermis, dentate nuclei, pons, and inferior olivary nuclei. The musculoskeletal system is secondarily affected through congenital contractures, feet, knees, wrists, fingers, and hip posture. Variable renal-pelvis and pulmonary findings occurred. (pagnamenta2015germlinerecessivemutations pages 2-4)

Suggested UBERON concepts include cerebral cortex, Sylvian fissure/perisylvian region, cerebellum, cerebellar vermis, dentate nucleus, pons, medulla oblongata/inferior olivary nucleus, skeletal muscle, hip joint, knee joint, wrist joint, and foot. No consistent lateralization was described for PMG—it was bilateral—although individual limb contractures could be asymmetric.

Tissue/cell/subcellular level

Affected tissue is principally developing nervous tissue and cortical/cerebellar architecture. Normal muscle histology provides no evidence for primary muscle degeneration. The implicated subcellular site is the plasma membrane and its phosphoinositide lipid pool; direct ultrastructural fetal data are lacking. (pagnamenta2015germlinerecessivemutations pages 6-7, pagnamenta2015germlinerecessivemutations pages 2-4)

8. Temporal development

The disorder begins antenatally during brain and motor-system development. PMG may be difficult to recognize before approximately 24 gestational weeks; targeted ultrasound and fetal MRI improve detection, although the third fetus was recognized at 16 weeks through a broader recurrent-malformation pattern. The three pregnancies ended at 34, 28, and 16 weeks. (pagnamenta2015germlinerecessivemutations pages 1-2, pagnamenta2015germlinerecessivemutations pages 2-4)

PMG, cerebellar hypoplasia, and congenital contractures are developmental and structurally fixed rather than relapsing. Progressive cerebellar atrophy, hypomyelination, spasticity, or neurologic decline occurs in some broader PI4KA genotypes, but there is no postnatal natural-history series for the complete fetal triad. No remission pattern or staged disease classification exists. Critical windows are fetal cortical organization, hindbrain development, and fetal movement; no proven therapeutic window has been defined.

9. Inheritance and population

  • Inheritance: autosomal recessive.
  • Recurrence: when both parents are carriers, each conception has 25% affected, 50% carrier, and 25% non-carrier probability.
  • Carriers: generally asymptomatic.
  • Penetrance/expressivity: penetrance of two severe alleles has not been quantified. Expressivity across all PI4KA disorders is broad, ranging from lethal congenital disease to childhood encephalopathy or later spastic paraplegia. (baple2022pi4karelateddisorder pages 1-3, baple2022pi4karelateddisorder pages 11-14, verdura2021biallelicpi4kavariants pages 1-2)
  • Mosaicism/anticipation: not reported.
  • Consanguinity: not required; original parents were unrelated.
  • Founder effect: a broader PI4KA phenotype has an Amish p.Tyr1623Asp founder allele reported at frequency 0.0006, but this is not the defining p.Arg796Ter/p.Asp1854Asn genotype and should not be assigned specifically to OMIM 616531. (baple2022pi4karelateddisorder pages 11-14)
  • Prevalence/incidence/carrier frequency: unknown. No cases-per-100,000 estimate, registry, or population-based incidence exists.
  • Demography: three defining fetuses were female and European ancestry; no valid sex ratio, ethnic predisposition, or geographic distribution can be inferred. (pagnamenta2015germlinerecessivemutations pages 2-4, pagnamenta2015germlinerecessivemutations pages 1-2)

