CDK8-Related Disorder

Mendelian MONDO:0032897 Pathograph 10 Show in embeddings browser Autosomal dominant intellectual disability Neurodevelopmental disorder CDK8-kinase module-associated disorder

CDK8-related disorder (IDDHBA) is a rare autosomal dominant neurodevelopmental disorder caused by heterozygous de novo missense variants in CDK8, which encodes the catalytic cyclin-dependent kinase of the CDK8 kinase module of the Mediator transcriptional coactivator complex. The kinase module is a dissociable four-subunit cap (a CDK8 or CDK19 kinase, cyclin C, a MED12 or MED12L scaffold, and a MED13 or MED13L subunit) that reversibly associates with core Mediator to gate RNA polymerase II transcription. Disease-causing CDK8 substitutions localize to the ATP-binding pocket of the kinase domain and act as hypomorphic/partial loss-of-function alleles that reduce phosphorylation of CDK8 substrates. Affected individuals have hypotonia, mild-to-moderate intellectual disability, behavioral abnormalities (autism spectrum disorder and/or ADHD), and variable facial dysmorphism, with congenital heart disease in roughly half and additional features including agenesis of the corpus callosum, ano-rectal malformations, seizures, and hearing loss.

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3
Pathophys.
7
Phenotypes
10
Pathograph
1
Genes
2
Medical Actions
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE NEUROLOGIC
⚙

Pathophysiology

3
CDK8 kinase module dysfunction
CDK8 is the catalytic kinase of the CDK8 kinase module (CKM), the dissociable regulatory cap of the Mediator complex. Disease-causing de novo missense variants cluster in the ATP-binding pocket of the kinase domain and behave as hypomorphic alleles, reducing phosphorylation of CDK8 substrates (e.g., STAT1-Ser727) and disrupting Mediator-dependent transcriptional regulation of developmental gene-expression programs. CDK8 belongs to the group of CDK8-kinase module-associated disease genes, alongside CDK19, MED12, MED12L, MED13, and MED13L.
CDK8 hgnc:1779 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CDK8 (hgnc:1779). hgnc:1779 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 Reduced CDK8 kinase activity disrupts Mediator-dependent transcription of neurodevelopmental gene-expression programs.
Cardiac and structural developmental dysregulation CKM dysfunction perturbs cardiac and other developmental programs, contributing to congenital heart disease and structural anomalies.
Show evidence (1 reference)
PMID:30905399 SUPPORT Human Clinical
"All predicted substitutions localize to the ATP-binding pocket of the kinase domain."
Localizes the pathogenic CDK8 substitutions to the kinase active site, supporting a kinase-activity loss mechanism.
Neurodevelopmental transcriptional dysregulation
Downstream of CDK8 kinase dysfunction, neuronal gene-expression programs are dysregulated during brain development, contributing to hypotonia, intellectual disability, and behavioral abnormalities.
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
Intellectual disability Disrupted neuronal developmental programs contribute to intellectual disability.
Hypotonia Disrupted neurodevelopmental programs contribute to hypotonia.
Behavioral abnormalities Neurodevelopmental transcriptional dysregulation contributes to autism spectrum disorder and ADHD.
Facial dysmorphism Disrupted craniofacial developmental programs contribute to variable facial dysmorphism.
Show evidence (1 reference)
PMID:30905399 SUPPORT Human Clinical
"Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism."
Documents the core neurodevelopmental phenotype downstream of CDK8 dysfunction.
Cardiac and structural developmental dysregulation
CDK8 kinase-module dysfunction perturbs cardiac and other developmental transcriptional programs, contributing to congenital heart disease (in about half of individuals) and additional structural anomalies including corpus callosum agenesis and ano-rectal malformations.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
heart morphogenesis GO:0003007 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated heart morphogenesis (GO:0003007). GO:0003007 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Congenital heart disease Perturbed cardiac transcriptional programs contribute to congenital heart disease.
Corpus callosum agenesis Disturbed midline/commissural morphogenesis contributes to agenesis of the corpus callosum.
Show evidence (1 reference)
PMID:30905399 SUPPORT Human Clinical
"Congenital heart disease occurred in six subjects; additional features present in multiple individuals included agenesis of the corpus callosum, ano-rectal malformations, seizures, and hearing"
Documents congenital heart disease and additional structural anomalies in the CDK8 cohort.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for CDK8-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

