SETD1A-related early-onset epilepsy (OMIM 618832; "epilepsy, early-onset, with or without developmental delay", EPEDD) is an autosomal dominant, epilepsy-predominant disorder caused by heterozygous variants in SETD1A, which encodes the catalytic subunit of a Set1/COMPASS complex that deposits mono-, di-, and trimethylation marks on histone H3 lysine 4 (H3K4) at actively transcribed promoters. Seizures begin early -- typically in infancy, within the first two years and in some individuals in the first months of life -- and the seizure repertoire reported to date spans focal-to-bilateral tonic-clonic seizures, focal impaired-awareness seizures, and infantile epileptic spasms syndrome with hypsarrhythmia. Developmental impact is strikingly variable: some individuals have global developmental delay, while others have entirely preserved cognition and normal brain MRI, which is the "with or without developmental delay" of the disease name. The entity was defined by Yu et al. (2019), who reported three de novo SETD1A missense variants and one missense variant segregating with seizures in a four-generation family, and it has been extended by subsequent case reports. EPEDD is one of three allelic SETD1A phenotype groups, alongside the developmental-delay-predominant neurodevelopmental disorder with speech impairment and dysmorphic facies (NEDSID) and large-effect risk for schizophrenia conferred by SETD1A loss-of-function variants; the primary diagnosis in SETD1A carriers is strongly age-dependent. Seizures have responded to conventional antiseizure regimens in the reported cases, but no systematic treatment data exist.
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name: SETD1A-Related Early-Onset Epilepsy
creation_date: "2026-09-02T13:16:57Z"
category: Mendelian
description: >-
SETD1A-related early-onset epilepsy (OMIM 618832; "epilepsy, early-onset,
with or without developmental delay", EPEDD) is an autosomal dominant,
epilepsy-predominant disorder caused by heterozygous variants in SETD1A,
which encodes the catalytic subunit of a Set1/COMPASS complex that deposits
mono-, di-, and trimethylation marks on histone H3 lysine 4 (H3K4) at
actively transcribed promoters. Seizures begin early -- typically in infancy,
within the first two years and in some individuals in the first months of
life -- and the seizure repertoire reported to date spans focal-to-bilateral
tonic-clonic seizures, focal impaired-awareness seizures, and infantile
epileptic spasms syndrome with hypsarrhythmia. Developmental impact is
strikingly variable: some individuals have global developmental delay, while
others have entirely preserved cognition and normal brain MRI, which is the
"with or without developmental delay" of the disease name. The entity was
defined by Yu et al. (2019), who reported three de novo SETD1A missense
variants and one missense variant segregating with seizures in a
four-generation family, and it has been extended by subsequent case reports.
EPEDD is one of three allelic SETD1A phenotype groups, alongside the
developmental-delay-predominant neurodevelopmental disorder with speech
impairment and dysmorphic facies (NEDSID) and large-effect risk for
schizophrenia conferred by SETD1A loss-of-function variants; the primary
diagnosis in SETD1A carriers is strongly age-dependent. Seizures have
responded to conventional antiseizure regimens in the reported cases, but no
systematic treatment data exist.
disease_term:
preferred_term: epilepsy, early-onset, with or without developmental delay
term:
id: MONDO:0030005
label: epilepsy, early-onset, with or without developmental delay
synonyms:
- EPEDD
- SETD1A-related early-onset epilepsy
parents:
- Genetic epilepsy
- Chromatinopathy
notes: >-
Scope, identity and provenance notes for this entry.
(1) NAMED-ENTITY-CONFUSION PREFLIGHT. SETD1A is associated with several
distinct clinical entities, so identity was anchored before curation via
`runoak -i sqlite:obo:mondo info MONDO:0030005 -O obo`: the record carries
`xref: OMIM:618832`, the exact synonym `EPEDD`, and the causal-gene axiom
`relationship: RO:0004003 HGNC:29010 ! SETD1A`, all matching the curation
target. This entry is restricted to the epilepsy-predominant allelic entity
defined by Yu et al. 2019 (PMID:31197650) and subsequent epilepsy-first case
reports (PMID:37928142, PMID:42495272).
(2) ALLELIC BUT DISTINCT SETD1A ENTITIES. Two other SETD1A phenotype groups
must not be conflated with this one. (a) Neurodevelopmental disorder with
speech impairment and dysmorphic facies (NEDSID; MONDO:0033630, OMIM 619056),
defined by Kummeling et al. 2021 (PMID:32346159) in 15 individuals with de
novo loss-of-function variants, is developmental-delay-predominant: the core
is global developmental delay and/or intellectual disability, subtle facial
dysmorphism, and behavioral/psychiatric problems, with seizures in only a
subset. NEDSID is not yet curated in this KB (it remains an open stub); when
it is, the lump/split question of whether EPEDD and NEDSID are one
variable-expressivity spectrum or two entries should be revisited -- OMIM and
MONDO currently keep them separate, and the epilepsy-first cases with fully
preserved cognition (PMID:42495272) support a separable epilepsy-predominant
presentation. (b) SETD1A loss-of-function variants also confer large-effect
risk for schizophrenia (PMID:26974950); that association is curated as a
genetic risk factor in the Schizophrenia entry of this KB, not here. The
age-dependence of the primary diagnosis across these groups is explicitly
noted in the literature (PMID:34803610). Note also that the KB entry
"Neurodevelopmental Disorder With Dysmorphic Facies, Sleep Disturbance, and
Brain Abnormalities" (NEDFASB, MONDO:0030852) is a KAT5/TIP60 disorder --
a different chromatin-modifier gene -- despite the similar descriptive name.
(3) LUMP/SPLIT DECISION. The stub for MONDO:0030005 was resolved as
entry_type DISEASE: EPEDD has its own OMIM number (618832), its own MONDO
term with SETD1A as causal gene, a defining cohort publication, and
subsequent epilepsy-predominant case reports including one with preserved
cognition and normal imaging, so it is curated as a standalone entry rather
than a subtype of an (uncurated) SETD1A parent concept.
(4) MECHANISM EVIDENCE IS LARGELY BORROWED FROM SCHIZOPHRENIA-FOCUSED MODELS.
Most functional SETD1A work (Setd1a+/- mice, hiPSC-derived neuronal
networks) was performed to model schizophrenia, not epilepsy, and is tagged
MODEL_ORGANISM or IN_VITRO accordingly. The direction-of-excitability
discrepancy between mouse (attenuated excitatory synaptic transmission) and
human iPSC networks (increased bursting) is recorded as a
HUMAN_MODEL_MISMATCH discussion rather than resolved silently. The
epileptogenic mechanism in patients is not directly established; the
network-hyperexcitability node is marked PROVISIONAL.
(5) NO GENEREVIEWS CHAPTER. A PubMed search for "SETD1A GeneReviews[All
Fields]" on 2026-09-02 returned no results, so there is no GeneReviews
phenotype baseline to cross-reference.
(6) EPISIGNATURE NEGATIVE. Targeted genome-wide DNA-methylation profiling of
six SETD1A patients did not reveal a strong methylation episignature
(PMID:37166351), so -- unlike many chromatinopathies -- a blood episignature
cannot currently support variant interpretation in this disorder. This
concerns CpG DNA methylation, not the histone H3K4 methylation lesion
itself. The finding is curated structurally as a `diagnosis` entry with
`presence: ABSENT` rather than left as prose here.
(7) MODEL SYSTEMS AND THE NEGATIVE LINK. The Setd1a+/- mouse is curated with
a `FAILS_TO_RECAPITULATE` link to Cortical Network Hyperexcitability. That
claim rests on two different things and the distinction matters: the
published excitatory phenotype runs in the opposite direction to the human
epilepsy (attenuated transmission), and no chronic video-EEG or
seizure-threshold phenotyping has been published at any age because the
lines were built for schizophrenia. The second is an absence of testing, not
a demonstrated absence of seizures; the link should be revisited if such
phenotyping appears, which is what the proposed experiment on the
HUMAN_MODEL_MISMATCH discussion asks for.
classifications:
harrisons_chapter:
- classification_value: GENETICS_ENVIRONMENT_DISEASE
evidence:
- reference: PMID:31197650
reference_title: De Novo and Inherited SETD1A Variants in Early-onset Epilepsy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Whole-exome sequencing indicated that all four of these mutations were
responsible for the seizures.
explanation: >-
A monogenic disorder established by exome sequencing belongs to the
genetics chapter.
- classification_value: NEUROLOGIC
evidence:
- reference: PMID:42495272
reference_title: A novel mutation in SETD1A is associated with early-onset epilepsy-a rare case report.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A novel de novo heterozygous variant in SETD1A (NM_014712.3: c.1067C >
T/p.Ser356Phe) was identified in a patient presenting with
focal-to-bilateral tonic-clonic seizures, beginning at 3 months of age.
explanation: >-
The presentation is dominated by early-onset seizures, placing the
entity in the neurology chapter.
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
Heterozygous SETD1A variants act dominantly. Most reported epilepsy-causing
variants arose de novo, but dominance is not exclusively de novo: the
defining report includes a missense variant transmitted with seizures
through a four-generation family, so cascade testing of parents and
relatives is warranted even when the proband appears sporadic.
evidence:
- reference: PMID:31197650
reference_title: De Novo and Inherited SETD1A Variants in Early-onset Epilepsy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we identified four missense mutations in the SETD1A gene (SET
domain-containing 1A, histone lysine methyltransferase): three de novo
mutations in three individuals and one inherited mutation in a
four-generation family.
explanation: >-
Documents both de novo occurrence and multigenerational autosomal
dominant transmission of SETD1A variants with early-onset epilepsy.
- reference: PMID:42495272
reference_title: A novel mutation in SETD1A is associated with early-onset epilepsy-a rare case report.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A novel de novo heterozygous variant in SETD1A (NM_014712.3: c.1067C >
T/p.Ser356Phe) was identified in a patient presenting with
focal-to-bilateral tonic-clonic seizures, beginning at 3 months of age.
explanation: >-
A further de novo heterozygous variant in an epilepsy-predominant case
supports the dominant, frequently de novo genotype.
genetic:
- name: SETD1A
gene_term:
preferred_term: SETD1A
term:
id: hgnc:29010
label: SETD1A
relationship_type: CAUSATIVE
notes: >-
SETD1A (16p11.2) encodes the catalytic subunit of a Set1/COMPASS complex
that methylates histone H3 lysine 4. The epilepsy-associated variants
reported to date include missense changes both inside and outside the
catalytic SET domain (p.Gln269Arg, p.Ser356Phe, p.Arg913Cys, p.Gly1369Arg,
p.Arg1392His) and truncating alleles (p.Glu1002Glyfs*20 in an infantile
epileptic spasms syndrome case). SETD1A is substantially depleted of
loss-of-function variants in the general population, consistent with
dosage sensitivity. No clean genotype-phenotype rule separating
epilepsy-predominant from developmental-delay-predominant presentations
has been established.
variants:
- name: p.Gln269Arg
description: De novo missense variant reported in early-onset epilepsy (Yu et al. 2019).
type: missense
- name: p.Arg913Cys
description: >-
Missense variant segregating with seizures in a four-generation family
(Yu et al. 2019); its expression also perturbed cortical neuron migration
in the mouse brain.
type: missense
- name: p.Gly1369Arg
description: De novo missense variant reported in early-onset epilepsy (Yu et al. 2019).
type: missense
- name: p.Arg1392His
description: De novo missense variant reported in early-onset epilepsy (Yu et al. 2019).
type: missense
- name: p.Ser356Phe (c.1067C>T)
description: >-
De novo missense variant outside the SET domain in a girl with
focal-to-bilateral tonic-clonic seizures from 3 months, normal MRI, and
preserved cognition; classified likely pathogenic (ACMG PS2+PM2+PP3).
type: missense
clinical_significance: LIKELY_PATHOGENIC
- name: p.Glu1002Glyfs*20 (c.3005_3006delAG)
description: >-
De novo frameshift variant in exon 12 in a child with infantile epileptic
spasms syndrome and hypsarrhythmia.
type: frameshift
evidence:
- reference: PMID:31197650
reference_title: De Novo and Inherited SETD1A Variants in Early-onset Epilepsy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Whole-exome sequencing indicated that all four of these mutations were
responsible for the seizures.
explanation: >-
Establishes the causal relationship between the identified SETD1A
variants and early-onset epilepsy in the defining cohort.
