CDK19-Related Disorder

Mendelian MONDO:0030059 Pathograph 7 Show in embeddings browser Autosomal dominant intellectual disability Neurodevelopmental disorder CDK8-kinase module-associated disorder

CDK19-related disorder (developmental and epileptic encephalopathy 87, DEE87) is a rare autosomal dominant neurodevelopmental disorder caused by heterozygous de novo missense variants in CDK19, which encodes a cyclin-dependent kinase that is the paralog of CDK8 and serves as an alternative catalytic kinase of the CDK8 kinase module of the Mediator transcriptional coactivator complex. This is the most epilepsy-predominant of the Mediator kinase-module disorders: affected individuals present with hypotonia, global developmental delay, epileptic encephalopathy (including infantile spasms), and dysmorphic features. Both loss-of-function and gain-of-function mechanisms have been reported for different alleles. The gene-disease relationship was established with Drosophila rescue and overexpression assays, in which human CDK19 rescues loss of the fly homolog Cdk8.

Ask OpenScientist

Ask a research question about CDK19-Related Disorder. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

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

2
Pathophys.
6
Phenotypes
7
Pathograph
1
Genes
3
Medical Actions
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE NEUROLOGIC
⚙

Pathophysiology

2
CDK19 kinase module dysfunction
CDK19 is a cyclin-dependent kinase and the paralog of CDK8, serving as an alternative catalytic kinase of the CDK8 kinase module (CKM) of the Mediator complex, which predominantly regulates gene transcription. De novo missense variants in the kinase domain disrupt CKM-dependent transcriptional regulation; different alleles act through loss-of- or gain-of-function mechanisms. CDK19 belongs to the group of CDK8-kinase module-associated disease genes, alongside CDK8, MED12, MED12L, MED13, and MED13L.
CDK19 hgnc:19338 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CDK19 (hgnc:19338). hgnc:19338 is a gene from the HUGO Gene Nomenclature Committee.
transcription by RNA polymerase II GO:0006366 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves transcription by RNA polymerase II (GO:0006366). GO:0006366 is a biological process from the Gene Ontology. regulation of gene expression GO:0010468 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated regulation of gene expression (GO:0010468). GO:0010468 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Neurodevelopmental transcriptional dysregulation CDK19 kinase dysfunction disrupts Mediator-dependent transcription of neurodevelopmental gene-expression programs, producing an epilepsy-predominant phenotype.
Show evidence (2 references)
PMID:32330417 SUPPORT Human Clinical
"We identified three unrelated individuals with de novo missense variants in CDK19, encoding a cyclin-dependent kinase protein family member that"
Establishes CDK19 as a Mediator kinase-module cyclin-dependent kinase disrupted by de novo variants.
PMID:32330417 SUPPORT Model Organism
"The few eclosing flies exhibit severe seizures and a reduced lifespan."
Drosophila knockdown recapitulates a seizure phenotype, supporting a conserved role for CDK19/Cdk8 in neuronal function.
Neurodevelopmental transcriptional dysregulation
Downstream of CDK19 kinase-module dysfunction, neuronal gene-expression programs are dysregulated during brain development, contributing to hypotonia, global developmental delay, and a prominent epileptic encephalopathy with dysmorphic features.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
regulation of neuron differentiation GO:0045664 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated regulation of neuron differentiation (GO:0045664). GO:0045664 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Global developmental delay Disrupted neuronal developmental programs contribute to global developmental delay.
Epileptic encephalopathy Disrupted cortical network excitability produces a prominent epileptic encephalopathy.
Hypotonia Disrupted neurodevelopmental programs contribute to hypotonia.
Dysmorphic features Disrupted craniofacial developmental programs contribute to dysmorphic features.
Show evidence (1 reference)
PMID:32330417 SUPPORT Human Clinical
"These individuals presented with hypotonia, global developmental delay, epileptic encephalopathy, and dysmorphic features."
Documents the core neurodevelopmental phenotype downstream of CDK19 dysfunction.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for CDK19-Related Disorder Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

