Basel-Vanagaite-Smirin-Yosef Syndrome

Mendelian MONDO:0014643 Pathograph 8 Show in embeddings browser Autosomal recessive intellectual disability Neurodevelopmental disorder Mediator complex-associated disorder

Basel-Vanagaite-Smirin-Yosef syndrome (BVSYS) is a rare autosomal recessive neurodevelopmental disorder caused by biallelic variants in MED25, which encodes a subunit of the tail module of the Mediator transcriptional coactivator complex. Founder missense alleles (p.Tyr39Cys; p.Ile173Thr) located in the von Willebrand factor type A (VWA) domain impair MED25 incorporation into the Mediator complex. The syndrome is characterized by severe intellectual disability with eye anomalies (cataract, microcornea, coloboma), brain anomalies (including polymicrogyria), cardiac and palatal anomalies, microcephaly, growth retardation, hypotonia, and seizures. Because MED25 acts in the constitutive tail module rather than the dissociable kinase module, BVSYS is one of the recessive "core-module" MEDopathies. Note: the historical MED25-CMT2B2 (axonal Charcot-Marie-Tooth) association has been formally reassigned to PNKP and is not part of this entry.

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

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE NEUROLOGIC
⚙

Pathophysiology

2
MED25 Mediator incorporation failure
MED25 is a subunit of the tail module of the Mediator complex. The disease-causing missense variants sit in the von Willebrand factor type A (VWA) domain responsible for MED25 recruitment into Mediator; co-immunoprecipitation shows the founder allele dramatically impairs MED25 interaction with the complex, disrupting Mediator-dependent transcription of developmental gene-expression programs.
MED25 hgnc:28845 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MED25 (hgnc:28845). hgnc:28845 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 multisystem developmental dysregulation Impaired MED25 incorporation disrupts Mediator-dependent transcription across neurodevelopmental, ocular, cardiac, and craniofacial developmental programs.
Show evidence (2 references)
PMID:25792360 SUPPORT In Vitro
"co-immunoprecipitation experiment demonstrated that this mutation dramatically impairs MED25 interaction with the Mediator complex in mammalian cells."
Functional evidence that the MED25 founder allele impairs incorporation into Mediator.
PMID:25792360 SUPPORT In Vitro
"The MED25 point mutation is located in the von Willebrand factor type A (MED25 VWA) domain which is responsible for MED25 recruitment into the Mediator complex"
Localizes the pathogenic variant to the domain mediating MED25 assembly into the complex.
Neurodevelopmental and multisystem developmental dysregulation
Downstream of MED25 Mediator-incorporation failure, developmental gene-expression programs are dysregulated across multiple systems, producing severe intellectual disability, microcephaly, eye anomalies (cataract, microcornea, coloboma), brain anomalies (including polymicrogyria), cardiac and palatal anomalies, and growth retardation.
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 eye development GO:0001654 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated eye development (GO:0001654). GO:0001654 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Severe intellectual disability Disrupted neuronal developmental programs contribute to severe intellectual disability.
Microcephaly Disrupted brain-growth programs contribute to microcephaly.
Eye abnormalities Disrupted ocular developmental programs contribute to cataract, microcornea, and coloboma.
Congenital heart defects Disrupted cardiac developmental programs contribute to congenital heart defects.
Growth retardation Disrupted growth-related transcriptional programs contribute to growth retardation.
Show evidence (1 reference)
PMID:25792360 SUPPORT Human Clinical
"a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability"
Documents the multisystem developmental phenotype downstream of MED25 dysfunction.
⬡