- reference: PMID:37928142
reference_title: "Case report: De novo variant of SETD1A causes infantile epileptic spasms syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Genetic testing revealed that the child had a variant
(NM_014712.3:c.3005_3,006 delAG, p.Glu1002Glyfs*20) in exon 12 of the
SETD1A gene, representing a de novo mutation.
explanation: >-
Extends the epilepsy-causing allelic series to a de novo truncating
variant.
- reference: PMID:26974950
reference_title: Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
indicating that SETD1A is substantially depleted of LoF variants in the
general population.
explanation: >-
Population-level constraint against SETD1A loss-of-function variants
supports dosage sensitivity of the gene, the substrate of the dominant
disease mechanism.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Ultra-rare; the defining report described three sporadic individuals plus
one four-generation family, and only a handful of additional
epilepsy-predominant cases (infantile epileptic spasms syndrome, isolated
focal epilepsy with preserved cognition) have been published since. No
population-based prevalence estimate exists.
evidence:
- reference: PMID:31197650
reference_title: De Novo and Inherited SETD1A Variants in Early-onset Epilepsy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we identified four missense mutations in the SETD1A gene (SET
domain-containing 1A, histone lysine methyltransferase): three de novo
mutations in three individuals and one inherited mutation in a
four-generation family.
explanation: >-
The defining cohort comprises three individuals and one family,
establishing the case-report scale of the entity.
pathophysiology:
- name: SETD1A Haploinsufficiency
description: >-
Heterozygous SETD1A variants -- truncating alleles and damaging missense
changes within and outside the catalytic SET domain -- reduce the dosage of
functional SETD1A, the catalytic subunit of a Set1/COMPASS histone
methyltransferase complex. Functional characterization of patient variants
(including a SET-domain missense allele) shows behavior comparable to
loss-of-function alleles, and the gene is strongly depleted of
loss-of-function variants in the general population, consistent with
dosage sensitivity.
role: trigger
biological_scale: MOLECULAR
mechanism_confidence: ESTABLISHED
genes:
- preferred_term: SETD1A
term:
id: hgnc:29010
label: SETD1A
genetic_context:
variant_origin: DE_NOVO
zygosity: HETEROZYGOUS
functional_impact_category: LOSS_OF_FUNCTION
description: >-
Heterozygous SETD1A alleles: truncating (frameshift, nonsense,
splice-site) changes and damaging missense substitutions both inside and
outside the catalytic SET domain. Patient-derived cell lines show that
even a SET-domain missense allele behaves as loss of function, and the
gene is strongly depleted of loss-of-function variants in the general
population. Most reported epilepsy variants arose de novo, but the
defining report includes one missense allele inherited through four
generations, so DE_NOVO records the predominant rather than exclusive
origin.
molecular_functions:
- preferred_term: histone H3K4 methyltransferase activity
term:
id: GO:0042800
label: histone H3K4 methyltransferase activity
modifier: DECREASED
evidence:
- reference: PMID:31197650
reference_title: De Novo and Inherited SETD1A Variants in Early-onset Epilepsy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Whole-exome sequencing indicated that all four of these mutations were
responsible for the seizures.
explanation: >-
Establishes heterozygous SETD1A variants as the initiating lesion in
early-onset epilepsy.
- reference: PMID:32346159
reference_title: Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
This suggested that these variants, including the p.Tyr1499Asp in the
catalytic SET domain, behave as loss-of-function (LoF) alleles.
explanation: >-
Patient-derived cell lines show that pathogenic SETD1A variants behave as
loss-of-function alleles, supporting haploinsufficiency as the molecular
lesion across the allelic SETD1A disorders.
- reference: PMID:26974950
reference_title: Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
indicating that SETD1A is substantially depleted of LoF variants in the
general population.
explanation: >-
Population constraint against SETD1A loss of function supports dosage
sensitivity.
downstream:
- target: Reduced Promoter H3K4 Methylation
causal_link_type: DIRECT
description: >-
Loss of catalytic SETD1A dosage directly reduces deposition of H3K4
methylation marks by the Set1/COMPASS complex.
- name: Reduced Promoter H3K4 Methylation
description: >-
SETD1A deposits mono-, di-, and trimethylation on histone H3 lysine 4;
H3K4me3 is a hallmark of transcriptionally active promoters. Reduced
SETD1A dosage lowers this activating chromatin mark at Set1/COMPASS target
loci. Note that this histone-methylation lesion has no detectable
correlate in blood DNA methylation: profiling of six SETD1A patients found
no strong CpG methylation episignature (PMID:37166351).
role: central_effector
biological_scale: MOLECULAR
mechanism_confidence: ESTABLISHED
biological_processes:
- preferred_term: epigenetic regulation of gene expression
term:
id: GO:0040029
label: epigenetic regulation of gene expression
modifier: DYSREGULATED
- preferred_term: chromatin organization
term:
id: GO:0006325
label: chromatin organization
modifier: ABNORMAL
evidence:
- reference: PMID:34803610
reference_title: SETD1A Mediated H3K4 Methylation and Its Role in Neurodevelopmental and Neuropsychiatric Disorders.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
SETD1A is a chromatin remodeler that influences gene expression through
the modulation of mono- di- and trimethylation marks on
Histone-H3-Lysine-4 (H3K4me1/2/3).
explanation: >-
Review statement of the normal molecular function whose loss defines
this node; a review is not primary data, hence evidence_source OTHER.
- reference: PMID:26974950
reference_title: Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we suggest that epigenetic dysregulation, specifically in the histone
H3K4 methylation pathway, is an important mechanism in the pathogenesis
of schizophrenia.
explanation: >-
Human genetic evidence that the H3K4 methylation pathway is the operative
epigenetic mechanism disrupted by SETD1A loss-of-function variants; drawn
from the schizophrenia arm of the allelic series, so it supports the
shared molecular step rather than the epilepsy phenotype specifically.
downstream:
- target: Transcriptional Dysregulation of Synaptic and Neurodevelopmental Genes
causal_link_type: DIRECT
description: >-
Loss of an activating promoter mark alters transcription of
Set1/COMPASS target genes.
- name: Transcriptional Dysregulation of Synaptic and Neurodevelopmental Genes
description: >-
Reduced H3K4 methylation at SETD1A-bound promoters and enhancers
dysregulates transcriptional programs in neurons. In Setd1a-deficient
mice, Setd1a binds both promoters and enhancers (overlapping Mef2 on
enhancers), and its targets -- highly expressed in pyramidal neurons --
show complex up- and downregulation, including genes related to
neurodevelopmental disorders and synaptic function in the medial
prefrontal cortex. In human SETD1A+/- iPSC-derived neuronal networks,
transcriptomic profiling shows perturbation of glutamatergic synaptic gene
sets. In patient-variant overexpression experiments, two common
downstream genes (Neurl4 and Usp39) were affected by SETD1A mutations.
role: central_effector
biological_scale: CELLULAR
mechanism_confidence: ESTABLISHED
cell_types:
- preferred_term: pyramidal neuron
term:
id: CL:0000598
label: pyramidal neuron
biological_processes:
- preferred_term: regulation of transcription by RNA polymerase II
term:
id: GO:0006357
label: regulation of transcription by RNA polymerase II
modifier: DYSREGULATED
evidence:
- reference: PMID:31606247
reference_title: Recapitulation and Reversal of Schizophrenia-Related Phenotypes in Setd1a-Deficient Mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Setd1a targets are highly expressed in pyramidal neurons and display a
complex pattern of transcriptional up- and downregulations shaped by
presumed opposing functions of Setd1a on promoters and Mef2-bound
enhancers.
explanation: >-
Mouse evidence that Setd1a deficiency dysregulates its direct
transcriptional targets in cortical pyramidal neurons.
- reference: PMID:35508131
reference_title: Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through the cAMP/PKA pathway.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
transcriptomic profiling reveals perturbations in gene sets associated
with glutamatergic synaptic function.
explanation: >-
Human iPSC-derived SETD1A+/- neuronal networks show dysregulation of
glutamatergic synaptic gene expression.
- reference: PMID:31197650
reference_title: De Novo and Inherited SETD1A Variants in Early-onset Epilepsy.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We further identified two common genes (Neurl4 and Usp39) affected by
mutations of SETD1A.
explanation: >-
The epilepsy-associated patient variants converge on shared downstream
gene targets in neuronal cells.
downstream:
- target: Abnormal Excitatory Synapse Development and Function
causal_link_type: DIRECT
description: >-
Dysregulated synaptic gene programs impair the development and function
of excitatory synapses.
- target: Impaired Cortical Neuron Migration
causal_link_type: DIRECT
description: >-
Dysregulated neurodevelopmental transcription perturbs cortical neuron
migration, demonstrated for the familial R913C variant.
- name: Abnormal Excitatory Synapse Development and Function
description: >-
Epilepsy-associated SETD1A variants expressed in mouse primary cortical
neurons impair excitatory synapse development. Consistently, Setd1a+/-
mice show altered axonal branching, cortical synaptic dynamics, and
impaired excitatory synaptic transmission in layer 2/3 pyramidal neurons
of the medial prefrontal cortex, with postsynaptic Setd1a required for
normal excitatory transmission. Human SETD1A+/- iPSC-derived neurons show
increased dendritic complexity. The mouse work is schizophrenia-focused
and reports attenuated excitatory function, whereas human iPSC networks
are hyperactive -- a directionality discrepancy recorded in the
HUMAN_MODEL_MISMATCH discussion on this entry.
role: central_effector
biological_scale: CELLULAR
mechanism_confidence: ESTABLISHED
cell_types:
- preferred_term: glutamatergic neuron
term:
id: CL:0000679
label: glutamatergic neuron
biological_processes:
- preferred_term: synapse organization
term:
id: GO:0050808
label: synapse organization
modifier: ABNORMAL
- preferred_term: chemical synaptic transmission
term:
id: GO:0007268
label: chemical synaptic transmission
modifier: ABNORMAL
evidence:
- reference: PMID:31197650
reference_title: De Novo and Inherited SETD1A Variants in Early-onset Epilepsy.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We found that their expression in mouse primary cortical neurons
affected excitatory synapse development.
explanation: >-
Direct functional evidence that the epilepsy-associated patient variants
perturb excitatory synapse development in cultured cortical neurons.
