Nizon-Isidor Syndrome

Mendelian MONDO:0030030 Pathograph 7 Show in embeddings browser Autosomal dominant intellectual disability Neurodevelopmental disorder CDK8-kinase module-associated disorder

Nizon-Isidor syndrome (NIZIDS) is a rare autosomal dominant neurodevelopmental disorder caused by heterozygous, predominantly de novo variants in MED12L, the autosomal paralog of the MED12 scaffold subunit of the CDK8 kinase module of the Mediator transcriptional coactivator complex. Variants (deletions, duplications, and single-nucleotide variants) act through haploinsufficiency and produce a demonstrable transcriptional defect in patient fibroblasts. All affected individuals present with intellectual disability and/or developmental delay including speech impairment; other features include autism spectrum disorder, aggressive behavior, corpus callosum abnormality, and mild facial morphological features. MED12L belongs to the group of CDK8-kinase module-associated disease genes, alongside MED12, MED13, MED13L, CDK8, and CDK19.

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

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE NEUROLOGIC
⚙

Pathophysiology

2
MED12L kinase-module haploinsufficiency
MED12L is the autosomal paralog of the MED12 scaffold in the CDK8 kinase module (CKM) of the Mediator complex. Heterozygous, predominantly de novo variants act through haploinsufficiency to disrupt CKM-dependent transcription; patient fibroblasts show a transcriptional defect (impaired recovery of RNA synthesis after UV irradiation), similar to that seen in MED12 and milder than in MED13L cells. MED12L belongs to the group of CDK8-kinase module-associated disease genes.
MED12L hgnc:16050 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MED12L (hgnc:16050). hgnc:16050 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 CKM haploinsufficiency disrupts Mediator-dependent transcription of neurodevelopmental gene-expression programs.
Show evidence (1 reference)
PMID:31155615 SUPPORT In Vitro
"MED12L fibroblasts for individual 1 and 2 show a defect in transcriptional activity as measured by recovery of RNA synthesis after UV irradiation."
Establishes a demonstrable transcriptional defect in patient fibroblasts as the disease mechanism.
Neurodevelopmental transcriptional dysregulation
Downstream of MED12L kinase-module haploinsufficiency, neurodevelopmental gene-expression programs are dysregulated, producing intellectual disability and/or developmental delay with speech impairment, autism spectrum disorder, aggressive behavior, corpus callosum abnormality, and mild facial morphological 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
Intellectual disability Disrupted neuronal developmental programs contribute to intellectual disability.
Delayed speech and language development Language acquisition is impaired downstream of neurodevelopmental transcriptional dysregulation.
Autism spectrum disorder Neurodevelopmental transcriptional dysregulation contributes to autism spectrum disorder.
Corpus callosum abnormality Disturbed midline/commissural morphogenesis contributes to corpus callosum abnormality.
Show evidence (1 reference)
PMID:31155615 SUPPORT Human Clinical
"Other features included autism spectrum disorder, aggressive behavior, corpus callosum abnormality, and mild facial morphological features."
Documents the neurobehavioral and structural features downstream of MED12L dysfunction.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Nizon-Isidor Syndrome 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
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:31155615 SUPPORT Human Clinical
"Other features included autism spectrum disorder, aggressive behavior, corpus callosum abnormality, and mild facial morphological features."
Documents mild facial morphological features as a reported feature.
Nervous System 5
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:31155615 SUPPORT Human Clinical
"All affected individuals presented with intellectual disability and/or developmental delay, including speech impairment."
Documents intellectual disability/developmental delay in affected individuals; the and/or disjunction does not fix a per-feature frequency, so no band is asserted.
Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31155615 SUPPORT Human Clinical
"All affected individuals presented with intellectual disability and/or developmental delay, including speech impairment."
Documents speech impairment as a prominent feature.
Autism spectrum disorder Autistic behavior 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:31155615 SUPPORT Human Clinical
"Other features included autism spectrum disorder, aggressive behavior, corpus callosum abnormality, and mild facial morphological features."
Documents autism spectrum disorder as a reported feature.
Aggressive behavior HP:0000718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aggressive behavior (HP:0000718). HP:0000718 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31155615 SUPPORT Human Clinical
"Other features included autism spectrum disorder, aggressive behavior, corpus callosum abnormality, and mild facial morphological features."
Documents aggressive behavior as a reported feature.
Corpus callosum abnormality Abnormal corpus callosum morphology HP:0001273 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal corpus callosum morphology (HP:0001273). HP:0001273 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31155615 SUPPORT Human Clinical
"Other features included autism spectrum disorder, aggressive behavior, corpus callosum abnormality, and mild facial morphological features."
Documents corpus callosum abnormality as a reported feature.
🧬

