Baraitser-Winter Cerebrofrontofacial Syndrome

Mendelian MONDO:0017579 Pathograph 24 Show in embeddings browser Rare neurodevelopmental syndrome Cortical malformation syndrome

Heterozygous de novo gain-of-function missense variants in the cytoplasmic actin genes ACTB and ACTG1 alter actin monomer conformation and filament dynamics in a dominant manner. Disrupted actin-driven cell motility impairs radial migration of cortical neurons and the migration of cranial neural crest cells, while also perturbing optic fissure closure. The result is a cortical malformation spectrum (pachygyria to lissencephaly) with intellectual disability and epilepsy, distinctive craniofacial dysmorphism, and ocular coloboma.

Ask OpenScientist

Ask a research question about Baraitser-Winter Cerebrofrontofacial Syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

6
Pathophys.
16
Phenotypes
1
Gaps
24
Pathograph
2
Genes
2
Medical Actions
2
Subtypes
1
References
1
Deep Research
◆

Subtypes

2
Baraitser-Winter syndrome 1 (ACTB) MONDO:0009470
ACTB hgnc:132
Caused by heterozygous gain-of-function de novo missense variants in ACTB (beta-actin). Associated with a broader range of severity; ACTB mutations are enriched among the most severe cases including full lissencephaly and additional congenital anomalies.
Baraitser-Winter syndrome 2 (ACTG1) MONDO:0013812
ACTG1 hgnc:144
Caused by heterozygous gain-of-function de novo missense variants in ACTG1 (gamma-actin). Nearly all patients have some degree of pachygyria. ACTG1 mutations at different positions also cause autosomal dominant non-syndromic hearing loss DFNA20/26.
?

Discussions and Knowledge Gaps

1
How faithfully do human iPSC-derived ACTB/ACTG1 cerebral organoids explain the full in vivo Baraitser-Winter cortical malformation spectrum, including pachygyria/lissencephaly, anterior-predominant gradients and genotype-specific ACTB versus ACTG1 severity?
HUMAN MODEL MISMATCH OPEN gap_bwcff_organoid_to_human_cortical_malformation_fidelity
Attached to
pathophysiology#ACTB/ACTG1 Gain-of-Function Variants Alter Actin Dynamics pathophysiology#Impaired Neuronal Radial Migration pathophysiology#Actin-Dependent Apical Progenitor Cleavage-Plane Defect pathophysiology#Cortical Dyslamination Leading to Intellectual Disability and Epilepsy
The existing human cohort evidence establishes ACTB/ACTG1 actinopathy with pachygyria, rare lissencephaly and neuronal heterotopia, while the newer human cerebral organoid evidence directly models ventricular-zone progenitor depletion and cleavage-plane defects. The open translatability question is whether the organoid progenitor phenotype is sufficient to explain the human cortical migration/lamination pattern, or whether later fetal tissue architecture, regional patterning, radial glial scaffold organization or variant-specific actin-binding effects are required to reproduce the in vivo malformation skeleton.
Proposed experiments
ACTB/ACTG1 isogenic cerebral organoid cortical-gradient panel
isogenic cerebral organoid actinopathy assay
exp_bwcff_isogenic_organoid_variant_gradient_panel
Generate matched patient-derived, CRISPR-corrected and knock-in human cerebral organoids for recurrent ACTB and ACTG1 Baraitser-Winter variants. Quantify apical progenitor architecture, spindle/cleavage orientation, radial glial scaffold organization, neuronal migration, cortical-plate-like layering and anterior/posterior patterning marker differences, then compare variant-specific outputs with human MRI and fetal cortical tissue when available.
Model systems
Human iPSC-derived Baraitser-Winter cerebral organoid
Patient-derived or genome-edited human cerebral organoids carrying ACTB or ACTG1 missense variants with isogenic corrected controls.
ORGANOID namo:Organoid link
human NCBITaxon:9606
cerebral cortex UBERON:0000956
neural progenitor cell CL:0011020 radial glial cell CL:0000681
Perturbations
ACTB/ACTG1 variant correction and knock-in
pathophysiology#ACTB/ACTG1 Gain-of-Function Variants Alter Actin Dynamics
Correct patient variants and introduce matched variants into control iPSCs to distinguish causal actinopathy effects from donor background.
Readouts
Progenitor orientation and cortical organization fidelity
pathophysiology#Actin-Dependent Apical Progenitor Cleavage-Plane Defect
Quantify VZ thickness, apical cytoskeletal architecture, cleavage-plane orientation, radial glial scaffolding, neuronal migration distance, cortical-plate-like organization and region-patterning markers.
immunostaining live imaging single-cell transcriptomic profiling
Direction: NEGATIVE
Controls
Isogenic corrected organoids
Matched organoids in which the ACTB or ACTG1 variant is corrected.
Isogenic knock-in organoids
Wild-type-background organoids carrying introduced ACTB or ACTG1 variants.
Decision criterion
The organoid model supports the human cortical-malformation skeleton if variant correction rescues progenitor orientation and neuronal organization, and if ACTB/ACTG1-specific organoid outputs match human genotype-severity patterns and regional MRI gradients. Persistent discordance would support an additional human fetal tissue or long-range migration branch not captured by current organoids.
Would support
pathophysiology#Actin-Dependent Apical Progenitor Cleavage-Plane Defect pathophysiology#Impaired Neuronal Radial Migration pathophysiology#Cortical Dyslamination Leading to Intellectual Disability and Epilepsy
Show evidence (2 references)
PMID:25052316 SUPPORT Human Clinical
"Nearly all patients with ACTG1 mutations, and around 60% of those with ACTB mutations have some degree of pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia."
Defines the human cortical malformation pattern that the organoid model should be tested against.
DOI:10.1101/2022.12.07.519435 SUPPORT In Vitro
"Various cytoskeletal and morphological irregularities of BWCFF-S VZ progenitors, notably in the apical region of these cells, seemingly contribute to their predominantly horizontal cleavage plane orientation."
Supports the organoid-specific progenitor mechanism whose fidelity to the broader human cortical malformation remains unresolved.
⚙