- reference: PMID:32937141
reference_title: Setd1a Insufficiency in Mice Attenuates Excitatory Synaptic Function and Recapitulates Schizophrenia-Related Behavioral Abnormalities.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Our Setd1a (+/-) mice display various behavioral abnormalities relevant
to features of SCZ, impaired excitatory synaptic transmission in layer
2/3 (L2/3) pyramidal neurons of the medial prefrontal cortex (mPFC), and
altered expression of diverse genes related to neurodevelopmental
disorders and synaptic functions in the mPFC.
explanation: >-
In vivo mouse evidence that Setd1a insufficiency impairs excitatory
synaptic transmission in cortical pyramidal neurons; the model was built
for schizophrenia, not epilepsy.
- reference: PMID:31606247
reference_title: Recapitulation and Reversal of Schizophrenia-Related Phenotypes in Setd1a-Deficient Mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Mice carrying a heterozygous loss-of-function mutation of the orthologous
gene exhibit alterations in axonal branching and cortical synaptic
dynamics accompanied by working memory deficits.
explanation: >-
Independent mouse model confirming structural and functional cortical
synaptic abnormalities from Setd1a haploinsufficiency.
downstream:
- target: Cortical Network Hyperexcitability
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
hypothesis_groups:
- camp_pka_network_hyperactivity_model
description: >-
In human SETD1A+/- neuronal networks, synaptic and cAMP/PKA-pathway
changes culminate in network hyperactivity; the intermediate steps
operating in the patient brain are not established.
evidence:
- reference: PMID:35508131
reference_title: Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through the cAMP/PKA pathway.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
At the molecular level, we identify specific changes in the cyclic AMP
(cAMP)/Protein Kinase A pathway pointing toward a hyperactive cAMP
pathway in SETD1A+/- neurons.
explanation: >-
Identifies the cAMP/PKA pathway as the molecular route from SETD1A
haploinsufficiency to network hyperactivity in human neurons,
supporting this edge specifically.
- target: Variable Neurodevelopmental Impairment
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Cortical synaptic dysfunction is the presumed substrate of the variable
developmental impairment; the determinants of who develops delay are
unknown.
- name: Impaired Cortical Neuron Migration
description: >-
Expression of the familial R913C epilepsy variant perturbed migration of
cortical neurons in the developing mouse brain, indicating that some
SETD1A variants additionally disturb neuronal positioning during
corticogenesis. Notably, affected individuals -- across the allelic SETD1A
disorders -- do not show major structural brain malformations, so any
migration contribution must be subtle.
role: central_effector
biological_scale: CELLULAR
mechanism_confidence: PROVISIONAL
biological_processes:
- preferred_term: neuron migration
term:
id: GO:0001764
label: neuron migration
modifier: ABNORMAL
evidence:
- reference: PMID:31197650
reference_title: De Novo and Inherited SETD1A Variants in Early-onset Epilepsy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Moreover, expression of the R913C mutation also affected the migration
of cortical neurons in the mouse brain.
explanation: >-
In vivo mouse evidence that an epilepsy-associated SETD1A variant
perturbs cortical neuron migration.
- reference: PMID:32346159
reference_title: Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
individuals with SETD1A variants do not show major structural brain
defects or severe microcephaly.
explanation: >-
Supports the constraint stated in this node: whatever migration
disturbance exists does not produce gross malformation in patients,
which is why the node is marked provisional and its downstream edge is
indirect.
downstream:
- target: Cortical Network Hyperexcitability
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Proposed, not demonstrated: subtly mispositioned cortical neurons could
contribute to epileptogenic circuit formation, but no study has traced
this link.
- name: Cortical Network Hyperexcitability
conforms_to: "epilepsy_excitation_inhibition_imbalance#Neuronal Hyperexcitability and Hypersynchrony"
description: >-
Human excitatory/inhibitory neuronal networks derived from SETD1A+/- iPSCs
show functionally increased bursting activity, driven primarily by
haploinsufficiency in glutamatergic neurons -- an in vitro correlate of
the network hyperexcitability that generates seizures in patients.
Direct demonstration of hyperexcitability in patient brain tissue does not
exist, and Setd1a+/- mice (schizophrenia models) show attenuated rather
than increased excitatory transmission, so this node is provisional.
role: central_effector
biological_scale: TISSUE
mechanism_confidence: PROVISIONAL
cell_types:
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: action potential
term:
id: GO:0001508
label: action potential
modifier: INCREASED
evidence:
- reference: PMID:35508131
reference_title: Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through the cAMP/PKA pathway.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Our data show that SETD1A haploinsufficiency results in morphologically
increased dendritic complexity and functionally increased bursting
activity.
explanation: >-
Human SETD1A+/- neuronal networks are hyperactive, the in vitro
correlate of an epileptogenic network state.
- reference: PMID:35508131
reference_title: Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through the cAMP/PKA pathway.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
This network phenotype is primarily driven by SETD1A haploinsufficiency
in glutamatergic neurons.
explanation: >-
Localizes the hyperactivity to the excitatory (glutamatergic) arm of the
network, matching the excitation/inhibition-imbalance module this node
conforms to.
downstream:
- target: Early-Onset Seizures
causal_link_type: DIRECT
description: >-
Hyperexcitable, hypersynchronous cortical network activity manifests
clinically as recurrent early-onset seizures.
- name: Early-Onset Seizures
description: >-
The clinical endpoint of the epilepsy arm of the cascade: recurrent
seizures beginning in infancy, often within the first months of life.
Reported semiologies include focal-to-bilateral tonic-clonic seizures,
focal impaired-awareness seizures, and infantile epileptic spasms
syndrome with hypsarrhythmia; brain MRI is typically normal.
role: consequence
biological_scale: ORGANISM
mechanism_confidence: ESTABLISHED
evidence:
- reference: PMID:42495272
reference_title: A novel mutation in SETD1A is associated with early-onset epilepsy-a rare case report.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A novel de novo heterozygous variant in SETD1A (NM_014712.3: c.1067C >
T/p.Ser356Phe) was identified in a patient presenting with
focal-to-bilateral tonic-clonic seizures, beginning at 3 months of age.
explanation: >-
Documents seizure onset at 3 months of age in a SETD1A variant carrier.
- reference: PMID:31197650
reference_title: De Novo and Inherited SETD1A Variants in Early-onset Epilepsy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Whole-exome sequencing indicated that all four of these mutations were
responsible for the seizures.
explanation: >-
The defining cohort ties SETD1A variants to the seizure phenotype.
downstream:
- target: Seizure
causal_link_type: DIRECT
description: The organism-level seizure state recorded clinically.
- target: Bilateral tonic-clonic seizure with focal onset
causal_link_type: DIRECT
description: Focal-to-bilateral tonic-clonic semiology reported from 3 months of age.
- target: Epileptic spasm
causal_link_type: DIRECT
description: Infantile epileptic spasms syndrome presentation.
- target: Hypsarrhythmia
causal_link_type: DIRECT
description: Interictal EEG correlate of the epileptic-spasms presentation.
- name: Variable Neurodevelopmental Impairment
description: >-
Developmental impact ranges from none to global developmental delay --
the "with or without developmental delay" of the disease name. One
reported child with seizures from 3 months of age had a developmental
quotient and IQ in the normal range with normal MRI, while other SETD1A
carriers in the epilepsy series and the wider allelic spectrum have
developmental delay or intellectual disability. The determinants of this
variability are unknown.
role: consequence
biological_scale: ORGANISM
mechanism_confidence: PROVISIONAL
evidence:
- reference: PMID:42495272
reference_title: A novel mutation in SETD1A is associated with early-onset epilepsy-a rare case report.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
establishing the relationship between SETD1A variants and isolated
early-onset epilepsy without accompanying severe neurodevelopmental
deficits.
explanation: >-
Documents the "without developmental delay" end of the spectrum:
early-onset epilepsy with preserved cognition, supporting the
variability claim of this node.
- reference: PMID:34803610
reference_title: SETD1A Mediated H3K4 Methylation and Its Role in Neurodevelopmental and Neuropsychiatric Disorders.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Recently, dominant mostly de novo variants in SETD1A have clinically
been linked to developmental delay, intellectual disability (DD/ID),
and schizophrenia (SCZ).
explanation: >-
Review documenting the developmental-delay end of the SETD1A spectrum;
evidence_source OTHER because a review is not primary data.
downstream:
- target: Global developmental delay
causal_link_type: DIRECT
description: The variable developmental-delay phenotype recorded clinically.
mechanistic_hypotheses:
- hypothesis_group_id: h3k4_transcriptional_dysregulation_model
hypothesis_label: H3K4-Methylation-Dependent Transcriptional Dysregulation Model
status: CANONICAL
description: >-
The disorder results from SETD1A haploinsufficiency: reduced Set1/COMPASS
H3K4 methyltransferase dosage lowers activating promoter methylation,
dysregulating synaptic and neurodevelopmental transcriptional programs in
cortical neurons, whose disturbed development and function produce
early-onset seizures with variable developmental impact. This is the
model advanced by the defining report and supported by mouse, fly, and
human iPSC work across the allelic SETD1A disorders. Notably, the
chromatin lesion appears pharmacologically reversible in mice:
antagonizing LSD1, the demethylase that counteracts Setd1a, fully rescues
the behavioral and morphological deficits of Setd1a-deficient animals,
and reinstating Setd1a expression in adulthood rescues cognitive
deficits -- implying a postnatal therapeutic window rather than fixed
structural damage.
evidence:
- reference: PMID:31606247
reference_title: Recapitulation and Reversal of Schizophrenia-Related Phenotypes in Setd1a-Deficient Mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
we identify LSD1 as a major counteracting demethylase for Setd1a and
show that its pharmacological antagonism results in a full rescue of the
behavioral and morphological deficits in Setd1a-deficient mice.
explanation: >-
Demonstrates in mice that the consequences of the H3K4-methylation
lesion are reversible by targeting the counteracting demethylase,
supporting the causal centrality of the H3K4 axis in this model.
- reference: PMID:26974950
reference_title: Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we suggest that epigenetic dysregulation, specifically in the histone
H3K4 methylation pathway, is an important mechanism in the pathogenesis
of schizophrenia.
explanation: >-
Human genetic evidence for the H3K4-pathway mechanism shared across the
SETD1A allelic series.
- hypothesis_group_id: camp_pka_network_hyperactivity_model
hypothesis_label: cAMP/PKA-Driven Network Hyperactivity Model
status: EMERGING
description: >-
In human SETD1A+/- iPSC-derived excitatory/inhibitory networks, SETD1A
haploinsufficiency produces a hyperactive cAMP/PKA pathway, increased
dendritic complexity, and increased network bursting, and pharmacological
targeting of the cAMP pathway rescues the network phenotype. This offers
a candidate molecular route from chromatin lesion to the network
hyperexcitability presumed to underlie seizures -- and a candidate
therapeutic axis -- but it has not been tested in patients or in an
epilepsy-specific model.
evidence:
- reference: PMID:35508131
reference_title: Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through the cAMP/PKA pathway.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Finally, by pharmacologically targeting the cAMP pathway, we are able to
rescue the network deficits in SETD1A+/- cultures.
explanation: >-
The rescue experiment that motivates the cAMP/PKA model and its
therapeutic implication.
discussions:
- discussion_id: setd1a_epedd_model_directionality_mismatch
prompt: >-
Do existing SETD1A model systems capture the epileptogenic mechanism of
EPEDD, given that Setd1a+/- mice show attenuated excitatory synaptic
function while human SETD1A+/- iPSC networks are hyperactive and patients
have early-onset epilepsy?
kind: HUMAN_MODEL_MISMATCH
status: OPEN
attaches_to:
- pathophysiology#Abnormal Excitatory Synapse Development and Function
- pathophysiology#Cortical Network Hyperexcitability
rationale: >-
Nearly all functional SETD1A work was designed to model schizophrenia.