Pathograph

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

7
Cardiovascular 1
Congenital heart defects Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital heart defect, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25792360 SUPPORT Human Clinical
"a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability"
Documents cardiac abnormalities as part of the syndrome.
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:25792360 SUPPORT Human Clinical
"a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability"
Documents microcephaly as a recurrent feature.
Nervous System 2
Severe intellectual disability HP:0010864 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe intellectual disability (HP:0010864). HP:0010864 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25792360 SUPPORT Human Clinical
"a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability"
Documents severe intellectual disability as a core feature; the snippet states the severity explicitly.
Polymicrogyria HP:0002126 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polymicrogyria (HP:0002126). HP:0002126 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32816121 SUPPORT Human Clinical
"This report further delineates the most common clinical features of BVSYS and points to polymicrogyria as a distinctive neuroradiological feature of this syndrome."
Establishes polymicrogyria as a distinctive neuroradiological finding in BVSYS.
Growth 1
Growth retardation Growth delay HP:0001510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth delay (HP:0001510). HP:0001510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25792360 SUPPORT Human Clinical
"a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability"
Documents growth retardation as a recurrent feature.
Other 2
Eye abnormalities Abnormality of the eye HP:0000478 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the eye (HP:0000478). HP:0000478 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25792360 SUPPORT Human Clinical
"a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability"
Documents eye abnormalities as a characteristic feature. The cited abstract states only "eye ... abnormalities"; the specific cataract/microcornea/coloboma anomalies appear in the full text and MONDO label but not in any quotable abstract, so the binding is kept at the level the evidence supports rather than split into specifically-termed phenotypes the snippet does not state.
Palatal abnormalities Abnormal palate morphology HP:0000174 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal palate morphology (HP:0000174). HP:0000174 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25792360 SUPPORT Human Clinical
"a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability"
Documents palatal abnormalities as part of the syndrome.
🧬

Genetic Associations

1
MED25 biallelic founder missense variants (Causative)
Gene: MED25 hgnc:28845 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MED25 (hgnc:28845). hgnc:28845 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal Recessive
Show evidence (2 references)
PMID:25792360 SUPPORT In Vitro
"co-immunoprecipitation experiment demonstrated that this mutation dramatically impairs MED25 interaction with the Mediator complex in mammalian cells."
Establishes the loss-of-incorporation mechanism for the MED25 founder allele.
PMID:30800049 SUPPORT Human Clinical
"Potentially causal homozygous variants in the MED25 (p.Ile173Thr) and COQ8A (p.Arg512Trp) genes were found."
Documents the recurrent MED25 p.Ile173Thr allele in a Lebanese patient (reported with a possible digenic COQ8A contribution).
💊

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, ophthalmologic and cardiac management, 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 and founder-allele population structure, with carrier testing for at-risk relatives.
Show evidence (1 reference)
PMID:25792360 SUPPORT Human Clinical
"we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four unrelated families"
A homozygous MED25 variant in patients from unrelated consanguineous 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 cohort comprised seven patients from four unrelated families; additional Lebanese and other families have since been reported (~22 patients total). No population-based prevalence estimate is available.
Show evidence (1 reference)
PMID:25792360 SUPPORT Human Clinical
"in seven patients from four unrelated families, all originating from the same village."
Documents the founder-population defining cohort size establishing BVSYS as ultra-rare.
{ }

