SETD1B-Related Neurodevelopmental Disorder

Mendelian MONDO:0033559 Pathograph 29 Show in embeddings browser Neurodevelopmental Disorder Genetic Disease

SETD1B-related neurodevelopmental disorder (SETD1B-NDD; also known as intellectual developmental disorder with seizures and language delay, IDDSELD; OMIM 619000) is an autosomal dominant Mendelian disorder caused by heterozygous loss-of-function variants in SETD1B, which encodes a lysine-specific histone H3K4 methyltransferase catalytic subunit of the SET1 complex. Haploinsufficiency dysregulates neuronal gene expression and neurodevelopment, producing a core phenotype of global developmental delay (speech and language predominant), intellectual disability, autism spectrum disorder or autism-like behaviors, variable epilepsy (including myoclonic absences in some individuals), and additional behavioral concerns. Most pathogenic variants arise de novo.

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1
Mappings
1
Inheritance
5
Pathophys.
21
Phenotypes
1
Gaps
29
Pathograph
1
Genes
7
Medical Actions
2
Differentials
6
References
1
Deep Research
🏷

Classifications

Harrison's Chapter
NEUROLOGIC GENETICS_ENVIRONMENT_DISEASE
🔗

Mappings

MONDO
MONDO:0033559 intellectual developmental disorder with seizures and language delay
skos:exactMatch MONDO
MONDO:0033559 is the intellectual developmental disorder with seizures and language delay concept; exact synonyms include SETD1B-NDD and SETD1B-Related Neurodevelopmental Disorder, with OMIM:619000 as an exact match and a causal gene relationship (RO:0004003) to HGNC:29187 (SETD1B).
👪

Inheritance

1
Autosomal dominant HP:0000006
SETD1B-NDD is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Vertical transmission from an affected mother to an affected child has been reported; each child of an affected individual has a 50% chance of inheriting the variant.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:36173874 SUPPORT Human Clinical
"SETD1B-NDD is an autosomal dominant disorder typically caused by a de novo pathogenic variant."
GeneReviews states autosomal dominant inheritance with typically de novo pathogenic variants.
PMID:36173874 SUPPORT Human Clinical
"Vertical transmission of a SETD1B pathogenic variant from an affected mother to an affected child has been reported in one family."
Documents rare vertical transmission, consistent with AD inheritance.
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Discussions and Knowledge Gaps

1
Why are males overrepresented and reportedly more severely affected in SETD1B-NDD cohorts, and are there sex-linked modifiers of penetrance or expressivity?
KNOWLEDGE GAP OPEN gap_setd1b_sex_bias
Attached to
pathophysiology#SETD1B Loss of Function
Published cohorts and GeneReviews-era summaries note male overrepresentation and more severe male phenotypes as an open mechanistic question without a demonstrated molecular explanation.
Show evidence (1 reference)
PMID:34345025 SUPPORT Human Clinical
"Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants."
Directly supports the observed sex bias while preserving the authors' explicit characterization of its mechanism as speculative.
⚙

Pathophysiology

5
SETD1B Loss of Function
De novo heterozygous variants in SETD1B (frameshift, nonsense, and missense alleles concentrated in functional domains including the SET domain) act through a loss-of-function / haploinsufficiency mechanism, reducing the catalytic histone H3K4 methyltransferase activity of the SET1 complex.
neuron CL:0000540
SETD1B hgnc:29187
histone H3K4 methyltransferase activity GO:0042800 ↓ DECREASED
Downstream
Reduced H3K4 Methylation Loss of SETD1B methyltransferase activity is expected to reduce H3K4 methylation at its target loci.
Generalized Spike-and-Wave Epileptiform Activity Generalized epileptiform activity occurs in some individuals with pathogenic SETD1B variants, although the intervening circuit mechanism remains unresolved.
Show evidence (3 references)
PMID:34345025 SUPPORT Human Clinical
"Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes."
Largest published cohort supports a loss-of-function mechanism for pathogenic SETD1B variants.
PMID:31110234 SUPPORT Human Clinical
"We identified a de novo frameshift variant (NM_015048.1:c.5644_5647del:p.(Ile1882Serfs*118)) in the last exon of SETD1B in a Japanese patient with autistic behavior, developmental delay, intellectual disability, and myoclonic seizures."
Documents a de novo frameshift predicted to disrupt the conserved carboxyl-terminus SET domain.
PMID:34345025 SUPPORT In Vitro
"Selected variants were functionally tested using in vitro and genome-wide methylation assays."
Adds assay-based functional evidence for selected SETD1B variants to the cohort evidence supporting a loss-of-function mechanism.
Reduced H3K4 Methylation
SETD1B is a catalytic component of the SET1 complex that deposits H3K4 methyl marks. Reduced H3K4 methylation is the expected biochemical consequence of SETD1B loss of function, but it has not been directly measured in disease-relevant neurons from affected individuals.
Downstream
Dysregulated Neuronal Gene Expression Altered H3K4 methylation is expected to disrupt transcriptional regulation at SETD1B target loci.
Show evidence (1 reference)
PMID:29322246 PARTIAL Human Clinical
"SETD1B (SET domain containing 1B) is a component of SET1 histone methyltransferase complex, which mediates the methylation of histone H3 on lysine 4 (H3K4)."
Establishes the biochemical premise for reduced H3K4 methylation after SETD1B loss of function; the disease-state reduction remains a mechanistic inference.
Dysregulated Neuronal Gene Expression
SETD1B normally supports transcriptional activation through H3K4 methylation. Dysregulated expression of neuronal target genes is a plausible downstream consequence of SETD1B loss of function, but the relevant target genes and disease-state transcriptional changes have not been directly established in affected human neurons.
neuron CL:0000540
regulation of transcription by RNA polymerase II GO:0006357 ⚠ ABNORMAL regulation of gene expression GO:0010468 ⚠ ABNORMAL
Downstream
Impaired Neurodevelopment This inferred transcriptional disruption provides a plausible route from SETD1B loss of function to impaired nervous-system development.
Show evidence (2 references)
PMID:31440728 PARTIAL Human Clinical
"SETD1B (SET domain containing 1B) encodes a histone H3 lysine 4 (H3K4) methyltransferase, which is involved in the epigenetic control of the chromatin structure and gene expression."
Establishes SETD1B's normal role in chromatin and gene-expression control; disease-state neuronal dysregulation remains inferred.
PMID:32546566 PARTIAL Human Clinical
"SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks."
Supports the mechanistic premise linking H3K4 methylation to transcriptional activation, without directly measuring affected neurons.
Impaired Neurodevelopment
SETD1B dysfunction impairs normal brain development independent of seizures; developmental delay characteristically precedes seizure onset and disproportionately affects speech and language, with autism/behavioral features and variable cognitive impairment.
neuron CL:0000540
nervous system development GO:0007399 ↓ DECREASED neuron differentiation GO:0030182 ↓ DECREASED
Downstream
Global Developmental Delay Developmental delay is the usual presenting manifestation.
Delayed Speech and Language Development Speech/language is disproportionately affected.
Intellectual Disability Mild-to-moderate intellectual disability is common.
Motor Delay Gross motor delay is common but not obligate.
Autistic Behavior ASD or autism-like behaviors are a defining feature.
Developmental Regression Language phenotype may include regression.
Behavioral Abnormalities Hyperactivity, aggression, anxiety, and sleep issues are frequent.
Hyperactivity Hyperactive behavior is among reported behavioral concerns.
Aggressive Behavior Aggressive behavior is among reported behavioral concerns.
Anxiety Anxiety is among reported behavioral concerns.
Sleep Disturbance Sleep disorders are among reported behavioral concerns.
Abnormal Facial Shape Craniofacial dysmorphism is reported in some individuals.
Feeding Difficulties Feeding issues are a less common associated feature.
Abnormality of the Eye Ophthalmologic manifestations are less common features.
Abnormality of the Musculoskeletal System Conserved musculoskeletal findings are part of the shared phenotype.
Spasticity Spasticity is a recognized manifestation requiring therapy.
Hearing Impairment Hearing impairment is a recognized manifestation requiring management.
Show evidence (3 references)
PMID:36173874 SUPPORT Human Clinical
"SETD1B-related neurodevelopmental disorder (SETD1B-NDD) is characterized by developmental delay (mainly affecting speech and language), intellectual disability, seizures, autism spectrum disorder or autism-like behaviors, and additional behavioral concerns."
GeneReviews defines the neurodevelopmental core phenotype.
PMID:34345025 SUPPORT Human Clinical
"Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes."
Cohort data map LoF to the core neurodevelopmental phenotype bundle.
PMID:34345025 SUPPORT Human Clinical
"Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity."
Directly supports primary neurodevelopmental impairment that is not solely secondary to seizures.
Generalized Spike-and-Wave Epileptiform Activity
EEG directly demonstrates interictal spike-and-slow-wave complexes and, during myoclonic absences, diffuse synchronous 3-Hz spike-and-wave bursts. These observations establish generalized epileptiform activity but do not identify a specific thalamocortical or excitation-inhibition mechanism.
Downstream
Seizures Generalized epileptiform activity is associated with seizures.
Myoclonic Absence Seizures Diffuse synchronous 3-Hz spike-and-wave bursts occur with bilateral myoclonic jerks and impaired consciousness during myoclonic absences.
Generalized Myoclonic Seizures Myoclonic seizures without absence features are another clinical expression of generalized epileptiform activity in SETD1B-NDD.
EEG with Generalized Epileptiform Discharges Interictal and ictal EEG recordings document generalized epileptiform discharges.
Show evidence (2 references)
PMID:31440728 SUPPORT Human Clinical
"His interictal electroencephalogram revealed a spike-and-slow wave complex dominant in the frontal area."
Documents the interictal generalized epileptiform abnormality with frontal predominance.
PMID:31440728 SUPPORT Human Clinical
"His ictal polygraphic and video-electroencephalogram showed a characteristic diffuse synchronous 3-Hz spike-and-wave burst associated with bilateral upper limb myoclonic jerks with impairment of consciousness."
Establishes the generalized 3-Hz spike-and-wave discharge time-locked to myoclonic jerks as the electroclinical correlate of the seizures.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for SETD1B-Related Neurodevelopmental Disorder Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