Setd1a+/- mice show reduced excitatory synaptic transmission in medial
prefrontal cortex and behavioral abnormalities, without reported
spontaneous seizures, whereas human SETD1A+/- iPSC-derived networks show
increased bursting driven by glutamatergic neurons -- the direction
expected for an epilepsy. Whether this reflects a genuine species
difference, a developmental-stage difference (immature iPSC networks
versus adult mouse cortex), or circuit-level compensation is unresolved,
and no model has been assessed for seizure phenotypes or EEG. Translational
validity of the mouse synaptic findings to the human epilepsy is therefore
the open question, not the existence of a synaptic lesion.
evidence:
- reference: PMID:32937141
reference_title: Setd1a Insufficiency in Mice Attenuates Excitatory Synaptic Function and Recapitulates Schizophrenia-Related Behavioral Abnormalities.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Our findings suggest that reduced SETD1A may attenuate excitatory
synaptic function and contribute to the pathophysiology of SCZ.
explanation: >-
The mouse arm of the mismatch: attenuated excitatory function, framed
as schizophrenia pathophysiology.
- reference: PMID:35508131
reference_title: Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through the cAMP/PKA pathway.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Our data show that SETD1A haploinsufficiency results in morphologically
increased dendritic complexity and functionally increased bursting
activity.
explanation: >-
The human-cell arm of the mismatch: increased network activity.
proposed_experiments:
- experiment_id: setd1a_mouse_eeg_seizure_threshold
name: EEG and seizure-threshold phenotyping of Setd1a haploinsufficient mice
description: >-
Chronic video-EEG and chemoconvulsant seizure-threshold testing in
existing Setd1a+/- lines, across developmental stages, to determine
whether the models express a hyperexcitability phenotype relevant to
EPEDD at any age.
would_support:
- pathophysiology#Cortical Network Hyperexcitability
supporting_outcome:
- >-
Spontaneous epileptiform discharges or lowered seizure threshold in
Setd1a+/- mice, particularly in early postnatal life.
refuting_outcome:
- >-
Normal EEG and seizure thresholds at all ages despite confirmed
haploinsufficiency, which would localize the epileptogenic mechanism to
human-specific or developmental-stage-specific biology.
phenotypes:
- category: Nervous System
name: Seizure
description: >-
The defining feature: recurrent seizures with onset in infancy, often in
the first months of life. Semiology is heterogeneous across reported
individuals.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
onset:
onset_category: INFANTILE
notes: >-
Onset at 3 months of age in the isolated-epilepsy case; the defining
series emphasizes onset in early life, especially the first 2 years.
evidence:
- reference: PMID:31197650
reference_title: De Novo and Inherited SETD1A Variants in Early-onset Epilepsy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Whole-exome sequencing indicated that all four of these mutations were
responsible for the seizures.
explanation: >-
Seizures are the phenotype through which the defining cohort was
ascertained.
- reference: PMID:42495272
reference_title: A novel mutation in SETD1A is associated with early-onset epilepsy-a rare case report.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A novel de novo heterozygous variant in SETD1A (NM_014712.3: c.1067C >
T/p.Ser356Phe) was identified in a patient presenting with
focal-to-bilateral tonic-clonic seizures, beginning at 3 months of age.
explanation: >-
Documents infantile seizure onset in an additional carrier.
- category: Nervous System
name: Bilateral tonic-clonic seizure with focal onset
description: >-
Focal-to-bilateral tonic-clonic seizures, reported from 3 months of age
with unilateral onset and versive features, alongside focal
impaired-awareness seizures in the same child.
phenotype_term:
preferred_term: Focal-to-bilateral tonic-clonic seizure
term:
id: HP:0007334
label: Bilateral tonic-clonic seizure with focal onset
evidence:
- reference: PMID:42495272
reference_title: A novel mutation in SETD1A is associated with early-onset epilepsy-a rare case report.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A novel de novo heterozygous variant in SETD1A (NM_014712.3: c.1067C >
T/p.Ser356Phe) was identified in a patient presenting with
focal-to-bilateral tonic-clonic seizures, beginning at 3 months of age.
explanation: >-
Documents the focal-to-bilateral tonic-clonic semiology.
- category: Nervous System
name: Focal impaired awareness seizure
description: >-
Focal seizures with impaired awareness, described in the isolated-epilepsy
case as transient staring spells with unilateral gaze deviation and brief
motor arrest lasting around ten seconds, followed by post-ictal confusion.
They occurred alongside the focal-to-bilateral tonic-clonic seizures in
the same child.
phenotype_term:
preferred_term: Focal impaired awareness seizure
term:
id: HP:0002384
label: Focal impaired awareness seizure
evidence:
- reference: PMID:42495272
reference_title: A novel mutation in SETD1A is associated with early-onset epilepsy-a rare case report.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
focal impaired awareness seizures characterized by transient staring
spells with unilateral gaze deviation and brief motor arrest lasting
approximately 10 s, followed by post-ictal confusion
explanation: >-
Documents focal impaired-awareness semiology in a SETD1A variant
carrier.
- category: Nervous System
name: Focal aware motor seizure
description: >-
Focal motor seizures with retained awareness, reported in the same child
as involuntary upper-limb myoclonic jerks and epileptic drop attacks.
phenotype_term:
preferred_term: Focal aware motor seizure
term:
id: HP:0020217
label: Focal aware motor seizure
evidence:
- reference: PMID:42495272
reference_title: A novel mutation in SETD1A is associated with early-onset epilepsy-a rare case report.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
focal aware motor seizures manifesting as involuntary upper-limb
myoclonic jerks and epileptic drop attacks
explanation: >-
Documents focal aware motor semiology in the same carrier.
- category: Nervous System
name: EEG abnormality
description: >-
Interictal EEG findings are abnormal but not specific to this disorder.
Reported patterns include paroxysmal sharp-slow wave complexes over the
bilateral frontal and right temporal regions in the focal-epilepsy case,
and hypsarrhythmia in the epileptic-spasms case (recorded separately).
Across the reviewed SETD1A epilepsy cases, EEG was otherwise nonspecific
with background slowing, sharp waves, or spike-and-waves.
phenotype_term:
preferred_term: EEG abnormality
term:
id: HP:0002353
label: EEG abnormality
evidence:
- reference: PMID:42495272
reference_title: A novel mutation in SETD1A is associated with early-onset epilepsy-a rare case report.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The EEG was recorded using the standard international 10-20 electrode
array, mainly presenting paroxysmal sharp-slow complex waves, with the
main areas being the bilateral frontal electrodes and the right temporal
region
explanation: >-
Documents the interictal EEG abnormality and its distribution in the
focal-epilepsy case.
- reference: PMID:37928142
reference_title: "Case report: De novo variant of SETD1A causes infantile epileptic spasms syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Except for our patient, who showed hypsarrhythmia on EEG, the other
cases were nonspecific, with background slowing, sharp waves, or
spike-and-waves.
explanation: >-
The authors' review of published SETD1A epilepsy cases establishes that
EEG is abnormal but nonspecific outside the epileptic-spasms
presentation.
- category: Nervous System
name: Epileptic spasm
description: >-
Infantile epileptic spasms syndrome has been reported as a presentation
of a de novo SETD1A frameshift variant.
phenotype_term:
preferred_term: Epileptic spasm
term:
id: HP:0011097
label: Epileptic spasm
onset:
onset_category: INFANTILE
evidence:
- reference: PMID:37928142
reference_title: "Case report: De novo variant of SETD1A causes infantile epileptic spasms syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Herein, we report a case of IESS caused by a SETD1A gene mutation.
explanation: >-
Reports infantile epileptic spasms syndrome as a SETD1A presentation.
- category: Nervous System
name: Hypsarrhythmia
description: >-
Chaotic high-amplitude interictal EEG pattern accompanying the epileptic
spasms presentation.
phenotype_term:
preferred_term: Hypsarrhythmia
term:
id: HP:0002521
label: Hypsarrhythmia
evidence:
- reference: PMID:37928142
reference_title: "Case report: De novo variant of SETD1A causes infantile epileptic spasms syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Herein, we report a case of IESS caused by a SETD1A gene mutation. Video
electroencephalography showed hypsarrhythmia.
explanation: >-
Documents hypsarrhythmia on video-EEG in the epileptic-spasms case.
- category: Nervous System
name: Global developmental delay
description: >-
Developmental delay is variable -- present in some individuals (the
epileptic-spasms case had delay as part of the IESS triad) and absent in
others, including a child with seizures from 3 months whose developmental
quotient and IQ were normal. The disease name's "with or without
developmental delay" encodes exactly this variability.
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
evidence:
- reference: PMID:34803610
reference_title: SETD1A Mediated H3K4 Methylation and Its Role in Neurodevelopmental and Neuropsychiatric Disorders.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Recently, dominant mostly de novo variants in SETD1A have clinically
been linked to developmental delay, intellectual disability (DD/ID),
and schizophrenia (SCZ).
explanation: >-
Review documenting developmental delay among the phenotypes of dominant
SETD1A variants; evidence_source OTHER because a review is not primary
data.
- reference: PMID:42495272
reference_title: A novel mutation in SETD1A is associated with early-onset epilepsy-a rare case report.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Neuroimaging revealed a normal brain MRI, and comprehensive
neuropsychological assessment indicated preserved cognitive function.
explanation: >-
Supports the "without" side of the variable-developmental-delay claim
stated in this phenotype's description: this carrier had entirely
preserved cognition, so the phenotype is inconstant rather than core.
treatments:
- name: Antiseizure Medication
description: >-
No disorder-specific therapy exists; management is conventional
antiseizure treatment chosen by semiology and syndrome. Across the three
treated cases with reported outcomes, phenobarbital significantly reduced
seizure frequency in the focal-epilepsy case, levetiracetam achieved
seizure freedom in a further case with recurrence four years later, and
valproic acid was added as adjunct after the epileptic spasms had already
responded to ACTH. Pyridoxine (vitamin B6) was given empirically on
admission in the spasms case, but the authors explicitly discounted a
pyridoxine-responsive mechanism, so it is not listed here as an active
agent -- ACTH is curated as its own treatment. These are single-case
observations, not comparative evidence.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: phenobarbital
term:
id: CHEBI:8069
label: phenobarbital
- preferred_term: levetiracetam
term:
id: CHEBI:6437
label: levetiracetam
- preferred_term: valproic acid
term:
id: CHEBI:39867
label: valproic acid
target_mechanisms:
- target: Early-Onset Seizures
description: >-
Symptomatic antiseizure treatment acting on the seizure endpoint rather
than the upstream chromatin mechanism.
evidence:
- reference: PMID:42495272
reference_title: A novel mutation in SETD1A is associated with early-onset epilepsy-a rare case report.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Following initiation of phenobarbital therapy, seizure frequency
decreased significantly.
explanation: >-
Documents a symptomatic antiseizure response acting on the seizure
endpoint in the focal-epilepsy case.
evidence:
- reference: PMID:42495272
reference_title: A novel mutation in SETD1A is associated with early-onset epilepsy-a rare case report.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Following initiation of phenobarbital therapy, seizure frequency
decreased significantly.
explanation: >-
The evidence behind the phenobarbital claim: seizure frequency fell
significantly after phenobarbital was started in the focal-epilepsy
case.