Source YAML

click to show 
name: Basel-Vanagaite-Smirin-Yosef Syndrome
creation_date: '2026-07-31T00:00:00Z'
category: Mendelian
synonyms:
- BVSYS
- MED25-related intellectual disability syndrome
- Eye-intellectual disability syndrome
- MED25-related multiple congenital anomalies-intellectual disability syndrome
description: >
  Basel-Vanagaite-Smirin-Yosef syndrome (BVSYS) is a rare autosomal recessive
  neurodevelopmental disorder caused by biallelic variants in MED25, which encodes a subunit
  of the tail module of the Mediator transcriptional coactivator complex. Founder missense
  alleles (p.Tyr39Cys; p.Ile173Thr) located in the von Willebrand factor type A (VWA) domain
  impair MED25 incorporation into the Mediator complex. The syndrome is characterized by severe
  intellectual disability with eye anomalies (cataract, microcornea, coloboma), brain anomalies
  (including polymicrogyria), cardiac and palatal anomalies, microcephaly, growth retardation,
  hypotonia, and seizures. Because MED25 acts in the constitutive tail module rather than the
  dissociable kinase module, BVSYS is one of the recessive "core-module" MEDopathies. Note: the
  historical MED25-CMT2B2 (axonal Charcot-Marie-Tooth) association has been formally reassigned
  to PNKP and is not part of this entry.
disease_term:
  preferred_term: Basel-Vanagaite-Smirin-Yosef syndrome
  term:
    id: MONDO:0014643
    label: congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome
parents:
- Autosomal recessive intellectual disability
- Neurodevelopmental disorder
- Mediator complex-associated disorder
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:25792360
      reference_title: "Homozygous MED25 mutation implicated in eye-intellectual disability syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four unrelated families"
      explanation: Supports classification as a heritable autosomal recessive genetic disorder.
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:25792360
      reference_title: "Homozygous MED25 mutation implicated in eye-intellectual disability syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four unrelated families"
      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 defining cohort comprised seven patients from four unrelated families;
    additional Lebanese and other families have since been reported (~22 patients total).
    No population-based prevalence estimate is available.
  evidence:
  - reference: PMID:25792360
    reference_title: "Homozygous MED25 mutation implicated in eye-intellectual disability syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in seven patients from four unrelated families, all originating from the same village."
    explanation: Documents the founder-population defining cohort size establishing BVSYS as ultra-rare.
pathophysiology:
- name: MED25 Mediator incorporation failure
  description: >
    MED25 is a subunit of the tail module of the Mediator complex. The disease-causing
    missense variants sit in the von Willebrand factor type A (VWA) domain responsible for
    MED25 recruitment into Mediator; co-immunoprecipitation shows the founder allele
    dramatically impairs MED25 interaction with the complex, disrupting Mediator-dependent
    transcription of developmental gene-expression programs.
  genes:
  - preferred_term: MED25
    term:
      id: hgnc:28845
      label: MED25
  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:25792360
    reference_title: "Homozygous MED25 mutation implicated in eye-intellectual disability syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "co-immunoprecipitation experiment demonstrated that this mutation dramatically impairs MED25 interaction with the Mediator complex in mammalian cells."
    explanation: Functional evidence that the MED25 founder allele impairs incorporation into Mediator.
  - reference: PMID:25792360
    reference_title: "Homozygous MED25 mutation implicated in eye-intellectual disability syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The MED25 point mutation is located in the von Willebrand factor type A (MED25 VWA) domain which is responsible for MED25 recruitment into the Mediator complex"
    explanation: Localizes the pathogenic variant to the domain mediating MED25 assembly into the complex.
  downstream:
  - target: Neurodevelopmental and multisystem developmental dysregulation
    description: >-
      Impaired MED25 incorporation disrupts Mediator-dependent transcription across
      neurodevelopmental, ocular, cardiac, and craniofacial developmental programs.
- name: Neurodevelopmental and multisystem developmental dysregulation
  description: >
    Downstream of MED25 Mediator-incorporation failure, developmental gene-expression programs
    are dysregulated across multiple systems, producing severe intellectual disability,
    microcephaly, eye anomalies (cataract, microcornea, coloboma), brain anomalies (including
    polymicrogyria), cardiac and palatal anomalies, and growth retardation.
  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: eye development
    term:
      id: GO:0001654
      label: eye development
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:25792360
    reference_title: "Homozygous MED25 mutation implicated in eye-intellectual disability syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability"
    explanation: Documents the multisystem developmental phenotype downstream of MED25 dysfunction.
  downstream:
  - target: Severe intellectual disability
    description: Disrupted neuronal developmental programs contribute to severe intellectual disability.
  - target: Microcephaly
    description: Disrupted brain-growth programs contribute to microcephaly.
  - target: Eye abnormalities
    description: Disrupted ocular developmental programs contribute to cataract, microcornea, and coloboma.
  - target: Congenital heart defects
    description: Disrupted cardiac developmental programs contribute to congenital heart defects.
  - target: Growth retardation
    description: Disrupted growth-related transcriptional programs contribute to growth retardation.
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: Severe intellectual disability
  description: >
    Severe intellectual disability is a core feature of Basel-Vanagaite-Smirin-Yosef syndrome.
  phenotype_term:
    preferred_term: Severe intellectual disability
    term:
      id: HP:0010864
