Guillouet-Gordon Syndrome

Mendelian MONDO:0979227 Pathograph 7 Show in embeddings browser Autosomal recessive intellectual disability Neurodevelopmental disorder Mediator complex-associated disorder

Guillouet-Gordon syndrome (GGNS) is a rare autosomal recessive multiple congenital anomalies-intellectual disability syndrome caused by biallelic variants in MED16, a subunit of the tail module of the Mediator transcriptional coactivator complex. First described in 2025, it is the most recently delineated MEDopathy. Intellectual disability, speech delay, and/or motor delay of variable severity are constant, associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot); visual impairment, deafness, and MRI abnormalities are also frequent. Most disease-causing variants cause nuclear-to-cytoplasmic mislocalization of MED16, and med16 zebrafish and Med16 knockout mice confirm a conserved developmental requirement.

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2
Pathophys.
8
Phenotypes
7
Pathograph
1
Genes
2
Medical Actions
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE NEUROLOGIC
⚙

Pathophysiology

2
MED16 Mediator mislocalization
MED16 is a subunit of the tail module of the Mediator complex. Most disease-causing variants cause mislocalization of MED16 from the nucleus to the cytoplasm, and 3D modeling indicates a destabilizing effect on protein structural elements, disrupting Mediator-dependent transcription of developmental gene-expression programs. Homozygous med16 zebrafish and Med16 knockout mice confirm a conserved developmental requirement. MED16 belongs to the group of Mediator complex-associated disease genes.
MED16 hgnc:17556 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MED16 (hgnc:17556). hgnc:17556 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 ↕ DYSREGULATED 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.
Downstream
Multisystem developmental dysregulation MED16 mislocalization disrupts Mediator-dependent transcription across neurodevelopmental, craniofacial, cardiac, and limb developmental programs.
Show evidence (1 reference)
PMID:40081376 SUPPORT In Vitro
"Immunofluorescence assays demonstrated protein mislocalization from the nucleus to the cytoplasm for 16 of the 17 variants studied."
Establishes nuclear-to-cytoplasmic mislocalization as the disease mechanism for most MED16 variants.
Multisystem developmental dysregulation
Downstream of MED16 mislocalization, developmental gene-expression programs are dysregulated across multiple systems, producing intellectual disability, speech and motor delay, craniofacial defects (micro/retrognathia, cleft palate, preauricular tags), extremity anomalies, congenital heart defects (predominantly tetralogy of Fallot), visual impairment, and deafness.
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 ↕ DYSREGULATED 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. heart morphogenesis GO:0003007 ↕ DYSREGULATED 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.
Downstream
Intellectual disability Disrupted neuronal developmental programs contribute to intellectual disability.
Cleft palate Disrupted craniofacial developmental programs contribute to cleft palate and other craniofacial defects.
Tetralogy of Fallot Disrupted cardiac developmental programs contribute to congenital heart defects, predominantly tetralogy of Fallot.
Limb anomalies Disrupted limb developmental programs contribute to anomalies of the extremities.
Show evidence (1 reference)
PMID:40081376 SUPPORT Human Clinical
"Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot)."
Documents the multisystem developmental phenotype downstream of MED16 dysfunction.
⬡

