PIP5K1C-related neurodevelopmental disorder, named in OMIM neurodevelopmental disorder with intellectual, visual, and language impairment (NEDVIL), is an ultra-rare dominant disorder caused by de novo heterozygous missense variants in PIP5K1C. The gene encodes PIP5KIgamma, the kinase that converts phosphatidylinositol 4-phosphate to phosphatidylinositol 4,5-bisphosphate, PI(4,5)P2. The disease variants increase PI(4,5)P2 production, so this is a gain-of-function disorder that, like the PI(4,5)P2 phosphatase diseases such as Lowe syndrome, raises PI(4,5)P2. The extra PI(4,5)P2 accumulates on early endosomes, where it recruits filamentous actin and disturbs endosomal trafficking. Affected children have intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities and dysmorphic features, and a zebrafish model reproduces defects of the forebrain, eyes and craniofacial skeleton. It is distinct from lethal congenital contracture syndrome 3, a recessive loss-of-function disorder of the same gene.
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Conditions with similar clinical presentations that must be differentiated from PIP5K1C-Related Neurodevelopmental Disorder:
name: PIP5K1C-Related Neurodevelopmental Disorder
creation_date: "2026-10-15T00:00:00Z"
category: Mendelian
description: >-
PIP5K1C-related neurodevelopmental disorder, named in OMIM neurodevelopmental
disorder with intellectual, visual, and language impairment (NEDVIL), is an
ultra-rare dominant disorder caused by de novo heterozygous missense variants
in PIP5K1C. The gene encodes PIP5KIgamma, the kinase that converts
phosphatidylinositol 4-phosphate to phosphatidylinositol 4,5-bisphosphate,
PI(4,5)P2. The disease variants increase PI(4,5)P2 production, so this is a
gain-of-function disorder that, like the PI(4,5)P2 phosphatase diseases such
as Lowe syndrome, raises PI(4,5)P2. The extra
PI(4,5)P2 accumulates on early endosomes, where it recruits filamentous actin
and disturbs endosomal trafficking. Affected children have intellectual
disability, developmental delay, acquired microcephaly, seizures, visual
abnormalities and dysmorphic features, and a zebrafish model reproduces
defects of the forebrain, eyes and craniofacial skeleton. It is distinct
from lethal congenital contracture syndrome 3, a recessive loss-of-function
disorder of the same gene.
notes: >-
The entry is anchored on MONDO:1010145 and PIP5K1C (hgnc:8996). The only
primary report is a cohort of nine unrelated children (PMID:37451268), which
is cached as abstract only. The deep-research report gives per-feature
counts from that paper's full text (for example seizures in 7 of 9), but the
numbers cannot be quoted from the cache, so no frequency band is recorded
and phenotypes are limited to those named in the abstract, plus the language
impairment named in the OMIM title, which carries no evidence item for this
reason.
Lethal congenital contracture syndrome 3 (LCCS3, MONDO:0012656) is caused by
biallelic PIP5K1C variants that abolish kinase activity (PMID:17701898). The
two diseases have opposite mechanisms and are kept apart; LCCS3 is listed as
a differential.
No GeneReviews chapter covers this disease; just check-genereviews reports
NO_CHAPTER against the 2026-09-10 Bookshelf index.
disease_term:
preferred_term: PIP5K1C-related neurodevelopmental disorder
term:
id: MONDO:1010145
label: PIP5K1C-related neurodevelopmental disorder
synonyms:
- NEDVIL
- neurodevelopmental disorder with intellectual, visual, and language impairment
- PIP5K1C gain-of-function neurodevelopmental disorder
parents:
- Mendelian Neurodevelopmental Disorder
- Disorder of Phosphoinositide Metabolism
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
Heterozygous variants. All reported cases arose de novo.
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features."
explanation: De novo heterozygous variants in nine unrelated children.
prevalence:
- population: Worldwide reported literature
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: Nine unrelated children in the single published cohort.
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features."
explanation: The published case count.
pathophysiology:
- name: De Novo Activating PIP5K1C Missense Variants
biological_scale: MOLECULAR
description: >-
Three recurrent heterozygous missense variants in the kinase domain of
PIP5KIgamma increase its output of PI(4,5)P2.
genes:
- preferred_term: PIP5K1C
term:
id: hgnc:8996
label: PIP5K1C
molecular_functions:
- preferred_term: 1-phosphatidylinositol-4-phosphate 5-kinase activity
term:
id: GO:0016308
label: 1-phosphatidylinositol-4-phosphate 5-kinase activity
modifier: INCREASED
genetic_context:
variant_origin: DE_NOVO
functional_impact_category: GAIN_OF_FUNCTION
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we describe a neurodevelopmental disorder associated with an increase in the production of PI(4,5)P2 and with PI-signaling dysfunction."
explanation: The variants raise PI(4,5)P2 production.
downstream:
- target: Increased Endosomal PI(4,5)P2
causal_link_type: DIRECT
description: Excess kinase activity enlarges the PI(4,5)P2 pool on early endosomes.
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We provide evidence that the PIP5K1C variants result in an increase of the endosomal PI(4,5)P2 pool, giving rise to ectopic recruitment of filamentous actin at early endosomes (EEs) that in turn causes dysfunction in EE trafficking."
explanation: The variants increase endosomal PI(4,5)P2.
- name: Increased Endosomal PI(4,5)P2
biological_scale: CELLULAR
description: >-
PI(4,5)P2 builds up on early endosomes, a compartment where it is normally
scarce.
chemical_entities:
- preferred_term: phosphatidylinositol 4,5-bisphosphate
term:
id: CHEBI:18348
label: 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
modifier: INCREASED
cellular_components:
- preferred_term: early endosome
term:
id: GO:0005769
label: early endosome
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We provide evidence that the PIP5K1C variants result in an increase of the endosomal PI(4,5)P2 pool, giving rise to ectopic recruitment of filamentous actin at early endosomes (EEs) that in turn causes dysfunction in EE trafficking."
explanation: Measured increase of the endosomal PI(4,5)P2 pool.
downstream:
- target: Ectopic F-actin Recruitment to Early Endosomes
causal_link_type: DIRECT
description: Endosomal PI(4,5)P2 recruits filamentous actin to early endosomes.
