MED11-Related Disorder

Mendelian MONDO:0957225 Pathograph 7 Show in embeddings browser Neurodevelopmental disorder Neurodegenerative disease Mediator complex-associated disorder

MED11-related disorder (NDDRSB) is a rare, lethal autosomal recessive neurodegenerative disorder caused by a recurrent homozygous C-terminal variant (p.Arg109Ter) in MED11, a subunit of the head module of the Mediator transcriptional coactivator complex. The truncation removes the conserved C-terminal residues and destabilizes the MED11-MED22-MED17 four-helix bundle, impairing Mediator-complex assembly. It is the most severe MEDopathy: affected individuals have congenital microcephaly, neonatal respiratory failure, profound neurodevelopmental impairment, an exaggerated startle response, refractory myoclonic seizures, progressive widespread neurodegeneration, and premature death. The variant does not abolish protein but disrupts the C-terminus, implicating Mediator-complex stability in brain development and neurodegeneration.

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

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE NEUROLOGIC
⚙

Pathophysiology

2
MED11 complex-stability failure
MED11 is a subunit of the head module of the Mediator complex. The recurrent homozygous C-terminal p.Arg109Ter variant does not abolish the protein but disrupts its conserved C-terminus, impairing binding to partner subunits and destabilizing the MED11-MED22-MED17 four-helix bundle. This implicates Mediator-complex stability, rather than simple loss of protein, in brain development and neurodegeneration. MED11 belongs to the group of Mediator complex-associated disease genes.
MED11 hgnc:32687 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MED11 (hgnc:32687). hgnc:32687 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
Progressive neurodegeneration Mediator-complex destabilization disrupts developmental and maintenance transcription, producing progressive widespread neurodegeneration.
Show evidence (1 reference)
PMID:36001086 SUPPORT Human Clinical
"Loss of the C-terminal of MED subunit 11 may affect its binding efficiency to other MED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration."
Establishes Mediator-complex destabilization as the disease mechanism.
Progressive neurodegeneration
Downstream of MED11 complex-stability failure, a severe neurodegenerative process produces congenital microcephaly, profound neurodevelopmental impairment, an exaggerated startle response, refractory myoclonic seizures, progressive widespread neurodegeneration, and premature death; neonatal respiratory failure is common.
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.
neuron apoptotic process GO:0051402 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased neuron apoptotic process (GO:0051402). GO:0051402 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Microcephaly The neurodegenerative process is accompanied by microcephaly.
Global developmental delay The disease produces profound neurodevelopmental impairment.
Exaggerated startle response Brain dysfunction produces an exaggerated startle response.
Myoclonic seizures Cortical dysfunction produces refractory myoclonic seizures.
Show evidence (1 reference)
PMID:36001086 SUPPORT Human Clinical
"The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death."
Documents the lethal neurodegenerative phenotype downstream of MED11 dysfunction.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for MED11-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
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36001086 SUPPORT Human Clinical
"The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death."
Documents microcephaly as a defining feature.
Nervous System 2
Global developmental delay 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:36001086 SUPPORT Human Clinical
"The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death."
Documents profound neurodevelopmental impairment.
Exaggerated startle response HP:0002267 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exaggerated startle response (HP:0002267). HP:0002267 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36001086 SUPPORT Human Clinical
"The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death."
Documents an exaggerated startle response as a characteristic feature.
Respiratory 1
Neonatal respiratory failure HP:0002878 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory failure (HP:0002878). HP:0002878 is a phenotype from the Human Phenotype Ontology.
Other 2
Myoclonic seizures HP:0032794 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myoclonic seizure (HP:0032794). HP:0032794 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36001086 SUPPORT Human Clinical
"The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death."
Documents refractory myoclonic seizures as a characteristic feature.
Progressive neurodegeneration HP:0002180 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurodegeneration (HP:0002180). HP:0002180 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36001086 SUPPORT Human Clinical
"The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death."
Documents progressive widespread neurodegeneration and premature death.
🧬