Pathophysiology

6
ACTB/ACTG1 Gain-of-Function Variants Alter Actin Dynamics
Heterozygous de novo gain-of-function missense variants in ACTB (beta-actin) or ACTG1 (gamma-actin) alter the actin monomer conformation in a dominant manner, disrupting the G-actin to F-actin treadmilling equilibrium. The recurrent mutations shift the balance toward increased filamentous actin (F-actin) stability and impaired dynamic turnover, producing defective lamellipodia and filopodia formation in migrating cells throughout embryogenesis.
actin cytoskeleton organization GO:0030036 actin filament polymerization GO:0030041
Downstream
Actin-Dependent Apical Progenitor Cleavage-Plane Defect The same ACTB/ACTG1-driven actin cytoskeletal dysregulation can also perturb ventricular-zone progenitor cleavage-plane orientation in human cortical organoids.
Impaired Neuronal Radial Migration Altered actin treadmilling impairs lamellipodia-driven radial migration of cortical neurons from the ventricular zone to laminar destinations.
Disrupted Optic Fissure Closure Causing Coloboma Actin-dependent cell movements required for optic fissure closure during embryonic weeks 5-7 are impaired, preventing complete closure.
Disrupted Neural Crest Cell Migration Producing Craniofacial Features Cranial neural crest cells depend on actin-driven lamellipodia for directed migration; gain-of-function mutations impair this, producing the characteristic craniofacial gestalt.
Short Stature
Shoulder Girdle Muscle Atrophy
Sensorineural Hearing Loss
Congenital Heart Defects
Renal Malformations
Gastrointestinal Dysfunction
Show evidence (2 references)
PMID:22366783 SUPPORT Human Clinical
"Using whole-exome sequencing of three proband-parent trios, we identified de novo missense changes in the cytoplasmic actin-encoding genes ACTB and ACTG1 in one and two probands, respectively."
Establishes that de novo missense mutations in cytoplasmic actin genes ACTB and ACTG1 are the molecular cause of Baraitser-Winter syndrome.
PMID:22366783 SUPPORT Human Clinical
"Sequencing of both genes in 15 additional affected individuals identified disease-causing mutations in all probands, including two recurrent de novo alterations (ACTB, encoding p.Arg196His, and ACTG1, encoding p.Ser155Phe)."
Confirms recurrent de novo mutations in ACTB and ACTG1 as the universal genetic basis of Baraitser-Winter syndrome in a cohort of 18 patients.
Impaired Neuronal Radial Migration
Proper radial migration of post-mitotic cortical neurons from the ventricular zone to their laminar destinations requires actin-driven lamellipodia protrusion guided by radial glial scaffolding. Gain-of-function actin mutations impair this motility, causing neurons to arrest at intermediate positions and producing pachygyria (the predominant brain malformation) or in severe cases lissencephaly. The characteristic anteroposterior severity gradient in BRWS reflects regional differences in the temporal window of actin-dependent migration.
neural progenitor cell CL:0011020 radial glial cell CL:0000681
neuron migration GO:0001764 cytoskeleton organization GO:0007010
Downstream
Cortical Dyslamination Leading to Intellectual Disability and Epilepsy Neurons arrested at incorrect laminar positions produce dyslaminated cortex with disrupted thalamocortical connectivity, causing intellectual disability and epileptogenesis.
Pachygyria
Show evidence (2 references)
PMID:22366783 SUPPORT Human Clinical
"we report a study of Baraitser-Winter syndrome, a well-defined disorder characterized by distinct craniofacial features, ocular colobomata and neuronal migration defect."
The foundational paper establishes neuronal migration defect as a core pathological feature of BRWS, directly linking ACTB/ACTG1 mutations to impaired cortical migration.
PMID:25052316 SUPPORT Human Clinical
"Nearly all patients with ACTG1 mutations, and around 60% of those with ACTB mutations have some degree of pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia."
Quantifies the frequency and gradient of cortical malformation across 42 cases, confirming that impaired neuronal migration is the central neuropathological mechanism.
Actin-Dependent Apical Progenitor Cleavage-Plane Defect
Human iPSC-derived cerebral organoids carrying patient ACTB or ACTG1 missense variants support a progenitor branch in which actin cytoskeletal irregularities at the apical region of ventricular-zone progenitors alter cleavage-plane orientation. This reduces ventricular-zone progenitor abundance and links the actinopathy to microcephaly and cortical growth defects, complementing the postmitotic neuronal-migration branch.
ventricular-zone neural progenitor cell CL:0011020 radial glial progenitor CL:0000681
ACTB hgnc:132 ACTG1 hgnc:144
actin cytoskeleton organization GO:0030036 ↕ DYSREGULATED mitotic spindle organization GO:0007052 ↕ DYSREGULATED
Downstream
Cortical Dyslamination Leading to Intellectual Disability and Epilepsy The progenitor cleavage-plane branch reduces cortical progenitor output and likely compounds the neuronal migration/dyslamination branch that drives neurological disability.
Microcephaly
Show evidence (3 references)
DOI:10.1101/2022.12.07.519435 SUPPORT In Vitro
"Here we used patient-derived cerebral organoids to gain insight into the pathogenesis underlying this cortical malformation."
Establishes a human cerebral organoid model as direct model-system evidence for the cortical malformation mechanism.
DOI:10.1101/2022.12.07.519435 SUPPORT In Vitro
"Cerebral organoids from induced pluripotent stem cells (iPSCs) of patients with the Baraitser-Winter- CerebroFrontoFacial syndrome (BWCFF-S), expressing either an ACTB or an ACTG1 missense mutation, are reduced in size, showing a thinner ventricular zone (VZ)."
Supports a human iPSC-derived organoid progenitor-pool branch for ACTB and ACTG1 disease.
DOI:10.1101/2022.12.07.519435 SUPPORT In Vitro
"This decrease in VZ progenitors is in turn associated with a striking change in the orientation of their cleavage plane from predominantly vertical (control) to predominantly horizontal (BWCFF-S), which is incompatible with increasing VZ progenitor abundance."
Links reduced ventricular-zone progenitors to altered cleavage-plane orientation in the organoid model.
Cortical Dyslamination Leading to Intellectual Disability and Epilepsy
Failure of neurons to reach their correct laminar positions produces a disorganised cortex with abnormally broad gyri (pachygyria) or absent gyri (lissencephaly). The resulting cortical dyslamination disrupts thalamocortical and cortico-cortical connectivity, manifesting as intellectual disability of variable severity and epileptogenesis with refractory seizures.
Downstream
Intellectual Disability
Seizures
Global Developmental Delay
Show evidence (1 reference)
PMID:25052316 SUPPORT Human Clinical
"Intellectual disability and epilepsy are variable in severity and largely correlate with CNS anomalies."
Confirms that intellectual disability and epilepsy severity are directly related to the extent of cortical dyslamination, linking impaired neuronal migration to downstream neurological consequences.
Disrupted Optic Fissure Closure Causing Coloboma
Closure of the choroidal fissure during embryonic weeks 5-7 requires coordinated actin-dependent cell migration in the optic cup. Gain-of-function actin mutations impair this process, preventing complete fissure closure and resulting in iris or retinal coloboma. This is a direct mechanistic consequence of disrupted actin dynamics, not an incidental feature.
cytoskeleton organization GO:0007010
Downstream
Iris Coloboma
Show evidence (1 reference)
PMID:25052316 SUPPORT Human Clinical
"Iris or retinal coloboma is present in many cases, as is sensorineural deafness."
Documents coloboma as a frequent feature in the 42-case cohort, consistent with the mechanism of impaired optic fissure closure secondary to actin cytoskeletal dysfunction.
Disrupted Neural Crest Cell Migration Producing Craniofacial Features
Cranial neural crest cells that populate the craniofacial mesenchyme use actin-driven lamellipodia for directed migration. Gain-of-function actin mutations impair this process, producing the characteristic craniofacial gestalt: hypertelorism, metopic ridge, bilateral ptosis, arched eyebrows, and broad nasal bridge. These features reflect defective neural crest morphogenetic movements during craniofacial development.
migratory cranial neural crest cell CL:0000008
neural crest cell migration GO:0001755
Downstream
Congenital Ptosis
Hypertelorism
Trigonocephaly or Metopic Ridge
Wide Nasal Bridge and Broad Nose
Show evidence (1 reference)
PMID:27625340 SUPPORT Human Clinical
"characterised by intellectual disability (mild to severe) and distinctive facial appearance (metopic ridging/trigonocephaly, bilateral ptosis, hypertelorism)."
Documents the core craniofacial phenotype of BRWS, consistent with disrupted neural crest cell migration during embryonic craniofacial development.
⬡

