MED27-Related Disorder

Mendelian MONDO:0859137 Pathograph 8 Show in embeddings browser Autosomal recessive intellectual disability Neurodevelopmental disorder Mediator complex-associated disorder

MED27-related disorder (NEDSCAC) is a rare autosomal recessive neurodevelopmental disorder caused by biallelic variants in MED27, which encodes a subunit of the structural core of the Mediator transcriptional coactivator complex. The phenotype is highly homogeneous: global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia, with congenital cataracts and seizures in severely affected individuals. Later international cohorts describe a variable ponto-cerebello-lental degeneration with movement disorders. Because MED27 acts in the constitutive core of Mediator rather than its dissociable kinase module, NEDSCAC is one of the recessive "core-module" MEDopathies, and MED27 appears particularly critical for cerebellar development.

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2
Pathophys.
6
Phenotypes
8
Pathograph
1
Genes
2
Medical Actions
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE NEUROLOGIC
⚙

Pathophysiology

2
MED27 core Mediator dysfunction
MED27 is a subunit of the structural core of the Mediator complex. Biallelic variants disrupt core-Mediator-dependent transcription of developmental gene-expression programs. The homogeneous phenotype and multiple biallelic families support a critical role for MED27 in normal human neural development, particularly for the cerebellum. MED27 belongs to the group of Mediator complex-associated disease genes.
MED27 hgnc:2377 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MED27 (hgnc:2377). hgnc:2377 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 and cerebellar developmental dysregulation Core-Mediator dysfunction disrupts neurodevelopmental transcriptional programs, with particular impact on cerebellar development.
Show evidence (1 reference)
PMID:33443317 SUPPORT Human Clinical
"Identification of multiple patients with biallelic MED27 variants supports the critical role of MED27 in normal human neural development, particularly for the cerebellum."
Establishes MED27's critical role in human neural (especially cerebellar) development.
Neurodevelopmental and cerebellar developmental dysregulation
Downstream of MED27 core-Mediator dysfunction, neurodevelopmental gene-expression programs are dysregulated, producing global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia, with cataracts and seizures in severely affected individuals.
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.
cerebellum development GO:0021549 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated cerebellum development (GO:0021549). GO:0021549 is a biological process from the Gene Ontology. ↕ DYSREGULATED
cerebellum UBERON:0002037 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebellum (UBERON:0002037). UBERON:0002037 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Intellectual disability Disrupted neuronal developmental programs contribute to intellectual disability.
Distal spasticity Disrupted motor developmental programs contribute to axial hypotonia with distal spasticity.
Dystonia Disrupted basal ganglia/cerebellar circuits contribute to dystonic movements.
Cerebellar hypoplasia Impaired cerebellar development produces cerebellar hypoplasia.
Cataracts Disrupted lens developmental programs contribute to cataracts in severely affected individuals.
Show evidence (1 reference)
PMID:33443317 SUPPORT Human Clinical
"Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia."
Documents the homogeneous neurodevelopmental and cerebellar phenotype downstream of MED27 dysfunction.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for MED27-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
Eye 1
Cataracts HP:0000518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cataract (HP:0000518). HP:0000518 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33443317 SUPPORT Human Clinical
"Seizures and cataracts were noted in severely affected individuals."
Documents cataracts in severely affected individuals.
Musculoskeletal 1
Distal spasticity HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33443317 SUPPORT Human Clinical
"Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia."
Documents distal spasticity as a characteristic 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:33443317 SUPPORT Human Clinical
"Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia."
Documents intellectual disability as a core feature.
Dystonia HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33443317 SUPPORT Human Clinical
"Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia."
Documents dystonic movements as a characteristic feature.
Cerebellar hypoplasia HP:0001321 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar hypoplasia (HP:0001321). HP:0001321 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33443317 SUPPORT Human Clinical
"Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia."
Documents cerebellar hypoplasia as a defining feature.
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:33443317 SUPPORT Human Clinical
"Seizures and cataracts were noted in severely affected individuals."
Documents seizures in severely affected individuals.
🧬