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We provide evidence that the PIP5K1C variants result in an increase of the endosomal PI(4,5)P2 pool, giving rise to ectopic recruitment of filamentous actin at early endosomes (EEs) that in turn causes dysfunction in EE trafficking."
explanation: The increased endosomal PI(4,5)P2 pool gives rise to ectopic actin recruitment.
- name: Ectopic F-actin Recruitment to Early Endosomes
biological_scale: CELLULAR
description: >-
Excess endosomal PI(4,5)P2 recruits filamentous actin, coating early
endosomes where actin is normally sparse.
biological_processes:
- preferred_term: actin cytoskeleton organization
term:
id: GO:0030036
label: actin cytoskeleton organization
modifier: ABNORMAL
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We provide evidence that the PIP5K1C variants result in an increase of the endosomal PI(4,5)P2 pool, giving rise to ectopic recruitment of filamentous actin at early endosomes (EEs) that in turn causes dysfunction in EE trafficking."
explanation: Ectopic recruitment of filamentous actin at early endosomes.
downstream:
- target: Early Endosome Trafficking Dysfunction
causal_link_type: DIRECT
description: The ectopic actin in turn disturbs early endosome trafficking.
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We provide evidence that the PIP5K1C variants result in an increase of the endosomal PI(4,5)P2 pool, giving rise to ectopic recruitment of filamentous actin at early endosomes (EEs) that in turn causes dysfunction in EE trafficking."
explanation: The source states that the actin recruitment in turn causes the trafficking dysfunction.
- name: Early Endosome Trafficking Dysfunction
biological_scale: CELLULAR
description: >-
Early endosome trafficking is disturbed. How this endosomal defect
produces the neurodevelopmental phenotype has not been shown in neurons.
biological_processes:
- preferred_term: endosomal transport
term:
id: GO:0016197
label: endosomal transport
modifier: ABNORMAL
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We provide evidence that the PIP5K1C variants result in an increase of the endosomal PI(4,5)P2 pool, giving rise to ectopic recruitment of filamentous actin at early endosomes (EEs) that in turn causes dysfunction in EE trafficking."
explanation: Dysfunction in early endosome trafficking.
downstream:
- target: Abnormal Forebrain Development
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: The developmental consequences are shown in zebrafish; the steps between endosomal dysfunction and the tissue defects are not known.
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In addition, we generated an in vivo zebrafish model that recapitulates the disorder we describe with developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities, further demonstrating the pathogenic effect of the PIP5K1C variants."
explanation: Variant expression in zebrafish causes forebrain defects.
- target: Abnormal Eye Development
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: The developmental consequences are shown in zebrafish; the steps between endosomal dysfunction and the tissue defects are not known.
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In addition, we generated an in vivo zebrafish model that recapitulates the disorder we describe with developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities, further demonstrating the pathogenic effect of the PIP5K1C variants."
explanation: Variant expression in zebrafish causes eye defects.
- target: Abnormal Craniofacial Development
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: The developmental consequences are shown in zebrafish; the steps between endosomal dysfunction and the tissue defects are not known.
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In addition, we generated an in vivo zebrafish model that recapitulates the disorder we describe with developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities, further demonstrating the pathogenic effect of the PIP5K1C variants."
explanation: Variant expression in zebrafish causes craniofacial defects.
- name: Abnormal Forebrain Development
biological_scale: TISSUE
mechanism_confidence: PROVISIONAL
description: >-
Developmental defects of the forebrain, shown in zebrafish and matching the
human microcephaly, intellectual disability and seizures.
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In addition, we generated an in vivo zebrafish model that recapitulates the disorder we describe with developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities, further demonstrating the pathogenic effect of the PIP5K1C variants."
explanation: Zebrafish forebrain defects.
downstream:
- target: Secondary microcephaly
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Impaired forebrain growth appears as acquired microcephaly.
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features."
explanation: Acquired microcephaly in the cohort.
- target: Intellectual disability
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Abnormal forebrain development underlies the cognitive phenotype.
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features."
explanation: Intellectual disability in the cohort.
- target: Global developmental delay
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Abnormal forebrain development underlies the developmental delay.
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features."
explanation: Developmental delay in the cohort.
- target: Seizure
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Abnormal forebrain development is the likely basis of the seizures.
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features."
explanation: Seizures in the cohort.
- target: Delayed speech and language development
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Abnormal forebrain development is the likely basis of the language
impairment. No quotable source is cached for this phenotype (see the
phenotype's notes), so the edge carries no evidence.
- name: Abnormal Eye Development
biological_scale: TISSUE
mechanism_confidence: PROVISIONAL
description: >-
Developmental defects of the eyes, shown in zebrafish and matching the
human visual abnormalities.
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In addition, we generated an in vivo zebrafish model that recapitulates the disorder we describe with developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities, further demonstrating the pathogenic effect of the PIP5K1C variants."
explanation: Zebrafish eye defects, reported as part of the forebrain defect.
downstream:
- target: Abnormality of vision
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Abnormal eye development appears as visual abnormalities.
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features."
explanation: Visual abnormalities in the cohort.
- name: Abnormal Craniofacial Development
biological_scale: TISSUE
mechanism_confidence: PROVISIONAL
description: >-
Craniofacial abnormalities, shown in zebrafish and matching the human
dysmorphic features.
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In addition, we generated an in vivo zebrafish model that recapitulates the disorder we describe with developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities, further demonstrating the pathogenic effect of the PIP5K1C variants."
explanation: Zebrafish craniofacial abnormalities.
downstream:
- target: Abnormal facial shape
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Abnormal craniofacial development appears as dysmorphic features.
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features."
explanation: Dysmorphic features in the cohort.
phenotypes:
- category: Neurological
name: Intellectual disability
description: Intellectual disability in the reported children.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features."
explanation: Intellectual disability in the nine children.