Pathograph

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

16
Cardiovascular 1
Congenital Heart Defects OCCASIONAL Abnormal heart morphology HP:0001627
Show evidence (1 reference)
PMID:25052316 SUPPORT Human Clinical
"Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases."
Verloes et al. document congenital heart defects in some patients in the 42-case cohort, supporting an occasional frequency.
Digestive 1
Gastrointestinal Dysfunction FREQUENT Abnormality of the gastrointestinal tract HP:0011024
Show evidence (1 reference)
PMID:26583190 SUPPORT Human Clinical
"Seizures, congenital heart defects, renal malformations, and gastrointestinal dysfunction are also common."
GeneReviews lists gastrointestinal dysfunction as a common feature of BWCFF syndrome requiring routine follow-up.
Ear 1
Sensorineural Hearing Loss FREQUENT Sensorineural hearing impairment HP:0000407
Show evidence (1 reference)
PMID:26583190 SUPPORT Human Clinical
"Many (but not all) affected individuals have pachygyria that is predominantly frontal, wasting of the shoulder girdle muscles, and sensory impairment due to iris or retinal coloboma and/or sensorineural deafness."
GeneReviews documents sensorineural deafness as a frequent sensory complication in BWCFF syndrome.
Eye 2
Congenital Ptosis VERY_FREQUENT Ptosis HP:0000508
Show evidence (1 reference)
PMID:25052316 SUPPORT Human Clinical
"hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows."
Lists congenital non-myopathic ptosis as a defining facial feature in the largest clinical series of BRWS.
Hypertelorism VERY_FREQUENT Hypertelorism HP:0000316
Show evidence (1 reference)
PMID:27625340 SUPPORT Human Clinical
"characterised by intellectual disability (mild to severe) and distinctive facial appearance (metopic ridging/trigonocephaly, bilateral ptosis, hypertelorism)."
Yates et al. review establishes hypertelorism as a defining craniofacial feature of BWCFF syndrome.
Head and Neck 1
Microcephaly Microcephaly HP:0000252
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:25052316 SUPPORT Human Clinical
"Microcephaly may develop with time."
Verloes et al. note progressive postnatal-onset microcephaly in the 42-case cohort, indicating a secondary effect of cortical malformation on brain growth.
Nervous System 3
Intellectual Disability VERY_FREQUENT Intellectual disability HP:0001249
Show evidence (1 reference)
PMID:26583190 SUPPORT Human Clinical
"Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome is a multiple congenital anomaly syndrome characterized by typical craniofacial features and intellectual disability."
GeneReviews defines intellectual disability as a cardinal feature of BWCFF syndrome.
Seizures FREQUENT Seizure HP:0001250
Show evidence (1 reference)
PMID:26583190 SUPPORT Human Clinical
"Seizures, congenital heart defects, renal malformations, and gastrointestinal dysfunction are also common."
GeneReviews identifies seizures as a common manifestation in BWCFF syndrome alongside other systemic features.
Global Developmental Delay VERY_FREQUENT Global developmental delay HP:0001263
Show evidence (1 reference)
PMID:26583190 SUPPORT Human Clinical
"Intellectual disability, which is common but variable, is related to the severity of the brain malformations."
GeneReviews links cognitive and developmental delay to the cortical malformation severity in BWCFF syndrome.
Growth 1
Short Stature FREQUENT Short stature HP:0004322
Show evidence (1 reference)
PMID:27625340 SUPPORT Human Clinical
"Other features include moderate short stature, contractures, congenital cardiac disease and genitourinary malformations."
Yates et al. identify short stature as a common feature of BWCFF syndrome alongside other systemic manifestations.
Other 6
Pachygyria FREQUENT Pachygyria HP:0001302
Show evidence (1 reference)
PMID:25052316 SUPPORT Human Clinical
"Nearly all patients with ACTG1 mutations, and around 60% of those with ACTB mutations have some degree of pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia."
Quantifies pachygyria frequency by subtype in 42 cases, establishing it as the primary cortical malformation with characteristic gradient.
Iris Coloboma FREQUENT Iris coloboma HP:0000612
Show evidence (1 reference)
PMID:25052316 SUPPORT Human Clinical
"Iris or retinal coloboma is present in many cases, as is sensorineural deafness."
Documents coloboma as a frequent feature of Baraitser-Winter syndrome in a 42-case cohort.
Trigonocephaly or Metopic Ridge FREQUENT Trigonocephaly HP:0000243
Show evidence (1 reference)
PMID:25052316 SUPPORT Human Clinical
"hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows."
Documents ridged metopic suture as a consistent craniofacial feature in the 42-case Verloes cohort.
Wide Nasal Bridge and Broad Nose VERY_FREQUENT Wide nasal bridge HP:0000431
Show evidence (1 reference)
PMID:25052316 SUPPORT Human Clinical
"hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows."
Documents broad nose with large tip as a defining facial feature in the comprehensive 42-case cohort.
Shoulder Girdle Muscle Atrophy FREQUENT Shoulder girdle muscle atrophy HP:0003724
Show evidence (1 reference)
PMID:25052316 SUPPORT Human Clinical
"Reduction of shoulder girdle muscle bulk and progressive joint stiffness is common. Early muscular involvement, occasionally with congenital arthrogryposis, may be present."
Verloes et al. identify shoulder girdle muscle reduction and joint stiffness as common features in 42 BRWS cases, with occasional arthrogryposis.
Renal Malformations OCCASIONAL Abnormal renal morphology HP:0012210
Show evidence (1 reference)
PMID:25052316 SUPPORT Human Clinical
"Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases."
Verloes et al. document renal tract anomalies in some patients in the 42-case cohort, establishing it as an occasional feature of BRWS.
🧬

Genetic Associations

2
ACTB gain-of-function variants (Causative de novo gain-of-function missense variants; recurrent p.Arg196His among the most common)
Gene: ACTB hgnc:132 relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:23756437 SUPPORT Human Clinical
"We suggest that mutations in ACTB cause a distinctly more severe phenotype than ACTG1 mutations, despite the structural similarity of beta- and gamma-actins and their overlapping expression pattern."
Di Donato et al. establish that ACTB mutations produce more severe BRWS than ACTG1 mutations, including cases formerly classified as Fryns-Aftimos syndrome.
ACTG1 gain-of-function variants (Causative de novo gain-of-function missense variants)
Gene: ACTG1 hgnc:144 relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:22366783 SUPPORT Human Clinical
"our results confirm that trio-based exome sequencing is a powerful approach to discover genes causing sporadic developmental disorders, emphasize the overlapping roles of cytoplasmic actin proteins in development and suggest that Baraitser-Winter syndrome is the predominant phenotype associated..."
Establishes ACTB and ACTG1 as the two genes whose mutation causes Baraitser-Winter syndrome, with ACTG1 being identified in two of the original three patients.
💊

Medical Actions

2
Antiepileptic Therapy
Action: Pharmacotherapy NCIT:C15986
Seizures in BRWS are often refractory and require optimisation of anti-epileptic drug management. No disease-specific therapies exist.
Show evidence (1 reference)
PMID:26583190 SUPPORT Human Clinical
"management of developmental delay and intellectual disability is tailored to the individual."
GeneReviews recommends tailored management including treatment of seizures through standard specialist care, reflecting the individualised nature of antiepileptic therapy in BRWS.
Multidisciplinary Supportive Care
Action: supportive care MAXO:0000950
Multidisciplinary supportive care including ophthalmological evaluation for coloboma, audiological evaluation for hearing loss, neurological follow-up for seizures, cardiac evaluation for congenital heart defects, and physiotherapy for musculoskeletal involvement.
Show evidence (1 reference)
PMID:26583190 SUPPORT Human Clinical
"Surveillance: Routine follow up recommended for neurodevelopmental assessment in all; follow up as needed for those with seizures (neurologic evaluation), coloboma or microphthalmia (ophthalmologic evaluation), hearing loss (audiologic evaluation), cardiac defects, renal tract anomalies, and..."
GeneReviews recommends routine multidisciplinary surveillance covering the major organ systems affected in BWCFF syndrome.
{ }

Source YAML

click to show 
name: Baraitser-Winter Cerebrofrontofacial Syndrome
creation_date: "2026-06-05T00:00:00Z"
description: >-
  Heterozygous de novo gain-of-function missense variants in the cytoplasmic actin genes ACTB and ACTG1 alter actin monomer conformation and filament dynamics in a dominant manner.
  Disrupted actin-driven cell motility impairs radial migration of cortical neurons and the migration of cranial neural crest cells, while also perturbing optic fissure closure.
  The result is a cortical malformation spectrum (pachygyria to lissencephaly) with intellectual disability and epilepsy, distinctive craniofacial dysmorphism, and ocular coloboma.
category: Mendelian
disease_term:
  preferred_term: Baraitser-Winter cerebrofrontofacial syndrome
  term:
    id: MONDO:0017579
    label: Baraitser-Winter cerebrofrontofacial syndrome
references:
- reference: PMID:26583190
  title: "Baraitser-Winter Cerebrofrontofacial Syndrome."
  tags:
  - GeneReviews

parents:
- Rare neurodevelopmental syndrome
- Cortical malformation syndrome

has_subtypes:
- name: BRWS1
  display_name: Baraitser-Winter syndrome 1 (ACTB)
  description: >
    Caused by heterozygous gain-of-function de novo missense variants in ACTB
    (beta-actin). Associated with a broader range of severity; ACTB mutations
    are enriched among the most severe cases including full lissencephaly and
    additional congenital anomalies.
  subtype_term:
    preferred_term: Baraitser-Winter syndrome 1
    term:
      id: MONDO:0009470
      label: Baraitser-Winter syndrome 1
  genes:
  - preferred_term: ACTB
    term:
      id: hgnc:132
      label: ACTB