6
Head and Neck 1
Dysmorphic features VERY_FREQUENT Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33495529 SUPPORT Human Clinical
"universal developmental delay and facial dysmorphism"
Quantitative cohort documents facial dysmorphism as universal, supporting the VERY_FREQUENT band.
Musculoskeletal 1
Hypotonia FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33495529 SUPPORT Human Clinical
"hypotonia (79%), seizures (64%), ophthalmologic anomalies (64%), and autism/autistic traits (56%)"
Quantitative cohort reports hypotonia in 79% of individuals, supporting the FREQUENT band.
Nervous System 2
Global developmental delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33495529 SUPPORT Human Clinical
"universal developmental delay and facial dysmorphism"
Quantitative 14-individual cohort documents developmental delay as universal, supporting the VERY_FREQUENT band.
Autistic behavior FREQUENT HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33495529 SUPPORT Human Clinical
"hypotonia (79%), seizures (64%), ophthalmologic anomalies (64%), and autism/autistic traits (56%)"
Quantitative cohort reports autism/autistic traits in 56% of individuals, supporting the FREQUENT band.
Other 2
Epileptic encephalopathy FREQUENT HP:0200134 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epileptic encephalopathy (HP:0200134). HP:0200134 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33495529 SUPPORT Human Clinical
"hypotonia (79%), seizures (64%), ophthalmologic anomalies (64%), and autism/autistic traits (56%)"
Quantitative cohort reports seizures in 64% of individuals, supporting the FREQUENT band.
PMID:33568421 SUPPORT Human Clinical
"We report a fifth affected individual, a 10-mo-old male patient who presented with a neurodevelopmental syndrome characterized by infantile spasms."
Documents infantile spasms as a form of the CDK19-related epileptic encephalopathy.
Ophthalmologic anomalies FREQUENT Abnormality of the eye HP:0000478 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the eye (HP:0000478). HP:0000478 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33495529 SUPPORT Human Clinical
"hypotonia (79%), seizures (64%), ophthalmologic anomalies (64%), and autism/autistic traits (56%)"
Quantitative cohort reports ophthalmologic anomalies in 64% of individuals, supporting the FREQUENT band.
🧬

Genetic Associations

1
CDK19 de novo missense variants (Causative)
Gene: CDK19 hgnc:19338 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CDK19 (hgnc:19338). hgnc:19338 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal Dominant
Show evidence (2 references)
PMID:32330417 SUPPORT Model Organism
"Loss of Cdk8, the fly homolog of CDK19, causes larval lethality, which is suppressed by expression of human CDK19 reference cDNA."
Cross-species rescue establishes functional conservation and supports the CDK19 gene-disease relationship.
PMID:33495529 SUPPORT In Vitro
"kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein."
Autophosphorylation assays show recurrent CDK19 variants act through both loss-of-function (Gly28Arg) and gain-of-function (Tyr32His) mechanisms, supporting the mixed-mechanism statement.
💊

Medical Actions

3
Antiseizure Pharmacotherapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: anticonvulsant agent NCIT:C264 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses anticonvulsant agent (NCIT:C264). NCIT:C264 is a therapeutic agent from the NCI Thesaurus.
Antiseizure medication is central to management given the predominant epileptic encephalopathy, including infantile spasms.
Supportive Care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Multidisciplinary supportive care including developmental therapies and neurologic management.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Genetic counseling is recommended; cases are de novo, warranting recurrence-risk assessment.
Show evidence (1 reference)
PMID:32330417 SUPPORT Human Clinical
"We identified three unrelated individuals with de novo missense variants in CDK19"
The de novo occurrence of the CDK19 variants informs the low-recurrence counseling recommendation.
📊

Prevalence

1
Worldwide
Cases In Literature <1 in 1,000,000
Ultra-rare. The syndrome-defining report described three unrelated individuals; subsequent reports have expanded the cohort. No population-based prevalence estimate is available.
Show evidence (1 reference)
PMID:32330417 SUPPORT Human Clinical
"We identified three unrelated individuals with de novo missense variants in CDK19"
Documents the small defining cohort establishing CDK19 as an ultra-rare disease gene.
{ }