10. Diagnostics

Clinical and imaging workflow

  1. Suspect a fetal akinesia/brain-malformation syndrome when prenatal ultrasound shows reduced movement, contractures, talipes, abnormal cortical sulcation, ventriculomegaly, or a small posterior fossa.
  2. Perform expert fetal neurosonography and fetal MRI, specifically evaluating bilateral perisylvian cortex, sulcation, cerebellar size/vermis, pons, ventricles, and corpus callosum.
  3. Document limb contractures and search for pulmonary, renal, gastrointestinal, and growth abnormalities.
  4. Obtain chromosomal microarray to identify pathogenic CNVs; a conventional karyotype was normal, 46,XX, in the first fetus.
  5. Use trio/family WES or WGS, or a comprehensive malformations-of-cortical-development/fetal-akinesia panel including PI4KA. Confirm variants and phase by parental Sanger testing.
  6. Ensure assay design distinguishes PI4KA from PI4KAP1/PI4KAP2 pseudogenes. RNA testing or functional kinase studies may help resolve splice variants or strong VUS, but are not routine diagnostic biomarkers. (pagnamenta2015germlinerecessivemutations pages 1-2, pagnamenta2015germlinerecessivemutations pages 8-9, baple2022pi4karelateddisorder pages 1-3)

WGS may add noncoding, structural-variant, and uniform CNV detection; WES was sufficient in the discovery family. Karyotyping/FISH, mitochondrial sequencing, and repeat-expansion testing are not first-line unless another diagnosis is suspected. No enzyme assay, metabolite, liquid biopsy, or validated circulating biomarker exists.

Diagnostic criterion

A definitive molecular diagnosis requires a compatible phenotype and biallelic pathogenic/likely pathogenic PI4KA variants, ideally confirmed in trans. A VUS alone neither establishes nor excludes the diagnosis. (baple2022pi4karelateddisorder pages 1-3)

Differential diagnosis

Important alternatives include congenital CMV or other prenatal insults; vascular/disruptive PMG; chromosomal CNVs such as 22q11.2 or 1p36 deletion; and monogenic PMG/fetal-akinesia disorders involving tubulin/cytoskeletal, phosphoinositide, ion-pump, or motor-neuron pathways. Specific gene differentials include PIK3CA, PIK3R2, AKT3, WDR62, TUBA1A, TUBB2B, COL4A1/COL4A2, BICD2, GRIN1, ATP1A2/ATP1A3, SMPD4, and ARL6IP1. For hypomyelination or intestinal/immunologic presentations, FAM126A and TTC7A are particularly relevant. (zhang2022asynonymousmutation pages 2-4, verdura2021biallelicpi4kavariants pages 1-2)

Screening

There is no newborn population screening. In a molecularly confirmed family, targeted carrier/cascade testing, prenatal diagnosis using chorionic-villus or amniotic-fluid DNA, and preimplantation genetic testing are appropriate.

11. Outcome and prognosis

No live-born natural-history cohort exists for the narrowly defined syndrome. Therefore, survival rate, life expectancy, mortality, recovery probability, disability scale, and prognostic biomarkers are unknown. The original pregnancies were terminated because of severe multiple congenital abnormalities, which indicates serious prenatal morbidity but does not establish inevitable lethality. (pagnamenta2015germlinerecessivemutations pages 2-4, pagnamenta2015germlinerecessivemutations pages 1-2)

Likely morbidity includes profound motor disability, feeding and respiratory risk, epilepsy, communication impairment, and orthopedic complications, based on anatomy and broader PI4KA disease; these are informed projections rather than measured outcomes for the complete triad. Residual PI4KA activity and severity of brainstem, cerebellar, pulmonary, gastrointestinal, and immune involvement are plausible prognostic variables, but none is validated.

12. Treatment and current applications

There is no approved disease-modifying, gene, cell, RNA, or PI4KA-targeted therapy. Real-world implementation is supportive and multidisciplinary:

  • PT/OT, stretching, positioning, splinting, mobility equipment, and orthopedic assessment for contractures and talipes.
  • Baclofen, diazepam, or botulinum toxin for clinically significant spasticity.
  • Standard antiseizure medication chosen by seizure type and EEG.
  • Speech-language therapy and augmentative communication.
  • Swallow evaluation, nutrition support, reflux treatment, and gastrostomy when necessary.
  • Respiratory monitoring where pulmonary hypoplasia, aspiration, or weakness is present.
  • Hearing, vision, developmental, neurologic, orthopedic, gastrointestinal, and immunologic follow-up guided by phenotype. (baple2022pi4karelateddisorder pages 1-3, baple2022pi4karelateddisorder pages 10-11)

Suggested NCIT intervention concepts include Physical Therapy, Occupational Therapy, Speech Therapy, Orthopedic Surgery, Gastrostomy, Anticonvulsant Therapy, Baclofen, Diazepam, and Botulinum Toxin Therapy; local NCIT codes should be release-validated.