- name: BRWS2
  display_name: Baraitser-Winter syndrome 2 (ACTG1)
  description: >
    Caused by heterozygous gain-of-function de novo missense variants in ACTG1
    (gamma-actin). Nearly all patients have some degree of pachygyria. ACTG1
    mutations at different positions also cause autosomal dominant non-syndromic
    hearing loss DFNA20/26.
  subtype_term:
    preferred_term: Baraitser-winter syndrome 2
    term:
      id: MONDO:0013812
      label: Baraitser-winter syndrome 2
  genes:
  - preferred_term: ACTG1
    term:
      id: hgnc:144
      label: ACTG1

pathophysiology:
- name: ACTB/ACTG1 Gain-of-Function Variants Alter Actin Dynamics
  description: >
    Heterozygous de novo gain-of-function missense variants in ACTB (beta-actin)
    or ACTG1 (gamma-actin) alter the actin monomer conformation in a dominant
    manner, disrupting the G-actin to F-actin treadmilling equilibrium. The
    recurrent mutations shift the balance toward increased filamentous actin
    (F-actin) stability and impaired dynamic turnover, producing defective
    lamellipodia and filopodia formation in migrating cells throughout
    embryogenesis.
  biological_processes:
  - preferred_term: actin cytoskeleton organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
  - preferred_term: actin filament polymerization
    term:
      id: GO:0030041
      label: actin filament polymerization
  evidence:
  - reference: PMID:22366783
    reference_title: "De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using whole-exome sequencing of three proband-parent trios, we
      identified de novo missense changes in the cytoplasmic actin-encoding
      genes ACTB and ACTG1 in one and two probands, respectively.
    explanation: >-
      Establishes that de novo missense mutations in cytoplasmic actin genes
      ACTB and ACTG1 are the molecular cause of Baraitser-Winter syndrome.
  - reference: PMID:22366783
    reference_title: "De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequencing of both genes in 15 additional affected individuals
      identified disease-causing mutations in all probands, including two
      recurrent de novo alterations (ACTB, encoding p.Arg196His, and ACTG1,
      encoding p.Ser155Phe).
    explanation: >-
      Confirms recurrent de novo mutations in ACTB and ACTG1 as the
      universal genetic basis of Baraitser-Winter syndrome in a cohort of 18
      patients.
  downstream:
  - target: Actin-Dependent Apical Progenitor Cleavage-Plane Defect
    description: >-
      The same ACTB/ACTG1-driven actin cytoskeletal dysregulation can also
      perturb ventricular-zone progenitor cleavage-plane orientation in human
      cortical organoids.
  - target: Impaired Neuronal Radial Migration
    description: >-
      Altered actin treadmilling impairs lamellipodia-driven radial migration
      of cortical neurons from the ventricular zone to laminar destinations.
  - target: Disrupted Optic Fissure Closure Causing Coloboma
    description: >-
      Actin-dependent cell movements required for optic fissure closure during
      embryonic weeks 5-7 are impaired, preventing complete closure.
  - target: Disrupted Neural Crest Cell Migration Producing Craniofacial Features
    description: >-
      Cranial neural crest cells depend on actin-driven lamellipodia for
      directed migration; gain-of-function mutations impair this, producing
      the characteristic craniofacial gestalt.
  - target: Short Stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Shoulder Girdle Muscle Atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Sensorineural Hearing Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Congenital Heart Defects
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Renal Malformations
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Gastrointestinal Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES

- name: Impaired Neuronal Radial Migration
  description: >
    Proper radial migration of post-mitotic cortical neurons from the
    ventricular zone to their laminar destinations requires actin-driven
    lamellipodia protrusion guided by radial glial scaffolding. Gain-of-function
    actin mutations impair this motility, causing neurons to arrest at
    intermediate positions and producing pachygyria (the predominant brain
    malformation) or in severe cases lissencephaly. The characteristic
    anteroposterior severity gradient in BRWS reflects regional differences
    in the temporal window of actin-dependent migration.
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  - preferred_term: radial glial cell
    term:
      id: CL:0000681
      label: radial glial cell
  biological_processes:
  - preferred_term: neuron migration
    term:
      id: GO:0001764
      label: neuron migration
  - preferred_term: cytoskeleton organization
    term:
      id: GO:0007010
      label: cytoskeleton organization
  evidence:
  - reference: PMID:22366783
    reference_title: "De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we report a study of Baraitser-Winter syndrome, a well-defined disorder
      characterized by distinct craniofacial features, ocular colobomata and
      neuronal migration defect.
    explanation: >-
      The foundational paper establishes neuronal migration defect as a core
      pathological feature of BRWS, directly linking ACTB/ACTG1 mutations to
      impaired cortical migration.
  - reference: PMID:25052316
    reference_title: "Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nearly all patients with ACTG1 mutations, and around 60% of those with
      ACTB mutations have some degree of pachygyria with anteroposterior
      severity gradient, rarely lissencephaly or neuronal heterotopia.
    explanation: >-
      Quantifies the frequency and gradient of cortical malformation across
      42 cases, confirming that impaired neuronal migration is the central
      neuropathological mechanism.
  downstream:
  - target: Cortical Dyslamination Leading to Intellectual Disability and Epilepsy
    description: >-
      Neurons arrested at incorrect laminar positions produce dyslaminated
      cortex with disrupted thalamocortical connectivity, causing intellectual
      disability and epileptogenesis.
  - target: Pachygyria
    causal_link_type: DIRECT

- name: Actin-Dependent Apical Progenitor Cleavage-Plane Defect
  description: >-
    Human iPSC-derived cerebral organoids carrying patient ACTB or ACTG1
    missense variants support a progenitor branch in which actin cytoskeletal
    irregularities at the apical region of ventricular-zone progenitors alter
    cleavage-plane orientation. This reduces ventricular-zone progenitor
    abundance and links the actinopathy to microcephaly and cortical growth
    defects, complementing the postmitotic neuronal-migration branch.
  genes:
  - preferred_term: ACTB
    term:
      id: hgnc:132
      label: ACTB
  - preferred_term: ACTG1
    term:
      id: hgnc:144
      label: ACTG1
  cell_types:
  - preferred_term: ventricular-zone neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  - preferred_term: radial glial progenitor
    term:
      id: CL:0000681
      label: radial glial cell
  biological_processes:
  - preferred_term: actin cytoskeleton organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
    modifier: DYSREGULATED
  - preferred_term: mitotic spindle organization
    term:
      id: GO:0007052
      label: mitotic spindle organization
    modifier: DYSREGULATED
  evidence:
  - reference: DOI:10.1101/2022.12.07.519435
    reference_title: "Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here we used patient-derived cerebral organoids to gain insight into
      the pathogenesis underlying this cortical malformation.
    explanation: >-
      Establishes a human cerebral organoid model as direct model-system
      evidence for the cortical malformation mechanism.
  - reference: DOI:10.1101/2022.12.07.519435
    reference_title: "Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cerebral organoids from induced pluripotent stem cells (iPSCs) of
      patients with the Baraitser-Winter- CerebroFrontoFacial syndrome
      (BWCFF-S), expressing either an ACTB or an ACTG1 missense mutation,
      are reduced in size, showing a thinner ventricular zone (VZ).
    explanation: >-
      Supports a human iPSC-derived organoid progenitor-pool branch for ACTB
      and ACTG1 disease.
  - reference: DOI:10.1101/2022.12.07.519435
    reference_title: "Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This decrease in VZ progenitors is in turn associated with a striking
      change in the orientation of their cleavage plane from predominantly
      vertical (control) to predominantly horizontal (BWCFF-S), which is
      incompatible with increasing VZ progenitor abundance.
    explanation: >-
      Links reduced ventricular-zone progenitors to altered cleavage-plane
      orientation in the organoid model.
  downstream:
  - target: Cortical Dyslamination Leading to Intellectual Disability and Epilepsy
    description: >-
      The progenitor cleavage-plane branch reduces cortical progenitor output
      and likely compounds the neuronal migration/dyslamination branch that
      drives neurological disability.
  - target: Microcephaly
    causal_link_type: DIRECT