- category: Neurological
name: Global developmental delay
description: Developmental delay in the reported children.
phenotype_term:
preferred_term: Developmental delay
term:
id: HP:0001263
label: Global developmental delay
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features."
explanation: Developmental delay in the nine children.
- category: Neurological
name: Secondary microcephaly
description: Microcephaly acquired after birth.
phenotype_term:
preferred_term: Acquired microcephaly
term:
id: HP:0005484
label: Secondary microcephaly
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features."
explanation: Acquired microcephaly in the cohort.
- category: Neurological
name: Seizure
description: Seizures in the reported children.
phenotype_term:
preferred_term: Seizures
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features."
explanation: Seizures in the cohort.
- category: Neurological
name: Delayed speech and language development
description: >-
Language impairment, part of the OMIM disease name (neurodevelopmental
disorder with intellectual, visual, and language impairment, 621635).
phenotype_term:
preferred_term: Language impairment
term:
id: HP:0000750
label: Delayed speech and language development
notes: >-
Carries no evidence item. The only primary report (PMID:37451268) is cached
as abstract only, and its abstract does not name speech or language; the
full text (PMC10432144) could not be fetched through just fetch-reference,
and Europe PMC returned a server error for its full-text XML. The
deep-research report gives speech or language delay in 9 of 9 children,
most of them nonverbal, from that paper's case table. Hypotonia (5 of 9)
and infantile spasms (3 of 9) are reported there too and are not curated
for the same reason.
- category: Ophthalmological
name: Abnormality of vision
description: >-
Visual abnormalities; the abstract does not say which. The specific ocular
findings are not curated because the full text is not cached.
phenotype_term:
preferred_term: Visual abnormalities
term:
id: HP:0000504
label: Abnormality of vision
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features."
explanation: Visual abnormalities in the cohort.
- category: Craniofacial
name: Abnormal facial shape
description: Dysmorphic facial features.
phenotype_term:
preferred_term: Dysmorphic features
term:
id: HP:0001999
label: Abnormal facial shape
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features."
explanation: Dysmorphic features in the cohort.
genetic:
- name: PIP5K1C
gene_term:
preferred_term: PIP5K1C
term:
id: hgnc:8996
label: PIP5K1C
association: Causative
relationship_type: CAUSATIVE
variant_origin: DE_NOVO
features: >-
PIP5K1C (19p13.3) encodes phosphatidylinositol 4-phosphate 5-kinase type
1 gamma. Heterozygous activating missense variants cause this disorder;
biallelic inactivating variants cause lethal congenital contracture
syndrome 3.
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features."
explanation: Identifies PIP5K1C as the causal gene.
differential_diagnoses:
- name: Lethal congenital contracture syndrome 3
disease_term:
preferred_term: lethal congenital contracture syndrome 3
term:
id: MONDO:0012656
label: lethal congenital contracture syndrome 3
distinguishing_features:
- Autosomal recessive, with biallelic PIP5K1C variants
- Loss of kinase activity and reduced PI(4,5)P2, the opposite of this disorder
- Lethal congenital arthrogryposis
evidence:
- reference: PMID:17701898
reference_title: "Lethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which encodes PIPKI gamma of the phophatidylinsitol pathway."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Thus, a defect in the phosphatidylinositol pathway leading to a decrease in synthesis of PIP(2), a molecule active in endocytosis of synaptic vesicle proteins, culminates in lethal congenital arthrogryposis."
explanation: The allelic recessive disorder has decreased PI(4,5)P2.
animal_models:
- name: Zebrafish expressing PIP5K1C disease variants
species: Zebrafish
genotype: PIP5K1C variant overexpression and base editing
publication: PMID:37451268
description: >-
Zebrafish carrying the human disease variants, used to test their
pathogenic effect in vivo.
modeled_mechanisms:
- target: Abnormal Forebrain Development
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
description: Reproduces the forebrain defects.
limitations: >-
Zebrafish development differs from human; cognition and seizures cannot
be read out in the same way, and only the abstract is cached, so the
specific readouts are not curated.
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In addition, we generated an in vivo zebrafish model that recapitulates the disorder we describe with developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities, further demonstrating the pathogenic effect of the PIP5K1C variants."
explanation: Zebrafish model of the developmental defects.
- target: Abnormal Eye Development
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
description: Reproduces the eye defects.
limitations: >-
Zebrafish development differs from human; cognition and seizures cannot
be read out in the same way, and only the abstract is cached, so the
specific readouts are not curated.
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In addition, we generated an in vivo zebrafish model that recapitulates the disorder we describe with developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities, further demonstrating the pathogenic effect of the PIP5K1C variants."
explanation: Zebrafish model of the developmental defects.
- target: Abnormal Craniofacial Development
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
description: Reproduces the craniofacial abnormalities.
limitations: >-
Zebrafish development differs from human; cognition and seizures cannot
be read out in the same way, and only the abstract is cached, so the
specific readouts are not curated.
evidence:
- reference: PMID:37451268
reference_title: "De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In addition, we generated an in vivo zebrafish model that recapitulates the disorder we describe with developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities, further demonstrating the pathogenic effect of the PIP5K1C variants."
explanation: Zebrafish model of the developmental defects.
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.
Record notes
The entry is anchored on MONDO:1010145 and PIP5K1C (hgnc:8996). The only primary report is a cohort of nine unrelated children (PMID:37451268), which is cached as abstract only. The deep-research report gives per-feature counts from that paper's full text (for example seizures in 7 of 9), but the numbers cannot be quoted from the cache, so no frequency band is recorded and phenotypes are limited to those named in the abstract, plus the language impairment named in the OMIM title, which carries no evidence item for this reason. Lethal congenital contracture syndrome 3 (LCCS3, MONDO:0012656) is caused by biallelic PIP5K1C variants that abolish kinase activity (PMID:17701898). The two diseases have opposite mechanisms and are kept apart; LCCS3 is listed as a differential. No GeneReviews chapter covers this disease; just check-genereviews reports NO_CHAPTER against the 2026-09-10 Bookshelf index.