- reference: PMID:37928142
reference_title: "Case report: De novo variant of SETD1A causes infantile epileptic spasms syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
One patient was treated with phenobarbital and seizure frequency was
reduced; however, no information was provided regarding subsequent
episodes. Another patient achieved seizure-free status after receiving
levetiracetam.
explanation: >-
The authors' literature review of SETD1A-related epilepsy records the
phenobarbital and levetiracetam responses that justify listing both as
agents; it also records that the reduction was not followed up in one
case.
- reference: PMID:37928142
reference_title: "Case report: De novo variant of SETD1A causes infantile epileptic spasms syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Since most patients do not become seizure-free with ACTH alone, we also
added valproic acid after 2 weeks of ACTH treatment.
explanation: >-
Establishes valproic acid as adjunctive therapy added after the ACTH
response, not as the agent that produced remission.
- name: Adrenocorticotropic Hormone Therapy
description: >-
ACTH is the guideline-standard therapy for infantile epileptic spasms
syndrome and is the agent that produced remission in the one reported
SETD1A-related IESS case: spasms stopped within three days of starting
ACTH (2 U/kg/day), treatment continued for four weeks and was then
switched to oral prednisone, with valproic acid added as adjunct. The
child remained seizure-free at follow-up. Pyridoxine had been given
empirically alongside ACTH from admission, but the authors concluded that
a pyridoxine-dependent mechanism was not involved -- spasms persisted on
pyridoxine alone and no ALDH7A1 alteration was found -- so the response is
attributed to ACTH. This is a single case, not evidence of a
SETD1A-specific ACTH effect.
therapeutic_modality: PEPTIDE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: adrenocorticotropic hormone
term:
id: CHEBI:3892
label: corticotropin
target_phenotypes:
- preferred_term: Epileptic spasm
term:
id: HP:0011097
label: Epileptic spasm
target_mechanisms:
- target: Early-Onset Seizures
description: >-
Hormonal therapy acting on the seizure endpoint; the mechanism by which
ACTH suppresses epileptic spasms is not SETD1A-specific and is not
established at the level of this pathograph.
evidence:
- reference: PMID:37928142
reference_title: "Case report: De novo variant of SETD1A causes infantile epileptic spasms syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The epileptic spasms disappeared after 3 days of ACTH administration.
explanation: >-
Documents that ACTH, not the co-administered pyridoxine, produced
seizure remission at the clinical endpoint.
evidence:
- reference: PMID:37928142
reference_title: "Case report: De novo variant of SETD1A causes infantile epileptic spasms syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The epileptic spasms disappeared after 3 days of ACTH administration.
explanation: >-
The primary observation: spasms remitted within three days of starting
ACTH.
- reference: PMID:37928142
reference_title: "Case report: De novo variant of SETD1A causes infantile epileptic spasms syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Since vitamin B6 had been used for several days, but spasms persisted
until ACTH was added and genetic testing did not suggest alterations in
a vitamin B6-related gene (e.g., ALDH7A1), we do not believe that
vitamin B6 deficiency was involved.
explanation: >-
The authors' own reasoning for attributing the response to ACTH rather
than pyridoxine, which is why pyridoxine is not curated as an active
agent in this entry.
- name: Genetic Counseling
description: >-
Counseling in this disorder has to cover two genuinely different
recurrence scenarios, because SETD1A epilepsy is dominant but not
exclusively de novo. Most reported probands carry de novo variants, where
sibling recurrence risk is low but non-zero because parental gonadal
mosaicism cannot be excluded by negative parental testing; but the
defining report also describes a missense variant transmitted with
seizures through four generations, where a carrier parent has a 50%
transmission risk per pregnancy. Parental testing therefore changes the
counseling substantially and should be offered rather than assumed
negative. Expressivity is markedly variable even within the allelic
spectrum -- from isolated epilepsy with normal cognition to global
developmental delay -- so a carrier relative's phenotype does not predict
a future child's.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:31197650
reference_title: De Novo and Inherited SETD1A Variants in Early-onset Epilepsy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we identified four missense mutations in the SETD1A gene (SET
domain-containing 1A, histone lysine methyltransferase): three de novo
mutations in three individuals and one inherited mutation in a
four-generation family.
explanation: >-
Establishes the two recurrence scenarios counseling has to cover: de
novo occurrence in most probands, and multigenerational dominant
transmission in at least one family.
- reference: PMID:42495272
reference_title: A novel mutation in SETD1A is associated with early-onset epilepsy-a rare case report.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Sanger sequencing further confirmed that this variant was a de novo
mutation, which only exists in the proband and absence in both parents
explanation: >-
Illustrates the parental-testing step that distinguishes the de novo
from the inherited counseling scenario.
animal_models:
- name: Setd1a haploinsufficient mouse
species: Mouse
genotype: Setd1a+/- (heterozygous loss-of-function / frameshift)
publication: PMID:32937141
description: >-
Two independently generated heterozygous Setd1a mouse lines. Mukai et al.
(PMID:31606247) report altered axonal branching, cortical synaptic
dynamics and working-memory deficits, plus reversibility on adult Setd1a
reinstatement or LSD1 antagonism; Nagahama et al. (PMID:32937141) carry a
frameshift mimicking a human loss-of-function allele and show impaired
excitatory synaptic transmission in layer 2/3 medial prefrontal cortex
pyramidal neurons. Both were built to model schizophrenia, and both are
curated here as one model record because they share the genotype and the
same relationship to this entry's pathograph.
modeled_mechanisms:
- target: Abnormal Excitatory Synapse Development and Function
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: >-
The mice reproduce the existence of a cortical excitatory synaptic
lesion downstream of Setd1a haploinsufficiency, together with the
transcriptional dysregulation of synaptic genes that this entry places
upstream of it.
limitations: >-
The synaptic deficit is characterized in adult medial prefrontal cortex
in the context of schizophrenia-related behavior, not in the developing
cortex at the ages when human seizures begin, and its direction
(attenuated excitatory transmission) is opposite to that seen in human
SETD1A+/- neuronal networks.
evidence:
- reference: PMID:32937141
reference_title: Setd1a Insufficiency in Mice Attenuates Excitatory Synaptic Function and Recapitulates Schizophrenia-Related Behavioral Abnormalities.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Our Setd1a (+/-) mice display various behavioral abnormalities
relevant to features of SCZ, impaired excitatory synaptic transmission
in layer 2/3 (L2/3) pyramidal neurons of the medial prefrontal cortex
(mPFC), and altered expression of diverse genes related to
neurodevelopmental disorders and synaptic functions in the mPFC.
explanation: >-
Establishes that the model reproduces a cortical excitatory synaptic
lesion and the accompanying synaptic-gene dysregulation.
readouts:
- name: Excitatory synaptic transmission in layer 2/3 mPFC pyramidal neurons
target: Abnormal Excitatory Synapse Development and Function
direction: DECREASED
interpretation: >-
Electrophysiological measure of the excitatory synaptic lesion in this
model; note the direction is opposite to the human iPSC network
finding.
biological_processes:
- preferred_term: chemical synaptic transmission
term:
id: GO:0007268
label: chemical synaptic transmission
modifier: DECREASED
evidence:
- reference: PMID:32937141
reference_title: Setd1a Insufficiency in Mice Attenuates Excitatory Synaptic Function and Recapitulates Schizophrenia-Related Behavioral Abnormalities.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Optogenetics-assisted selective stimulation of presynaptic neurons
combined with Setd1a KD reveals that Setd1a at postsynaptic site is
essential for excitatory synaptic transmission.
explanation: >-
Reports the measurement behind this readout and localizes the
requirement to the postsynaptic side.
- target: Cortical Network Hyperexcitability
relationship: FAILS_TO_RECAPITULATE
fidelity: LOW
description: >-
No Setd1a+/- mouse study reports spontaneous seizures, epileptiform
EEG, or a lowered seizure threshold, and the measured direction of
change in excitatory synaptic function is the opposite of a
hyperexcitable state. The mouse therefore does not model the
epileptogenic step of this entry's pathograph, which is the substance
of the HUMAN_MODEL_MISMATCH discussion.
limitations: >-
Two limitations, and they are different. First, the phenotype: these
lines show attenuated -- not increased -- excitatory synaptic
transmission, so on the one relevant measure they run against the human
epilepsy. Second, ascertainment: they were built and phenotyped for
schizophrenia-related behavior and cognition, so no chronic video-EEG
or chemoconvulsant seizure-threshold testing has been published at any
age. A negative on an assay that was never run is weaker than a
demonstrated absence of seizures, and this link should be revisited if
such phenotyping is reported.
evidence:
- reference: PMID:32937141
reference_title: Setd1a Insufficiency in Mice Attenuates Excitatory Synaptic Function and Recapitulates Schizophrenia-Related Behavioral Abnormalities.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Our findings suggest that reduced SETD1A may attenuate excitatory
synaptic function and contribute to the pathophysiology of SCZ.
explanation: >-
The authors' own summary: the model's excitatory phenotype is
attenuation framed as schizophrenia pathophysiology, not the network
hyperexcitability this node asserts.
- reference: PMID:31606247
reference_title: Recapitulation and Reversal of Schizophrenia-Related Phenotypes in Setd1a-Deficient Mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Mice carrying a heterozygous loss-of-function mutation of the
orthologous gene exhibit alterations in axonal branching and cortical
synaptic dynamics accompanied by working memory deficits.
explanation: >-
The second line's reported phenotype is likewise synaptic and
cognitive, with no seizure or epileptiform finding, supporting the
failure-to-recapitulate claim for the hyperexcitability node.
evidence:
- reference: PMID:31606247
reference_title: Recapitulation and Reversal of Schizophrenia-Related Phenotypes in Setd1a-Deficient Mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Reinstating Setd1a expression in adulthood rescues cognitive deficits.
explanation: >-
Supports treating the mouse as informative for SETD1A biology in this
entry: the phenotype is Setd1a-dose-dependent and reversible, so it is
attributable to the gene rather than to a developmental artifact of the
line.
experimental_models:
- name: SETD1A+/- human iPSC-derived excitatory/inhibitory neuronal network
description: >-
CRISPR-Cas9-engineered human induced pluripotent stem cells carrying a
heterozygous SETD1A loss-of-function mutation, differentiated into mixed
excitatory/inhibitory neuronal networks and recorded on multi-electrode
arrays. This is the only model system in which SETD1A haploinsufficiency
has been shown to produce a hyperactive network state, and the effect is
reversible by cAMP/PKA-pathway inhibition.
experimental_model_type: IPSC_DERIVED_MODEL
cell_source: iPSC-derived
culture_system: Multi-electrode-array neuronal network culture
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
cell_types:
- preferred_term: glutamatergic neuron
term:
id: CL:0000679
label: glutamatergic neuron
publication: PMID:35508131
modeled_mechanisms:
- target: Cortical Network Hyperexcitability
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
SETD1A haploinsufficiency in a human neuronal network produces increased
bursting driven by glutamatergic neurons -- the in vitro counterpart of
the hyperexcitable, hypersynchronous state this node asserts.
limitations: >-
An in vitro network of immature iPSC-derived neurons is not cortical
tissue: it lacks laminar architecture, long-range connectivity, and the
developmental age at which human seizures begin, and network bursting on
a multi-electrode array is not a seizure. The donor lines carry
engineered rather than patient EPEDD variants, and the parent study was
designed around schizophrenia risk, not epilepsy.
evidence:
- reference: PMID:35508131
reference_title: Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through the cAMP/PKA pathway.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
This network phenotype is primarily driven by SETD1A
haploinsufficiency in glutamatergic neurons.
explanation: >-
Establishes that the model's network phenotype arises from the
excitatory arm, matching the excitation/inhibition-imbalance framing
of this node.
readouts:
- name: Neuronal network bursting activity
target: Cortical Network Hyperexcitability
direction: INCREASED
interpretation: >-
Multi-electrode-array measure of network-level hypersynchrony, the
outcome measure grounding the RECAPITULATES claim.
biological_processes:
- preferred_term: action potential
term:
id: GO:0001508
label: action potential
modifier: INCREASED
evidence:
- reference: PMID:35508131
reference_title: Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through the cAMP/PKA pathway.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Our data show that SETD1A haploinsufficiency results in
morphologically increased dendritic complexity and functionally
increased bursting activity.
explanation: >-
Reports the bursting measurement and its direction in the SETD1A+/-
networks.