      label: Severe intellectual disability
  evidence:
  - reference: PMID:25792360
    reference_title: "Homozygous MED25 mutation implicated in eye-intellectual disability syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability"
    explanation: Documents severe intellectual disability as a core feature; the snippet states the severity explicitly.
- category: Clinical
  name: Microcephaly
  description: >
    Microcephaly is a recurrent feature of the syndrome.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:25792360
    reference_title: "Homozygous MED25 mutation implicated in eye-intellectual disability syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability"
    explanation: Documents microcephaly as a recurrent feature.
- category: Ophthalmologic
  name: Eye abnormalities
  description: >
    Eye anomalies, including cataract, microcornea, and coloboma, are characteristic of the
    syndrome and give it its "eye-intellectual disability syndrome" designation.
  phenotype_term:
    preferred_term: Abnormality of the eye
    term:
      id: HP:0000478
      label: Abnormality of the eye
  evidence:
  - reference: PMID:25792360
    reference_title: "Homozygous MED25 mutation implicated in eye-intellectual disability syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability"
    explanation: >-
      Documents eye abnormalities as a characteristic feature. The cited abstract states
      only "eye ... abnormalities"; the specific cataract/microcornea/coloboma anomalies
      appear in the full text and MONDO label but not in any quotable abstract, so the
      binding is kept at the level the evidence supports rather than split into
      specifically-termed phenotypes the snippet does not state.
- category: Craniofacial
  name: Palatal abnormalities
  description: >
    Palatal anomalies are part of the craniofacial spectrum of the syndrome.
  phenotype_term:
    preferred_term: Abnormal palate morphology
    term:
      id: HP:0000174
      label: Abnormal palate morphology
  evidence:
  - reference: PMID:25792360
    reference_title: "Homozygous MED25 mutation implicated in eye-intellectual disability syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability"
    explanation: Documents palatal abnormalities as part of the syndrome.
- category: Cardiovascular
  name: Congenital heart defects
  description: >
    Cardiac abnormalities are reported as part of the multisystem phenotype.
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:25792360
    reference_title: "Homozygous MED25 mutation implicated in eye-intellectual disability syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability"
    explanation: Documents cardiac abnormalities as part of the syndrome.
- category: Growth
  name: Growth retardation
  description: >
    Growth retardation is a recurrent feature of the syndrome.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:25792360
    reference_title: "Homozygous MED25 mutation implicated in eye-intellectual disability syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability"
    explanation: Documents growth retardation as a recurrent feature.
- category: Neurologic
  name: Polymicrogyria
  description: >
    Bilateral perisylvian polymicrogyria has been reported as a distinctive neuroradiological
    feature of Basel-Vanagaite-Smirin-Yosef syndrome, refining the non-specific "brain
    abnormalities" of the original description.
  phenotype_term:
    preferred_term: Polymicrogyria
    term:
      id: HP:0002126
      label: Polymicrogyria
  evidence:
  - reference: PMID:32816121
    reference_title: "Improving the phenotype description of Basel-Vanagaite-Smirin-Yosef syndrome, MED25-related: polymicrogyria as a distinctive neuroradiological finding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report further delineates the most common clinical features of BVSYS and points to polymicrogyria as a distinctive neuroradiological feature of this syndrome."
    explanation: Establishes polymicrogyria as a distinctive neuroradiological finding in BVSYS.
genetic:
- name: MED25 biallelic founder missense variants
  association: Causative
  gene_term:
    preferred_term: MED25
    term:
      id: hgnc:28845
      label: MED25
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:25792360
      reference_title: "Homozygous MED25 mutation implicated in eye-intellectual disability syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four unrelated families"
      explanation: Homozygous MED25 founder alleles causing disease are consistent with autosomal recessive inheritance.
  features: >
    Biallelic founder missense alleles (p.Tyr39Cys; p.Ile173Thr) in the von Willebrand factor
    type A domain that impair MED25 incorporation into the Mediator complex.
  evidence:
  - reference: PMID:25792360
    reference_title: "Homozygous MED25 mutation implicated in eye-intellectual disability syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "co-immunoprecipitation experiment demonstrated that this mutation dramatically impairs MED25 interaction with the Mediator complex in mammalian cells."
    explanation: Establishes the loss-of-incorporation mechanism for the MED25 founder allele.
  - reference: PMID:30800049
    reference_title: "COQ8A and MED25 Mutations in a Child with Intellectual Disability, Microcephaly, Seizures, and Spastic Ataxia: Synergistic Effect of Digenic Variants?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Potentially causal homozygous variants in the MED25 (p.Ile173Thr) and COQ8A (p.Arg512Trp) genes were found."
    explanation: Documents the recurrent MED25 p.Ile173Thr allele in a Lebanese patient (reported with a possible digenic COQ8A contribution).
treatments:
- name: Supportive Care
  description: >
    Multidisciplinary supportive care including developmental therapies, ophthalmologic and
    cardiac management, 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 and
    founder-allele population structure, with carrier testing for at-risk relatives.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:25792360
    reference_title: "Homozygous MED25 mutation implicated in eye-intellectual disability syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four unrelated families"
    explanation: A homozygous MED25 variant in patients from unrelated consanguineous families establishes the autosomal recessive basis that warrants carrier and recurrence-risk counseling.