Genetic Associations

1
MED27 biallelic variants (Causative)
Gene: MED27 hgnc:2377 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MED27 (hgnc:2377). hgnc:2377 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal Recessive
Show evidence (1 reference)
PMID:33443317 SUPPORT Human Clinical
"Identification of multiple patients with biallelic MED27 variants supports the critical role of MED27 in normal human neural development, particularly for the cerebellum."
Multiple biallelic families support the MED27 gene-disease relationship.
💊

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, movement-disorder management, ophthalmologic management for cataracts, and seizure 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 given the autosomal recessive inheritance, with carrier testing for at-risk relatives.
Show evidence (1 reference)
PMID:33443317 SUPPORT Human Clinical
"biallelic putative disease-causing variants in MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome."
Biallelic variants across unrelated families establish the autosomal recessive basis that warrants carrier and recurrence-risk counseling.
📊

Prevalence

1
Worldwide
Cases In Literature <1 in 1,000,000
Ultra-rare. The syndrome-defining cohort comprised 16 patients from 11 families; later international cohorts have expanded the number. No population-based prevalence estimate is available.
Show evidence (1 reference)
PMID:33443317 SUPPORT Human Clinical
"biallelic putative disease-causing variants in MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome."
Documents the defining cohort size establishing MED27 as an ultra-rare disease gene.
{ }