21
Digestive 1
Feeding Difficulties Feeding difficulties HP:0011968
Frequency omitted: GeneReviews calls these less common without a proportion.
Show evidence (1 reference)
PMID:36173874 SUPPORT Human Clinical
"Less common features include ophthalmologic manifestations and feeding issues."
GeneReviews lists feeding issues among less common features.
Ear 1
Hearing Impairment Hearing impairment HP:0000365
Frequency and hearing-loss subtype are omitted because the available summary does not quantify prevalence or specify conductive versus sensorineural loss.
Show evidence (1 reference)
PMID:36173874 SUPPORT Human Clinical
"routine management of ophthalmologic issues and hearing impairment"
GeneReviews identifies hearing impairment as a manifestation requiring routine management.
Head and Neck 1
Abnormal Facial Shape Abnormal facial shape HP:0001999
Show evidence (1 reference)
PMID:29322246 SUPPORT Human Clinical
"Our cases showed epilepsy, developmental delay, intellectual disabilities, autistic behavior and craniofacial dysmorphic features, which are consistent with those of individuals with de novo 12q24.31 deletions."
Documents craniofacial dysmorphism in SETD1B point-variant cases.
Musculoskeletal 1
Spasticity Spasticity HP:0001257
Frequency is omitted because the management summary does not report a prevalence estimate.
Show evidence (1 reference)
PMID:36173874 SUPPORT Human Clinical
"standard orthopedic management and therapies for spasticity"
GeneReviews identifies spasticity as a manifestation requiring therapy.
Nervous System 13
Global Developmental Delay VERY_FREQUENT Global developmental delay HP:0001263
Show evidence (2 references)
PMID:34345025 SUPPORT Human Clinical
"Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes."
Global developmental delay is named as part of the core clinical phenotype in the largest cohort, supporting the VERY_FREQUENT band.
PMID:36173874 SUPPORT Human Clinical
"SETD1B-related neurodevelopmental disorder (SETD1B-NDD) is characterized by developmental delay (mainly affecting speech and language), intellectual disability, seizures, autism spectrum disorder or autism-like behaviors, and additional behavioral concerns."
GeneReviews lists developmental delay first among the defining clinical characteristics.
Delayed Speech and Language Development VERY_FREQUENT Delayed speech and language development HP:0000750
Show evidence (2 references)
PMID:36173874 SUPPORT Human Clinical
"Speech delay and/or language disorder has been reported in most affected individuals."
GeneReviews states speech/language involvement occurs in most affected individuals, mapping to the VERY_FREQUENT band (80-100%).
PMID:32546566 SUPPORT Human Clinical
"Here we present clinical reports of four patients with rare coding variants in SETD1B that demonstrate a shared phenotype, including intellectual disability, language delay, conserved musculoskeletal findings and seizures that may be treatment-refractory."
Independent case series confirming language delay as part of the shared phenotype.
Developmental Regression Developmental regression HP:0002376
Frequency is deliberately omitted: the cohort study reports regression as part of the language phenotype without quantifying the proportion affected.
Show evidence (1 reference)
PMID:34345025 SUPPORT Human Clinical
"resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes"
Explicitly includes regression within the core language phenotype of the disorder.
Intellectual Disability FREQUENT Intellectual disability HP:0001249
Show evidence (2 references)
PMID:36173874 SUPPORT Human Clinical
"Delay in gross motor skills and mild-to-moderate intellectual disability are common."
GeneReviews describes mild-to-moderate intellectual disability as common, mapping to the FREQUENT band (30-79%), and supports the mild-to-moderate severity qualifier.
PMID:34345025 SUPPORT Human Clinical
"Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures."
Confirms intellectual disability as a defining component of the syndrome.
Motor Delay FREQUENT Motor delay HP:0001270
Show evidence (2 references)
PMID:36173874 SUPPORT Human Clinical
"Delay in gross motor skills and mild-to-moderate intellectual disability are common."
GeneReviews describes gross motor delay as common, mapping to the FREQUENT band (30-79%).
PMID:31440728 PARTIAL Human Clinical
"Although his motor development was normal, his language development was markedly delayed."
Illustrates that motor delay is not obligate and that the language-motor dissociation can be marked in individual cases.
Seizures VERY_FREQUENT Seizure HP:0001250
The deep-research report also describes focal and generalized tonic-clonic seizures and 7 of 26 individuals with refractory epilepsy. These full-text-only observations are not promoted to structured phenotype or frequency assertions because the cached source contains only the abstract.
Show evidence (2 references)
PMID:36173874 SUPPORT Human Clinical
"Most affected individuals have seizures with variable onset and seizure type."
GeneReviews states seizures occur in most affected individuals, mapping to the VERY_FREQUENT band (80-100%), and that onset and type vary.
PMID:32546566 SUPPORT Human Clinical
"Here we present clinical reports of four patients with rare coding variants in SETD1B that demonstrate a shared phenotype, including intellectual disability, language delay, conserved musculoskeletal findings and seizures that may be treatment-refractory."
Documents that seizures form part of the shared phenotype and may be treatment-refractory.
Generalized Myoclonic Seizures Generalized myoclonic seizure HP:0002123
Show evidence (1 reference)
PMID:31110234 SUPPORT Human Clinical
"We identified a de novo frameshift variant (NM_015048.1:c.5644_5647del:p.(Ile1882Serfs*118)) in the last exon of SETD1B in a Japanese patient with autistic behavior, developmental delay, intellectual disability, and myoclonic seizures."
Documents myoclonic seizures in a molecularly confirmed individual whose seizures were not characterized as myoclonic absences.
Autistic Behavior Autistic behavior HP:0000729
Frequency is deliberately omitted: GeneReviews names autism spectrum disorder among the defining characteristics without giving a proportion.
Show evidence (2 references)
PMID:36173874 SUPPORT Human Clinical
"SETD1B-related neurodevelopmental disorder (SETD1B-NDD) is characterized by developmental delay (mainly affecting speech and language), intellectual disability, seizures, autism spectrum disorder or autism-like behaviors, and additional behavioral concerns."
GeneReviews includes autism spectrum disorder or autism-like behaviors among the defining clinical characteristics.
PMID:29322246 SUPPORT Human Clinical
"Our cases showed epilepsy, developmental delay, intellectual disabilities, autistic behavior and craniofacial dysmorphic features, which are consistent with those of individuals with de novo 12q24.31 deletions."
Documents autistic behavior in the first individuals reported with de novo SETD1B point variants.
Behavioral Abnormalities FREQUENT Atypical behavior HP:0000708
Show evidence (1 reference)
PMID:36173874 SUPPORT Human Clinical
"Behavioral issues including hyperactivity, aggression, anxiety, and sleep disorders have been reported in approximately half of individuals."
GeneReviews quantifies behavioral issues at approximately half of individuals, mapping to the FREQUENT band (30-79%).
Hyperactivity Hyperactivity HP:0000752
Frequency is deliberately omitted: the approximately-half figure in GeneReviews applies to behavioral issues collectively, not to hyperactivity individually.
Show evidence (2 references)
PMID:36173874 SUPPORT Human Clinical
"Behavioral issues including hyperactivity, aggression, anxiety, and sleep disorders have been reported in approximately half of individuals."
GeneReviews names hyperactivity as one of the reported behavioral issues.
PMID:31440728 SUPPORT Human Clinical
"poorly interacted with others and showed hyperactive behavior."
Case-level documentation of hyperactive behavior in a molecularly confirmed individual.
Aggressive Behavior Aggressive behavior HP:0000718
Frequency omitted: GeneReviews figure is for behavioral issues collectively.
Show evidence (1 reference)
PMID:36173874 SUPPORT Human Clinical
"Behavioral issues including hyperactivity, aggression, anxiety, and sleep disorders have been reported in approximately half of individuals."
GeneReviews names aggression among reported behavioral issues.
Anxiety Anxiety HP:0000739
Frequency omitted: collective behavioral-issues band only.
Show evidence (1 reference)
PMID:36173874 SUPPORT Human Clinical
"Behavioral issues including hyperactivity, aggression, anxiety, and sleep disorders have been reported in approximately half of individuals."
GeneReviews names anxiety among reported behavioral issues.
Sleep Disturbance Sleep disturbance HP:0002360
Frequency omitted: collective behavioral-issues band only.
Show evidence (1 reference)
PMID:36173874 SUPPORT Human Clinical
"Behavioral issues including hyperactivity, aggression, anxiety, and sleep disorders have been reported in approximately half of individuals."
GeneReviews names sleep disorders among reported behavioral issues.
Other 4
Myoclonic Absence Seizures Myoclonic absence seizure HP:0011150
Frequency is deliberately omitted. The 2/3 proportion comes from a small, ascertainment-biased series; the largest cohort describes epilepsy phenotypes only as variable, so no defensible frequency band can be assigned.
Show evidence (2 references)
PMID:31440728 SUPPORT Human Clinical
"Therefore, this report supports the indication that SETD1B may be a causative gene for neurodevelopmental disorders and suggests that epilepsy with myoclonic absences may be a characteristic feature of SETD1B-related disorders."
Directly proposes myoclonic absence epilepsy as a characteristic feature of SETD1B-related disorders.
PMID:31440728 SUPPORT Human Clinical
"Epilepsy with myoclonic absences is a specific seizure type characterized by bilateral rhythmic clonic jerks with impairment of consciousness."
Defines the semiology of the seizure type used for this phenotype annotation.
EEG with Generalized Epileptiform Discharges EEG with generalized epileptiform discharges HP:0011198
Show evidence (1 reference)
PMID:31440728 SUPPORT Human Clinical
"His interictal electroencephalogram revealed a spike-and-slow wave complex dominant in the frontal area."
Documents the generalized interictal epileptiform EEG abnormality.
Abnormality of the Eye Abnormality of the eye HP:0000478
Frequency omitted: GeneReviews calls these less common without a proportion. Preferred_term is intentionally broader than a specific ocular finding because GeneReviews does not enumerate a single ocular phenotype.
Show evidence (1 reference)
PMID:36173874 SUPPORT Human Clinical
"Less common features include ophthalmologic manifestations and feeding issues."
GeneReviews lists ophthalmologic manifestations among less common features.
Abnormality of the Musculoskeletal System Abnormality of the musculoskeletal system HP:0033127
Frequency is omitted because the available abstract identifies a conserved finding in a four-person series without reporting a broader cohort proportion or a specific musculoskeletal subtype.
Show evidence (1 reference)
PMID:32546566 SUPPORT Human Clinical
"Here we present clinical reports of four patients with rare coding variants in SETD1B that demonstrate a shared phenotype, including intellectual disability, language delay, conserved musculoskeletal findings and seizures that may be treatment-refractory."
The case series identifies conserved musculoskeletal findings within the shared phenotype.
🧬