- name: Cortical Dyslamination Leading to Intellectual Disability and Epilepsy
  description: >
    Failure of neurons to reach their correct laminar positions produces a
    disorganised cortex with abnormally broad gyri (pachygyria) or absent gyri
    (lissencephaly). The resulting cortical dyslamination disrupts
    thalamocortical and cortico-cortical connectivity, manifesting as
    intellectual disability of variable severity and epileptogenesis with
    refractory seizures.
  evidence:
  - reference: PMID:25052316
    reference_title: "Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intellectual disability and epilepsy are variable in severity and
      largely correlate with CNS anomalies.
    explanation: >-
      Confirms that intellectual disability and epilepsy severity are directly
      related to the extent of cortical dyslamination, linking impaired
      neuronal migration to downstream neurological consequences.
  downstream:
  - target: Intellectual Disability
    causal_link_type: DIRECT
  - target: Seizures
    causal_link_type: DIRECT
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES

- name: Disrupted Optic Fissure Closure Causing Coloboma
  description: >
    Closure of the choroidal fissure during embryonic weeks 5-7 requires
    coordinated actin-dependent cell migration in the optic cup. Gain-of-function
    actin mutations impair this process, preventing complete fissure closure and
    resulting in iris or retinal coloboma. This is a direct mechanistic
    consequence of disrupted actin dynamics, not an incidental feature.
  biological_processes:
  - preferred_term: cytoskeleton organization
    term:
      id: GO:0007010
      label: cytoskeleton organization
  evidence:
  - reference: PMID:25052316
    reference_title: "Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Iris or retinal coloboma is present in many cases, as is sensorineural
      deafness.
    explanation: >-
      Documents coloboma as a frequent feature in the 42-case cohort,
      consistent with the mechanism of impaired optic fissure closure
      secondary to actin cytoskeletal dysfunction.
  downstream:
  - target: Iris Coloboma
    causal_link_type: DIRECT

- name: Disrupted Neural Crest Cell Migration Producing Craniofacial Features
  description: >
    Cranial neural crest cells that populate the craniofacial mesenchyme use
    actin-driven lamellipodia for directed migration. Gain-of-function actin
    mutations impair this process, producing the characteristic craniofacial
    gestalt: hypertelorism, metopic ridge, bilateral ptosis, arched eyebrows,
    and broad nasal bridge. These features reflect defective neural crest
    morphogenetic movements during craniofacial development.
  cell_types:
  - preferred_term: migratory cranial neural crest cell
    term:
      id: CL:0000008
      label: migratory cranial neural crest cell
  biological_processes:
  - preferred_term: neural crest cell migration
    term:
      id: GO:0001755
      label: neural crest cell migration
  evidence:
  - reference: PMID:27625340
    reference_title: "Baraitser-Winter cerebrofrontofacial syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterised by intellectual disability (mild to severe) and
      distinctive facial appearance (metopic ridging/trigonocephaly, bilateral
      ptosis, hypertelorism).
    explanation: >-
      Documents the core craniofacial phenotype of BRWS, consistent with
      disrupted neural crest cell migration during embryonic craniofacial
      development.
  downstream:
  - target: Congenital Ptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypertelorism
    causal_link_type: DIRECT
  - target: Trigonocephaly or Metopic Ridge
    causal_link_type: DIRECT
  - target: Wide Nasal Bridge and Broad Nose
    causal_link_type: DIRECT

phenotypes:
- name: Pachygyria
  description: >
    Pachygyria with anteroposterior severity gradient is the hallmark cortical
    malformation. ACTG1 mutations cause pachygyria in nearly all cases; ACTB
    mutations in approximately 60%. Lissencephaly occurs in more severe cases,
    predominantly with ACTB mutations.
  category: Neurological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Pachygyria
    term:
      id: HP:0001302
      label: Pachygyria
  evidence:
  - reference: PMID:25052316
    reference_title: "Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nearly all patients with ACTG1 mutations, and around 60% of those with
      ACTB mutations have some degree of pachygyria with anteroposterior
      severity gradient, rarely lissencephaly or neuronal heterotopia.
    explanation: >-
      Quantifies pachygyria frequency by subtype in 42 cases, establishing it
      as the primary cortical malformation with characteristic gradient.

- name: Microcephaly
  description: >
    Postnatal-onset microcephaly may develop over time in some patients,
    reflecting progressive secondary effects of cortical dyslamination on
    brain growth.
  category: Neurological
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:25052316
    reference_title: "Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microcephaly may develop with time.
    explanation: >-
      Verloes et al. note progressive postnatal-onset microcephaly in the
      42-case cohort, indicating a secondary effect of cortical malformation
      on brain growth.

- name: Intellectual Disability
  description: Intellectual disability of variable severity, correlated with the degree of cortical malformation.
  category: Neurological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:26583190
    reference_title: "Baraitser-Winter Cerebrofrontofacial Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome is a multiple
      congenital anomaly syndrome characterized by typical craniofacial
      features and intellectual disability.
    explanation: >-
      GeneReviews defines intellectual disability as a cardinal feature of
      BWCFF syndrome.

- name: Seizures
  description: Epileptic seizures of variable severity, often refractory.
  category: Neurological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:26583190
    reference_title: "Baraitser-Winter Cerebrofrontofacial Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizures, congenital heart defects, renal malformations, and
      gastrointestinal dysfunction are also common.
    explanation: >-
      GeneReviews identifies seizures as a common manifestation in BWCFF
      syndrome alongside other systemic features.

- name: Global Developmental Delay
  description: Delays in motor and cognitive milestones.
  category: Neurological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:26583190
    reference_title: "Baraitser-Winter Cerebrofrontofacial Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intellectual disability, which is common but variable, is related to
      the severity of the brain malformations.
    explanation: >-
      GeneReviews links cognitive and developmental delay to the cortical
      malformation severity in BWCFF syndrome.

- name: Iris Coloboma
  description: >
    Iris or retinal coloboma due to failure of optic fissure closure. A
    distinctive ocular feature present in many cases.
  category: Ophthalmological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Iris coloboma
    term:
      id: HP:0000612
      label: Iris coloboma
  evidence:
  - reference: PMID:25052316
    reference_title: "Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Iris or retinal coloboma is present in many cases, as is sensorineural
      deafness.
    explanation: >-
      Documents coloboma as a frequent feature of Baraitser-Winter syndrome
      in a 42-case cohort.

- name: Congenital Ptosis
  description: >
    Bilateral congenital non-myopathic ptosis is a cardinal craniofacial
    feature, reflecting disrupted neural crest cell migration affecting
    levator palpebrae muscle development.
  category: Ophthalmological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Congenital ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:25052316
    reference_title: "Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypertelorism, broad nose with large tip and prominent root, congenital
      non-myopathic ptosis, ridged metopic suture and arched eyebrows.
    explanation: >-
      Lists congenital non-myopathic ptosis as a defining facial feature in
      the largest clinical series of BRWS.

- name: Hypertelorism
  description: Widely spaced eyes, a consistent craniofacial feature.
  category: Craniofacial
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:27625340
    reference_title: "Baraitser-Winter cerebrofrontofacial syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterised by intellectual disability (mild to severe) and
      distinctive facial appearance (metopic ridging/trigonocephaly, bilateral
      ptosis, hypertelorism).
    explanation: >-
      Yates et al. review establishes hypertelorism as a defining craniofacial
      feature of BWCFF syndrome.

- name: Trigonocephaly or Metopic Ridge
  description: >
    Ridged metopic suture or trigonocephaly (metopic synostosis) is a
    characteristic craniofacial feature resulting from early fusion or
    prominence of the metopic suture. Reflects the impact of disrupted neural
    crest cell migration on calvarial bone morphogenesis.
  category: Craniofacial
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Trigonocephaly
    term:
      id: HP:0000243
      label: Trigonocephaly
  evidence:
  - reference: PMID:25052316
    reference_title: "Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypertelorism, broad nose with large tip and prominent root, congenital
      non-myopathic ptosis, ridged metopic suture and arched eyebrows.
    explanation: >-
      Documents ridged metopic suture as a consistent craniofacial feature in
      the 42-case Verloes cohort.