Genetic Associations

1
MED11 homozygous C-terminal variant (Causative)
Gene: MED11 hgnc:32687 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MED11 (hgnc:32687). hgnc:32687 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal Recessive
Show evidence (1 reference)
PMID:36001086 SUPPORT In Vitro
"Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits."
Establishes the complex-destabilization (not protein-loss) mechanism.
💊

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
Supportive and palliative care, including respiratory support and seizure management, given the lethal course.
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:36001086 SUPPORT Human Clinical
"In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families."
A recurrent homozygous variant transmitted in unrelated families establishes 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 defining report described seven affected individuals from five unrelated families sharing the recurrent homozygous p.Arg109Ter variant. No population-based prevalence estimate is available.
Show evidence (1 reference)
PMID:36001086 SUPPORT Human Clinical
"In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families."
Only seven individuals from five families are described, establishing MED11 disease as ultra-rare.
{ }

Source YAML

click to show 
name: MED11-Related Disorder
creation_date: '2026-07-31T00:00:00Z'
category: Mendelian
synonyms:
- Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities
- NDDRSB
- MED11-related lethal neurodegenerative disease
description: >
  MED11-related disorder (NDDRSB) is a rare, lethal autosomal recessive neurodegenerative
  disorder caused by a recurrent homozygous C-terminal variant (p.Arg109Ter) in MED11, a subunit
  of the head module of the Mediator transcriptional coactivator complex. The truncation removes
  the conserved C-terminal residues and destabilizes the MED11-MED22-MED17 four-helix bundle,
  impairing Mediator-complex assembly. It is the most severe MEDopathy: affected individuals have
  congenital microcephaly, neonatal respiratory failure, profound neurodevelopmental impairment,
  an exaggerated startle response, refractory myoclonic seizures, progressive widespread
  neurodegeneration, and premature death. The variant does not abolish protein but disrupts the
  C-terminus, implicating Mediator-complex stability in brain development and neurodegeneration.
disease_term:
  preferred_term: Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities
  term:
    id: MONDO:0957225
    label: neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities
parents:
- Neurodevelopmental disorder
- Neurodegenerative disease
- Mediator complex-associated disorder
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:36001086
      reference_title: "A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families."
      explanation: Supports classification as a heritable autosomal recessive genetic disorder.
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:36001086
      reference_title: "A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death."
      explanation: Supports classification as a neurodevelopmental / neurodegenerative disorder.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Ultra-rare. The defining report described seven affected individuals from five unrelated
    families sharing the recurrent homozygous p.Arg109Ter variant. No population-based
    prevalence estimate is available.
  evidence:
  - reference: PMID:36001086
    reference_title: "A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families."
    explanation: Only seven individuals from five families are described, establishing MED11 disease as ultra-rare.
pathophysiology:
- name: MED11 complex-stability failure
  description: >
    MED11 is a subunit of the head module of the Mediator complex. The recurrent homozygous
    C-terminal p.Arg109Ter variant does not abolish the protein but disrupts its conserved
    C-terminus, impairing binding to partner subunits and destabilizing the MED11-MED22-MED17
    four-helix bundle. This implicates Mediator-complex stability, rather than simple loss of
    protein, in brain development and neurodegeneration. MED11 belongs to the group of Mediator
    complex-associated disease genes.
  genes:
  - preferred_term: MED11
    term:
      id: hgnc:32687
      label: MED11
  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:36001086
    reference_title: "A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss of the C-terminal of MED subunit 11 may affect its binding efficiency to other MED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration."
    explanation: Establishes Mediator-complex destabilization as the disease mechanism.
  downstream:
  - target: Progressive neurodegeneration
    description: >-
      Mediator-complex destabilization disrupts developmental and maintenance transcription,
      producing progressive widespread neurodegeneration.
- name: Progressive neurodegeneration
  description: >
    Downstream of MED11 complex-stability failure, a severe neurodegenerative process produces
    congenital microcephaly, profound neurodevelopmental impairment, an exaggerated startle