Genetic Associations

1
SETD1B (Causative)
Gene: SETD1B hgnc:29187 relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:34345025 SUPPORT Human Clinical
"Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes."
Supports SETD1B LoF as the genetic cause.
PMID:36173874 SUPPORT Human Clinical
"The diagnosis of SETD1B-NDD is established in a proband with developmental delay / intellectual disability and a heterozygous pathogenic variant in SETD1B identified by molecular genetic testing."
GeneReviews diagnostic criterion anchors SETD1B as the causative gene.
💊

Medical Actions

7
Anti-Seizure Medication
Category: Therapeutic Action: Pharmacotherapy NCIT:C15986
Agent: valproic acid CHEBI:39867
Standard treatment uses antiseizure medication in those with seizures. Valproic acid and several other agents have been used in reported cases, but no disorder-specific preferred medication or efficacy has been established, and some individuals have treatment-refractory epilepsy.
Mechanism Target:
MODULATES Generalized Spike-and-Wave Epileptiform Activity — Antiseizure medications are used to suppress the clinical expression of generalized epileptiform activity, although response varies and no disorder-specific preferred agent is established.
Show evidence (1 reference)
PMID:36173874 PARTIAL Human Clinical
"standard treatment with anti-seizure medication in those with seizures"
GeneReviews supports antiseizure therapy for the clinical manifestation; it does not establish an agent-specific electrophysiologic mechanism in SETD1B-NDD.
Target Phenotypes: Seizure HP:0001250
Show evidence (2 references)
PMID:36173874 SUPPORT Human Clinical
"standard treatment with anti-seizure medication in those with seizures"
GeneReviews management recommends standard ASM therapy.
PMID:31440728 SUPPORT Human Clinical
"His seizures were refractory to antiepileptic drugs including valproate, ethosuximide, levetiracetam, clobazam, and topiramate."
Documents valproate use in a treatment-refractory individual; it does not establish valproate as preferred or effective for SETD1B-NDD.
Developmental Support Services
Category: Therapeutic Action: supportive care Ontology label: Supportive Care NCIT:C15747
Developmental support services and educational intervention.
Show evidence (1 reference)
PMID:36173874 SUPPORT Human Clinical
"Developmental support services and educational intervention"
GeneReviews lists developmental support as first-line management.
Orthopedic and Spasticity Management
Category: Therapeutic Action: supportive care Ontology label: Supportive Care NCIT:C15747
Standard orthopedic management and individualized therapy are recommended for musculoskeletal manifestations and spasticity.
Target Phenotypes: Abnormality of the musculoskeletal system HP:0033127 Spasticity HP:0001257
Show evidence (1 reference)
PMID:36173874 SUPPORT Human Clinical
"standard orthopedic management and therapies for spasticity"
GeneReviews recommends orthopedic management and therapy directed at spasticity.
Ophthalmologic Management
Category: Monitoring Action: ophthalmologist evaluation Ontology label: Eye Examination NCIT:C38060
Routine ophthalmologic management is recommended when eye manifestations are present.
Show evidence (1 reference)
PMID:36173874 SUPPORT Human Clinical
"routine management of ophthalmologic issues and hearing impairment"
GeneReviews recommends routine management of ophthalmologic issues.
Audiologic Management
Category: Monitoring Action: audiologist evaluation Ontology label: Audiometric Test NCIT:C38036
Routine audiologic management is recommended when hearing impairment is present.
Show evidence (1 reference)
PMID:36173874 SUPPORT Human Clinical
"routine management of ophthalmologic issues and hearing impairment"
GeneReviews recommends routine management of hearing impairment.
Genetic Counseling
Category: Counseling / Informational Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240
Genetic counseling regarding autosomal dominant inheritance, typically de novo occurrence, 50% transmission risk when a parent is affected, and option of prenatal / preimplantation testing once the variant is known.
Show evidence (1 reference)
PMID:36173874 SUPPORT Human Clinical
"Each child of an individual with SETD1B-NDD has a 50% chance of inheriting the pathogenic variant."
GeneReviews genetic counseling content.
Multidisciplinary Surveillance
Category: Monitoring Action: supportive care Ontology label: Supportive Care NCIT:C15747
At each visit assess growth, feeding, developmental progress, seizure changes, behavior, sleep, musculoskeletal issues, mobility, and social-work / care-coordination needs.
Show evidence (1 reference)
PMID:36173874 SUPPORT Human Clinical
"At each visit, assessment of growth, feeding, developmental progress, changes in seizures, behavioral issues, sleep issues, musculoskeletal issues, mobility, and need for social work support and care coordination."
GeneReviews surveillance recommendations.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from SETD1B-Related Neurodevelopmental Disorder:

12q24.31 Microdeletion Syndrome
Overlapping Features Overlapping neurodevelopmental phenotype with SETD1B as a critical gene in the 12q24.31 deletion interval.
Distinguishing Features
  • Contiguous-gene 12q24.31 deletions may include additional genes beyond SETD1B, whereas SETD1B-NDD is defined by a pathogenic SETD1B sequence variant (molecular distinction).
Show evidence (1 reference)
PMID:29322246 SUPPORT Human Clinical
"Our cases showed epilepsy, developmental delay, intellectual disabilities, autistic behavior and craniofacial dysmorphic features, which are consistent with those of individuals with de novo 12q24.31 deletions."
Links SETD1B point-variant phenotype to the 12q24.31 deletion phenotype.
Epilepsy with Myoclonic Absences
Overlapping Features Electroclinical syndrome that can be caused by several genes; SETD1B is one genetic etiology associated with this seizure type in some individuals.
Distinguishing Features
  • EMA is an electroclinical diagnosis; SETD1B-NDD is defined by the SETD1B pathogenic variant plus the broader neurodevelopmental phenotype.
Show evidence (1 reference)
PMID:31440728 SUPPORT Human Clinical
"Epilepsy with myoclonic absences is a specific seizure type characterized by bilateral rhythmic clonic jerks with impairment of consciousness."
Establishes EMA as an electroclinical seizure syndrome that must be distinguished from the broader molecularly defined SETD1B-NDD.
{ }