7
Cardiovascular 1
Congenital heart disease FREQUENT Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital heart defect, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT Human Clinical
"Congenital heart defects (CHDs) were present in six of the twelve subjects; the defects were classified"
Six of twelve cohort subjects (50%) had congenital heart defects, supporting the FREQUENT band.
Head and Neck 1
Facial dysmorphism 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:30905399 SUPPORT Human Clinical
"Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism."
Documents variable facial dysmorphism as a feature.
Musculoskeletal 1
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT Human Clinical
"Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism."
Documents hypotonia as a core feature.
Nervous System 4
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT Human Clinical
"Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism."
Documents mild-to-moderate intellectual disability as a core feature.
Behavioral abnormalities Atypical behavior HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Behavioral abnormality, annotated with Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT Human Clinical
"Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism."
Documents behavioral disorders as a core feature.
Corpus callosum agenesis Agenesis of corpus callosum HP:0001274 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Agenesis of corpus callosum (HP:0001274). HP:0001274 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT Human Clinical
"Congenital heart disease occurred in six subjects; additional features present in multiple individuals included agenesis of the corpus callosum, ano-rectal malformations, seizures, and hearing"
Documents agenesis of the corpus callosum among recurrent features.
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT Human Clinical
"Congenital heart disease occurred in six subjects; additional features present in multiple individuals included agenesis of the corpus callosum, ano-rectal malformations, seizures, and hearing"
Documents seizures among recurrent features in the cohort.
🧬

Genetic Associations

1
CDK8 de novo missense variants (Causative)
Gene: CDK8 hgnc:1779 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CDK8 (hgnc:1779). hgnc:1779 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal Dominant
Show evidence (1 reference)
PMID:30905399 SUPPORT Human Clinical
"All predicted substitutions localize to the ATP-binding pocket of the kinase domain."
Documents the clustering of pathogenic CDK8 variants in the kinase active site.
💊

Medical Actions

2
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, behavioral interventions, and cardiac and neurologic management as needed.
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; most cases are de novo, warranting recurrence-risk assessment and parental testing.
Show evidence (1 reference)
PMID:30905399 SUPPORT Human Clinical
"Here, using whole-exome or whole-genome sequencing and by international collaboration, we report de novo mutations in CDK8, which has not been previously associated with a congenital disorder, in 12 unrelated individuals with overlapping phenotypes."
The predominantly de novo occurrence of the CDK8 variants informs the low-recurrence counseling recommendation and parental testing.
📊

Prevalence

1
Worldwide
Cases In Literature <1 in 1,000,000
Ultra-rare. The syndrome-defining cohort comprised 12 individuals with 8 different de novo CDK8 variants; additional cases have since been reported. No population-based prevalence estimate is available.
Show evidence (1 reference)
PMID:30905399 SUPPORT Human Clinical
"All predicted substitutions localize to the ATP-binding pocket of the kinase domain."
Documents the mutational mechanism in the defining cohort establishing CDK8 as an ultra-rare disease gene.
{ }