- name: Network deficit rescue by cAMP/PKA pathway inhibition
target: Cortical Network Hyperexcitability
direction: RESTORED
interpretation: >-
Pharmacological reversal of the hyperactive network state, which is
what makes the cAMP/PKA route a candidate therapeutic axis rather than
a correlate.
evidence:
- reference: PMID:35508131
reference_title: Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through the cAMP/PKA pathway.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Finally, by pharmacologically targeting the cAMP pathway, we are
able to rescue the network deficits in SETD1A+/- cultures.
explanation: >-
Reports the rescue arm of this model.
evidence:
- reference: PMID:35508131
reference_title: Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through the cAMP/PKA pathway.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Using CRISPR-Cas9, we generate excitatory/inhibitory neuronal networks
from human induced pluripotent stem cells with a SETD1A heterozygous LoF
mutation (SETD1A+/-).
explanation: >-
Describes the construction of the model system and establishes that it
carries the disease-relevant heterozygous SETD1A lesion in human
neurons.
diagnosis:
- name: Trio Exome or Genome Sequencing
description: >-
Molecular diagnosis rests on identifying a heterozygous pathogenic or
likely pathogenic SETD1A variant. Trio whole-exome or whole-genome
sequencing is the modality used in essentially every reported case,
because parental sequencing is what establishes de novo status -- which
is both a major ACMG pathogenicity criterion (PS2) for these variants and
the fact that separates the two recurrence-risk scenarios. Sanger
sequencing is used to confirm the variant and its segregation.
diagnosis_term:
preferred_term: whole exome sequencing
term:
id: NCIT:C101295
label: Whole Exome Sequencing
evidence:
- reference: PMID:42495272
reference_title: A novel mutation in SETD1A is associated with early-onset epilepsy-a rare case report.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, whole-exome sequencing and Sanger sequencing were performed on a
4-year-old Chinese girl with early-onset epilepsy and her unaffected
parents.
explanation: >-
Documents the trio exome-plus-Sanger workflow as the diagnostic route in
a reported case.
- reference: PMID:31197650
reference_title: De Novo and Inherited SETD1A Variants in Early-onset Epilepsy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Whole-exome sequencing indicated that all four of these mutations were
responsible for the seizures.
explanation: >-
Exome sequencing is the modality through which the defining cohort's
variants were identified.
- name: DNA Methylation Episignature Testing
presence: ABSENT
description: >-
Not diagnostically informative for SETD1A, which is the point worth
recording. Many chromatinopathies have a reproducible peripheral-blood
DNA-methylation episignature that resolves variants of uncertain
significance, and SETD1A's paralog SETD2 does. Targeted profiling of more
than two million CpGs in six SETD1A patients found no strong episignature,
so a negative methylation test does not argue against a SETD1A diagnosis
and this assay should not be used for variant interpretation here. Note
this concerns CpG DNA methylation and is not evidence against the histone
H3K4 methylation lesion, which is a different mark measured by different
assays.
evidence:
- reference: PMID:37166351
reference_title: Epigenotype-genotype-phenotype correlations in SETD1A and SETD2 chromatin disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A comparison of methylation profiles in patients with SETD1A variants (n
= 6) did not reveal evidence of a strong methylation episignature.
explanation: >-
The negative result establishing that episignature testing is not a
usable diagnostic aid in this disorder.
- reference: PMID:37166351
reference_title: Epigenotype-genotype-phenotype correlations in SETD1A and SETD2 chromatin disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Specific methylation episignatures have been detected for a range of
chromatin gene-related NDDs and have impacted clinical practice by
improving the interpretation of variant pathogenicity.
explanation: >-
Establishes the expectation this disorder departs from: episignatures
are clinically useful across chromatin-gene NDDs generally, which is why
their absence in SETD1A is a substantive test-selection point.
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.
Create: SETD1A-Related Early-Onset Epilepsy · 2026-09-02T13:35:19Z · View source
De novo curation of EPEDD (MONDO:0030005, OMIM 618832), the epilepsy-predominant SETD1A allelic entity, resolving the stub as entry_type DISEASE. Identity was anchored by NEC preflight against the local MONDO release (xref OMIM:618832, synonym EPEDD, RO:0004003 hgnc:29010 SETD1A); a claude_code deep-research report was generated and passed just preflight-dr (PASS, SETD1A mentioned 66 times). The report's reference_validation flagged needs_review (one unsupported quote attributed to PMID:26974950; three off-topic references; unresolved term HP:0000342; obsolete GO:0051568) - no quote, unresolved reference, or flagged term from the report was used: every snippet was copied directly from references_cache abstracts and every CURIE was re-verified against OLS/local OAK adapters, deliberately avoiding obsolete GO:0051568 in favor of GO:0040029/GO:0006325. Curated an 8-node causal chain (SETD1A haploinsufficiency -> reduced promoter H3K4 methylation -> transcriptional dysregulation of synaptic/neurodevelopmental genes -> abnormal excitatory synapse development, impaired cortical neuron migration -> cortical network hyperexcitability -> early-onset seizures; plus variable neurodevelopmental impairment), conforming the hyperexcitability node to epilepsy_excitation_inhibition_imbalance#Neuronal Hyperexcitability and Hypersynchrony on the strength of human SETD1A+/- iPSC network hyperactivity (PMID:35508131). Key sources: PMID:31197650 (defining Yu 2019 cohort), PMID:42495272 and PMID:37928142 (epilepsy-first case reports), PMID:32346159 (NEDSID differentiation), PMID:26974950, PMID:31606247, PMID:32937141, PMID:35508131, PMID:34803610, PMID:37166351. Schizophrenia-focused model evidence is tagged MODEL_ORGANISM/IN_VITRO and the mouse-vs-human direction-of-excitability discrepancy is recorded as a HUMAN_MODEL_MISMATCH discussion with a proposed EEG/seizure-threshold experiment. Allelic differentiation from NEDSID (MONDO:0033630, still an open stub) and from SETD1A schizophrenia-risk content in Schizophrenia.yaml is recorded in notes; the NEDDFSB entry named in the assignment turned out to be the KAT5 disorder, so cross-reference was redirected to the true SETD1A entities. No GeneReviews chapter exists (PubMed search 2026-09-02). Validated with just validate (schema+terms clean), 42/42 snippets verified, and the batched just validate-disorders gate.
Overview. SETD1A-related early-onset epilepsy is a rare, monogenic neurodevelopmental disorder caused by heterozygous (typically de novo) loss-of-function or missense variants in SETD1A (SET Domain Containing 1A), a gene encoding the catalytic subunit of the human COMPASS (Complex Proteins Associated with Set1) histone H3 lysine-4 (H3K4) methyltransferase complex. SETD1A haploinsufficiency produces a clinically heterogeneous, age-dependent spectrum: infants and young children most often present with global developmental delay, hypotonia, dysmorphic facial features, and early-onset epilepsy, while older children, adolescents, and adults are more likely to present with intellectual disability, autism-spectrum features, obsessive-compulsive symptoms, and — in a genome-wide-significant fraction of cases — schizophrenia and other psychotic disorders (PMID:26974950, PMID:32346159).
Two overlapping, allelic OMIM phenotype entries currently describe the SETD1A clinical spectrum: - EPEO2 — Epilepsy, Early-Onset, 2, With or Without Developmental Delay (OMIM #618832): an autosomal dominant disorder with generalized tonic-clonic seizure onset in the first days, months, or years of life, with highly variable severity — from normal psychomotor development and normal neuroimaging to developmental delay with brain-imaging abnormalities. Caused by heterozygous missense mutations, first delineated by Yu et al. (PMID:31197650). - NEDSID — Neurodevelopmental Disorder with Speech Impairment and Dysmorphic Facies (OMIM #619056): developmental delay with mild-to-moderate intellectual disability or learning difficulties, behavioral/psychiatric abnormalities, delayed speech/language, dysmorphic facies, distal limb anomalies, GI/feeding difficulties, and hypotonia. Delineated in 15 patients by Kummeling et al. (PMID:32346159).
The disorder is also frequently discussed under the umbrella name "SETD1A-associated neurodevelopmental disorder" (or "SETD1A syndrome") spanning both entries, since the epilepsy and dysmorphic-ID phenotypes overlap substantially and are caused by variants in the same gene, sometimes in the same family.
Key identifiers: - Gene (OMIM): 611052 – SET Domain-Containing Protein 1A; SETD1A - Phenotype (OMIM): #618832 (EPEO2); #619056 (NEDSID) - HGNC: hgnc:17284 (SETD1A) — NCBI Gene ID 9739 - Orphanet: Listed under gene page for SETD1A; disease-causing mutations associated with "Non-specific syndromic intellectual disability" (ORPHA:528084); a dedicated ORPHA number specific to the epilepsy phenotype was not identified in this search - MeSH: Epilepsy (D004827); Intellectual Disability (D008607) — no SETD1A-specific MeSH descriptor exists - MONDO: not directly resolved in this search; likely maps to a SETD1A-related neurodevelopmental disorder term cross-referencing OMIM 618832/619056 - ICD-10/11: G40.- (Epilepsy) with Q87.8 (other specified congenital malformation syndromes) as adjunct — no disease-specific code - Gene aliases: KMT2F, Set1, Set1A, EPEDD, NEDSID
Data provenance. Nearly all published knowledge derives from aggregated case series and case reports (individual clinical/genetic case reports plus pooled cohort analyses from exome-sequencing studies of schizophrenia/developmental-disorder cohorts — e.g., the DDD study, Finnish SISu/birth-cohort exomes), not from a disease registry or large natural-history study. This is an ultra-rare, only recently delineated (2016 onward) gene-disease association.
Disease causal factor: Purely genetic/monogenic. Heterozygous de novo (occasionally inherited, autosomal dominant) loss-of-function or missense variants in SETD1A are sufficient to cause disease; there is no known environmental, infectious, or multifactorial trigger required.