Source YAML

click to show 
name: SETD1B-Related Neurodevelopmental Disorder
creation_date: "2026-07-25T01:27:23Z"
category: Mendelian
synonyms:
- SETD1B-NDD
- SETD1B-related neurodevelopmental disorder
- intellectual developmental disorder with seizures and language delay
- IDDSELD
description: >-
  SETD1B-related neurodevelopmental disorder (SETD1B-NDD; also known as
  intellectual developmental disorder with seizures and language delay,
  IDDSELD; OMIM 619000) is an autosomal dominant Mendelian disorder caused by
  heterozygous loss-of-function variants in SETD1B, which encodes a lysine-specific
  histone H3K4 methyltransferase catalytic subunit of the SET1 complex.
  Haploinsufficiency dysregulates neuronal gene expression and neurodevelopment,
  producing a core phenotype of global developmental delay (speech and language
  predominant), intellectual disability, autism spectrum disorder or autism-like
  behaviors, variable epilepsy (including myoclonic absences in some individuals),
  and additional behavioral concerns. Most pathogenic variants arise de novo.
disease_term:
  preferred_term: intellectual developmental disorder with seizures and language delay
  term:
    id: MONDO:0033559
    label: intellectual developmental disorder with seizures and language delay
parents:
- Neurodevelopmental Disorder
- Genetic Disease
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      SETD1B-NDD is a monogenic neurodevelopmental disorder with epilepsy and is
      classified under Harrison's neurologic disorders.
    evidence:
    - reference: PMID:36173874
      reference_title: SETD1B-Related Neurodevelopmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        SETD1B-related neurodevelopmental disorder (SETD1B-NDD) is characterized by developmental delay (mainly affecting speech and language), intellectual disability, seizures, autism spectrum disorder or autism-like behaviors, and additional behavioral concerns.
      explanation: >-
        GeneReviews defines SETD1B-NDD as a neurodevelopmental disorder with
        seizures, supporting neurologic classification.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      Autosomal dominant Mendelian disorder caused by heterozygous SETD1B
      pathogenic variants.
    evidence:
    - reference: PMID:36173874
      reference_title: SETD1B-Related Neurodevelopmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        SETD1B-NDD is an autosomal dominant disorder typically caused by a de novo pathogenic variant.
      explanation: >-
        GeneReviews establishes Mendelian autosomal dominant genetics.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0033559
      label: intellectual developmental disorder with seizures and language delay
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0033559 is the intellectual developmental disorder with seizures and
      language delay concept; exact synonyms include SETD1B-NDD and
      SETD1B-Related Neurodevelopmental Disorder, with OMIM:619000 as an exact
      match and a causal gene relationship (RO:0004003) to HGNC:29187 (SETD1B).
references:
- reference: PMID:36173874
  title: SETD1B-Related Neurodevelopmental Disorder.
  tags:
  - GeneReviews
- reference: PMID:34345025
  title: Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.
- reference: PMID:32546566
  title: SETD1B-associated neurodevelopmental disorder.
- reference: PMID:31440728
  title: "De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences."
- reference: PMID:31110234
  title: A novel de novo frameshift variant in SETD1B causes epilepsy.
- reference: PMID:29322246
  title: "De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism."
inheritance:
- name: Autosomal dominant
  description: >-
    SETD1B-NDD is an autosomal dominant disorder typically caused by a de novo
    pathogenic variant. Vertical transmission from an affected mother to an
    affected child has been reported; each child of an affected individual has a
    50% chance of inheriting the variant.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SETD1B-NDD is an autosomal dominant disorder typically caused by a de novo pathogenic variant.
    explanation: >-
      GeneReviews states autosomal dominant inheritance with typically de novo
      pathogenic variants.
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Vertical transmission of a SETD1B pathogenic variant from an affected mother to an affected child has been reported in one family.
    explanation: >-
      Documents rare vertical transmission, consistent with AD inheritance.
pathophysiology:
- name: SETD1B Loss of Function
  biological_scale: MOLECULAR
  description: >-
    De novo heterozygous variants in SETD1B (frameshift, nonsense, and missense
    alleles concentrated in functional domains including the SET domain) act
    through a loss-of-function / haploinsufficiency mechanism, reducing the
    catalytic histone H3K4 methyltransferase activity of the SET1 complex.
  genes:
  - preferred_term: SETD1B
    term:
      id: hgnc:29187
      label: SETD1B
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  molecular_functions:
  - preferred_term: histone H3K4 methyltransferase activity
    term:
      id: GO:0042800
      label: histone H3K4 methyltransferase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:34345025
    reference_title: Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes.
    explanation: >-
      Largest published cohort supports a loss-of-function mechanism for
      pathogenic SETD1B variants.
  - reference: PMID:31110234
    reference_title: A novel de novo frameshift variant in SETD1B causes epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a de novo frameshift variant (NM_015048.1:c.5644_5647del:p.(Ile1882Serfs*118)) in the last exon of SETD1B in a Japanese patient with autistic behavior, developmental delay, intellectual disability, and myoclonic seizures.
    explanation: >-
      Documents a de novo frameshift predicted to disrupt the conserved
      carboxyl-terminus SET domain.
  - reference: PMID:34345025
    reference_title: Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Selected variants were functionally tested using in vitro and genome-wide methylation assays.
    explanation: >-
      Adds assay-based functional evidence for selected SETD1B variants to the
      cohort evidence supporting a loss-of-function mechanism.
  downstream:
  - target: Reduced H3K4 Methylation
    description: >-
      Loss of SETD1B methyltransferase activity is expected to reduce H3K4
      methylation at its target loci.
    evidence:
    - reference: PMID:29322246
      reference_title: "De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        SETD1B (SET domain containing 1B) is a component of SET1 histone methyltransferase complex, which mediates the methylation of histone H3 on lysine 4 (H3K4).
      explanation: >-
        Establishes the biochemical premise for this explicitly inferred edge.
  - target: Generalized Spike-and-Wave Epileptiform Activity
    description: >-
      Generalized epileptiform activity occurs in some individuals with
      pathogenic SETD1B variants, although the intervening circuit mechanism
      remains unresolved.
    evidence:
    - reference: PMID:31440728
      reference_title: "De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        His ictal polygraphic and video-electroencephalogram showed a characteristic diffuse synchronous 3-Hz spike-and-wave burst associated with bilateral upper limb myoclonic jerks with impairment of consciousness.
      explanation: >-
        Documents generalized spike-and-wave activity in a molecularly
        characterized SETD1B case without resolving the intervening circuit.
- name: Reduced H3K4 Methylation
  biological_scale: MOLECULAR
  description: >-
    SETD1B is a catalytic component of the SET1 complex that deposits H3K4
    methyl marks. Reduced H3K4 methylation is the expected biochemical
    consequence of SETD1B loss of function, but it has not been directly
    measured in disease-relevant neurons from affected individuals.
  evidence:
  - reference: PMID:29322246
    reference_title: "De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SETD1B (SET domain containing 1B) is a component of SET1 histone methyltransferase complex, which mediates the methylation of histone H3 on lysine 4 (H3K4).
    explanation: >-
      Establishes the biochemical premise for reduced H3K4 methylation after
      SETD1B loss of function; the disease-state reduction remains a mechanistic
      inference.
  downstream:
  - target: Dysregulated Neuronal Gene Expression
    description: >-
      Altered H3K4 methylation is expected to disrupt transcriptional regulation
      at SETD1B target loci.
    evidence:
    - reference: PMID:32546566
      reference_title: SETD1B-associated neurodevelopmental disorder.
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks.
      explanation: >-
        Supports the biochemical link between H3K4 methylation and
        transcriptional activation; disease-state neuronal dysregulation
        remains inferred.
- name: Dysregulated Neuronal Gene Expression
  biological_scale: CELLULAR
  description: >-
    SETD1B normally supports transcriptional activation through H3K4
    methylation. Dysregulated expression of neuronal target genes is a plausible
    downstream consequence of SETD1B loss of function, but the relevant target
    genes and disease-state transcriptional changes have not been directly
    established in affected human neurons.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: 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: ABNORMAL
  - preferred_term: regulation of gene expression
    term:
      id: GO:0010468
      label: regulation of gene expression
    modifier: ABNORMAL
  evidence:
  - reference: PMID:31440728
    reference_title: "De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SETD1B (SET domain containing 1B) encodes a histone H3 lysine 4 (H3K4) methyltransferase, which is involved in the epigenetic control of the chromatin structure and gene expression.
    explanation: >-
      Establishes SETD1B's normal role in chromatin and gene-expression control;
      disease-state neuronal dysregulation remains inferred.
  - reference: PMID:32546566
    reference_title: SETD1B-associated neurodevelopmental disorder.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks.
    explanation: >-
      Supports the mechanistic premise linking H3K4 methylation to
      transcriptional activation, without directly measuring affected neurons.
  downstream:
  - target: Impaired Neurodevelopment
    description: >-
      This inferred transcriptional disruption provides a plausible route from
      SETD1B loss of function to impaired nervous-system development.
    evidence:
    - reference: PMID:34345025
      reference_title: Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes.
      explanation: >-
        Connects SETD1B loss of function to the neurodevelopmental phenotype
        while leaving the intermediate transcriptional step explicitly
        inferential.
- name: Impaired Neurodevelopment
  biological_scale: TISSUE
  description: >-
    SETD1B dysfunction impairs normal brain development independent of seizures;
    developmental delay characteristically precedes seizure onset and
    disproportionately affects speech and language, with autism/behavioral
    features and variable cognitive impairment.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: nervous system development
    term:
      id: GO:0007399
      label: nervous system development
    modifier: DECREASED
  - preferred_term: neuron differentiation
    term:
      id: GO:0030182
      label: neuron differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SETD1B-related neurodevelopmental disorder (SETD1B-NDD) is characterized by developmental delay (mainly affecting speech and language), intellectual disability, seizures, autism spectrum disorder or autism-like behaviors, and additional behavioral concerns.
    explanation: >-
      GeneReviews defines the neurodevelopmental core phenotype.
  - reference: PMID:34345025
    reference_title: Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes.
    explanation: >-
      Cohort data map LoF to the core neurodevelopmental phenotype bundle.