- name: Wide Nasal Bridge and Broad Nose
  description: Broad nasal bridge with large nasal tip is a prominent craniofacial feature.
  category: Craniofacial
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Wide nasal bridge
    term:
      id: HP:0000431
      label: Wide nasal bridge
  evidence:
  - reference: PMID:25052316
    reference_title: "Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypertelorism, broad nose with large tip and prominent root, congenital
      non-myopathic ptosis, ridged metopic suture and arched eyebrows.
    explanation: >-
      Documents broad nose with large tip as a defining facial feature in the
      comprehensive 42-case cohort.

- name: Short Stature
  description: Moderate short stature is a common systemic feature.
  category: Growth
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:27625340
    reference_title: "Baraitser-Winter cerebrofrontofacial syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other features include moderate short stature, contractures, congenital
      cardiac disease and genitourinary malformations.
    explanation: >-
      Yates et al. identify short stature as a common feature of BWCFF
      syndrome alongside other systemic manifestations.

- name: Shoulder Girdle Muscle Atrophy
  description: >
    Reduction of shoulder girdle muscle bulk is a recognised feature of BRWS,
    sometimes associated with progressive joint stiffness. Early muscular
    involvement may present as arthrogryposis in some cases.
  category: Musculoskeletal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Shoulder girdle muscle atrophy
    term:
      id: HP:0003724
      label: Shoulder girdle muscle atrophy
  evidence:
  - reference: PMID:25052316
    reference_title: "Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Reduction of shoulder girdle muscle bulk and progressive joint stiffness
      is common. Early muscular involvement, occasionally with congenital
      arthrogryposis, may be present.
    explanation: >-
      Verloes et al. identify shoulder girdle muscle reduction and joint
      stiffness as common features in 42 BRWS cases, with occasional
      arthrogryposis.

- name: Sensorineural Hearing Loss
  description: >
    Sensorineural hearing impairment affecting both subtypes, though more
    frequently reported in BRWS2 (ACTG1) given gamma-actin's role in auditory
    hair cell stereocilia.
  category: Auditory
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Sensorineural hearing loss
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:26583190
    reference_title: "Baraitser-Winter Cerebrofrontofacial Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many (but not all) affected individuals have pachygyria that is
      predominantly frontal, wasting of the shoulder girdle muscles, and
      sensory impairment due to iris or retinal coloboma and/or sensorineural
      deafness.
    explanation: >-
      GeneReviews documents sensorineural deafness as a frequent sensory
      complication in BWCFF syndrome.

- name: Congenital Heart Defects
  description: >
    Structural cardiac anomalies occur in some patients with BWCFF syndrome.
  category: Cardiovascular
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:25052316
    reference_title: "Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cleft lip and palate, hallux duplex, congenital heart defects and renal
      tract anomalies are seen in some cases.
    explanation: >-
      Verloes et al. document congenital heart defects in some patients in
      the 42-case cohort, supporting an occasional frequency.

- name: Renal Malformations
  description: Renal tract anomalies are seen in some patients.
  category: Renal
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Abnormal renal morphology
    term:
      id: HP:0012210
      label: Abnormal renal morphology
  evidence:
  - reference: PMID:25052316
    reference_title: "Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cleft lip and palate, hallux duplex, congenital heart defects and renal
      tract anomalies are seen in some cases.
    explanation: >-
      Verloes et al. document renal tract anomalies in some patients in the
      42-case cohort, establishing it as an occasional feature of BRWS.

- name: Gastrointestinal Dysfunction
  description: >
    Gastrointestinal problems are reported in some patients with BWCFF syndrome.
    GeneReviews recommends routine surveillance and follow-up for gastrointestinal
    dysfunction as part of standard management.
  category: Gastrointestinal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormality of the gastrointestinal tract
    term:
      id: HP:0011024
      label: Abnormality of the gastrointestinal tract
  evidence:
  - reference: PMID:26583190
    reference_title: "Baraitser-Winter Cerebrofrontofacial Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizures, congenital heart defects, renal malformations, and
      gastrointestinal dysfunction are also common.
    explanation: >-
      GeneReviews lists gastrointestinal dysfunction as a common feature of
      BWCFF syndrome requiring routine follow-up.

genetic:
- name: ACTB gain-of-function variants
  gene_term:
    preferred_term: ACTB
    term:
      id: hgnc:132
      label: ACTB
  association: >-
    Causative de novo gain-of-function missense variants; recurrent p.Arg196His
    among the most common
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: BRWS1
  notes: >
    Most pathogenic variants are de novo missense substitutions. ACTB mutations
    are enriched among severe phenotypes including lissencephaly and additional
    congenital anomalies. Autosomal dominant inheritance.
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:23756437
    reference_title: "Severe forms of Baraitser-Winter syndrome are caused by ACTB mutations rather than ACTG1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We suggest that mutations in ACTB cause a distinctly more severe
      phenotype than ACTG1 mutations, despite the structural similarity of
      beta- and gamma-actins and their overlapping expression pattern.
    explanation: >-
      Di Donato et al. establish that ACTB mutations produce more severe
      BRWS than ACTG1 mutations, including cases formerly classified as
      Fryns-Aftimos syndrome.

- name: ACTG1 gain-of-function variants
  gene_term:
    preferred_term: ACTG1
    term:
      id: hgnc:144
      label: ACTG1
  association: Causative de novo gain-of-function missense variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: BRWS2
  notes: >
    Mutations cluster at positions equivalent to ACTB hotspots. ACTG1 variants
    at different positions cause autosomal dominant non-syndromic hearing loss
    DFNA20/26. Nearly all BRWS2 patients have some degree of pachygyria.
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:22366783
    reference_title: "De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      our results confirm that trio-based exome sequencing is a powerful
      approach to discover genes causing sporadic developmental disorders,
      emphasize the overlapping roles of cytoplasmic actin proteins in
      development and suggest that Baraitser-Winter syndrome is the
      predominant phenotype associated with mutation of these two genes.
    explanation: >-
      Establishes ACTB and ACTG1 as the two genes whose mutation causes
      Baraitser-Winter syndrome, with ACTG1 being identified in two of the
      original three patients.

treatments:
- name: Antiepileptic Therapy
  description: >
    Seizures in BRWS are often refractory and require optimisation of
    anti-epileptic drug management. No disease-specific therapies exist.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:26583190
    reference_title: "Baraitser-Winter Cerebrofrontofacial Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      management of developmental delay and intellectual disability is
      tailored to the individual.
    explanation: >-
      GeneReviews recommends tailored management including treatment of
      seizures through standard specialist care, reflecting the individualised
      nature of antiepileptic therapy in BRWS.

- name: Multidisciplinary Supportive Care
  description: >
    Multidisciplinary supportive care including ophthalmological evaluation for
    coloboma, audiological evaluation for hearing loss, neurological follow-up
    for seizures, cardiac evaluation for congenital heart defects, and
    physiotherapy for musculoskeletal involvement.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:26583190
    reference_title: "Baraitser-Winter Cerebrofrontofacial Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surveillance: Routine follow up recommended for neurodevelopmental
      assessment in all; follow up as needed for those with seizures
      (neurologic evaluation), coloboma or microphthalmia (ophthalmologic
      evaluation), hearing loss (audiologic evaluation), cardiac defects,
      renal tract anomalies, and gastrointestinal dysfunction.
    explanation: >-
      GeneReviews recommends routine multidisciplinary surveillance covering
      the major organ systems affected in BWCFF syndrome.