Pathograph

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

8
Cardiovascular 1
Tetralogy of Fallot HP:0001636 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tetralogy of Fallot (HP:0001636). HP:0001636 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40081376 SUPPORT Human Clinical
"Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot)."
Documents tetralogy of Fallot as the predominant congenital heart defect.
Ear 1
Deafness FREQUENT Hearing impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40081376 SUPPORT Human Clinical
"Visual impairment, deafness, and magnetic resonance imaging (MRI) abnormalities were also frequent."
Documents deafness as a frequent feature.
Eye 1
Visual impairment FREQUENT HP:0000505 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Visual impairment (HP:0000505). HP:0000505 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40081376 SUPPORT Human Clinical
"Visual impairment, deafness, and magnetic resonance imaging (MRI) abnormalities were also frequent."
Documents visual impairment as a frequent feature.
Head and Neck 1
Cleft palate HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40081376 SUPPORT Human Clinical
"Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot)."
Documents cleft palate among the variable craniofacial defects.
Limbs 1
Limb anomalies Abnormal limb bone morphology HP:0002813 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Limb anomalies, annotated with Abnormal limb bone morphology (HP:0002813). HP:0002813 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40081376 SUPPORT Human Clinical
"Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot)."
Documents anomalies of the extremities as part of the spectrum.
Nervous System 3
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:40081376 SUPPORT Human Clinical
"Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot)."
Documents intellectual disability as a constant feature.
Speech delay 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:40081376 SUPPORT Human Clinical
"Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot)."
Documents speech delay as a constant developmental feature.
Motor delay HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40081376 SUPPORT Human Clinical
"Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot)."
Documents motor delay as a constant developmental feature.
🧬

Genetic Associations

1
MED16 biallelic variants (Causative)
Gene: MED16 hgnc:17556 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MED16 (hgnc:17556). hgnc:17556 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal Recessive
Show evidence (1 reference)
PMID:40081376 SUPPORT Human Clinical
"we report the identification of 25 individuals from 18 families with bi-allelic MED16 variants who have a multiple congenital anomalies (MCAs)-intellectual disability syndrome."
Establishes the biallelic MED16 gene-disease relationship in a large multi-family cohort.
💊

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, cardiac and craniofacial surgical management, and ophthalmologic and audiologic 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:40081376 SUPPORT Human Clinical
"Overall, we describe an autosomal recessive MCAs-intellectual disability MEDopathy"
The autosomal recessive basis established here warrants carrier and recurrence-risk counseling.
📊

Prevalence

1
Worldwide
Cases In Literature <1 in 1,000,000
Ultra-rare. The defining 2025 cohort comprised 25 individuals from 18 families. No population-based prevalence estimate is available.
Show evidence (1 reference)
PMID:40081376 SUPPORT Human Clinical
"we report the identification of 25 individuals from 18 families with bi-allelic MED16 variants who have a multiple congenital anomalies (MCAs)-intellectual disability syndrome."
Documents the defining cohort size establishing MED16 as an ultra-rare disease gene.
{ }