  - reference: PMID:34345025
    reference_title: Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity.
    explanation: >-
      Directly supports primary neurodevelopmental impairment that is not solely
      secondary to seizures.
  downstream:
  - target: Global Developmental Delay
    description: Developmental delay is the usual presenting manifestation.
    evidence:
    - reference: PMID:34345025
      reference_title: Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes.
      explanation: >-
        Identifies global developmental delay as part of the core phenotype
        resulting from SETD1B loss of function.
  - target: Delayed Speech and Language Development
    description: Speech/language is disproportionately affected.
    evidence:
    - reference: PMID:36173874
      reference_title: SETD1B-Related Neurodevelopmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Speech delay and/or language disorder has been reported in most affected individuals.
      explanation: >-
        Directly supports speech and language impairment as a major
        neurodevelopmental outcome.
  - target: Intellectual Disability
    description: Mild-to-moderate intellectual disability is common.
    evidence:
    - reference: PMID:36173874
      reference_title: SETD1B-Related Neurodevelopmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Delay in gross motor skills and mild-to-moderate intellectual disability are common.
      explanation: >-
        Directly supports the common mild-to-moderate intellectual-disability
        outcome.
  - target: Motor Delay
    description: Gross motor delay is common but not obligate.
    evidence:
    - reference: PMID:36173874
      reference_title: SETD1B-Related Neurodevelopmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Delay in gross motor skills and mild-to-moderate intellectual disability are common.
      explanation: >-
        Directly supports gross motor delay as a common developmental outcome.
  - target: Autistic Behavior
    description: ASD or autism-like behaviors are a defining feature.
    evidence:
    - reference: PMID:36173874
      reference_title: SETD1B-Related Neurodevelopmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        SETD1B-related neurodevelopmental disorder (SETD1B-NDD) is characterized by developmental delay (mainly affecting speech and language), intellectual disability, seizures, autism spectrum disorder or autism-like behaviors, and additional behavioral concerns.
      explanation: >-
        Directly includes autism spectrum disorder or autism-like behavior in
        the defining neurodevelopmental phenotype.
  - target: Developmental Regression
    description: Language phenotype may include regression.
    evidence:
    - reference: PMID:34345025
      reference_title: Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes.
      explanation: >-
        Explicitly includes regression within the language phenotype linked to
        SETD1B loss of function.
  - target: Behavioral Abnormalities
    description: Hyperactivity, aggression, anxiety, and sleep issues are frequent.
    evidence:
    - reference: PMID:36173874
      reference_title: SETD1B-Related Neurodevelopmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Behavioral issues including hyperactivity, aggression, anxiety, and sleep disorders have been reported in approximately half of individuals.
      explanation: >-
        Directly supports the collective behavioral-abnormality outcome and
        its approximate frequency.
  - target: Hyperactivity
    description: Hyperactive behavior is among reported behavioral concerns.
    evidence:
    - reference: PMID:36173874
      reference_title: SETD1B-Related Neurodevelopmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Behavioral issues including hyperactivity, aggression, anxiety, and sleep disorders have been reported in approximately half of individuals.
      explanation: >-
        Directly names hyperactivity among reported behavioral outcomes.
  - target: Aggressive Behavior
    description: Aggressive behavior is among reported behavioral concerns.
    evidence:
    - reference: PMID:36173874
      reference_title: SETD1B-Related Neurodevelopmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Behavioral issues including hyperactivity, aggression, anxiety, and sleep disorders have been reported in approximately half of individuals.
      explanation: >-
        Directly names aggression among reported behavioral outcomes.
  - target: Anxiety
    description: Anxiety is among reported behavioral concerns.
    evidence:
    - reference: PMID:36173874
      reference_title: SETD1B-Related Neurodevelopmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Behavioral issues including hyperactivity, aggression, anxiety, and sleep disorders have been reported in approximately half of individuals.
      explanation: >-
        Directly names anxiety among reported behavioral outcomes.
  - target: Sleep Disturbance
    description: Sleep disorders are among reported behavioral concerns.
    evidence:
    - reference: PMID:36173874
      reference_title: SETD1B-Related Neurodevelopmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Behavioral issues including hyperactivity, aggression, anxiety, and sleep disorders have been reported in approximately half of individuals.
      explanation: >-
        Directly names sleep disorders among reported behavioral outcomes.
  - target: Abnormal Facial Shape
    description: Craniofacial dysmorphism is reported in some individuals.
    evidence:
    - reference: PMID:29322246
      reference_title: "De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our cases showed epilepsy, developmental delay, intellectual disabilities, autistic behavior and craniofacial dysmorphic features, which are consistent with those of individuals with de novo 12q24.31 deletions.
      explanation: >-
        Directly documents craniofacial dysmorphic features in individuals with
        de novo SETD1B variants.
  - target: Feeding Difficulties
    description: Feeding issues are a less common associated feature.
    evidence:
    - reference: PMID:36173874
      reference_title: SETD1B-Related Neurodevelopmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Less common features include ophthalmologic manifestations and feeding issues.
      explanation: >-
        Directly supports feeding issues as a less common outcome.
  - target: Abnormality of the Eye
    description: Ophthalmologic manifestations are less common features.
    evidence:
    - reference: PMID:36173874
      reference_title: SETD1B-Related Neurodevelopmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Less common features include ophthalmologic manifestations and feeding issues.
      explanation: >-
        Directly supports ophthalmologic manifestations as a less common
        outcome.
  - target: Abnormality of the Musculoskeletal System
    description: Conserved musculoskeletal findings are part of the shared phenotype.
    evidence:
    - reference: PMID:32546566
      reference_title: SETD1B-associated neurodevelopmental disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here we present clinical reports of four patients with rare coding variants in SETD1B that demonstrate a shared phenotype, including intellectual disability, language delay, conserved musculoskeletal findings and seizures that may be treatment-refractory.
      explanation: >-
        The case series identifies conserved musculoskeletal findings within the
        shared SETD1B-associated phenotype.
  - target: Spasticity
    description: Spasticity is a recognized manifestation requiring therapy.
    evidence:
    - reference: PMID:36173874
      reference_title: SETD1B-Related Neurodevelopmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        standard orthopedic management and therapies for spasticity
      explanation: >-
        GeneReviews management guidance establishes spasticity as a manifestation
        requiring directed therapy.
  - target: Hearing Impairment
    description: Hearing impairment is a recognized manifestation requiring management.
    evidence:
    - reference: PMID:36173874
      reference_title: SETD1B-Related Neurodevelopmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        routine management of ophthalmologic issues and hearing impairment
      explanation: >-
        GeneReviews management guidance establishes hearing impairment as a
        recognized manifestation.
- name: Generalized Spike-and-Wave Epileptiform Activity
  biological_scale: TISSUE
  conforms_to: "epilepsy_excitation_inhibition_imbalance#Neuronal Hyperexcitability and Hypersynchrony"
  description: >-
    EEG directly demonstrates interictal spike-and-slow-wave complexes and,
    during myoclonic absences, diffuse synchronous 3-Hz spike-and-wave bursts.
    These observations establish generalized epileptiform activity but do not
    identify a specific thalamocortical or excitation-inhibition mechanism.
  evidence:
  - reference: PMID:31440728
    reference_title: "De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His interictal electroencephalogram revealed a spike-and-slow wave complex dominant in the frontal area.
    explanation: >-
      Documents the interictal generalized epileptiform abnormality with frontal
      predominance.
  - reference: PMID:31440728
    reference_title: "De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His ictal polygraphic and video-electroencephalogram showed a characteristic diffuse synchronous 3-Hz spike-and-wave burst associated with bilateral upper limb myoclonic jerks with impairment of consciousness.
    explanation: >-
      Establishes the generalized 3-Hz spike-and-wave discharge time-locked to
      myoclonic jerks as the electroclinical correlate of the seizures.
  downstream:
  - target: Seizures
    description: Generalized epileptiform activity is associated with seizures.
    evidence:
    - reference: PMID:31440728
      reference_title: "De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        His ictal polygraphic and video-electroencephalogram showed a characteristic diffuse synchronous 3-Hz spike-and-wave burst associated with bilateral upper limb myoclonic jerks with impairment of consciousness.
      explanation: >-
        Directly records generalized spike-and-wave activity during a clinical
        seizure.
  - target: Myoclonic Absence Seizures
    description: >-
      Diffuse synchronous 3-Hz spike-and-wave bursts occur with bilateral
      myoclonic jerks and impaired consciousness during myoclonic absences.
    evidence:
    - reference: PMID:31440728
      reference_title: "De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        His ictal polygraphic and video-electroencephalogram showed a characteristic diffuse synchronous 3-Hz spike-and-wave burst associated with bilateral upper limb myoclonic jerks with impairment of consciousness.
      explanation: >-
        Directly establishes the electroclinical transition from the observed
        discharge to a myoclonic absence seizure.
  - target: Generalized Myoclonic Seizures
    description: >-
      Myoclonic seizures without absence features are another clinical
      expression of generalized epileptiform activity in SETD1B-NDD.
    evidence:
    - reference: PMID:31110234
      reference_title: A novel de novo frameshift variant in SETD1B causes epilepsy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We identified a de novo frameshift variant (NM_015048.1:c.5644_5647del:p.(Ile1882Serfs*118)) in the last exon of SETD1B in a Japanese patient with autistic behavior, developmental delay, intellectual disability, and myoclonic seizures.
      explanation: >-
        Documents myoclonic seizures in a molecularly confirmed individual;
        the available abstract does not resolve a more specific circuit.
  - target: EEG with Generalized Epileptiform Discharges
    description: >-
      Interictal and ictal EEG recordings document generalized epileptiform
      discharges.
    evidence:
    - reference: PMID:31440728
      reference_title: "De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        His interictal electroencephalogram revealed a spike-and-slow wave complex dominant in the frontal area.