Review round 1: split bundled nodes, add language impairment · 2026-10-15T10:00:06Z · View source
Addressed review on PR 14311. Split the actin/trafficking node into Ectopic F-actin Recruitment to Early Endosomes and Early Endosome Trafficking Dysfunction, linked by a DIRECT edge (the source says the actin recruitment in turn causes the trafficking dysfunction); endosomal transport modifier changed from DECREASED to ABNORMAL. Split the forebrain/eye/craniofacial node into three TISSUE nodes, routed the phenotype edges by organ, and repointed the zebrafish model link at all three. Reworded the Lowe syndrome sentence in the description, which had called the two disorders mirror images while saying both raise PI(4,5)P2. Added Delayed speech and language development (HP:0000750), named in the OMIM title, without an evidence item: the full text (PMC10432144) could not be fetched through just fetch-reference and Europe PMC returned a server error, and the abstract does not mention language. Hypotonia and infantile spasms stay uncurated for the same reason. Kept 'base editing' in the animal model genotype; the deep-research report describes an endogenous zebrafish base-editing experiment at Glu146. Snippets 32/32 verified; validate, validate-terms, check-causal-targets and check-entity-refs pass.
Create: PIP5K1C-Related Neurodevelopmental Disorder · 2026-10-15T09:00:03Z · View source
New entry for PIP5K1C-related neurodevelopmental disorder (MONDO:1010145, NEDVIL, PIP5K1C gain of function). Source report: research/PIP5K1C-Related_Neurodevelopmental_Disorder-deep-research-perplexity.md, generated with Perplexity sonar-deep-research at reasoning_effort=low, because two runs at the default effort were disconnected at about 300 seconds. Reference validation resolved 15/15 references and flagged one off-topic (PMID:34211152, an ACMG sequencing guideline), which is not cited. preflight-dr returned WARN because its heuristic lexicon counted the disease abbreviation NEDVIL as a second gene; the report is about PIP5K1C and keeps the recessive allelic disease LCCS3 separate. The only primary report (PMID:37451268) is cached as abstract only, so the report's per-feature counts from its full text were not curated and phenotypes are limited to those named in the abstract. LCCS3 (PMID:17701898) is a differential. Validated with just validate, count-verified-snippets (24/24), validate-terms, check-genereviews (NO_CHAPTER), check-causal-targets and the gene-grounding gate.
Current assessment (15 October 2026). PIP5K1C-related neurodevelopmental disorder is an ultra-rare, autosomal-dominant developmental disorder caused by recurrent de novo gain-of-function missense variants in PIP5K1C. The best-defined phenotype is now named neurodevelopmental disorder with intellectual, visual, and language impairment (NEDVIL; OMIM 621635). It is mechanistically and clinically distinct from lethal congenital contracture syndrome 3 (LCCS3; OMIM 611369), which results from biallelic loss-of-function PIP5K1C variants. The foundational human evidence remains a 2023 cohort of nine unrelated children, so frequencies and prognosis should be treated as provisional. [31][10]
Principal primary source: Morleo M, et al. American Journal of Human Genetics. Published online 13 July 2023; issue date 3 August 2023. PMID 37451268; PMCID PMC10432144; DOI 10.1016/j.ajhg.2023.06.012; URL: https://pubmed.ncbi.nlm.nih.gov/37451268/ [31]
NEDVIL is a congenital/early-childhood-onset Mendelian neurodevelopmental syndrome characterized by global developmental delay, intellectual and severe language impairment, motor delay, frequent epilepsy, acquired microcephaly, visual or ophthalmologic abnormalities, and a recognizable but variable craniofacial/skeletal phenotype. In the original cohort, all nine affected children had heterozygous de novo missense variants that increased PIP5KIγ activity and endosomal phosphatidylinositol-4,5-bisphosphate—PI(4,5)P₂—production. [31]
The defining abstract states:
“We identified three de novo heterozygous missense variants in PIP5K1C … in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features.” — Morleo et al., 2023, PMID 37451268. [31]
| Resource | Identifier/name | Status or interpretation |
|---|---|---|
| OMIM disease | 621635 — Neurodevelopmental disorder with intellectual, visual, and language impairment | Current specific Mendelian phenotype; synonym NEDVIL. [10] |
| OMIM gene | 606102 — PIP5K1C | Gene record; chromosome 19p13.3. [5] |
| HGNC | HGNC:8996 — PIP5K1C | Approved gene symbol. [22] |
| MONDO supplied in request | MONDO:1010145 | Could not be independently confirmed in the accessible MONDO/MedGen records; retain only as a provisional knowledge-base mapping pending direct ontology-release validation. |
| Other MONDO mappings encountered | MONDO:0100038, “complex neurodevelopmental disorder,” and broader NDD mappings | GenCC currently uses MONDO:0100038 for the dominant gene–disease assertion; this is broader than NEDVIL. [3][41] |
| MedGen | UID 1057551 — NEDVIL | Linked to PIP5K1C and OMIM 621635. [76] |
| Orphanet | No disease-specific NEDVIL ORPHAcode located | The gene page lists PIP5K1C and ORPHA:160322 as a gene-related record, not a clearly disease-specific NEDVIL code. [1][6] |
| ICD-10/ICD-11 | No specific code | Code manifestations as appropriate, e.g., developmental disorder/intellectual disability, epilepsy, microcephaly, and visual impairment; avoid treating those nonspecific codes as equivalent to NEDVIL. |
| MeSH | No specific disease heading identified | “Neurodevelopmental Disorders,” “Intellectual Disability,” “Epilepsy,” and “Microcephaly” are potential broader indexing concepts. |
| Distinct allelic disease | LCCS3, OMIM 611369; MONDO:0012656 | Biallelic loss-of-function disorder; not a synonym for NEDVIL. [8][25] |
Common names: PIP5K1C-related neurodevelopmental disorder; PIP5K1C gain-of-function neurodevelopmental disorder; NEDVIL; neurodevelopmental syndrome associated with altered phosphoinositide signaling.