Source YAML

click to show 
name: Guillouet-Gordon Syndrome
creation_date: '2026-07-31T00:00:00Z'
category: Mendelian
synonyms:
- GGNS
- MED16-related MEDopathy
- MED16-related multiple congenital anomalies-intellectual disability syndrome
description: >
  Guillouet-Gordon syndrome (GGNS) is a rare autosomal recessive multiple congenital
  anomalies-intellectual disability syndrome caused by biallelic variants in MED16, a subunit
  of the tail module of the Mediator transcriptional coactivator complex. First described in
  2025, it is the most recently delineated MEDopathy. Intellectual disability, speech delay,
  and/or motor delay of variable severity are constant, associated with variable combinations
  of craniofacial defects (micro/retrognathia, cleft palate, preauricular tags), anomalies of
  the extremities, and heart defects (predominantly tetralogy of Fallot); visual impairment,
  deafness, and MRI abnormalities are also frequent. Most disease-causing variants cause
  nuclear-to-cytoplasmic mislocalization of MED16, and med16 zebrafish and Med16 knockout mice
  confirm a conserved developmental requirement.
disease_term:
  preferred_term: Guillouet-Gordon syndrome
  term:
    id: MONDO:0979227
    label: Guillouet-Gordon syndrome
parents:
- Autosomal recessive intellectual disability
- Neurodevelopmental disorder
- Mediator complex-associated disorder
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:40081376
      reference_title: "Bi-allelic MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Overall, we describe an autosomal recessive MCAs-intellectual disability MEDopathy"
      explanation: Supports classification as a heritable autosomal recessive genetic disorder.
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:40081376
      reference_title: "Bi-allelic MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot)."
      explanation: Supports classification as a neurodevelopmental / neurologic multiple-congenital-anomaly disorder.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Ultra-rare. The defining 2025 cohort comprised 25 individuals from 18 families. No
    population-based prevalence estimate is available.
  evidence:
  - reference: PMID:40081376
    reference_title: "Bi-allelic MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report the identification of 25 individuals from 18 families with bi-allelic MED16 variants who have a multiple congenital anomalies (MCAs)-intellectual disability syndrome."
    explanation: Documents the defining cohort size establishing MED16 as an ultra-rare disease gene.
pathophysiology:
- name: MED16 Mediator mislocalization
  description: >
    MED16 is a subunit of the tail module of the Mediator complex. Most disease-causing
    variants cause mislocalization of MED16 from the nucleus to the cytoplasm, and 3D modeling
    indicates a destabilizing effect on protein structural elements, disrupting
    Mediator-dependent transcription of developmental gene-expression programs. Homozygous
    med16 zebrafish and Med16 knockout mice confirm a conserved developmental requirement.
    MED16 belongs to the group of Mediator complex-associated disease genes.
  genes:
  - preferred_term: MED16
    term:
      id: hgnc:17556
      label: MED16
  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:40081376
    reference_title: "Bi-allelic MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Immunofluorescence assays demonstrated protein mislocalization from the nucleus to the cytoplasm for 16 of the 17 variants studied."
    explanation: Establishes nuclear-to-cytoplasmic mislocalization as the disease mechanism for most MED16 variants.
  downstream:
  - target: Multisystem developmental dysregulation
    description: >-
      MED16 mislocalization disrupts Mediator-dependent transcription across neurodevelopmental,
      craniofacial, cardiac, and limb developmental programs.
- name: Multisystem developmental dysregulation
  description: >
    Downstream of MED16 mislocalization, developmental gene-expression programs are dysregulated
    across multiple systems, producing intellectual disability, speech and motor delay,
    craniofacial defects (micro/retrognathia, cleft palate, preauricular tags), extremity
    anomalies, congenital heart defects (predominantly tetralogy of Fallot), visual impairment,
    and deafness.
  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
  - preferred_term: heart morphogenesis
    term:
      id: GO:0003007
      label: heart morphogenesis
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:40081376
    reference_title: "Bi-allelic MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot)."
    explanation: Documents the multisystem developmental phenotype downstream of MED16 dysfunction.
  downstream:
  - target: Intellectual disability
    description: Disrupted neuronal developmental programs contribute to intellectual disability.
  - target: Cleft palate
    description: Disrupted craniofacial developmental programs contribute to cleft palate and other craniofacial defects.
  - target: Tetralogy of Fallot
    description: Disrupted cardiac developmental programs contribute to congenital heart defects, predominantly tetralogy of Fallot.
  - target: Limb anomalies
    description: Disrupted limb developmental programs contribute to anomalies of the extremities.
phenotypes:
- category: Clinical
  name: Intellectual disability
  # frequency intentionally omitted: the source states the ID/speech/motor triad
  # was "constant" as an "and/or" group, not per-feature; no defensible band.
  description: >