Genetic risk factors: - SETD1A is exceptionally constrained against loss-of-function variation in the general population — in the founding study, only 2 LoF variants were found among 45,376 non-schizophrenia ExAC exomes, placing SETD1A "among the 3% most constrained genes in the human genome" (PMID:26974950). - Loss-of-function variant classes: nonsense, frameshift, canonical splice-site variants (most causing NEDSID/severe phenotype), and a small number of missense variants (largely reported in the EPEO2/epilepsy phenotype). - A recurrent splice-acceptor variant (c.4582-2delAG, NM_014712.3, exon 16) has arisen independently multiple times (≥7 occurrences across cohorts, including de novo events), consistent with a mutational hotspot (PMID:26974950). - No common susceptibility loci or polygenic risk modifiers specific to the SETD1A-driven phenotype have been reported; however, an intronic SNP (rs11150601) has been separately associated with female schizophrenia risk in the UK Biobank — this is a common-variant association distinct from the rare monogenic LoF mechanism and should not be conflated with it.
Environmental risk factors: None established. Case reports occasionally note nonspecific perinatal factors (e.g., one infantile-spasms case followed mild birth asphyxia and low birth weight; PMID for case: PMC10620521/Frontiers in Neurology 2023, DOI 10.3389/fneur.2023.1278035) but these appear coincidental rather than causal, given the driving de novo genetic lesion.
Protective factors: None identified in the literature for humans. In mice, pharmacological rescue (see Mechanism, below) demonstrates that circuit/cognitive deficits are reversible in adulthood, implying the deficit is a dynamic functional state rather than irreversible structural damage — a form of "protective" pharmacological intervention rather than a naturally occurring protective genetic/environmental factor.
Gene-environment interactions: Not established; no CTD/PheGenI data specific to SETD1A gene-environment interaction were identified.
Phenotype frequency data are drawn primarily from two pooled cohorts: the original Nature Neuroscience schizophrenia/DDD meta-analysis (PMID:26974950, n=14 LoF carriers), and the Kummeling et al. 2021 NEDSID cohort (PMID:32346159, n=15). Because case ascertainment differs (psychiatric-genetics cohort vs. pediatric neurodevelopmental cohort), frequencies below should be read as convergent signal rather than a single denominator.
| Phenotype | Onset | Severity/course | Frequency | Suggested HPO |
|---|---|---|---|---|
| Generalized tonic-clonic seizures | First days to years of life (EPEO2) | Highly variable; some patients seizure-free with treatment, others drug-resistant | ~38% of reported SETD1A patients (pooled from prior literature per PMC10620521 review); ~1/10 schizophrenia LoF carriers had childhood epilepsy (PMID:26974950) | HP:0002069 (Bilateral tonic-clonic seizure) / HP:0001250 (Seizure) |
| Focal seizures with impaired awareness / motor seizures | Infancy (e.g., 3 months in one missense case) | Responsive to phenobarbital in reported case | Case-level (Frontiers 2026 case report, DOI 10.3389/fnins.2026.1864983) | HP:0002384 (Focal-onset seizure) |
| Infantile epileptic spasms syndrome (hypsarrhythmia + spasms + developmental arrest) | 6 months | Rapidly responsive to ACTH in the single reported case | First reported case: PMC10620521 (2023) | HP:0011097 (Epileptic spasm); HP:0012469 (Infantile spasms) |
| EEG abnormalities (background slowing, sharp waves, paroxysmal sharp-slow complexes) | Variable | Nonspecific | Frequent across case reports | HP:0002353 (EEG abnormality) |
| Global developmental delay | Infancy/early childhood | Mild to severe, variable | Predominant feature; present in most non-isolated-epilepsy cases (PMID:32346159; PMID:26974950) | HP:0001263 (Global developmental delay) |
| Intellectual disability / learning difficulties | Childhood onward | Mild to severe | 7/10 schizophrenia LoF carriers had learning difficulties (PMID:26974950); core NEDSID feature | HP:0001249 (Intellectual disability) |
| Delayed speech and language | Early childhood | Variable | Core NEDSID feature | HP:0000750 (Delayed speech and language development) |
| Hypotonia | Infancy | Variable | Core NEDSID feature | HP:0001252 (Hypotonia) |
Suggested HPO: HP:0000708 (Behavioral abnormality); HP:0000717 (Autism); HP:0000709 (Psychosis, historically used)/HP:0031466 (or nearest available psychosis term); HP:0000722 (Obsessive-compulsive behavior)
Quality of life impact: No disease-specific EQ-5D/SF-36 data exist. Impact is inferred from the underlying phenotypes: epilepsy (seizure-related risk/burden), intellectual disability (educational/functional impact), and psychiatric illness (frequently requiring long-term hospitalization) — collectively substantial but unquantified in validated QOL instruments.
Causal gene: SETD1A (HGNC:17284; NCBI Gene 9739; OMIM *611052), located at cytoband 16p11.2, chr16:30,957,294–30,984,664 (GRCh38), spanning 23 exons and encoding a 1,707-amino-acid, ~186 kDa protein. Note: this locus lies just telomeric to (and is distinct from) the classic recurrent 16p11.2 BP4-BP5 microdeletion/duplication CNV region associated with autism/schizophrenia risk; SETD1A disease is caused by intragenic point/small indel variants, not the recurrent CNV.
Pathogenic variant spectrum: - NEDSID cohort (Kummeling et al. 2021, PMID:32346159): 14 distinct de novo heterozygous variants in 15 unrelated patients — 5 nonsense, 6 frameshift, 2 splice-site, 1 missense; all predicted to disrupt or delete the C-terminal SET catalytic domain (truncating variants correlate with more severe phenotype). - EPEO2 cohort (Yu et al. 2019, PMID:31197650): Four missense variants — p.Arg913Cys (R913C, inherited in a 4-generation family), p.Gln269Arg (Q269R, de novo), p.Gly1369Arg (G1369R, de novo), p.Arg1392His (R1392H, de novo) — all previously implicated in schizophrenia/developmental-disorder cohorts, now shown to cause early-onset epilepsy. - Additional individual case variants: p.Ser356Phe (missense, de novo; isolated epilepsy phenotype, Frontiers 2026 case, DOI 10.3389/fnins.2026.1864983); p.Glu1002Glyfs20 (frameshift, de novo; infantile epileptic spasms, PMC10620521); p.Gly708Argfs117 (frameshift, de novo; NEDSID-type with seizures, PMC9300109); p.Leu699Ter (nonsense, de novo; congenital cardiac/airway phenotype without epilepsy, PMC10063285). - Recurrent hotspot: c.4582-2delAG (splice acceptor, exon 16) — found ≥7 times independently across schizophrenia/developmental-disorder cohorts (PMID:26974950).
Variant classification: Almost uniformly classified pathogenic/likely pathogenic per ACMG/AMP criteria (typically PVS1+PS2+PM2 for truncating de novo variants; PS2+PM2+PP3 for missense de novo variants). ClinVar entries exist per-variant (e.g., VCV000533549) but no gene-wide systematic ClinVar tabulation of counts by variant class was retrievable in this search.
Population frequency: SETD1A LoF variants are essentially absent from the general population (2/45,376 non-schizophrenia ExAC exomes; PMID:26974950); gnomAD constraint metrics were not directly retrievable in this search but the gene's extreme depletion of LoF variants in population data is well established and consistent with a highly LoF-intolerant gene (historically near-ceiling pLI).
Somatic vs. germline: All reported disease-causing variants are germline (constitutional), predominantly de novo.
Functional consequence: Loss of function / haploinsufficiency is the dominant mechanism for both the epilepsy (missense, partial LOF) and NEDSID (truncating, more complete LOF) ends of the spectrum — i.e., use functional_impact_category: LOSS_OF_FUNCTION (with PARTIAL_LOSS_OF_FUNCTION plausible for hypomorphic missense alleles) rather than gain-of-function or dominant-negative, though formal functional classification per-variant (e.g., dominant-negative testing) has not been systematically reported.
Modifier genes: None established.
Epigenetic information: Targeted episignature profiling (>2 million CpGs) in 6 SETD1A patients found no strong disease-specific DNA methylation episignature (only 7 significant differentially methylated positions, indistinguishable from controls) — a notable negative finding that contrasts with its paralog SETD2, which shows strong, subgroup-specific episignatures (PMID:37166351). This suggests SETD1A haploinsufficiency's downstream chromatin effects are not readily captured by peripheral-blood methylation arrays, despite robust effects on H3K4 methylation and, in mouse cortex, ribosomal-gene-associated DNA methylation (see Mechanism).
Chromosomal abnormalities: No recurrent CNV/translocation mechanism is described; disease arises from intragenic SNVs/small indels. One case report described an 852 kb CNV deletion encompassing SETD1A as a cause of the episignature-cohort phenotype (PMID:37166351).
No environmental toxins, occupational exposures, dietary factors, or infectious triggers have been implicated in SETD1A-related disease causation or modification. This is consistent with a fully penetrant, single-gene dominant mechanism. Isolated perinatal complications noted in case reports (mild birth asphyxia, low birth weight) appear incidental rather than causally linked.
Upstream vs. downstream: The variant itself (upstream) → chromatin/H3K4 methylation change (proximal) → transcriptional dysregulation of neurodevelopmental, synaptic, mitochondrial and cAMP-pathway genes (intermediate) → circuit-level hyperexcitability/hypersynchrony and progenitor/migration timing defects (downstream, most proximal to phenotype).
Cell types involved: glutamatergic (excitatory) cortical pyramidal neurons (primary driver of the network phenotype; CL:0000679 glutamatergic neuron / CL:0000598 pyramidal neuron), GABAergic interneurons (secondary/less penetrant contribution; CL:0000617 GABAergic neuron), neural stem/progenitor cells (CL:0000047 neuronal stem cell / CL:0002608 embryonic neuroepithelial progenitor cell), induced pluripotent stem cells (CL:0002248 iPSC) and embryonic stem cells (CL:0002322 ESC) used as model systems.
Suggested GO terms: GO:0051568 (histone H3-K4 methylation), GO:0035097 (histone methyltransferase complex), GO:0000993 (RNA polymerase II complex binding — WDR82 recruitment), GO:0060070 (canonical Wnt signaling pathway), GO:0050808 (synapse organization), GO:0007268 (chemical synaptic transmission), GO:0007612 (learning), GO:0007613 (memory), GO:0007190 (activation of adenylate cyclase activity), GO:0006119 (oxidative phosphorylation / mitochondrial respiratory chain complex I assembly).
Suggested UBERON/CL for anatomy: UBERON:0000956 (cerebral cortex), UBERON:0001950 (neocortex), UBERON:0002021/UBERON:0002616 (hippocampal formation, implicated via memory studies), CL:0000540 (neuron).
Pharmacotherapy (symptomatic, seizure control):
- Standard antiseizure medications have been used empirically, with reported efficacy in individual cases: phenobarbital (significant reduction in seizure frequency in one focal-seizure case), valproic acid (used in combination with ACTH for infantile spasms), levetiracetam (initial seizure control in a generalized tonic-clonic seizure case, later recurrence). No SETD1A-specific antiseizure drug trial or guideline exists; treatment is empirical, following standard pediatric epilepsy/infantile-spasms protocols.
- ACTH (adrenocorticotropic hormone) — used per standard infantile-epileptic-spasms-syndrome protocol; achieved rapid (within 3 days) and durable (10-month) seizure freedom in the single reported SETD1A-IESS case, with prednisone substituted after 4 weeks.
- Vitamin B6 (pyridoxine, CHEBI:16709) — used empirically alongside ACTH in the infantile spasms case (standard practice to exclude/treat pyridoxine-dependent epilepsy pending genetic confirmation).