discussions:
- discussion_id: gap_bwcff_organoid_to_human_cortical_malformation_fidelity
  prompt: >-
    How faithfully do human iPSC-derived ACTB/ACTG1 cerebral organoids explain
    the full in vivo Baraitser-Winter cortical malformation spectrum,
    including pachygyria/lissencephaly, anterior-predominant gradients and
    genotype-specific ACTB versus ACTG1 severity?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#ACTB/ACTG1 Gain-of-Function Variants Alter Actin Dynamics
  - pathophysiology#Impaired Neuronal Radial Migration
  - pathophysiology#Actin-Dependent Apical Progenitor Cleavage-Plane Defect
  - pathophysiology#Cortical Dyslamination Leading to Intellectual Disability and Epilepsy
  rationale: >-
    The existing human cohort evidence establishes ACTB/ACTG1 actinopathy with
    pachygyria, rare lissencephaly and neuronal heterotopia, while the newer
    human cerebral organoid evidence directly models ventricular-zone
    progenitor depletion and cleavage-plane defects. The open translatability
    question is whether the organoid progenitor phenotype is sufficient to
    explain the human cortical migration/lamination pattern, or whether
    later fetal tissue architecture, regional patterning, radial glial scaffold
    organization or variant-specific actin-binding effects are required to
    reproduce the in vivo malformation skeleton.
  evidence:
  - reference: PMID:25052316
    reference_title: "Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nearly all patients with ACTG1 mutations, and around 60% of those with
      ACTB mutations have some degree of pachygyria with anteroposterior
      severity gradient, rarely lissencephaly or neuronal heterotopia.
    explanation: >-
      Defines the human cortical malformation pattern that the organoid
      model should be tested against.
  - reference: DOI:10.1101/2022.12.07.519435
    reference_title: "Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Various cytoskeletal and morphological irregularities of BWCFF-S VZ
      progenitors, notably in the apical region of these cells, seemingly
      contribute to their predominantly horizontal cleavage plane
      orientation.
    explanation: >-
      Supports the organoid-specific progenitor mechanism whose fidelity to
      the broader human cortical malformation remains unresolved.
  proposed_experiments:
  - experiment_id: exp_bwcff_isogenic_organoid_variant_gradient_panel
    name: ACTB/ACTG1 isogenic cerebral organoid cortical-gradient panel
    description: >-
      Generate matched patient-derived, CRISPR-corrected and knock-in human
      cerebral organoids for recurrent ACTB and ACTG1 Baraitser-Winter
      variants. Quantify apical progenitor architecture, spindle/cleavage
      orientation, radial glial scaffold organization, neuronal migration,
      cortical-plate-like layering and anterior/posterior patterning marker
      differences, then compare variant-specific outputs with human MRI and
      fetal cortical tissue when available.
    experiment_type:
      preferred_term: isogenic cerebral organoid actinopathy assay
    model_systems:
    - name: Human iPSC-derived Baraitser-Winter cerebral organoid
      description: >-
        Patient-derived or genome-edited human cerebral organoids carrying
        ACTB or ACTG1 missense variants with isogenic corrected controls.
      experimental_model_type: ORGANOID
      namo_type: namo:Organoid
      organism:
        preferred_term: human
        term:
          id: NCBITaxon:9606
          label: Homo sapiens
      tissue_term:
        preferred_term: cerebral cortex
        term:
          id: UBERON:0000956
          label: cerebral cortex
      cell_types:
      - preferred_term: neural progenitor cell
        term:
          id: CL:0011020
          label: neural progenitor cell
      - preferred_term: radial glial cell
        term:
          id: CL:0000681
          label: radial glial cell
      cell_source: Patient-derived or isogenic engineered human induced pluripotent stem cells
      culture_system: Three-dimensional cerebral organoid with imaging and single-cell readouts
    perturbations:
    - name: ACTB/ACTG1 variant correction and knock-in
      target: pathophysiology#ACTB/ACTG1 Gain-of-Function Variants Alter Actin Dynamics
      description: >-
        Correct patient variants and introduce matched variants into
        control iPSCs to distinguish causal actinopathy effects from donor
        background.
    readouts:
    - name: Progenitor orientation and cortical organization fidelity
      target: pathophysiology#Actin-Dependent Apical Progenitor Cleavage-Plane Defect
      description: >-
        Quantify VZ thickness, apical cytoskeletal architecture,
        cleavage-plane orientation, radial glial scaffolding, neuronal
        migration distance, cortical-plate-like organization and
        region-patterning markers.
      assays:
      - preferred_term: immunostaining
      - preferred_term: live imaging
      - preferred_term: single-cell transcriptomic profiling
      direction: NEGATIVE
    controls:
    - name: Isogenic corrected organoids
      description: Matched organoids in which the ACTB or ACTG1 variant is corrected.
    - name: Isogenic knock-in organoids
      description: Wild-type-background organoids carrying introduced ACTB or ACTG1 variants.
    decision_criterion: >-
      The organoid model supports the human cortical-malformation skeleton if
      variant correction rescues progenitor orientation and neuronal
      organization, and if ACTB/ACTG1-specific organoid outputs match human
      genotype-severity patterns and regional MRI gradients. Persistent
      discordance would support an additional human fetal tissue or
      long-range migration branch not captured by current organoids.
    would_support:
    - pathophysiology#Actin-Dependent Apical Progenitor Cleavage-Plane Defect
    - pathophysiology#Impaired Neuronal Radial Migration
    - pathophysiology#Cortical Dyslamination Leading to Intellectual Disability and Epilepsy
📚

References & Deep Research

References

1
PMID:26583190
Baraitser-Winter Cerebrofrontofacial Syndrome.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Baraitser–Winter Cerebrofrontofacial Syndrome (BWCFF) — Comprehensive Disease Characteristics Report
Edison Scientific Literature 35 citations 2026-06-11T20:25:02.565930

Baraitser–Winter Cerebrofrontofacial Syndrome (BWCFF) — Comprehensive Disease Characteristics Report

Target disease

Disease name: Baraitser–Winter cerebrofrontofacial syndrome (BWCFF)
Category: Mendelian (autosomal dominant actinopathy)
MONDO ID: Not located in the retrieved sources (should be added from MONDO/NCBI resources in a follow-on curation step).

Executive overview (current understanding)

Baraitser–Winter cerebrofrontofacial syndrome is a rare neurodevelopmental multiple-congenital-anomaly syndrome characterized by a distinctive craniofacial gestalt, ocular coloboma, and cortical malformations consistent with a neuronal migration disorder (often pachygyria/lissencephaly spectrum), with variable intellectual disability, epilepsy, and sensorineural hearing loss. It is caused predominantly by heterozygous de novo missense variants in the cytoplasmic actin genes ACTB (β-actin) or ACTG1 (γ-actin), with genotype–phenotype differences across genes and across specific amino-acid substitutions. (nie2022identificationofa pages 1-2, riviere2012denovomutations pages 9-12, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5)

A key primary-discovery abstract quote (2012) captures the defining causal model: - “Using whole-exome sequencing of three proband-parent trios, we identified de novo missense changes in the cytoplasmic actin–encoding genes ACTB and ACTG1…” (Rivière et al., Nature Genetics, 2012; DOI: https://doi.org/10.1038/ng.1091) (riviere2012denovomutations pages 5-9)

1. Disease information

1.1 What is the disease?

BWCFF is a molecularly defined actinopathy combining craniofacial dysmorphism and anterior-predominant cortical malformations (pachygyria/lissencephaly), frequently with ptosis, hypertelorism, arched eyebrows, broad nasal tip, ocular coloboma, developmental delay/intellectual disability, seizures, and sensorineural hearing loss. (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 3-4, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 1-2)

1.2 Key identifiers and synonyms

The literature uses OMIM disease identifiers #243310 and #614583 (sometimes treated as “types”), and discusses overlap/reclassification with Fryns–Aftimos syndrome (OMIM 606155). (riviere2012denovomutations pages 5-9, donato2014severeformsof pages 1-3, aiyar2019prenatalpresentationin pages 2-3, dawidziuk2022denovoactg1 pages 1-2)