Source YAML

click to show 
name: MED27-Related Disorder
creation_date: '2026-07-31T00:00:00Z'
category: Mendelian
synonyms:
- NEDSCAC
- Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia
- MED27-related developmental delay, dystonia and cerebellar hypoplasia
- Ponto-cerebello-lental degeneration
description: >
  MED27-related disorder (NEDSCAC) is a rare autosomal recessive neurodevelopmental disorder
  caused by biallelic variants in MED27, which encodes a subunit of the structural core of the
  Mediator transcriptional coactivator complex. The phenotype is highly homogeneous: global
  developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic
  movements, and cerebellar hypoplasia, with congenital cataracts and seizures in severely
  affected individuals. Later international cohorts describe a variable ponto-cerebello-lental
  degeneration with movement disorders. Because MED27 acts in the constitutive core of Mediator
  rather than its dissociable kinase module, NEDSCAC is one of the recessive "core-module"
  MEDopathies, and MED27 appears particularly critical for cerebellar development.
disease_term:
  preferred_term: Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia
  term:
    id: MONDO:0859137
    label: neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia
parents:
- Autosomal recessive intellectual disability
- Neurodevelopmental disorder
- Mediator complex-associated disorder
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:33443317
      reference_title: "MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "biallelic putative disease-causing variants in MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome."
      explanation: Supports classification as a heritable autosomal recessive genetic disorder.
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:33443317
      reference_title: "MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia."
      explanation: Supports classification as a neurodevelopmental / neurologic disorder with a movement-disorder component.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Ultra-rare. The syndrome-defining cohort comprised 16 patients from 11 families;
    later international cohorts have expanded the number. No population-based prevalence
    estimate is available.
  evidence:
  - reference: PMID:33443317
    reference_title: "MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic putative disease-causing variants in MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome."
    explanation: Documents the defining cohort size establishing MED27 as an ultra-rare disease gene.
pathophysiology:
- name: MED27 core Mediator dysfunction
  description: >
    MED27 is a subunit of the structural core of the Mediator complex. Biallelic variants
    disrupt core-Mediator-dependent transcription of developmental gene-expression programs.
    The homogeneous phenotype and multiple biallelic families support a critical role for MED27
    in normal human neural development, particularly for the cerebellum. MED27 belongs to the
    group of Mediator complex-associated disease genes.
  genes:
  - preferred_term: MED27
    term:
      id: hgnc:2377
      label: MED27
  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:33443317
    reference_title: "MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of multiple patients with biallelic MED27 variants supports the critical role of MED27 in normal human neural development, particularly for the cerebellum."
    explanation: Establishes MED27's critical role in human neural (especially cerebellar) development.
  downstream:
  - target: Neurodevelopmental and cerebellar developmental dysregulation
    description: >-
      Core-Mediator dysfunction disrupts neurodevelopmental transcriptional programs, with
      particular impact on cerebellar development.
- name: Neurodevelopmental and cerebellar developmental dysregulation
  description: >
    Downstream of MED27 core-Mediator dysfunction, neurodevelopmental gene-expression programs
    are dysregulated, producing global developmental delay, intellectual disability, axial
    hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia, with
    cataracts and seizures in severely affected individuals.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  biological_processes:
  - preferred_term: cerebellum development
    term:
      id: GO:0021549
      label: cerebellum development
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:33443317
    reference_title: "MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia."
    explanation: Documents the homogeneous neurodevelopmental and cerebellar phenotype downstream of MED27 dysfunction.
  downstream:
  - target: Intellectual disability
    description: Disrupted neuronal developmental programs contribute to intellectual disability.
  - target: Distal spasticity
    description: Disrupted motor developmental programs contribute to axial hypotonia with distal spasticity.
  - target: Dystonia
    description: Disrupted basal ganglia/cerebellar circuits contribute to dystonic movements.
  - target: Cerebellar hypoplasia
    description: Impaired cerebellar development produces cerebellar hypoplasia.
  - target: Cataracts
    description: Disrupted lens developmental programs contribute to cataracts in severely affected individuals.
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: >
    Global developmental delay and intellectual disability are core features of MED27-related
    disorder.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:33443317
    reference_title: "MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia."
    explanation: Documents intellectual disability as a core feature.
- category: Clinical
  name: Distal spasticity
  description: >
    Axial hypotonia with distal spasticity is characteristic of MED27-related disorder.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:33443317
    reference_title: "MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia."
    explanation: Documents distal spasticity as a characteristic feature.
- category: Clinical
  name: Dystonia
  description: >
    Dystonic movements are a characteristic movement-disorder feature.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:33443317
    reference_title: "MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia."
    explanation: Documents dystonic movements as a characteristic feature.
- category: Clinical
  name: Cerebellar hypoplasia
  description: >
    Cerebellar hypoplasia on brain imaging is a defining feature of MED27-related disorder.
  phenotype_term:
    preferred_term: Cerebellar hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
  evidence:
  - reference: PMID:33443317
    reference_title: "MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia."
    explanation: Documents cerebellar hypoplasia as a defining feature.
- category: Clinical
  name: Cataracts
  description: >
    Cataracts were noted in severely affected individuals.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:33443317
    reference_title: "MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seizures and cataracts were noted in severely affected individuals."
    explanation: Documents cataracts in severely affected individuals.
- category: Clinical
  name: Seizures
  description: >
    Seizures were noted in severely affected individuals.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33443317
    reference_title: "MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seizures and cataracts were noted in severely affected individuals."
    explanation: Documents seizures in severely affected individuals.
genetic:
- name: MED27 biallelic variants
  association: Causative
  gene_term:
    preferred_term: MED27
    term:
      id: hgnc:2377
      label: MED27
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:33443317
      reference_title: "MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "biallelic putative disease-causing variants in MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome."
      explanation: Biallelic MED27 variants across multiple families are consistent with autosomal recessive inheritance.
  features: >
    Biallelic (homozygous or compound heterozygous) MED27 variants.
  evidence:
  - reference: PMID:33443317
    reference_title: "MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of multiple patients with biallelic MED27 variants supports the critical role of MED27 in normal human neural development, particularly for the cerebellum."
    explanation: Multiple biallelic families support the MED27 gene-disease relationship.
treatments:
- name: Supportive Care
  description: >
    Multidisciplinary supportive care including developmental therapies, movement-disorder
    management, ophthalmologic management for cataracts, and seizure management as needed.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Genetic Counseling
  description: >
    Genetic counseling is recommended given the autosomal recessive inheritance, with carrier
    testing for at-risk relatives.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:33443317
    reference_title: "MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic putative disease-causing variants in MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome."
    explanation: Biallelic variants across unrelated families establish the autosomal recessive basis that warrants carrier and recurrence-risk counseling.