- NCIT term: NCIT:C15986 (Pharmacotherapy) as the general treatment_term, with therapeutic_agent bound to specific agents (e.g., valproic acid CHEBI:39867, levetiracetam CHEBI:6437).
Ketogenic diet: Not specifically reported as trialed or validated for SETD1A-related epilepsy in the retrieved literature; SETD1A is not among the genetic etiologies with an established ketogenic-diet response signature (unlike SCN1A/Dravet, TSC1/TSC2, or UBE3A/Angelman).
Gene/precision therapy: No gene therapy, ASO, or targeted molecular therapy currently exists or is in clinical trials for SETD1A-related disease. However, preclinical mouse work provides proof-of-concept for a mechanistically targeted approach: the LSD1/KDM1A demethylase inhibitor ORY-1001 rescued cognitive and synaptic-circuit deficits when administered to adult Setd1a+/- mice (PMID:31606247), and pharmacological cAMP/PKA-pathway inhibitors (adenylyl cyclase inhibitor SQ22536; PKA inhibitors H89, KT5720) normalized hyperactive network activity in human SETD1A+/− iPSC-neuron models (PMID:35508131) — both representing candidate repurposable small-molecule strategies, though neither has reached clinical testing.
Supportive/rehabilitative care: Developmental/early-intervention services, speech-language therapy (NCIT:C159273), occupational/physical therapy (NCIT:C15302, NCIT:C121351), and psychiatric management (for later-emerging schizophrenia/bipolar/OCD features) are used as clinically indicated, following standard neurodevelopmental-disorder supportive-care pathways rather than a disease-specific protocol.
Genetic counseling: Recommended given autosomal dominant inheritance with possible germline mosaicism and documented instances of familial transmission (NCIT:C15240, Genetic Counseling).
Experimental treatments: No SETD1A-specific registered clinical trials (ClinicalTrials.gov) were identified in this search.
Treatment outcomes / algorithm: No systematic treatment-response data or standardized treatment algorithm exists; management is individualized, symptom-driven, and extrapolated from general pediatric epilepsy and neurodevelopmental-disorder practice.
No naturally occurring SETD1A-associated disease has been reported in non-human species (companion animals, livestock, or wildlife) in the retrieved literature; no OMIA entries or veterinary case series were identified. This is consistent with the disorder being a very recently characterized human monogenic condition studied primarily through engineered (not spontaneous) animal and cellular models.
| Model | Type | Key findings | Fidelity/limitations | Reference |
|---|---|---|---|---|
| Setd1a+/- mouse (constitutive heterozygous knockout) | Genetic (germline heterozygous) | Reduced excitatory synaptic transmission in mPFC L2/3 pyramidal neurons, reduced spine density, altered axonal branching, working-memory deficits, aberrant visual-cortex ensemble oscillations; deficits reversible in adulthood by LSD1 inhibitor ORY-1001 | Recapitulates cognitive/synaptic schizophrenia-relevant phenotypes; germline model may not capture developmental-timing-specific effects of a true haploinsufficient human genotype; epilepsy/seizure phenotype not directly reported in this model (behavioral/synaptic focus, not seizure monitoring) | PMID:31606247, PMID:32937141 |
| Setd1a+/- mouse (multi-omics developmental time-course, E14.5–P70) | Genetic | Consistent downregulation of mitochondrial-pathway genes across all ages; age-specific (peak E18) synaptosomal protein disruption (delayed Syt2 upregulation); widespread ribosomal-gene-associated DNA hypomethylation enriched for schizophrenia GWAS genes | Establishes developmental critical window and metabolic/epigenetic mechanism; again schizophrenia/synaptic-focused rather than seizure-focused | PMC9476630 (DOI 10.1093/hmg/ddac105); Schizophrenia Bulletin DOI 10.1093/schbul/sbaf091 |
| Setd1a+/- mouse — sex-dependent effects study | Genetic | Examines whether developmental/behavioral phenotypes differ by sex | Directly relevant to potential sex-modulated expressivity noted in humans; details of sex-specific findings not fully extracted in this search | PMC11324134 |
| Drosophila melanogaster dSet1/kmt2f knockdown | Genetic (RNAi/mutant, invertebrate) | dSet1 required specifically in postmitotic adult neurons for normal memory formation, complementing developmental phenotypes seen with germline loss | Confirms an evolutionarily conserved postmitotic/adult-brain requirement for SETD1A-family function, independent of any developmental confound; invertebrate nervous system has obvious translational limits (no cortical lamination, no direct seizure correlate) | PMID:32346159 |
| Human iPSC-derived neurons (isogenic CRISPR SETD1A+/− pairs, glutamatergic/GABAergic co-cultures) | Cellular (human, in vitro) | Increased dendritic complexity, increased network bursting/hypersynchrony driven by glutamatergic neurons, hyperactive cAMP/PKA signaling (elevated ADCY2/3/8, reduced PDE12/7A/1A, elevated cAMP and pCREB), rescued by PKA/adenylyl-cyclase inhibitors and ORY-1001 | Directly models human genotype and is the most epilepsy-mechanism-relevant system to date (network hyperexcitability/hypersynchrony is directly analogous to an ictogenic phenotype), but is a 2D dissociated-culture system lacking whole-brain circuit context, and derives from an exon-16 truncating genotype rather than the missense EPEO2 alleles specifically | PMID:35508131 (Cell Reports 2022); PMID:40962831 (Mol Psychiatry 2025, exon-16 premature-termination isogenic pairs) |
| Human iPSC-derived neurons — metabolic/mitochondrial study | Cellular (human, in vitro) | Reduced neurite outgrowth and spontaneous activity, altered metabolic capacity; rescued by metabolic-intermediate supplementation | Complements mouse mitochondrial-pathway findings; again schizophrenia-phenotype-focused | PMC9800576 (DOI 10.1038/s41537-022-00326-9) |
| Embryonic mouse cortex in utero electroporation (p.R913C missense variant) | Induced/genetic (mosaic overexpression) | Accelerated neuronal migration to superficial cortical layers | Directly tests a human EPEO2 missense allele in a developmental migration assay; mosaic overexpression paradigm differs from constitutive heterozygosity | Referenced in PMC8595121 review |
Overall model-system summary: No single model currently recapitulates the full human triad of early-onset seizures + developmental delay + later psychiatric illness. Mouse germline knockouts best capture the synaptic/cognitive and mitochondrial/epigenetic axes; human iPSC-neuron networks best capture the network-hyperexcitability axis most directly relevant to seizure genesis; Drosophila establishes a conserved postmitotic neuronal requirement. A model with directly recorded electrographic seizures (EEG-monitored in vivo) attributable to Setd1a haploinsufficiency was not identified in this search and represents a notable gap for future work — this is a HUMAN_MODEL_MISMATCH-type gap worth flagging explicitly in a dismech entry (mouse/iPSC evidence strongly supports a hyperexcitable-network mechanism, but translational confirmation via a genuine in vivo seizure/EEG phenotype in the mouse model is not yet reported).
| Category | Term |
|---|---|
| Gene | HGNC (hgnc:17284, SETD1A) |
| Disease (OMIM) | #618832 EPEO2; #619056 NEDSID |
| Key phenotypes (HPO) | HP:0001250 Seizure; HP:0002069 Bilateral tonic-clonic seizure; HP:0011097 Epileptic spasm; HP:0012469 Infantile spasms; HP:0001263 Global developmental delay; HP:0001249 Intellectual disability; HP:0000750 Delayed speech and language development; HP:0001252 Hypotonia; HP:0001999 Abnormal facial shape; HP:0000717 Autism; HP:0000708 Behavioral abnormality; HP:0000722 Obsessive-compulsive behavior; HP:0002353 EEG abnormality |
| Biological processes (GO) | GO:0051568 histone H3-K4 methylation; GO:0035097 histone methyltransferase complex; GO:0060070 canonical Wnt signaling pathway; GO:0050808 synapse organization; GO:0007268 chemical synaptic transmission; GO:0007190 activation of adenylate cyclase activity |
| Cell types (CL) | CL:0000679 glutamatergic neuron; CL:0000598 pyramidal neuron; CL:0000617 GABAergic neuron; CL:0000047 neuronal stem cell |
| Anatomy (UBERON) | UBERON:0000955 brain; UBERON:0000956 cerebral cortex; UBERON:0002616 hippocampal formation |
| Chemicals (CHEBI) | CHEBI:39867 valproic acid; CHEBI:6437 levetiracetam; CHEBI:16709 pyridoxine (vitamin B6) |
| Treatments (NCIT) | NCIT:C15986 Pharmacotherapy; NCIT:C15302 Physical Therapy; NCIT:C159273 Speech Therapy; NCIT:C15240 Genetic Counseling |
Data gaps flagged for curation: No formal prevalence/incidence figures; no gene-wide ClinVar variant-count tabulation retrieved; no in vivo (EEG-confirmed) mouse seizure model; no SETD1A-specific clinical trial or ketogenic-diet response data; MONDO ID not directly confirmed in this search and should be verified against the MONDO release before entry creation.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 21 |
| Resolved | 21 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 1 |
| Quoted claims found in source | 0 |
| Quoted claims not found in source | 1 |
| References weighed for topical relevance | 21 |
| On topic | 18 |
| Off topic | 0 |
Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:
Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.
PMID:26974950 (abstract only): "among the 3% most constrained genes in the human genome"Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 63 |
| Resolved | 58 |
| Unresolved (possible confabulation) | 1 |
| Obsolete | 1 |
| Unverifiable | 3 |
| Terms whose name was checked | 37 |
| Terms named correctly | 27 |
| Terms named as a different term | 4 |
| Terms whose name is worth a second look | 6 |
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:
HP:0000238 (1 mention) - the report calls it "Frontal bossing"; HP calls it HydrocephalusHP:0005605 (1 mention) - the report calls it "Capillary hemangioma"; HP calls it Large cafe-au-lait macules with irregular marginsGO:0006119 (1 mention) - the report calls it "oxidative phosphorylation / mitochondrial respiratory chain complex I assembly"; GO calls it oxidative phosphorylationUBERON:0002616 (2 mentions) - the report calls it "hippocampal formation, implicated via memory studies"; UBERON calls it regional part of brainThese identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:
HP:0000342 (1 mention), reported as "Narrow nasal bridge" - HP does not contain this termThese terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
GO:0051568 (obsolete histone H3-K4 methylation) (2 mentions)The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
HP:0002384 (1 mention) - the report calls it "Focal-onset seizure"; HP calls it Focal impaired awareness seizure, and lists "Focal dyscognitive seizure" among its other namesHP:0000709 (1 mention) - the report calls it "Psychosis, historically used"; HP calls it PsychosisHP:0100258 (1 mention) - the report calls it "Preaxial polydactyly, N/A generically"; HP calls it Preaxial polydactylyGO:0051568 (2 mentions) - the report calls it "histone H3-K4 methylation"; GO calls it obsolete histone H3-K4 methylation, and lists "histone H3 K4 methylation" among its other namesGO:0000993 (1 mention) - the report calls it "RNA polymerase II complex binding — WDR82 recruitment"; GO calls it RNA polymerase II complex bindingUBERON:0002204 (1 mention) - the report calls it "skeletal system"; UBERON calls it musculoskeletal systemThe report gives these identifiers more than one name of its own:
MGI:2446244 - called "Setd1a", "Orthology:* The mouse ortholog is Setd1a"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.