      explanation: >-
        Directly supports the interictal generalized epileptiform EEG finding.
phenotypes:
- category: Developmental
  name: Global Developmental Delay
  description: >
    Global developmental delay is a core feature and the usual presenting
    manifestation, affecting language most prominently but also motor and adaptive
    domains.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:34345025
    reference_title: Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes.
    explanation: >-
      Global developmental delay is named as part of the core clinical phenotype
      in the largest cohort, supporting the VERY_FREQUENT band.
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SETD1B-related neurodevelopmental disorder (SETD1B-NDD) is characterized by developmental delay (mainly affecting speech and language), intellectual disability, seizures, autism spectrum disorder or autism-like behaviors, and additional behavioral concerns.
    explanation: >-
      GeneReviews lists developmental delay first among the defining clinical
      characteristics.
- category: Developmental
  name: Delayed Speech and Language Development
  description: >
    Speech delay and/or language disorder is the most consistently reported feature
    and is disproportionately severe relative to other developmental domains.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Speech delay and/or language disorder has been reported in most affected individuals.
    explanation: >-
      GeneReviews states speech/language involvement occurs in most affected
      individuals, mapping to the VERY_FREQUENT band (80-100%).
  - reference: PMID:32546566
    reference_title: SETD1B-associated neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we present clinical reports of four patients with rare coding variants in SETD1B that demonstrate a shared phenotype, including intellectual disability, language delay, conserved musculoskeletal findings and seizures that may be treatment-refractory.
    explanation: >-
      Independent case series confirming language delay as part of the shared
      phenotype.
- category: Developmental
  name: Developmental Regression
  description: >
    Language delay in this disorder may include regression, with loss of previously
    acquired language skills rather than simple delay in acquisition.
  notes: >-
    Frequency is deliberately omitted: the cohort study reports regression as part
    of the language phenotype without quantifying the proportion affected.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:34345025
    reference_title: Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes
    explanation: >-
      Explicitly includes regression within the core language phenotype of the
      disorder.
- category: Cognitive
  name: Intellectual Disability
  description: >
    Intellectual disability is typically mild to moderate. Reported IQ measurements
    in individual cases fall in the mild range, and cognitive outcome is variable.
  frequency: FREQUENT
  diagnostic: true
  severity: MILD
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Delay in gross motor skills and mild-to-moderate intellectual disability are common.
    explanation: >-
      GeneReviews describes mild-to-moderate intellectual disability as common,
      mapping to the FREQUENT band (30-79%), and supports the mild-to-moderate
      severity qualifier.
  - reference: PMID:34345025
    reference_title: Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures.
    explanation: >-
      Confirms intellectual disability as a defining component of the syndrome.
- category: Developmental
  name: Motor Delay
  description: >
    Delay in gross motor skill acquisition is common, though generally less severe
    than the language delay; motor development is normal in some individuals.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Delay in gross motor skills and mild-to-moderate intellectual disability are common.
    explanation: >-
      GeneReviews describes gross motor delay as common, mapping to the FREQUENT
      band (30-79%).
  - reference: PMID:31440728
    reference_title: "De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although his motor development was normal, his language development was markedly delayed.
    explanation: >-
      Illustrates that motor delay is not obligate and that the language-motor
      dissociation can be marked in individual cases.
- category: Neurologic
  name: Seizures
  description: >
    Most affected individuals develop seizures, with variable age of onset and
    seizure type. Seizures may be refractory to multiple antiseizure medications.
    Seizure onset characteristically follows the onset of developmental delay.
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: >-
    The deep-research report also describes focal and generalized tonic-clonic
    seizures and 7 of 26 individuals with refractory epilepsy. These
    full-text-only observations are not promoted to structured phenotype or
    frequency assertions because the cached source contains only the abstract.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most affected individuals have seizures with variable onset and seizure type.
    explanation: >-
      GeneReviews states seizures occur in most affected individuals, mapping to
      the VERY_FREQUENT band (80-100%), and that onset and type vary.
  - reference: PMID:32546566
    reference_title: SETD1B-associated neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we present clinical reports of four patients with rare coding variants in SETD1B that demonstrate a shared phenotype, including intellectual disability, language delay, conserved musculoskeletal findings and seizures that may be treatment-refractory.
    explanation: >-
      Documents that seizures form part of the shared phenotype and may be
      treatment-refractory.
- category: Neurologic
  name: Myoclonic Absence Seizures
  description: >
    Epilepsy with myoclonic absences, a rare generalized seizure type comprising
    bilateral rhythmic myoclonic jerks with impaired consciousness on a 3-Hz
    generalized spike-and-wave background, is a distinctive seizure phenotype of
    SETD1B-related disorders. It was present in two of three individuals in the
    index Japanese series, though it is not universal across the wider cohort.
  notes: >-
    Frequency is deliberately omitted. The 2/3 proportion comes from a small,
    ascertainment-biased series; the largest cohort describes epilepsy phenotypes
    only as variable, so no defensible frequency band can be assigned.
  phenotype_term:
    preferred_term: Myoclonic absence seizure
    term:
      id: HP:0011150
      label: Myoclonic absence seizure
  evidence:
  - reference: PMID:31440728
    reference_title: "De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, this report supports the indication that SETD1B may be a causative gene for neurodevelopmental disorders and suggests that epilepsy with myoclonic absences may be a characteristic feature of SETD1B-related disorders.
    explanation: >-
      Directly proposes myoclonic absence epilepsy as a characteristic feature of
      SETD1B-related disorders.
  - reference: PMID:31440728
    reference_title: "De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Epilepsy with myoclonic absences is a specific seizure type characterized by bilateral rhythmic clonic jerks with impairment of consciousness.
    explanation: >-
      Defines the semiology of the seizure type used for this phenotype
      annotation.
- category: Neurologic
  name: Generalized Myoclonic Seizures
  description: >
    Myoclonic seizures without absence features have also been reported, including
    in an individual with a de novo frameshift variant disrupting the SET domain.
  phenotype_term:
    preferred_term: Generalized myoclonic seizure
    term:
      id: HP:0002123
      label: Generalized myoclonic seizure
  evidence:
  - reference: PMID:31110234
    reference_title: A novel de novo frameshift variant in SETD1B causes epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a de novo frameshift variant (NM_015048.1:c.5644_5647del:p.(Ile1882Serfs*118)) in the last exon of SETD1B in a Japanese patient with autistic behavior, developmental delay, intellectual disability, and myoclonic seizures.
    explanation: >-
      Documents myoclonic seizures in a molecularly confirmed individual whose
      seizures were not characterized as myoclonic absences.
- category: Neurologic
  name: EEG with Generalized Epileptiform Discharges
  description: >
    Interictal EEG shows generalized spike-and-slow-wave complexes, frontally
    dominant in the reported case, and ictal recordings show diffuse synchronous
    3-Hz spike-and-wave bursts.
  phenotype_term:
    preferred_term: EEG with generalized epileptiform discharges
    term:
      id: HP:0011198
      label: EEG with generalized epileptiform discharges
  evidence:
  - reference: PMID:31440728
    reference_title: "De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His interictal electroencephalogram revealed a spike-and-slow wave complex dominant in the frontal area.
    explanation: >-
      Documents the generalized interictal epileptiform EEG abnormality.
- category: Behavioral
  name: Autistic Behavior
  description: >
    Autism spectrum disorder or autism-like behaviors are a defining component of
    the phenotype. Formal ASD diagnoses have been made in molecularly confirmed
    individuals.
  diagnostic: true
  notes: >-
    Frequency is deliberately omitted: GeneReviews names autism spectrum disorder
    among the defining characteristics without giving a proportion.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SETD1B-related neurodevelopmental disorder (SETD1B-NDD) is characterized by developmental delay (mainly affecting speech and language), intellectual disability, seizures, autism spectrum disorder or autism-like behaviors, and additional behavioral concerns.
    explanation: >-
      GeneReviews includes autism spectrum disorder or autism-like behaviors among
      the defining clinical characteristics.
  - reference: PMID:29322246
    reference_title: "De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our cases showed epilepsy, developmental delay, intellectual disabilities, autistic behavior and craniofacial dysmorphic features, which are consistent with those of individuals with de novo 12q24.31 deletions.
    explanation: >-
      Documents autistic behavior in the first individuals reported with de novo
      SETD1B point variants.
- category: Behavioral
  name: Behavioral Abnormalities
  description: >
    Behavioral concerns beyond autism are reported in about half of affected
    individuals and include hyperactivity, aggression, anxiety, and sleep
    disorders.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Behavioral issues including hyperactivity, aggression, anxiety, and sleep disorders have been reported in approximately half of individuals.
    explanation: >-
      GeneReviews quantifies behavioral issues at approximately half of
      individuals, mapping to the FREQUENT band (30-79%).
- category: Behavioral
  name: Hyperactivity
  description: >
    Hyperactive behavior is among the reported behavioral concerns and has been
    documented in individual case reports.
  notes: >-
    Frequency is deliberately omitted: the approximately-half figure in
    GeneReviews applies to behavioral issues collectively, not to hyperactivity
    individually.
  phenotype_term:
    preferred_term: Hyperactivity
    term:
      id: HP:0000752
      label: Hyperactivity
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Behavioral issues including hyperactivity, aggression, anxiety, and sleep disorders have been reported in approximately half of individuals.
    explanation: >-
      GeneReviews names hyperactivity as one of the reported behavioral issues.
  - reference: PMID:31440728
    reference_title: "De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      poorly interacted with others and showed hyperactive behavior.
    explanation: >-
      Case-level documentation of hyperactive behavior in a molecularly confirmed
      individual.