Management of intestinal atresia, inflammatory bowel disease, or immunodeficiency belongs mainly to the broader PI4KA spectrum. Parenteral nutrition, intestinal surgery/transplant, immunoglobulin replacement, immunosuppression, or HSCT may be considered according to the actual phenotype, but evidence is sparse and intestinal benefit from HSCT is uncertain. Leflunomide remains investigational. (baple2022pi4karelateddisorder pages 10-11, zhang2022asynonymousmutation pages 4-6)

No treatment-response percentage, pharmacogenomic rule, or disease-specific adverse-event dataset is available. No relevant interventional ClinicalTrials.gov study was recovered.

13. Prevention

Primary lifestyle or environmental prevention is not available because the disorder is inherited and congenital. Effective prevention is reproductive/genetic:

  • genetic counseling and parental phase confirmation;
  • targeted carrier testing of at-risk relatives;
  • prenatal molecular diagnosis after chorionic-villus sampling or amniocentesis;
  • preimplantation genetic testing for monogenic disease;
  • fetal ultrasound/MRI for early structural assessment. (baple2022pi4karelateddisorder pages 1-3, baple2022pi4karelateddisorder pages 11-14)

Secondary prevention consists of early recognition and planning of neonatal neurologic, respiratory, feeding, orthopedic, and seizure care. Tertiary prevention includes contracture management, aspiration and malnutrition prevention, seizure control, and surveillance for complications. Vaccination, public-health sanitation, environmental remediation, behavioral intervention, and prophylactic medication do not prevent the genetic syndrome.

14. Other species and natural disease

No naturally occurring veterinary syndrome confidently attributable to orthologous PI4KA variants was identified, and there is no zoonotic or cross-species transmission. The disorder is inherited, not infectious.

Orthologous PI4KA function is evolutionarily conserved. Experimental disruption affects Mus musculus (NCBI Taxon 10090), Danio rerio (7955), Drosophila melanogaster (7227), and Saccharomyces cerevisiae (4932). These findings support fundamental biological essentiality but are induced/model phenotypes, not documented natural veterinary disease. (pagnamenta2015germlinerecessivemutations pages 6-7, pagnamenta2015germlinerecessivemutations pages 8-9)

15. Model organisms and experimental systems

  • Mouse: conventional Pi4ka knockout reportedly causes early embryonic lethality. Acute pharmacologic inhibition in adults causes cardiovascular-collapse-like death, while inducible whole-body inactivation causes gastrointestinal necrosis before brain consequences can be evaluated. These models demonstrate essentiality but poorly recapitulate the human cortical triad. (pagnamenta2015germlinerecessivemutations pages 6-7, pagnamenta2015germlinerecessivemutations pages 8-9)
  • Zebrafish: Pi4ka downregulation disrupts brain, heart, trunk, and pectoral-fin development. It provides a developmental vertebrate model but lacks demonstrated faithful bilateral perisylvian PMG, a human gyral phenotype. (pagnamenta2015germlinerecessivemutations pages 6-7)
  • Drosophila/yeast: orthologue inactivation is lethal; useful for conserved phosphoinositide biology, but anatomically remote from human cortical malformation. (pagnamenta2015germlinerecessivemutations pages 6-7)
  • Cellular systems: COS-7 expression/immunoprecipitation directly established p.Asp1854Asn catalytic inactivity. Patient fibroblasts and PBMCs from the broader disorder support reduced PI4KA abundance/activity and altered phosphoinositide pools. (pagnamenta2015germlinerecessivemutations pages 4-6, verdura2021biallelicpi4kavariants pages 1-2)
  • Unavailable models: no reported disease-specific p.Arg796Ter/p.Asp1854Asn knock-in mouse, cerebral organoid, patient-derived iPSC neural model, single-cell atlas, or spatial-transcriptomic model was found.