Source YAML

click to show 
name: CDK8-Related Disorder
creation_date: '2026-07-31T00:00:00Z'
category: Mendelian
synonyms:
- Intellectual developmental disorder with hypotonia and behavioral abnormalities
- IDDHBA
- CDK8-associated neurodevelopmental disorder
- CDK8-related syndromic developmental disorder
description: >
  CDK8-related disorder (IDDHBA) is a rare autosomal dominant neurodevelopmental disorder
  caused by heterozygous de novo missense variants in CDK8, which encodes the catalytic
  cyclin-dependent kinase of the CDK8 kinase module of the Mediator transcriptional
  coactivator complex. The kinase module is a dissociable four-subunit cap (a CDK8 or CDK19
  kinase, cyclin C, a MED12 or MED12L scaffold, and a MED13 or MED13L subunit) that reversibly
  associates with core Mediator to gate RNA polymerase II transcription. Disease-causing CDK8
  substitutions localize to the ATP-binding pocket of the kinase domain and act as
  hypomorphic/partial loss-of-function alleles that reduce phosphorylation of CDK8 substrates.
  Affected individuals have hypotonia, mild-to-moderate intellectual disability, behavioral
  abnormalities (autism spectrum disorder and/or ADHD), and variable facial dysmorphism, with
  congenital heart disease in roughly half and additional features including agenesis of the
  corpus callosum, ano-rectal malformations, seizures, and hearing loss.
disease_term:
  preferred_term: Intellectual developmental disorder with hypotonia and behavioral abnormalities
  term:
    id: MONDO:0032897
    label: intellectual developmental disorder with hypotonia and behavioral abnormalities
parents:
- Autosomal dominant intellectual disability
- Neurodevelopmental disorder
- CDK8-kinase module-associated disorder
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:30905399
      reference_title: "De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we report CDK8 mutations (located at 13q12.13) that cause a phenotypically related disorder."
      explanation: Supports classification as a heritable genetic disorder caused by CDK8 variants.
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:30905399
      reference_title: "De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism."
      explanation: Supports classification as a neurodevelopmental / neurologic disorder.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Ultra-rare. The syndrome-defining cohort comprised 12 individuals with 8 different
    de novo CDK8 variants; additional cases have since been reported. No population-based
    prevalence estimate is available.
  evidence:
  - reference: PMID:30905399
    reference_title: "De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All predicted substitutions localize to the ATP-binding pocket of the kinase domain."
    explanation: Documents the mutational mechanism in the defining cohort establishing CDK8 as an ultra-rare disease gene.
pathophysiology:
- name: CDK8 kinase module dysfunction
  description: >
    CDK8 is the catalytic kinase of the CDK8 kinase module (CKM), the dissociable regulatory
    cap of the Mediator complex. Disease-causing de novo missense variants cluster in the
    ATP-binding pocket of the kinase domain and behave as hypomorphic alleles, reducing
    phosphorylation of CDK8 substrates (e.g., STAT1-Ser727) and disrupting Mediator-dependent
    transcriptional regulation of developmental gene-expression programs. CDK8 belongs to the
    group of CDK8-kinase module-associated disease genes, alongside CDK19, MED12, MED12L, MED13,
    and MED13L.
  genes:
  - preferred_term: CDK8
    term:
      id: hgnc:1779
      label: CDK8
  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:30905399
    reference_title: "De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All predicted substitutions localize to the ATP-binding pocket of the kinase domain."
    explanation: Localizes the pathogenic CDK8 substitutions to the kinase active site, supporting a kinase-activity loss mechanism.
  downstream:
  - target: Neurodevelopmental transcriptional dysregulation
    description: >-
      Reduced CDK8 kinase activity disrupts Mediator-dependent transcription of
      neurodevelopmental gene-expression programs.
  - target: Cardiac and structural developmental dysregulation
    description: >-
      CKM dysfunction perturbs cardiac and other developmental programs, contributing to
      congenital heart disease and structural anomalies.
- name: Neurodevelopmental transcriptional dysregulation
  description: >
    Downstream of CDK8 kinase dysfunction, neuronal gene-expression programs are dysregulated
    during brain development, contributing to hypotonia, intellectual disability, and behavioral
    abnormalities.
  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:30905399
    reference_title: "De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism."
    explanation: Documents the core neurodevelopmental phenotype downstream of CDK8 dysfunction.
  downstream:
  - target: Intellectual disability
    description: Disrupted neuronal developmental programs contribute to intellectual disability.
  - target: Hypotonia
    description: Disrupted neurodevelopmental programs contribute to hypotonia.
  - target: Behavioral abnormalities
    description: Neurodevelopmental transcriptional dysregulation contributes to autism spectrum disorder and ADHD.
  - target: Facial dysmorphism
    description: Disrupted craniofacial developmental programs contribute to variable facial dysmorphism.
- name: Cardiac and structural developmental dysregulation
  description: >
    CDK8 kinase-module dysfunction perturbs cardiac and other developmental transcriptional
    programs, contributing to congenital heart disease (in about half of individuals) and
    additional structural anomalies including corpus callosum agenesis and ano-rectal
    malformations.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: heart morphogenesis
    term:
      id: GO:0003007
      label: heart morphogenesis
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:30905399