Source YAML

click to show 
name: CDK19-Related Disorder
creation_date: '2026-07-31T00:00:00Z'
category: Mendelian
synonyms:
- Developmental and epileptic encephalopathy 87
- DEE87
- CDK19-related developmental and epileptic encephalopathy
- CDK19-associated neurodevelopmental disorder
description: >
  CDK19-related disorder (developmental and epileptic encephalopathy 87, DEE87) is a rare
  autosomal dominant neurodevelopmental disorder caused by heterozygous de novo missense
  variants in CDK19, which encodes a cyclin-dependent kinase that is the paralog of CDK8 and
  serves as an alternative catalytic kinase of the CDK8 kinase module of the Mediator
  transcriptional coactivator complex. This is the most epilepsy-predominant of the Mediator
  kinase-module disorders: affected individuals present with hypotonia, global developmental
  delay, epileptic encephalopathy (including infantile spasms), and dysmorphic features. Both
  loss-of-function and gain-of-function mechanisms have been reported for different alleles.
  The gene-disease relationship was established with Drosophila rescue and overexpression
  assays, in which human CDK19 rescues loss of the fly homolog Cdk8.
disease_term:
  preferred_term: Developmental and epileptic encephalopathy 87
  term:
    id: MONDO:0030059
    label: developmental and epileptic encephalopathy, 87
parents:
- Autosomal dominant intellectual disability
- Neurodevelopmental disorder
- CDK8-kinase module-associated disorder
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:32330417
      reference_title: "De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We identified three unrelated individuals with de novo missense variants in CDK19"
      explanation: Supports classification as a heritable genetic disorder caused by de novo CDK19 variants.
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:32330417
      reference_title: "De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These individuals presented with hypotonia, global developmental delay, epileptic encephalopathy, and dysmorphic features."
      explanation: Supports classification as a neurodevelopmental / neurologic disorder with epileptic encephalopathy.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Ultra-rare. The syndrome-defining report described three unrelated individuals;
    subsequent reports have expanded the cohort. No population-based prevalence estimate
    is available.
  evidence:
  - reference: PMID:32330417
    reference_title: "De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified three unrelated individuals with de novo missense variants in CDK19"
    explanation: Documents the small defining cohort establishing CDK19 as an ultra-rare disease gene.
pathophysiology:
- name: CDK19 kinase module dysfunction
  description: >
    CDK19 is a cyclin-dependent kinase and the paralog of CDK8, serving as an alternative
    catalytic kinase of the CDK8 kinase module (CKM) of the Mediator complex, which
    predominantly regulates gene transcription. De novo missense variants in the kinase domain
    disrupt CKM-dependent transcriptional regulation; different alleles act through loss-of- or
    gain-of-function mechanisms. CDK19 belongs to the group of CDK8-kinase module-associated
    disease genes, alongside CDK8, MED12, MED12L, MED13, and MED13L.
  genes:
  - preferred_term: CDK19
    term:
      id: hgnc:19338
      label: CDK19
  biological_processes:
  - preferred_term: transcription by RNA polymerase II
    term:
      id: GO:0006366
      label: transcription by RNA polymerase II
  - preferred_term: regulation of gene expression
    term:
      id: GO:0010468
      label: regulation of gene expression
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:32330417
    reference_title: "De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified three unrelated individuals with de novo missense variants in CDK19, encoding a cyclin-dependent kinase protein family member that"
    explanation: Establishes CDK19 as a Mediator kinase-module cyclin-dependent kinase disrupted by de novo variants.
  - reference: PMID:32330417
    reference_title: "De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The few eclosing flies exhibit severe seizures and a reduced lifespan."
    explanation: Drosophila knockdown recapitulates a seizure phenotype, supporting a conserved role for CDK19/Cdk8 in neuronal function.
  downstream:
  - target: Neurodevelopmental transcriptional dysregulation
    description: >-
      CDK19 kinase dysfunction disrupts Mediator-dependent transcription of neurodevelopmental
      gene-expression programs, producing an epilepsy-predominant phenotype.
- name: Neurodevelopmental transcriptional dysregulation
  description: >
    Downstream of CDK19 kinase-module dysfunction, neuronal gene-expression programs are
    dysregulated during brain development, contributing to hypotonia, global developmental
    delay, and a prominent epileptic encephalopathy with dysmorphic features.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: regulation of neuron differentiation
    term:
      id: GO:0045664
      label: regulation of neuron differentiation
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:32330417
    reference_title: "De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These individuals presented with hypotonia, global developmental delay, epileptic encephalopathy, and dysmorphic features."
    explanation: Documents the core neurodevelopmental phenotype downstream of CDK19 dysfunction.
  downstream:
  - target: Global developmental delay
    description: Disrupted neuronal developmental programs contribute to global developmental delay.
  - target: Epileptic encephalopathy
    description: Disrupted cortical network excitability produces a prominent epileptic encephalopathy.
  - target: Hypotonia
    description: Disrupted neurodevelopmental programs contribute to hypotonia.
  - target: Dysmorphic features
    description: Disrupted craniofacial developmental programs contribute to dysmorphic features.
phenotypes:
# Frequency bands are taken from the quantitative 14-individual cohort in PMID:33495529
# (universal developmental delay and facial dysmorphism; hypotonia 79%, seizures 64%,
# ophthalmologic anomalies 64%, autism/autistic traits 56%), not from the undifferentiated
# 3-individual narrative in PMID:32330417.
- category: Clinical
  name: Global developmental delay
  frequency: VERY_FREQUENT
  description: >
    Developmental delay is a universal feature of CDK19-related disorder.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:33495529
    reference_title: "CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "universal developmental delay and facial dysmorphism"
    explanation: Quantitative 14-individual cohort documents developmental delay as universal, supporting the VERY_FREQUENT band.
- category: Clinical
  name: Dysmorphic features
  frequency: VERY_FREQUENT
  description: >
    Facial dysmorphism is a universal feature of CDK19-related disorder.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:33495529
    reference_title: "CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "universal developmental delay and facial dysmorphism"
    explanation: Quantitative cohort documents facial dysmorphism as universal, supporting the VERY_FREQUENT band.
- category: Clinical
  name: Epileptic encephalopathy
  frequency: FREQUENT
  description: >
    Epileptic encephalopathy, including infantile spasms, is the predominant clinical feature.
    Seizures were reported in 64% of the quantitative cohort.
  phenotype_term:
    preferred_term: Epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  evidence:
  - reference: PMID:33495529
    reference_title: "CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypotonia (79%), seizures (64%), ophthalmologic anomalies (64%), and autism/autistic traits (56%)"
    explanation: Quantitative cohort reports seizures in 64% of individuals, supporting the FREQUENT band.
  - reference: PMID:33568421
    reference_title: "A novel variant of CDK19 causes a severe neurodevelopmental disorder with infantile spasms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a fifth affected individual, a 10-mo-old male patient who presented with a neurodevelopmental syndrome characterized by infantile spasms."
    explanation: Documents infantile spasms as a form of the CDK19-related epileptic encephalopathy.
- category: Clinical
  name: Hypotonia
  frequency: FREQUENT
  description: >
    Hypotonia was reported in 79% of the quantitative cohort.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:33495529
    reference_title: "CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypotonia (79%), seizures (64%), ophthalmologic anomalies (64%), and autism/autistic traits (56%)"
    explanation: Quantitative cohort reports hypotonia in 79% of individuals, supporting the FREQUENT band.
- category: Behavioral
  name: Autistic behavior
  frequency: FREQUENT
  description: >
    Autism/autistic traits were reported in 56% of the quantitative cohort.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:33495529
    reference_title: "CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypotonia (79%), seizures (64%), ophthalmologic anomalies (64%), and autism/autistic traits (56%)"
    explanation: Quantitative cohort reports autism/autistic traits in 56% of individuals, supporting the FREQUENT band.
- category: Ophthalmologic
  name: Ophthalmologic anomalies
  frequency: FREQUENT
  description: >
    Ophthalmologic anomalies were reported in 64% of the quantitative cohort.
  phenotype_term:
    preferred_term: Abnormality of the eye
    term:
      id: HP:0000478
      label: Abnormality of the eye
  evidence:
  - reference: PMID:33495529
    reference_title: "CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypotonia (79%), seizures (64%), ophthalmologic anomalies (64%), and autism/autistic traits (56%)"
    explanation: Quantitative cohort reports ophthalmologic anomalies in 64% of individuals, supporting the FREQUENT band.
genetic:
- name: CDK19 de novo missense variants
  association: Causative
  gene_term:
    preferred_term: CDK19
    term:
      id: hgnc:19338
      label: CDK19
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:32330417
      reference_title: "De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We identified three unrelated individuals with de novo missense variants in CDK19"
      explanation: Heterozygous de novo CDK19 missense variants are consistent with autosomal dominant inheritance.
  features: >
    Heterozygous de novo kinase-domain missense variants; both loss-of-function and
    gain-of-function mechanisms have been reported for different alleles.
  evidence:
  - reference: PMID:32330417
    reference_title: "De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Loss of Cdk8, the fly homolog of CDK19, causes larval lethality, which is suppressed by expression of human CDK19 reference cDNA."
    explanation: Cross-species rescue establishes functional conservation and supports the CDK19 gene-disease relationship.
  - reference: PMID:33495529
    reference_title: "CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein."
    explanation: Autophosphorylation assays show recurrent CDK19 variants act through both loss-of-function (Gly28Arg) and gain-of-function (Tyr32His) mechanisms, supporting the mixed-mechanism statement.
treatments:
- name: Antiseizure Pharmacotherapy
  description: >
    Antiseizure medication is central to management given the predominant epileptic
    encephalopathy, including infantile spasms.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anticonvulsant agent
      term:
        id: NCIT:C264
        label: Anticonvulsant Agent
- name: Supportive Care
  description: >
    Multidisciplinary supportive care including developmental therapies and neurologic
    management.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Genetic Counseling
  description: >
    Genetic counseling is recommended; cases are de novo, warranting recurrence-risk assessment.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:32330417
    reference_title: "De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified three unrelated individuals with de novo missense variants in CDK19"
    explanation: The de novo occurrence of the CDK19 variants informs the low-recurrence counseling recommendation.