Genetic Associations

1
MED12L haploinsufficiency (Causative)
Gene: MED12L hgnc:16050 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MED12L (hgnc:16050). hgnc:16050 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal Dominant
Show evidence (1 reference)
PMID:31155615 SUPPORT Human Clinical
"Three individuals had a MED12L deletion or duplication."
Documents the copy-number and point-variant spectrum of MED12L disease alleles.
💊

Medical Actions

3
Speech and Language Therapy
Action: speech therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is speech therapy, annotated with Speech Language Therapy (NCIT:C159273). NCIT:C159273 is a clinical intervention from the NCI Thesaurus. Ontology label: Speech Language Therapy NCIT:C159273
Speech and language therapy addresses the prominent speech impairment.
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 and behavioral interventions.
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.
Show evidence (1 reference)
PMID:31155615 SUPPORT Human Clinical
"Overall data suggest that MED12L haploinsufficiency is responsible for intellectual disability and transcriptional defect."
The identified single-locus MED12L haploinsufficiency mechanism is the genetic basis that warrants recurrence-risk counseling.
📊

Prevalence

1
Worldwide
Cases In Literature <1 in 1,000,000
Ultra-rare. The syndrome-defining report described seven individuals from seven families; subsequent case series have added further individuals (~a dozen published). No population-based prevalence estimate is available.
Show evidence (1 reference)
PMID:31155615 SUPPORT Human Clinical
"we report here the involvement of MED12L in human disease as has been seen for other subunits of the kinase module of the mediator complex, through transcriptional defect."
Establishes MED12L as an ultra-rare Mediator kinase-module disease gene.
{ }