    Intellectual disability of variable severity is a constant feature.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:40081376
    reference_title: "Bi-allelic MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot)."
    explanation: Documents intellectual disability as a constant feature.
- category: Clinical
  name: Speech delay
  # frequency intentionally omitted: snippet says "constant" (an "and/or" group
  # claim), which does not support FREQUENT or any other per-feature band.
  description: >
    Speech delay of variable severity is a constant developmental feature.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:40081376
    reference_title: "Bi-allelic MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot)."
    explanation: Documents speech delay as a constant developmental feature.
- category: Clinical
  name: Motor delay
  # frequency intentionally omitted: snippet says "constant" (an "and/or" group
  # claim), which does not support FREQUENT or any other per-feature band.
  description: >
    Motor delay of variable severity is a constant developmental feature.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:40081376
    reference_title: "Bi-allelic MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot)."
    explanation: Documents motor delay as a constant developmental feature.
- category: Craniofacial
  name: Cleft palate
  # frequency intentionally omitted: the source reports only "variable
  # combinations" of craniofacial defects, giving no per-feature rate.
  description: >
    Cleft palate is among the variable craniofacial defects, alongside micro/retrognathia and
    preauricular tags.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:40081376
    reference_title: "Bi-allelic MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot)."
    explanation: Documents cleft palate among the variable craniofacial defects.
- category: Cardiovascular
  name: Tetralogy of Fallot
  # frequency intentionally omitted: "predominantly tetralogy of Fallot" ranks it
  # among heart defects but gives no rate across the cohort.
  description: >
    Congenital heart defects, predominantly tetralogy of Fallot, occur in a subset of individuals.
  phenotype_term:
    preferred_term: Tetralogy of Fallot
    term:
      id: HP:0001636
      label: Tetralogy of Fallot
  evidence:
  - reference: PMID:40081376
    reference_title: "Bi-allelic MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot)."
    explanation: Documents tetralogy of Fallot as the predominant congenital heart defect.
- category: Skeletal
  name: Limb anomalies
  # frequency intentionally omitted: the source reports only "variable
  # combinations" including extremity anomalies, giving no per-feature rate.
  description: >
    Anomalies of the extremities are part of the variable multiple-congenital-anomaly spectrum.
  phenotype_term:
    preferred_term: Limb anomalies
    term:
      id: HP:0002813
      label: Abnormal limb bone morphology
  evidence:
  - reference: PMID:40081376
    reference_title: "Bi-allelic MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot)."
    explanation: Documents anomalies of the extremities as part of the spectrum.
- category: Ophthalmologic
  name: Visual impairment
  frequency: FREQUENT
  description: >
    Visual impairment is a frequent feature.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: PMID:40081376
    reference_title: "Bi-allelic MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Visual impairment, deafness, and magnetic resonance imaging (MRI) abnormalities were also frequent."
    explanation: Documents visual impairment as a frequent feature.
- category: Audiologic
  name: Deafness
  frequency: FREQUENT
  description: >
    Deafness is a frequent feature.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:40081376
    reference_title: "Bi-allelic MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Visual impairment, deafness, and magnetic resonance imaging (MRI) abnormalities were also frequent."
    explanation: Documents deafness as a frequent feature.
genetic:
- name: MED16 biallelic variants
  association: Causative
  gene_term:
    preferred_term: MED16
    term:
      id: hgnc:17556
      label: MED16
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:40081376
      reference_title: "Bi-allelic MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Overall, we describe an autosomal recessive MCAs-intellectual disability MEDopathy"
      explanation: Bi-allelic MED16 variants across many families support autosomal recessive inheritance.
  features: >
    Biallelic protein-truncating and missense/in-frame-duplication variants; most cause
    nuclear-to-cytoplasmic mislocalization of MED16.
  evidence:
  - reference: PMID:40081376
    reference_title: "Bi-allelic MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report the identification of 25 individuals from 18 families with bi-allelic MED16 variants who have a multiple congenital anomalies (MCAs)-intellectual disability syndrome."
    explanation: Establishes the biallelic MED16 gene-disease relationship in a large multi-family cohort.
treatments:
- name: Supportive Care
  description: >
    Multidisciplinary supportive care including developmental therapies, cardiac and
    craniofacial surgical management, and ophthalmologic and audiologic 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:40081376
    reference_title: "Bi-allelic MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, we describe an autosomal recessive MCAs-intellectual disability MEDopathy"
    explanation: The autosomal recessive basis established here warrants carrier and recurrence-risk counseling.