- category: Behavioral
  name: Aggressive Behavior
  description: >
    Aggressive behavior is among the behavioral issues reported in approximately
    half of individuals (as a collective category).
  notes: >-
    Frequency omitted: GeneReviews figure is for behavioral issues collectively.
  phenotype_term:
    preferred_term: Aggressive behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Behavioral issues including hyperactivity, aggression, anxiety, and sleep disorders have been reported in approximately half of individuals.
    explanation: >-
      GeneReviews names aggression among reported behavioral issues.
- category: Behavioral
  name: Anxiety
  description: >
    Anxiety is among the reported behavioral concerns.
  notes: >-
    Frequency omitted: collective behavioral-issues band only.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Behavioral issues including hyperactivity, aggression, anxiety, and sleep disorders have been reported in approximately half of individuals.
    explanation: >-
      GeneReviews names anxiety among reported behavioral issues.
- category: Behavioral
  name: Sleep Disturbance
  description: >
    Sleep disorders are among the reported behavioral concerns.
  notes: >-
    Frequency omitted: collective behavioral-issues band only.
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Behavioral issues including hyperactivity, aggression, anxiety, and sleep disorders have been reported in approximately half of individuals.
    explanation: >-
      GeneReviews names sleep disorders among reported behavioral issues.
- category: Craniofacial
  name: Abnormal Facial Shape
  description: >
    Craniofacial dysmorphic features have been reported in individuals with de
    novo SETD1B variants and in overlapping 12q24.31 deletions.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:29322246
    reference_title: "De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our cases showed epilepsy, developmental delay, intellectual disabilities, autistic behavior and craniofacial dysmorphic features, which are consistent with those of individuals with de novo 12q24.31 deletions.
    explanation: >-
      Documents craniofacial dysmorphism in SETD1B point-variant cases.
- category: Digestive
  name: Feeding Difficulties
  description: >
    Feeding issues are a less common feature noted in GeneReviews.
  notes: >-
    Frequency omitted: GeneReviews calls these less common without a proportion.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Less common features include ophthalmologic manifestations and feeding issues.
    explanation: >-
      GeneReviews lists feeding issues among less common features.
- category: Eye
  name: Abnormality of the Eye
  description: >
    Ophthalmologic manifestations are less common features of SETD1B-NDD.
  notes: >-
    Frequency omitted: GeneReviews calls these less common without a proportion.
    Preferred_term is intentionally broader than a specific ocular finding because
    GeneReviews does not enumerate a single ocular phenotype.
  phenotype_term:
    preferred_term: Abnormality of the eye
    term:
      id: HP:0000478
      label: Abnormality of the eye
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Less common features include ophthalmologic manifestations and feeding issues.
    explanation: >-
      GeneReviews lists ophthalmologic manifestations among less common features.
- category: Musculoskeletal
  name: Abnormality of the Musculoskeletal System
  description: >
    Conserved musculoskeletal findings have been reported as part of the shared
    SETD1B-associated phenotype.
  notes: >-
    Frequency is omitted because the available abstract identifies a conserved
    finding in a four-person series without reporting a broader cohort proportion
    or a specific musculoskeletal subtype.
  phenotype_term:
    preferred_term: Abnormality of the musculoskeletal system
    term:
      id: HP:0033127
      label: Abnormality of the musculoskeletal system
  evidence:
  - reference: PMID:32546566
    reference_title: SETD1B-associated neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we present clinical reports of four patients with rare coding variants in SETD1B that demonstrate a shared phenotype, including intellectual disability, language delay, conserved musculoskeletal findings and seizures that may be treatment-refractory.
    explanation: >-
      The case series identifies conserved musculoskeletal findings within the
      shared phenotype.
- category: Neurologic
  name: Spasticity
  description: >
    Spasticity is a recognized neurologic manifestation for which GeneReviews
    recommends directed therapy.
  notes: >-
    Frequency is omitted because the management summary does not report a
    prevalence estimate.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      standard orthopedic management and therapies for spasticity
    explanation: >-
      GeneReviews identifies spasticity as a manifestation requiring therapy.
- category: Ear
  name: Hearing Impairment
  description: >
    Hearing impairment is a recognized manifestation for which routine
    management is recommended.
  notes: >-
    Frequency and hearing-loss subtype are omitted because the available summary
    does not quantify prevalence or specify conductive versus sensorineural loss.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      routine management of ophthalmologic issues and hearing impairment
    explanation: >-
      GeneReviews identifies hearing impairment as a manifestation requiring
      routine management.
genetic:
- name: SETD1B
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: SETD1B
    term:
      id: hgnc:29187
      label: SETD1B
  notes: >-
    Heterozygous germline de novo missense and frameshift loss-of-function
    variants in SETD1B cause the disorder. MONDO relationship RO:0004003 links
    MONDO:0033559 to HGNC:29187 / SETD1B.
  evidence:
  - reference: PMID:34345025
    reference_title: Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes.
    explanation: >-
      Supports SETD1B LoF as the genetic cause.
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of SETD1B-NDD is established in a proband with developmental delay / intellectual disability and a heterozygous pathogenic variant in SETD1B identified by molecular genetic testing.
    explanation: >-
      GeneReviews diagnostic criterion anchors SETD1B as the causative gene.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Diagnosis is established in a proband with developmental delay / intellectual
    disability and a heterozygous pathogenic SETD1B variant identified by
    molecular genetic testing.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of SETD1B-NDD is established in a proband with developmental delay / intellectual disability and a heterozygous pathogenic variant in SETD1B identified by molecular genetic testing.
    explanation: >-
      Defines the molecular diagnostic criteria.
- name: SETD1B Genome-Wide DNA Methylation Episignature Assay
  description: >-
    Genome-wide DNA methylation profiling can provide orthogonal functional
    support when assessing selected SETD1B variants. It is an adjunct to
    clinical and sequence interpretation, not a standalone diagnostic
    replacement.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  results: >-
    A SETD1B-consistent methylation profile can support variant interpretation
    in the appropriate clinical context.
  evidence:
  - reference: PMID:34345025
    reference_title: Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Selected variants were functionally tested using in vitro and genome-wide methylation assays.
    explanation: >-
      The cohort used genome-wide methylation assays for functional assessment
      of selected variants; the abstract does not establish standalone
      diagnostic sensitivity or specificity.
differential_diagnoses:
- name: 12q24.31 Microdeletion Syndrome
  description: >-
    Overlapping neurodevelopmental phenotype with SETD1B as a critical gene in
    the 12q24.31 deletion interval.
  distinguishing_features:
  - >-
    Contiguous-gene 12q24.31 deletions may include additional genes beyond
    SETD1B, whereas SETD1B-NDD is defined by a pathogenic SETD1B sequence
    variant (molecular distinction).
  evidence:
  - reference: PMID:29322246
    reference_title: "De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our cases showed epilepsy, developmental delay, intellectual disabilities, autistic behavior and craniofacial dysmorphic features, which are consistent with those of individuals with de novo 12q24.31 deletions.
    explanation: >-
      Links SETD1B point-variant phenotype to the 12q24.31 deletion phenotype.
- name: Epilepsy with Myoclonic Absences
  description: >-
    Electroclinical syndrome that can be caused by several genes; SETD1B is one
    genetic etiology associated with this seizure type in some individuals.
  distinguishing_features:
  - >-
    EMA is an electroclinical diagnosis; SETD1B-NDD is defined by the SETD1B
    pathogenic variant plus the broader neurodevelopmental phenotype.
  evidence:
  - reference: PMID:31440728
    reference_title: "De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Epilepsy with myoclonic absences is a specific seizure type characterized by bilateral rhythmic clonic jerks with impairment of consciousness.
    explanation: >-
      Establishes EMA as an electroclinical seizure syndrome that must be
      distinguished from the broader molecularly defined SETD1B-NDD.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Before the 2021 Genet Med cohort expansion, clinical features had been
    described for 11 patients with (likely) pathogenic SETD1B sequence variants;
    that study additionally characterized 36 unpublished individuals, confirming
    ultra-rare ascertainment.
  evidence:
  - reference: PMID:34345025
    reference_title: Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants
    explanation: >-
      Quantifies early published case counts for SETD1B sequence variants.
  - reference: PMID:34345025
    reference_title: Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a cohort of 36 unpublished individuals with SETD1B sequence variants
    explanation: >-
      Documents the size of the expanded unpublished clinical cohort.
treatments:
- name: Anti-Seizure Medication
  description: >-
    Standard treatment uses antiseizure medication in those with seizures.
    Valproic acid and several other agents have been used in reported cases, but
    no disorder-specific preferred medication or efficacy has been established,
    and some individuals have treatment-refractory epilepsy.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: valproic acid
      term:
        id: CHEBI:39867
        label: valproic acid
  target_mechanisms:
  - target: Generalized Spike-and-Wave Epileptiform Activity
    treatment_effect: MODULATES
    description: >-
      Antiseizure medications are used to suppress the clinical expression of
      generalized epileptiform activity, although response varies and no
      disorder-specific preferred agent is established.
    evidence:
    - reference: PMID:36173874
      reference_title: SETD1B-Related Neurodevelopmental Disorder.
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        standard treatment with anti-seizure medication in those with seizures
      explanation: >-
        GeneReviews supports antiseizure therapy for the clinical manifestation;
        it does not establish an agent-specific electrophysiologic mechanism in
        SETD1B-NDD.
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      standard treatment with anti-seizure medication in those with seizures
    explanation: >-
      GeneReviews management recommends standard ASM therapy.
  - reference: PMID:31440728
    reference_title: "De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His seizures were refractory to antiepileptic drugs including valproate, ethosuximide, levetiracetam, clobazam, and topiramate.
    explanation: >-
      Documents valproate use in a treatment-refractory individual; it does not
      establish valproate as preferred or effective for SETD1B-NDD.
- name: Developmental Support Services
  description: >-
    Developmental support services and educational intervention.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Developmental support services and educational intervention
    explanation: >-
      GeneReviews lists developmental support as first-line management.
- name: Orthopedic and Spasticity Management
  description: >-
    Standard orthopedic management and individualized therapy are recommended
    for musculoskeletal manifestations and spasticity.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Abnormality of the musculoskeletal system
    term:
      id: HP:0033127
      label: Abnormality of the musculoskeletal system
  - preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      standard orthopedic management and therapies for spasticity
    explanation: >-
      GeneReviews recommends orthopedic management and therapy directed at
      spasticity.
- name: Ophthalmologic Management
  description: >-
    Routine ophthalmologic management is recommended when eye manifestations
    are present.
  action_category: MONITORING
  treatment_term:
    preferred_term: ophthalmologist evaluation
    term:
      id: NCIT:C38060
      label: Eye Examination
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      routine management of ophthalmologic issues and hearing impairment
    explanation: >-
      GeneReviews recommends routine management of ophthalmologic issues.
- name: Audiologic Management
  description: >-
    Routine audiologic management is recommended when hearing impairment is
    present.
  action_category: MONITORING
  treatment_term:
    preferred_term: audiologist evaluation
    term:
      id: NCIT:C38036
      label: Audiometric Test
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      routine management of ophthalmologic issues and hearing impairment
    explanation: >-
      GeneReviews recommends routine management of hearing impairment.
- name: Genetic Counseling
  description: >-
    Genetic counseling regarding autosomal dominant inheritance, typically de
    novo occurrence, 50% transmission risk when a parent is affected, and option
    of prenatal / preimplantation testing once the variant is known.
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each child of an individual with SETD1B-NDD has a 50% chance of inheriting the pathogenic variant.
    explanation: >-
      GeneReviews genetic counseling content.
- name: Multidisciplinary Surveillance
  description: >-
    At each visit assess growth, feeding, developmental progress, seizure
    changes, behavior, sleep, musculoskeletal issues, mobility, and social-work /
    care-coordination needs.
  action_category: MONITORING
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:36173874
    reference_title: SETD1B-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At each visit, assessment of growth, feeding, developmental progress, changes in seizures, behavioral issues, sleep issues, musculoskeletal issues, mobility, and need for social work support and care coordination.
    explanation: >-
      GeneReviews surveillance recommendations.
discussions:
- discussion_id: gap_setd1b_sex_bias
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why are males overrepresented and reportedly more severely affected in
    SETD1B-NDD cohorts, and are there sex-linked modifiers of penetrance or
    expressivity?
  rationale: >-
    Published cohorts and GeneReviews-era summaries note male
    overrepresentation and more severe male phenotypes as an open mechanistic
    question without a demonstrated molecular explanation.
  evidence:
  - reference: PMID:34345025
    reference_title: Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants.
    explanation: >-
      Directly supports the observed sex bias while preserving the authors'
      explicit characterization of its mechanism as speculative.
  attaches_to:
  - "pathophysiology#SETD1B Loss of Function"
📚