Source granularity: Published information is aggregated from standardized clinical assessments of individual research/clinical cases, not routine population EHR data. Eight cases were identified by exome sequencing and one by genome sequencing; two were enrolled through the Undiagnosed Diseases Network or Telethon Undiagnosed Disease Program, while others were clinically ascertained and connected through Matchmaker Exchange/GeneMatcher. [53]
The established cause is a germline heterozygous activating missense variant in the catalytic domain of PIP5KIγ, encoded by PIP5K1C. Three recurrent variants accounted for the original nine cases:
These variants elevate PI(4,5)P₂, unlike LCCS3-associated biallelic variants that abolish or markedly reduce enzyme function and PI(4,5)P₂ synthesis. [5][19]
| Factor class | Evidence for NEDVIL |
|---|---|
| Causal genetic risk | A de novo activating PIP5K1C variant is the principal known risk and is sufficient to cause disease. |
| Parental age | Not assessed in the nine-person cohort. |
| Sex | Six males and three females were reported, but this sample is too small to establish a sex effect. |
| Family history | Usually negative because variants are de novo; parental germline mosaicism remains theoretically possible. |
| Environmental, infectious, lifestyle or occupational risks | None established. |
| Susceptibility loci/modifier genes | None validated. Other rare variants were evaluated in the discovery study, but no modifier was established. |
| Genetic protective factors | None known. The milder phenotype in one mosaic individual suggests that lower variant allele burden may reduce severity, but this is an observation, not an established protective allele. |
| Environmental protective factors | None demonstrated. |
| Gene–environment interaction | No disease-specific interaction has been studied. Seizure burden, access to therapy, nutrition, intercurrent illness, and sensory support could modify function or complications without altering the primary genetic cause. |
The mosaic p.Tyr221Cys individual was the least severely affected and had an IQ of 67, providing preliminary evidence for a dosage relationship; this is based on one case and requires replication. [40]
Frequencies below are from only nine affected individuals aged 3–15 years and are not population estimates. [32]
| Phenotype type | Phenotype and suggested HPO term | Frequency | Onset, severity and course | Functional/QOL effect |
|---|---|---|---|---|
| Developmental sign | Global developmental delay — HP:0001263 | 9/9 | Infancy/early childhood; moderate to profound; chronic | Dependence for age-appropriate mobility, communication and self-care |
| Motor sign | Motor delay — HP:0001270 | 9/9 | Early childhood; variable | Four or more individuals remained non-ambulatory; independent walking, when attained, could be delayed to 2–5 years |
| Behavioral/developmental sign | Speech/language delay — HP:0000750; absent speech HP:0001344 where applicable | 9/9 | Early and persistent; usually severe | Most were nonverbal or used very few words; major communication limitation |
| Neurocognitive sign | Intellectual disability — HP:0001249 | 9/9 | Developmental; moderate to severe/profound in most | IQs reported were 52, 57 and 67; marked adaptive-function impact |
| Neurologic sign | Seizure — HP:0001250 | 7/9 | Childhood; variable; sometimes severe | Medication burden, injury risk and developmental interference |
| Neurologic sign | Infantile spasms — HP:0012469 | 3/9 | Infancy | Three children developed severe developmental and epileptic encephalopathy |
| Growth sign | Acquired/postnatal microcephaly — HP:0005484/HP:0011451 | 7/9 | Usually emerged after birth | Marker of altered brain growth; direct QOL effect not separately measured |
| Neurologic sign | Hypotonia — HP:0001252 | 5/9 | Childhood; variable | Likely contributes to delayed sitting, walking, posture and therapy needs |
| Sensory/ocular | Visual impairment — HP:0000505, with variable ocular findings | 8/9 | Infancy/childhood; variable | Impairs orientation, communication, learning and mobility |
| Ocular | Strabismus — HP:0000486 | Several cases | Childhood; variable | May affect binocular vision and require ophthalmic treatment |
| Ocular | Optic atrophy — HP:0000648 / pale optic nerves | 2/9 optic-nerve abnormalities | Childhood | Potential irreversible visual loss |
| Ocular | Cerebral visual impairment — HP:0100704 | Reported/probable in several | Childhood | Visual-processing limitations despite variable ocular anatomy |
| Skeletal | Skeletal abnormality | 6/9 | Congenital or childhood; heterogeneous | Can affect gait, posture and need for orthopedics |
| Cranial | Craniosynostosis — HP:0001363 | Confirmed bilateral coronal synostosis in 1/9 | Congenital | One child required clinical management; not a universal feature |
| Skeletal | Scoliosis — HP:0002650 | 1 reported | Childhood | Potential mobility and respiratory consequences with progression |
| Craniofacial sign | Prominent maxilla/upper lip | 9/9 | Congenital/persistent | Primarily diagnostic/dysmorphologic |
| Craniofacial sign | Micrognathia — HP:0000347 | 6/9 | Congenital or historical | Potential feeding/airway implications, although these were not quantified |
| Craniofacial sign | Long ears — HP:0000400 | 6/9 | Congenital | Primarily dysmorphic |
| Craniofacial sign | Hypertelorism — HP:0000316 | Common, exact denominator not provided | Congenital | Primarily diagnostic |
| Neuroimaging sign | Abnormal white-matter signal — HP:0002500 | Multiple cases | Childhood; nonspecific and inconsistent | Prognostic meaning unknown |
| Neuroimaging sign | Focal dysgyria/cortical malformation — HP:0032046 or closest curated term | Several possible cases | Congenital | May contribute to epilepsy/developmental impairment, but causality is unproven |
Additional findings included myopia, hyperopia, astigmatism, nystagmus, delayed or deficient myelination, abnormal ventricular contours, cerebral atrophy, Chiari I malformation, hypoplastic anterior temporal lobes, coronal synostosis, prominent metopic ridge, talipes equinovarus, coxa valga, camptodactyly, clinodactyly, pes planus, and small feet. MRI findings were heterogeneous and were considered normal, nonspecific, or inconsistent on centralized review in the subset available. [53]
No disease-specific EQ-5D, SF-36, PROMIS, caregiver-burden or adaptive-behavior study has been published. The principal expected QOL burdens arise from nonverbal status, impaired mobility, epilepsy, visual impairment, intellectual disability, and lifelong dependence.