Source YAML

click to show 
name: Nizon-Isidor Syndrome
creation_date: '2026-07-31T00:00:00Z'
category: Mendelian
synonyms:
- NIZIDS
- MED12L-related intellectual disability
- MED12L-related neurodevelopmental disorder
description: >
  Nizon-Isidor syndrome (NIZIDS) is a rare autosomal dominant neurodevelopmental disorder
  caused by heterozygous, predominantly de novo variants in MED12L, the autosomal paralog of the
  MED12 scaffold subunit of the CDK8 kinase module of the Mediator transcriptional coactivator
  complex. Variants (deletions, duplications, and single-nucleotide variants) act through
  haploinsufficiency and produce a demonstrable transcriptional defect in patient fibroblasts.
  All affected individuals present with intellectual disability and/or developmental delay
  including speech impairment; other features include autism spectrum disorder, aggressive
  behavior, corpus callosum abnormality, and mild facial morphological features. MED12L belongs
  to the group of CDK8-kinase module-associated disease genes, alongside MED12, MED13, MED13L,
  CDK8, and CDK19.
disease_term:
  preferred_term: Nizon-Isidor syndrome
  term:
    id: MONDO:0030030
    label: Nizon-Isidor syndrome
parents:
- Autosomal dominant intellectual disability
- Neurodevelopmental disorder
- CDK8-kinase module-associated disorder
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:31155615
      reference_title: "Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We describe an international cohort of seven affected individuals harboring variants involving MED12L identified by array CGH, exome or genome sequencing."
      explanation: Supports classification as a heritable genetic disorder caused by MED12L variants.
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:31155615
      reference_title: "Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All affected individuals presented with intellectual disability and/or developmental delay, including speech impairment."
      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 report described seven individuals from seven families;
    subsequent case series have added further individuals (~a dozen published). No
    population-based prevalence estimate is available.
  evidence:
  - reference: PMID:31155615
    reference_title: "Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report here the involvement of MED12L in human disease as has been seen for other subunits of the kinase module of the mediator complex, through transcriptional defect."
    explanation: Establishes MED12L as an ultra-rare Mediator kinase-module disease gene.
pathophysiology:
- name: MED12L kinase-module haploinsufficiency
  description: >
    MED12L is the autosomal paralog of the MED12 scaffold in the CDK8 kinase module (CKM) of the
    Mediator complex. Heterozygous, predominantly de novo variants act through haploinsufficiency
    to disrupt CKM-dependent transcription; patient fibroblasts show a transcriptional defect
    (impaired recovery of RNA synthesis after UV irradiation), similar to that seen in MED12 and
    milder than in MED13L cells. MED12L belongs to the group of CDK8-kinase module-associated
    disease genes.
  genes:
  - preferred_term: MED12L
    term:
      id: hgnc:16050
      label: MED12L
  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:31155615
    reference_title: "Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "MED12L fibroblasts for individual 1 and 2 show a defect in transcriptional activity as measured by recovery of RNA synthesis after UV irradiation."
    explanation: Establishes a demonstrable transcriptional defect in patient fibroblasts as the disease mechanism.
  downstream:
  - target: Neurodevelopmental transcriptional dysregulation
    description: >-
      CKM haploinsufficiency disrupts Mediator-dependent transcription of neurodevelopmental
      gene-expression programs.
- name: Neurodevelopmental transcriptional dysregulation
  description: >
    Downstream of MED12L kinase-module haploinsufficiency, neurodevelopmental gene-expression
    programs are dysregulated, producing intellectual disability and/or developmental delay with
    speech impairment, autism spectrum disorder, aggressive behavior, corpus callosum
    abnormality, and mild facial morphological 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:31155615
    reference_title: "Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other features included autism spectrum disorder, aggressive behavior, corpus callosum abnormality, and mild facial morphological features."
    explanation: Documents the neurobehavioral and structural features downstream of MED12L dysfunction.
  downstream:
  - target: Intellectual disability
    description: Disrupted neuronal developmental programs contribute to intellectual disability.
  - target: Delayed speech and language development
    description: Language acquisition is impaired downstream of neurodevelopmental transcriptional dysregulation.
  - target: Autism spectrum disorder
    description: Neurodevelopmental transcriptional dysregulation contributes to autism spectrum disorder.
  - target: Corpus callosum abnormality
    description: Disturbed midline/commissural morphogenesis contributes to corpus callosum abnormality.
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: >
    Intellectual disability and/or developmental delay is present in all affected individuals.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:31155615
    reference_title: "Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals presented with intellectual disability and/or developmental delay, including speech impairment."
    explanation: Documents intellectual disability/developmental delay in affected individuals; the and/or disjunction does not fix a per-feature frequency, so no band is asserted.
- category: Clinical
  name: Delayed speech and language development
  description: >
    Speech impairment is a prominent developmental feature.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:31155615
    reference_title: "Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals presented with intellectual disability and/or developmental delay, including speech impairment."
    explanation: Documents speech impairment as a prominent feature.
- category: Behavioral
  name: Autism spectrum disorder
  description: >
    Autism spectrum disorder is a reported neurobehavioral feature.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:31155615
    reference_title: "Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other features included autism spectrum disorder, aggressive behavior, corpus callosum abnormality, and mild facial morphological features."
    explanation: Documents autism spectrum disorder as a reported feature.
- category: Behavioral
  name: Aggressive behavior
  description: >
    Aggressive behavior is a reported neurobehavioral feature.
  phenotype_term:
    preferred_term: Aggressive behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  evidence:
  - reference: PMID:31155615
    reference_title: "Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other features included autism spectrum disorder, aggressive behavior, corpus callosum abnormality, and mild facial morphological features."
    explanation: Documents aggressive behavior as a reported feature.
- category: Neurologic
  name: Corpus callosum abnormality
  description: >
    Corpus callosum abnormality is reported in a subset of individuals.
  phenotype_term:
    preferred_term: Abnormal corpus callosum morphology
    term:
      id: HP:0001273
      label: Abnormal corpus callosum morphology
  evidence:
  - reference: PMID:31155615
    reference_title: "Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other features included autism spectrum disorder, aggressive behavior, corpus callosum abnormality, and mild facial morphological features."
    explanation: Documents corpus callosum abnormality as a reported feature.
- category: Craniofacial
  name: Facial dysmorphism
  description: >
    Mild facial morphological features are common but non-specific.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:31155615
    reference_title: "Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other features included autism spectrum disorder, aggressive behavior, corpus callosum abnormality, and mild facial morphological features."
    explanation: Documents mild facial morphological features as a reported feature.
genetic:
- name: MED12L haploinsufficiency
  association: Causative
  gene_term:
    preferred_term: MED12L
    term:
      id: hgnc:16050
      label: MED12L
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:31155615
      reference_title: "Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Overall data suggest that MED12L haploinsufficiency is responsible for intellectual disability and transcriptional defect."
      explanation: Heterozygous, mostly de novo MED12L variants acting through haploinsufficiency are consistent with autosomal dominant inheritance.
  features: >
    Heterozygous deletions, duplications, and single-nucleotide variants; mostly de novo;
    haploinsufficiency with a demonstrable transcriptional defect in patient fibroblasts.
  evidence:
  - reference: PMID:31155615
    reference_title: "Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three individuals had a MED12L deletion or duplication."
    explanation: Documents the copy-number and point-variant spectrum of MED12L disease alleles.
treatments:
- name: Speech and Language Therapy
  description: >
    Speech and language therapy addresses the prominent speech impairment.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
- name: Supportive Care
  description: >
    Multidisciplinary supportive care including developmental and behavioral interventions.
  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.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:31155615
    reference_title: "Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall data suggest that MED12L haploinsufficiency is responsible for intellectual disability and transcriptional defect."
    explanation: The identified single-locus MED12L haploinsufficiency mechanism is the genetic basis that warrants recurrence-risk counseling.