    response, refractory myoclonic seizures, progressive widespread neurodegeneration, and
    premature death; neonatal respiratory failure is common.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: neuron apoptotic process
    term:
      id: GO:0051402
      label: neuron apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:36001086
    reference_title: "A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death."
    explanation: Documents the lethal neurodegenerative phenotype downstream of MED11 dysfunction.
  downstream:
  - target: Microcephaly
    description: The neurodegenerative process is accompanied by microcephaly.
  - target: Global developmental delay
    description: The disease produces profound neurodevelopmental impairment.
  - target: Exaggerated startle response
    description: Brain dysfunction produces an exaggerated startle response.
  - target: Myoclonic seizures
    description: Cortical dysfunction produces refractory myoclonic seizures.
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: Microcephaly
  description: >
    Microcephaly is a defining feature of MED11-related disorder.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:36001086
    reference_title: "A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death."
    explanation: Documents microcephaly as a defining feature.
- category: Clinical
  name: Global developmental delay
  description: >
    Profound neurodevelopmental impairment is present in all affected individuals.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:36001086
    reference_title: "A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death."
    explanation: Documents profound neurodevelopmental impairment.
- category: Clinical
  name: Exaggerated startle response
  description: >
    An exaggerated startle response with hyperkinetic movements is characteristic.
  phenotype_term:
    preferred_term: Exaggerated startle response
    term:
      id: HP:0002267
      label: Exaggerated startle response
  evidence:
  - reference: PMID:36001086
    reference_title: "A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death."
    explanation: Documents an exaggerated startle response as a characteristic feature.
- category: Clinical
  name: Myoclonic seizures
  description: >
    Refractory myoclonic seizures are a characteristic feature.
  phenotype_term:
    preferred_term: Myoclonic seizure
    term:
      id: HP:0032794
      label: Myoclonic seizure
  evidence:
  - reference: PMID:36001086
    reference_title: "A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death."
    explanation: Documents refractory myoclonic seizures as a characteristic feature.
- category: Clinical
  name: Progressive neurodegeneration
  description: >
    Progressive widespread neurodegeneration leading to premature death defines the lethal
    course of MED11-related disorder.
  phenotype_term:
    preferred_term: Neurodegeneration
    term:
      id: HP:0002180
      label: Neurodegeneration
  evidence:
  - reference: PMID:36001086
    reference_title: "A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death."
    explanation: Documents progressive widespread neurodegeneration and premature death.
- category: Respiratory
  name: Neonatal respiratory failure
  description: >
    Neonatal respiratory failure is a defining feature of MED11-related disorder and is named
    in the disorder's OMIM/MONDO designation (NDDRSB); affected neonates may require intubation
    and some die of cardiorespiratory insufficiency. Recorded without a snippet-validated
    evidence item and with frequency omitted: the feature is part of the disease definition and
    full-text reports, but the fetched abstract of the defining paper (PMID:36001086) contains
    no verbatim respiratory-failure sentence, so no exact quote is available. Modeled so the
    name-defining phenotype is queryable.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
genetic:
- name: MED11 homozygous C-terminal variant
  association: Causative
  gene_term:
    preferred_term: MED11
    term:
      id: hgnc:32687
      label: MED11
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:36001086
      reference_title: "A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families."
      explanation: A recurrent homozygous MED11 variant causing disease is consistent with autosomal recessive inheritance.
  features: >
    Recurrent homozygous C-terminal nonsense variant p.Arg109Ter that destabilizes the
    MED11-MED22-MED17 four-helix bundle without abolishing protein.
  evidence:
  - reference: PMID:36001086
    reference_title: "A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits."
    explanation: Establishes the complex-destabilization (not protein-loss) mechanism.
treatments:
- name: Supportive Care
  description: >
    Supportive and palliative care, including respiratory support and seizure management,
    given the lethal course.
  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:36001086
    reference_title: "A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families."
    explanation: A recurrent homozygous variant transmitted in unrelated families establishes the autosomal recessive basis that warrants carrier and recurrence-risk counseling.