| Field | Annotation |
|---|---|
| Gene | PIP5K1C |
| HGNC | HGNC:8996 |
| OMIM | 606102 |
| Location | 19p13.3 |
| Protein | Phosphatidylinositol-4-phosphate 5-kinase type 1 gamma, PIP5KIγ/PIP5Kγ |
| UniProt | O60331 |
| Enzyme function | Phosphorylates phosphatidylinositol 4-phosphate, PI4P, to form PI(4,5)P₂ |
| Important processes | Actin organization, receptor and endosomal trafficking, clathrin/AP-2-mediated endocytosis, synaptic-vesicle endocytosis/exocytosis and cell adhesion/migration [61] |
| Variant, NM_012398.3 | Protein | Cases in 2023 cohort | Origin | Functional consequence | Population/classification evidence |
|---|---|---|---|---|---|
| c.436G>A | p.(Glu146Lys) | 1 | De novo germline | Gain of function; surface-charge reversal may alter interactions | ClinVar VCV001172539; numerical gnomAD frequency not reported in the article |
| c.614A>G | p.(Tyr205Cys) | 2 | De novo germline | Gain of function; near ATP-binding region; increased PI(4,5)P₂ | ClinVar VCV001809611; absent/ultra-rare population evidence used in filtering |
| c.662A>G | p.(Tyr221Cys) | 6 | De novo; constitutional in five and mosaic in one | Gain of function; near ATP-binding region; increased PI(4,5)P₂ | ClinVar VCV001172538; ClinVar classifies it as pathogenic and reports absence from gnomAD. [46] |
All are missense substitutions in the amino-terminal portion of the kinase domain. Structural modeling suggested that Tyr205Cys and Tyr221Cys enlarge the ATP-binding-pocket cavity, potentially improving ATP access, whereas Glu146Lys changes local surface charge; those structural effects are inferred, while excess PI(4,5)P₂ production was experimentally demonstrated. [53]
Biallelic loss-of-function PIP5K1C variants cause LCCS3: severe fetal akinesia/arthrogryposis, muscle atrophy, growth restriction and early death from respiratory insufficiency. The original homozygous p.Asp253Asn variant abolished kinase activity. A 2024 report added compound-heterozygous frameshifts c.949_952dup, p.(Ser318Ilefs28), and c.688_689del, p.(Gly230Glnfs114), in two affected fetuses. PMID 38491417, published 15 March 2024; URL: https://pubmed.ncbi.nlm.nih.gov/38491417/ [34]
Important curation rule: do not merge dominant gain-of-function NEDVIL with recessive loss-of-function LCCS3 into a single phenotype.
No toxin, radiation, pollution, diet, smoking, alcohol, occupation, lifestyle behavior or infectious agent is known to initiate NEDVIL. It is not infectious, contagious or zoonotic. Environmental and health-care factors may influence secondary outcomes—especially seizure control, nutrition, contractures, communication and visual development—but they are not established causes.
Consequently:
Morleo et al. summarized the central result as:
“The PIP5K1C variants result in an increase of the endosomal PI(4,5)P2 pool, giving rise to ectopic recruitment of filamentous actin at early endosomes … that in turn causes dysfunction in EE trafficking.” [31]
| Evidence system | Result | Interpretation |
|---|---|---|
| Patient fibroblasts, p.Tyr205Cys | Total PI(4,5)P₂ increased 1.6-fold; early-endosomal PI(4,5)P₂ increased 2.4-fold | Direct human-cell evidence of gain of function |
| Patient fibroblasts | Approximately 80% of EEA1-positive endosomes associated with actin versus approximately 20% in controls | Excess PI(4,5)P₂ drives abnormal endosomal F-actin |
| Patient fibroblasts | Transferrin binding was reduced and recycling was slower, while normalized internalization rate was comparable | Defective surface receptor re-exposure/endosomal recycling |
| Transfected fibroblast/HeLa models | All three NEDVIL variants generated more PI(4,5)P₂ than wild-type PIP5KIγ under comparable expression | Variant-specific biochemical activation |
| Protein turnover | Wild type and dominant variants had half-lives around six hours | Disease is not primarily due to increased protein stability |
| Zebrafish mRNA overexpression | Variant-injected larvae developed microcephaly, eye loss/microphthalmia and altered craniofacial cartilage | In-vivo developmental pathogenicity |
| Endogenous zebrafish base editing | Approximately 30% of embryos edited at the homologous Glu146 site had microphthalmia and/or microcephaly | Independent in-vivo genetic support |
The authors caution that “the mechanistic link bridging these PIP5K1C gain-of-function variants … and the clinical manifestation … remain[s] to be determined and need[s] to be explored in neuronal tissue.” Thus, the lipid/endosome defect is demonstrated, but its precise neuronal-cell-type consequences remain partly inferred. [53]
| Category | Suggested terms |
|---|---|
| Molecular function | GO:0016308, 1-phosphatidylinositol-4-phosphate 5-kinase activity; GO:0016301, kinase activity |
| Biological process | GO:0006661, phosphatidylinositol biosynthetic process; GO:0006897, endocytosis; GO:0045022, early endosome to late endosome transport; GO:0030036, actin cytoskeleton organization; GO:0048488, synaptic vesicle endocytosis |
| Cellular component | GO:0005769, early endosome; GO:0005886, plasma membrane; GO:0015629, actin cytoskeleton; GO:0030666, endocytic vesicle membrane; GO:0098794, postsynapse |
| Chemicals | PI4P — CHEBI:17526 or release-equivalent curated phosphoinositide term; PI(4,5)P₂ — CHEBI:18348 or release-equivalent term; ATP — CHEBI:15422 |
| Relevant cells | Neuron — CL:0000540; glutamatergic neuron — CL:0000679; GABAergic neuron — CL:0000617; retinal neuron — use the appropriate subtype; fibroblast — CL:0000057 |
| Biological tissues | Cerebral cortex, forebrain, retina/optic pathway, craniofacial cartilage and skeletal tissue |
No disease-specific transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic or integrated multi-omic patient dataset has been reported. The direct lipid-immunostaining and trafficking assays are currently the most informative molecular profiling.