    reference_title: "De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital heart disease occurred in six subjects; additional features present in multiple individuals included agenesis of the corpus callosum, ano-rectal malformations, seizures, and hearing"
    explanation: Documents congenital heart disease and additional structural anomalies in the CDK8 cohort.
  downstream:
  - target: Congenital heart disease
    description: Perturbed cardiac transcriptional programs contribute to congenital heart disease.
  - target: Corpus callosum agenesis
    description: Disturbed midline/commissural morphogenesis contributes to agenesis of the corpus callosum.
phenotypes:
# frequency: bands omitted where the source gives only undifferentiated
# narrative support (per docs/frequency-evidence-guidelines.md); retained only
# where a count or all-patients statement in the cited snippet backs a band.
- category: Clinical
  name: Intellectual disability
  description: >
    Mild-to-moderate intellectual disability is a core feature of CDK8-related disorder.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:30905399
    reference_title: "De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism."
    explanation: Documents mild-to-moderate intellectual disability as a core feature.
- category: Clinical
  name: Hypotonia
  description: >
    Infantile hypotonia is a common feature of CDK8-related disorder.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:30905399
    reference_title: "De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism."
    explanation: Documents hypotonia as a core feature.
- category: Behavioral
  name: Behavioral abnormalities
  description: >
    Behavioral abnormalities including autism spectrum disorder and/or ADHD are common,
    particularly in older individuals.
  phenotype_term:
    preferred_term: Behavioral abnormality
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:30905399
    reference_title: "De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism."
    explanation: Documents behavioral disorders as a core feature.
- category: Clinical
  name: Facial dysmorphism
  description: >
    Variable, non-specific facial dysmorphism is reported in CDK8-related disorder.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:30905399
    reference_title: "De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism."
    explanation: Documents variable facial dysmorphism as a feature.
- category: Cardiovascular
  name: Congenital heart disease
  frequency: FREQUENT
  description: >
    Congenital heart disease occurred in about half of individuals in the defining cohort.
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:30905399
    reference_title: "De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital heart defects (CHDs) were present in six of the twelve subjects; the defects were classified"
    explanation: Six of twelve cohort subjects (50%) had congenital heart defects, supporting the FREQUENT band.
- category: Clinical
  name: Corpus callosum agenesis
  description: >
    Agenesis of the corpus callosum is reported in multiple individuals.
  phenotype_term:
    preferred_term: Agenesis of corpus callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
  evidence:
  - reference: PMID:30905399
    reference_title: "De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital heart disease occurred in six subjects; additional features present in multiple individuals included agenesis of the corpus callosum, ano-rectal malformations, seizures, and hearing"
    explanation: Documents agenesis of the corpus callosum among recurrent features.
- category: Clinical
  name: Seizures
  description: >
    Seizures are reported in a subset of individuals.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:30905399
    reference_title: "De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital heart disease occurred in six subjects; additional features present in multiple individuals included agenesis of the corpus callosum, ano-rectal malformations, seizures, and hearing"
    explanation: Documents seizures among recurrent features in the cohort.
genetic:
- name: CDK8 de novo missense variants
  association: Causative
  gene_term:
    preferred_term: CDK8
    term:
      id: hgnc:1779
      label: CDK8
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:30905399
      reference_title: "De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Here, using whole-exome or whole-genome sequencing and by international collaboration, we report de novo mutations in CDK8, which has not been previously associated with a congenital disorder, in 12 unrelated individuals with overlapping phenotypes."
      explanation: Heterozygous de novo CDK8 missense variants are consistent with autosomal dominant inheritance.
  features: >
    Heterozygous de novo missense variants clustered in the ATP-binding pocket of the CDK8
    kinase domain, acting as hypomorphic/partial loss-of-function alleles.
  evidence:
  - reference: PMID:30905399
    reference_title: "De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All predicted substitutions localize to the ATP-binding pocket of the kinase domain."
    explanation: Documents the clustering of pathogenic CDK8 variants in the kinase active site.
treatments:
- name: Supportive Care
  description: >
    Multidisciplinary supportive care including developmental therapies, behavioral
    interventions, and cardiac and neurologic management as needed.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Genetic Counseling
  description: >
    Genetic counseling is recommended; most cases are de novo, warranting recurrence-risk
    assessment and parental testing.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:30905399
    reference_title: "De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, using whole-exome or whole-genome sequencing and by international collaboration, we report de novo mutations in CDK8, which has not been previously associated with a congenital disorder, in 12 unrelated individuals with overlapping phenotypes."
    explanation: The predominantly de novo occurrence of the CDK8 variants informs the low-recurrence counseling recommendation and parental testing.