References & Deep Research

References

6
PMID:36173874
SETD1B-Related Neurodevelopmental Disorder.
No top-level findings curated for this source.
PMID:34345025
Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.
No top-level findings curated for this source.
PMID:32546566
SETD1B-associated neurodevelopmental disorder.
No top-level findings curated for this source.
PMID:31440728
De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences.
No top-level findings curated for this source.
PMID:31110234
A novel de novo frameshift variant in SETD1B causes epilepsy.
No top-level findings curated for this source.
PMID:29322246
De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism.
No top-level findings curated for this source.

Deep Research

1
Asta ▸
Asta Literature Retrieval: SETD1B-Related Neurodevelopmental Disorder
Asta Scientific Corpus MCP Retrieval 5 citations

Asta Literature Retrieval: SETD1B-Related Neurodevelopmental Disorder

This is a retrieval-and-synthesis artifact generated from the Ai2 Asta Scientific Corpus MCP. Retrieval was deliberately restricted to the six PMIDs already cited by the disorder entry. Asta indexed five of them. The GeneReviews record (PMID:36173874) was not present in Asta and is therefore not represented as an Asta result.

Executive synthesis

The retrieved literature supports a coherent disease model in which heterozygous SETD1B variants, especially truncating variants and damaging missense variants in functional domains, impair a COMPASS-family histone H3 lysine-4 methyltransferase. The strongest cohort study combines clinical phenotyping with protein modeling, in-vitro assays, and genome-wide DNA methylation profiling and concludes that loss of function is the predominant mechanism. SETD1B normally contributes H3K4 mono-, di-, and trimethylation at enhancers and promoters associated with active chromatin and transcription.

The clinical consequence is best framed as a developmental encephalopathy with or without epilepsy, rather than an epileptic encephalopathy in which seizures alone cause the developmental impairment. In the largest retrieved cohort, developmental delay generally preceded seizure onset, and some affected individuals remained seizure-free into childhood or adolescence. The recurring phenotype comprises global developmental delay, disproportionate speech and language impairment (sometimes including regression), intellectual disability, autism or autistic behavior, other behavioral concerns, sleep disturbance, and variable epilepsy.

Myoclonic absence epilepsy is a distinctive recurrent presentation, with documented diffuse synchronous 3-Hz spike-and-wave activity and bilateral upper limb myoclonus with impaired consciousness. It is not the only seizure phenotype: focal and generalized tonic-clonic seizures also occur. The largest cohort reported that epilepsy was controlled or partly controlled in most affected individuals, while 7 of 26 remained refractory.

The evidence is strongest for SETD1B loss of function, altered epigenetic regulation, and the human neurodevelopmental/epilepsy phenotype. It is weaker for the intermediate neuron-level causal chain. Reduced neuronal H3K4me3, memory-circuit dysfunction, and excitation/inhibition imbalance are biologically plausible interpretations, but the retrieved studies do not directly measure these events in affected human cortex. Those steps should remain explicitly labeled as mechanistic inference rather than direct human evidence.

Mechanistic evidence

SETD1B function and loss-of-function mechanism

SETD1B encodes a 1,966-amino-acid histone methyltransferase in a COMPASS multisubunit complex. The retrieved full text identifies an N-terminal RNA recognition motif and C-terminal N-SET, catalytic SET, and post-SET domains. H3K4me3 is associated with promoters and transcription start sites, whereas H3K4me1 and H3K4me2 are enriched at enhancers. This provides the molecular bridge from SETD1B dysfunction to altered chromatin state and transcription.

The 2021 cohort supplies the strongest disease-specific evidence. It studied 36 additional individuals, evaluated selected variants with protein modeling and in-vitro assays, and applied genome-wide methylation signatures. Its abstract states: “Our data present evidence for a loss-of-function mechanism of SETD1B variants.” Pathogenic and likely pathogenic variants included truncating and missense alleles; most pathogenic missense variants localized to the SET-domain region. A SETD1B-specific peripheral-blood DNA methylation episignature provides orthogonal evidence that pathogenic alleles alter epigenetic regulation.

The 2019 myoclonic-absence study proposed that damaging variants in the SET or RNA-recognition domains disrupt H3K4 methyltransferase activity. That paper also linked H3K4 trimethylation to learning and memory biology, but its specific proposal that reduced neuronal H3K4me3 causes cognitive impairment is an inference from prior experimental literature, not a direct measurement in the reported patient.

Neurodevelopment independent of seizures

Across the expanded cohort, the emerging phenotype included developmental and language delay, intellectual disability, autism, behavioral abnormalities, and epilepsy. Importantly, “Developmental delay appeared to precede seizure onset.” The full-text discussion further reports seizure-free affected individuals, supporting a primary developmental effect of SETD1B dysfunction rather than developmental impairment solely secondary to epileptic activity.

This temporal relationship supports the disorder entry's separation of impaired neurodevelopment from downstream cortical hyperexcitability. It does not, however, identify the vulnerable neuronal subtype or directly establish which dysregulated target genes drive language, cognition, or autism-related phenotypes.

Epilepsy and electroclinical phenotype

The 2019 Epilepsia Open report gives the most specific electroclinical evidence. Its proband had myoclonic absences with a “diffuse synchronous 3-Hz spike-and-wave burst” and bilateral upper-limb myoclonic jerks with impaired consciousness. Together with an earlier similarly affected individual, this supports myoclonic absences as a characteristic but non-universal feature.

The broader cohort showed a wider seizure spectrum, including focal and generalized tonic-clonic onset. It also revised the earlier impression that epilepsy is predominantly refractory: most cases were controlled or partly controlled, with “7/26 (27%) remaining refractory to treatment.” This heterogeneity argues against treating a single seizure type or treatment course as defining for SETD1B-NDD.

Variant interpretation and genotype-phenotype evidence

The retrieved studies collectively report de novo missense, nonsense, and frameshift variants, plus rare inherited and biallelic observations in the expanded cohort. The 2021 study's convergence of segregation, domain location, protein modeling, functional assays, and methylation episignature is more informative than in-silico prediction alone.

Clear genotype-phenotype rules remain limited. The largest cohort noted male overrepresentation and greater severity but explicitly presented sex-linked susceptibility as speculation. Likewise, the available studies do not establish that a particular domain or variant class reliably predicts epilepsy, language regression, or intellectual-disability severity.

Treatment relevance

The retrieved corpus supports symptomatic seizure management but does not identify a validated disease-modifying therapy or a treatment that restores SETD1B-dependent chromatin regulation. It also does not establish one preferred antiseizure medication. The evidence instead emphasizes variable seizure types and variable treatment response. Clinical management recommendations in the disorder entry come primarily from GeneReviews, which Asta did not index in this run and which should be evaluated through the repository's cached reference rather than attributed to Asta.

Evidence boundaries and research gaps

  • Directly supported: heterozygous SETD1B variants cause a recognizable neurodevelopmental syndrome; loss of function is the leading mechanism; SETD1B participates in H3K4 methylation and transcriptional regulation; developmental impairment can precede epilepsy; epilepsy is variable, with recurrent myoclonic absences.
  • Supported but incompletely resolved: variant-specific functional effects, peripheral-blood methylation episignatures, and possible sex-related severity.
  • Mechanistic inference: reduced H3K4me3 in disease-relevant human neurons, specific dysregulated neuronal gene programs, hippocampal memory-circuit dysfunction, and cortical excitation/inhibition imbalance.
  • Key experimental gaps: patient-derived neuronal or brain-organoid chromatin profiling, cell-type-resolved transcriptional effects, electrophysiology that connects SETD1B loss to network hyperexcitability, longitudinal genotype-phenotype studies, and mechanism-guided therapeutic rescue.

Relevant papers

[1] De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism

  • PMID: 29322246
  • DOI: 10.1007/s00439-017-1863-y
  • Year / venue: 2018, Human Genetics
  • Asta paper: https://www.semanticscholar.org/paper/ce187267dfeebb671bc271c20207f0e830a6da3b
  • Asta citation count at retrieval: 69
  • Retrieval note: Asta returned metadata and a generated summary but withheld the publisher-elided abstract.

[2] A novel de novo frameshift variant in SETD1B causes epilepsy

  • PMID: 31110234
  • DOI: 10.1038/s10038-019-0617-1
  • Year / venue: 2019, Journal of Human Genetics
  • Asta paper: https://www.semanticscholar.org/paper/5ba138b33985cd70bbf8c073685ad8936e8ecf8b
  • Asta citation count at retrieval: 16
  • Retrieval note: Asta returned metadata and a generated summary but withheld the publisher-elided abstract.

[3] De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences

  • PMID: 31440728
  • PMCID: PMC6698685
  • DOI: 10.1002/epi4.12339
  • Year / venue: 2019, Epilepsia Open
  • Asta paper: https://www.semanticscholar.org/paper/ec992046d25ad045791449841ef944a42f78f2a3
  • Asta citation count at retrieval: 36
  • Retrieval contribution: detailed SETD1B domain rationale, the hypothesized H3K4me3-to-neurodevelopment link, and the characteristic myoclonic-absence electroclinical phenotype.

[4] SETD1B-associated neurodevelopmental disorder

  • PMID: 32546566
  • DOI: 10.1136/jmedgenet-2019-106756
  • Year / venue: 2020, Journal of Medical Genetics
  • Asta paper: https://www.semanticscholar.org/paper/fb5fee7d7d6e3d272ee889b47f3713c2084cf057
  • Asta citation count at retrieval: 35
  • Retrieval contribution: four-patient series supporting intellectual disability, language delay, musculoskeletal findings, and variably treatment-refractory seizures.

[5] Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

  • PMID: 34345025
  • PMCID: PMC8553606
  • DOI: 10.1038/s41436-021-01246-2
  • Year / venue: 2021, Genetics in Medicine
  • Asta paper: https://www.semanticscholar.org/paper/31db64baf9273aac9188052c80957f185c727806
  • Asta citation count at retrieval: 32
  • Retrieval contribution: largest cohort, functional and methylation studies, loss-of-function conclusion, phenotype expansion, developmental-before-seizure temporal evidence, seizure heterogeneity, and treatment-response estimate.

Existing reference not indexed by Asta

  • PMID:36173874 — SETD1B-Related Neurodevelopmental Disorder (GeneReviews). Asta returned “Paper with id PMID:36173874 not found.” It remains an important clinical baseline in the disorder entry, but no claim in this report is presented as an Asta retrieval from that record.