| Level | Structures/cells | Suggested ontology terms | Evidence |
|---|---|---|---|
| Primary organ | Brain/central nervous system | Brain UBERON:0000955; forebrain UBERON:0001890; cerebral cortex UBERON:0000956 | Developmental impairment, epilepsy, microcephaly; heterogeneous MRI abnormalities |
| Sensory system | Eye, optic nerve and cerebral visual pathways | Eye UBERON:0000970; optic nerve UBERON:0000966; retina UBERON:0000966 should be release-checked because identifiers may differ | Strabismus, cerebral visual impairment, optic atrophy, refractive errors |
| Craniofacial system | Cranial sutures, maxilla, mandible and facial skeleton | Skull UBERON:0003129; mandible UBERON:0001684 | Coronal synostosis, metopic ridging, prominent maxilla and micrognathia |
| Musculoskeletal system | Spine, hips, hands, feet and joints | Vertebral column UBERON:0001130; limb joint UBERON:0000982 | Scoliosis, coxa valga, talipes, camptodactyly and clinodactyly |
| Cellular | Developing neurons and neural progenitors are biologically plausible targets; direct patient-neuronal evidence is lacking | Neuron CL:0000540; neural progenitor cell CL:0000047 | Inferred from phenotype and zebrafish forebrain defects |
| Subcellular | Plasma membrane, early endosome, cytosol, actin cytoskeleton and synaptic compartments | GO:0005886, GO:0005769, GO:0005829, GO:0015629 | Direct biochemical/cell-biological evidence [61][69] |
No consistent laterality is established. Eye and brain findings may be bilateral or asymmetric depending on the manifestation.
| Characteristic | Current evidence |
|---|---|
| Inheritance | Autosomal dominant |
| Typical origin | De novo |
| Penetrance | Appears high for established activating variants, but cannot be quantified from nine ascertained cases |
| Expressivity | Variable; moderate-to-profound developmental disability, variable epilepsy and visual/skeletal involvement |
| Mosaicism | One postzygotic mosaic p.Tyr221Cys case, with comparatively mild presentation |
| Germline mosaicism | Not reported but cannot be excluded; recurrence risk is therefore low but above zero after a confirmed de novo result |
| Anticipation | Not applicable/no evidence |
| Founder effect | None identified for NEDVIL |
| Consanguinity | Not relevant to the usual dominant de novo phenotype; important in recessive LCCS3 |
| Carrier frequency | Not established; conventional unaffected “carriers” are not expected for highly penetrant activating variants |
| Prevalence/incidence | Unknown; no registry-based estimate |
| Sex ratio | Six male:three female in the discovery cohort; insufficient evidence for sex bias |
| Geographic/ethnic distribution | Cases were unrelated and internationally ascertained; no ethnic or geographic enrichment demonstrated |
| Age distribution | Published individuals were 3–15 years old at last evaluation |
At the time of the 2023 report, only nine molecularly confirmed NEDVIL cases were described. Therefore, neither prevalence per 100,000 nor annual incidence can be calculated responsibly.
| Test | Utility |
|---|---|
| Trio WES | High; identified eight of the original nine cases |
| Trio WGS | High; identified one original case and can better detect structural/noncoding variation and mosaicism |
| NDD/epilepsy panel | Reasonable if PIP5K1C is included and coverage is adequate |
| Single-gene sequencing | Appropriate after a highly suggestive phenotype or known familial variant; less efficient for nonspecific DD/ID |
| CMA | Useful for the broader DD/ID differential but will usually miss the causal single-nucleotide variants |
| Karyotype/FISH | Not routinely informative unless another chromosomal disorder is suspected |
| RNA sequencing | Research/adjunctive use for suspected splice variants; no established NEDVIL RNA signature |
| Mitochondrial/repeat-expansion testing | Not indicated specifically unless the phenotype suggests an alternative disorder |
| Biochemical assay | No validated clinical PI(4,5)P₂ or PIP5KIγ enzyme diagnostic assay |
| Prenatal testing | Targeted testing is possible once a familial pathogenic variant is known |
No standardized clinical criteria or laboratory biomarker can replace molecular diagnosis.
Broad differentials include genetic developmental and epileptic encephalopathies, phosphoinositide disorders such as Lowe syndrome and other PI-metabolism disorders, syndromic microcephaly with visual impairment, tubulinopathies/cortical-malformation syndromes, and other disorders with severe speech impairment and craniosynostosis. Distinguishing NEDVIL requires the characteristic PIP5K1C activating variant and, when needed, functional evidence.
There is no approved disease-modifying treatment, no published NEDVIL treatment trial, and no reliable treatment-response percentage. Management is multidisciplinary and manifestation-directed.
| Intervention | Indication/strategy | Suggested NCIT concept |
|---|---|---|
| Antiseizure medication | Select according to seizure type and standard pediatric epilepsy practice; urgent treatment of infantile spasms | Anticonvulsant therapy; NCIT:C15313 or current release equivalent |
| Ketogenic diet, epilepsy surgery or neuromodulation | Consider only for refractory epilepsy after specialist evaluation; no NEDVIL-specific outcomes | Ketogenic diet; epilepsy surgery; vagus nerve stimulation |
| Physical therapy | Hypotonia, gross-motor delay, contracture prevention, mobility | Physical therapy NCIT:C15300 or release equivalent |
| Occupational therapy | Fine-motor skills, adaptive equipment, self-care and sensory needs | Occupational therapy |
| Speech-language therapy | Severe receptive/expressive language impairment | Speech therapy |
| AAC | Early augmentative and alternative communication for nonverbal/minimally verbal individuals | Assistive communication device/intervention |
| Vision services | Refraction, strabismus management, low-vision and cerebral-visual-impairment habilitation | Ophthalmologic examination; vision rehabilitation |
| Nutritional/feeding support | Poor oral intake, dysphagia or growth problems | Nutritional support; feeding therapy |
| Orthopedic care | Scoliosis, talipes, hip/hand/foot abnormalities | Orthopedic procedure/orthosis as appropriate |
| Craniofacial surgery | Confirmed clinically significant craniosynostosis | Craniosynostosis repair |
| Psychological/social support | Family support, individualized education plan, respite and disability services | Supportive care |
Because disease variants increase PIP5KIγ activity, selective kinase inhibition is mechanistically attractive. Morleo et al. stated, “From a clinical point of view, PIP5Ks represent attractive therapeutic targets,” but no rescue was demonstrated in patient neurons or affected children. [109]
UNC3230 lowers PIP₂ in dorsal-root-ganglion neurons and reduced nociceptive hypersensitivity in mouse pain models, but it also inhibits PIP4K2C and has not been tested as NEDVIL therapy. PMID 24853942. [110] In 2024, medicinal-chemistry work reported novel potent bicyclic-pyrazole PIP5K1C inhibitors, but these remain preclinical and have no established pediatric CNS safety, selectivity, dosing or developmental benefit. [107]
Gene replacement would be biologically inappropriate without allele-specific control because NEDVIL is a gain-of-function disorder. Potential future strategies include allele-selective silencing, targeted RNA interference/ASOs or selective PIP5KIγ inhibition, but none has entered disease-specific clinical testing.