These models are best applied to PI4KA catalytic function, phosphoinositide homeostasis, membrane trafficking, myelination, and developmental essentiality. A human cortical organoid or conditional neural-lineage knock-in model would be needed to test the inferred sequence from PI(4)P deficiency to cortical dyslamination and fetal motor dysfunction.

Evidence appraisal

The causal gene assignment is strong because the variants segregated recessively in three affected siblings, were the only plausible variants in the shared interval, and p.Asp1854Asn abolished kinase activity. Nevertheless, syndrome-specific phenotype frequencies, prognosis, and management evidence remain weak because all defining cases came from one family and none contributed postnatal natural history. Later PI4KA studies strengthen gene-level causality and reveal a broad allelic spectrum, but they should not be used to inflate evidence for the exact PMG–cerebellar hypoplasia–arthrogryposis triad. (pagnamenta2015germlinerecessivemutations pages 1-2, pagnamenta2015germlinerecessivemutations pages 4-6, verdura2021biallelicpi4kavariants pages 1-2)

References

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  15. (zhang2022asynonymousmutation pages 2-4): Kaihui Zhang, Lili Kang, Haozheng Zhang, Lu Bai, Huanping Pang, Qinghua Liu, Xinyi Zhang, Dong Chen, Haihua Yu, Yuqiang Lv, Min Gao, Yi Liu, Zhongtao Gai, Dong Wang, and Xiaoying Li. A synonymous mutation in pi4ka impacts the transcription and translation process of gene expression. Frontiers in Immunology, Oct 2022. URL: https://doi.org/10.3389/fimmu.2022.987666, doi:10.3389/fimmu.2022.987666. This article has 15 citations and is from a peer-reviewed journal.

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  17. (pagnamenta2015germlinerecessivemutations pages 8-9): Alistair T. Pagnamenta, Malcolm F. Howard, Eva Wisniewski, Niko Popitsch, Samantha J.L. Knight, David A. Keays, Gerardine Quaghebeur, Helen Cox, Phillip Cox, Tamas Balla, Jenny C. Taylor, and Usha Kini. Germline recessive mutations in pi4ka are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis. Human Molecular Genetics, 24:3732-3741, Apr 2015. URL: https://doi.org/10.1093/hmg/ddv117, doi:10.1093/hmg/ddv117. This article has 96 citations and is from a domain leading peer-reviewed journal.

  18. (zhang2022asynonymousmutation pages 4-6): Kaihui Zhang, Lili Kang, Haozheng Zhang, Lu Bai, Huanping Pang, Qinghua Liu, Xinyi Zhang, Dong Chen, Haihua Yu, Yuqiang Lv, Min Gao, Yi Liu, Zhongtao Gai, Dong Wang, and Xiaoying Li. A synonymous mutation in pi4ka impacts the transcription and translation process of gene expression. Frontiers in Immunology, Oct 2022. URL: https://doi.org/10.3389/fimmu.2022.987666, doi:10.3389/fimmu.2022.987666. This article has 15 citations and is from a peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 4
Resolved 4
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 4
On topic 3
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 11
Resolved 11
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 2
Terms named correctly 0
Terms named as a different term 0
Terms whose name is worth a second look 2

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:

  • GO:0004430 (1 mention) - the report calls it "GO molecular function: phosphatidylinositol 4-kinase activity"; GO calls it 1-phosphatidylinositol 4-kinase activity**
  • GO:0005886 (1 mention) - the report calls it "GO cellular component: plasma membrane"; GO calls it plasma membrane**, and lists "integral component of plasma membrane" among its other names

Every term resolved, and every label the report gave matched.