There is no lifestyle, vaccine or environmental intervention that prevents a spontaneous de novo mutation. General preconception health measures do not specifically alter NEDVIL risk.
There is no newborn biochemical screening program for NEDVIL and insufficient evidence to support population screening.
Prevent secondary complications through seizure control, aspiration and nutrition surveillance, mobility/contracture programs, scoliosis monitoring, visual habilitation, communication support and individualized educational planning.
| Species | Taxon | Ortholog/model relevance | Natural disease |
|---|---|---|---|
| Human, Homo sapiens | NCBI Taxon 9606 | PIP5K1C, HGNC:8996 | NEDVIL and LCCS3 |
| Mouse, Mus musculus | 10090 | Pip5k1c, MGI:1298224 | Experimental alleles cause neonatal/embryonic lethality and neurologic, synaptic, visual and homeostatic abnormalities. [96] |
| Zebrafish, Danio rerio | 7955 | Paralogs pip5k1ca and pip5k1cb | Engineered gain-of-function models reproduce microcephaly, eye and craniofacial abnormalities. [7][90] |
No well-established naturally occurring PIP5K1C-associated veterinary syndrome, breed predisposition or OMIA disease entry was identified. Consequently, no VBO breed term is applicable. There is no zoonotic transmission or cross-species contagion.
The pathway is evolutionarily conserved: zebrafish pip5k1ca and pip5k1cb proteins were reported as approximately 71% and 62% identical to human PIP5KIγ, respectively, supporting comparative functional modeling.
| Model | Genetic/manipulation type | Phenotype and application | Limitations/resources |
|---|---|---|---|
| Patient dermal fibroblasts | Endogenous heterozygous p.Tyr205Cys | Increased total/endosomal PI(4,5)P₂, excess early-endosomal F-actin, impaired transferrin recycling | Non-neuronal; available evidence came from one affected individual |
| HeLa/control fibroblast overexpression | Wild type, three dominant variants and recessive p.Asp253Asn comparator | Demonstrated variant-dependent PI(4,5)P₂ gain of function and endosomal actin recruitment | Overexpression may exceed physiological protein levels |
| Zebrafish mRNA model | One-cell-stage expression of human mutant mRNA | p.Glu146Lys: 46% eye/microcephaly plus 3.4% severe no-eye phenotype; p.Tyr205Cys: 32.7% plus 6.7%; p.Tyr221Cys: 32% plus 14% | Transient overexpression; mortality 27%–57.5%; not a stable heterozygous humanized line [90] |
| Zebrafish base-editing model | Endogenous pip5k1ca Glu146-region edit | About 30% developed microphthalmia and/or microcephaly | Editing mosaicism and imperfect amino-acid equivalence; only one variant modeled |
| Global mouse knockout | Pip5k1c null | Roughly 50% reduction in brain PIP₂, impaired mobility/feeding, synaptic-vesicle defects and death within 24 hours | Models loss of function/LCCS3 biology, not dominant NEDVIL gain of function [72][74] |
| Conditional sensory-neuron mouse knockout | Tissue-specific Pip5k1c deletion | Early-onset proprioceptive deficit and altered pain signaling | Relevant to neuronal function but opposite molecular direction from NEDVIL [104] |
| Future preferred models | Heterozygous knock-in mouse, patient iPSC-derived cortical neurons/retinal organoids, cerebral organoids | Could test cell-type specificity, neuronal trafficking, network excitability, variant dosage and therapeutic rescue | No such published NEDVIL model was located |
In the landmark knockout mouse study, reduced brain PI(4,5)P₂ produced decreased miniature-current frequency, enhanced synaptic depression, a smaller readily releasable vesicle pool, delayed endocytosis and slower vesicle recycling. PMID 15386003. This establishes that tightly regulated PIP5KIγ activity is essential for synaptic-vesicle trafficking, although it models deficient rather than excessive kinase activity. [72]
Checked with linkml-reference-validator 0.3.0.
| Outcome | Count |
|---|---|
| References checked | 15 |
| Resolved | 15 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 15 |
| On topic | 5 |
| Off topic | 1 |
These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:
PMID:34211152 (2 mentions) - Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG).Weighed against this report's own most characteristic terms: nedvil, variant, pip5k1c, developmental, visual, phenotype, epilepsy, microcephaly, disease, impairment, novo, craniofacial, abnormalitie, severe, disorder, affected, function, mosaicism, dominant, individual.
All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 60 |
| Resolved | 57 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 3 |
| Terms whose name was checked | 1 |
| Terms named correctly | 0 |
| Terms named as a different term | 1 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:1010145 (2 mentions) - the report calls it "MONDO supplied in request"; MONDO calls it PIP5K1C-related neurodevelopmental disorderThe report gives these identifiers more than one name of its own:
HGNC:8996 - called "PIP5K1C", "HGNC"Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.