Identifier type Value Notes/definition Source
Preferred disease name / synonym Baraitser–Winter cerebrofrontofacial syndrome (BWCFF) Unified designation proposed for previously separated clinical labels including Baraitser–Winter syndrome / Baraitser–Winter malformation syndrome and some Fryns–Aftimos / cerebrofrontofacial presentations; rare autosomal-dominant developmental disorder linked to ACTB or ACTG1 variants. (nie2022identificationofa pages 1-2, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 2-3, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 1-2) Nie et al., 2022, Front Genet. https://doi.org/10.3389/fgene.2022.828120 ; Verloes et al., 2015, Eur J Hum Genet. https://doi.org/10.1038/ejhg.2014.95
OMIM disease # OMIM 243310 Explicitly cited in multiple papers for Baraitser–Winter syndrome / BWCFF. (riviere2012denovomutations pages 5-9, nie2022identificationofa pages 1-2, donato2014severeformsof pages 1-3, aiyar2019prenatalpresentationin pages 2-3, dawidziuk2022denovoactg1 pages 1-2) Rivière et al., 2012, Nat Genet. https://doi.org/10.1038/ng.1091 ; Nie et al., 2022, Front Genet. https://doi.org/10.3389/fgene.2022.828120 ; Donato et al., 2014, Eur J Hum Genet. https://doi.org/10.1038/ejhg.2013.130 ; Aiyar et al., 2019, Clin Dysmorphol. https://doi.org/10.1097/MCD.0000000000000266 ; Dawidziuk et al., 2022, Int J Mol Sci. https://doi.org/10.3390/ijms23020692
OMIM disease # / syndrome type label OMIM 614583 Cited as the second OMIM Baraitser–Winter entry / “type” in literature; associated with ACTG1-related disease in syndrome-type usage. (donato2014severeformsof pages 1-3, aiyar2019prenatalpresentationin pages 2-3, dawidziuk2022denovoactg1 pages 1-2) Donato et al., 2014, Eur J Hum Genet. https://doi.org/10.1038/ejhg.2013.130 ; Aiyar et al., 2019, Clin Dysmorphol. https://doi.org/10.1097/MCD.0000000000000266 ; Dawidziuk et al., 2022, Int J Mol Sci. https://doi.org/10.3390/ijms23020692
Other OMIM overlap OMIM 606155 (Fryns–Aftimos syndrome) Reported phenotypic overlap/reclassification; some patients originally labeled Fryns–Aftimos were found to harbor ACTB mutations and are considered within the Baraitser–Winter spectrum. (riviere2012denovomutations pages 5-9, donato2014severeformsof pages 1-3) Rivière et al., 2012, Nat Genet. https://doi.org/10.1038/ng.1091 ; Donato et al., 2014, Eur J Hum Genet. https://doi.org/10.1038/ejhg.2013.130
Syndrome type label BRWS1 Used in recent literature for ACTB-associated Baraitser–Winter syndrome. (dawidziuk2022denovoactg1 pages 1-2) Dawidziuk et al., 2022, Int J Mol Sci. https://doi.org/10.3390/ijms23020692
Syndrome type label BRWS2 Used in recent literature for ACTG1-associated Baraitser–Winter syndrome. (dawidziuk2022denovoactg1 pages 1-2) Dawidziuk et al., 2022, Int J Mol Sci. https://doi.org/10.3390/ijms23020692
Historical synonym Baraitser–Winter syndrome Short disease name used throughout early and later primary literature; characterized by craniofacial anomalies, ocular coloboma, and neuronal migration defects. (riviere2012denovomutations pages 5-9, donato2014severeformsof pages 1-3) Rivière et al., 2012, Nat Genet. https://doi.org/10.1038/ng.1091 ; Donato et al., 2014, Eur J Hum Genet. https://doi.org/10.1038/ejhg.2013.130
Historical synonym Baraitser–Winter malformation syndrome (BWMS) Legacy label included under unified BWCFF terminology. (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 1-2) Verloes et al., 2015, Eur J Hum Genet. https://doi.org/10.1038/ejhg.2014.95
Historical/overlap labels Fryns–Aftimos (FA), cerebrofrontofacial syndrome / CFF (including CFF3) Previously separate labels now considered overlapping with BWCFF in mutation-positive cases. (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 2-3, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 1-2) Verloes et al., 2015, Eur J Hum Genet. https://doi.org/10.1038/ejhg.2014.95
Causal gene ACTB One of the two cytoplasmic actin genes causing BWCFF; ACTB located at 7p22.1 in Verloes et al. (nie2022identificationofa pages 1-2, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 2-3, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 1-2) Nie et al., 2022, Front Genet. https://doi.org/10.3389/fgene.2022.828120 ; Verloes et al., 2015, Eur J Hum Genet. https://doi.org/10.1038/ejhg.2014.95
Causal gene ACTG1 One of the two cytoplasmic actin genes causing BWCFF; ACTG1 located at 17q25.3 in Verloes et al. (nie2022identificationofa pages 1-2, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 2-3, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 1-2) Nie et al., 2022, Front Genet. https://doi.org/10.3389/fgene.2022.828120 ; Verloes et al., 2015, Eur J Hum Genet. https://doi.org/10.1038/ejhg.2014.95
Gene transcript accession (explicitly stated) ACTB: NM_001101.3 Explicit transcript accession provided in mutation table/source description. (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 2-3) Verloes et al., 2015, Eur J Hum Genet. https://doi.org/10.1038/ejhg.2014.95
Gene transcript accession (explicitly stated) ACTG1: NM_001199954.1 Explicit transcript accession provided in mutation table/source description. (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 2-3) Verloes et al., 2015, Eur J Hum Genet. https://doi.org/10.1038/ejhg.2014.95

Table: This table compiles the main disease identifiers, synonyms, overlap labels, and causal genes used in the primary literature for Baraitser–Winter cerebrofrontofacial syndrome. It is useful for harmonizing nomenclature and linking OMIM disease entries with ACTB/ACTG1-mediated disease subtypes.

ICD-10/ICD-11, MeSH, Orphanet IDs: Not identified in the retrieved corpus; should be curated from OMIM/Orphanet/NCBI MeSH/WHO ICD resources.

1.3 Data provenance

Evidence here is derived primarily from: - Aggregated disease-level resources and cohorts (notably the 42-case molecularly confirmed series). (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 1-2, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 35d77931, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 95e3b204, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 87756bb4) - Individual case reports and short series with deep phenotyping (ophthalmology/audiology/prenatal). (kim2024ocularfindingsin pages 1-2, aiyar2019prenatalpresentationin pages 2-3, ghiselli2024hearinglossin pages 4-6)

2. Etiology

2.1 Disease causal factors

Primary cause: Germline heterozygous variants in ACTB or ACTG1 affecting cytoplasmic actin function (actin polymerization/dynamics and actin-binding protein interactions). Classical BWCFF is dominated by missense (single amino-acid substitution) variants and is typically de novo. (riviere2012denovomutations pages 9-12, brown2017theclinicalmanifestations pages 4-4, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 2-3)

Key causal-gene statements: - “Baraitser–Winter cerebrofrontofacial syndrome… is a rare autosomal-dominant developmental disorder associated with variants in the genes ACTB or ACTG1.” (Nie et al., Frontiers in Genetics, 2022; DOI: https://doi.org/10.3389/fgene.2022.828120) (nie2022identificationofa pages 1-2)

2.2 Risk factors

Genetic risk factor: carrying a pathogenic/likely pathogenic heterozygous ACTB or ACTG1 variant; most are de novo, but familial transmission with variable expressivity can occur (autosomal dominant). (brown2017theclinicalmanifestations pages 4-4, brown2017theclinicalmanifestations pages 2-3)

Environmental risk factors: Not established in the retrieved literature (no consistent environmental exposures implicated).

2.3 Protective factors

Not established in the retrieved literature.

2.4 Gene–environment interactions

No gene–environment interactions were identified in the retrieved literature.

3. Phenotypes (with onset, frequency, and HPO suggestions)

The largest quantitative dataset in the retrieved evidence is the 42-case molecularly confirmed delineation (33 ACTB, 9 ACTG1), with clinical feature frequencies extracted from Table 2 and associated text. (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 35d77931, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 95e3b204, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 87756bb4)

Phenotype (plain language) Suggested HPO term(s) Frequency overall and/or by gene Notes (severity/onset/progression) Key source
Hypertelorism / telecanthus HP:0000316 Hypertelorism; HP:0000506 Telecanthus 39/41 (~95%) overall; ACTB 32 cases reported with hypertelorism/telecanthus; ACTG1 7/9 with hypertelorism/telecanthus (~78%) Typically congenital, part of the characteristic facial gestalt Verloes 2015 cohort/Table 2 (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 2-3, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 35d77931, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 95e3b204, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 87756bb4)
Congenital bilateral ptosis HP:0000508 Ptosis 37/40 (~93%) overall Usually congenital and one of the most recognizable presenting signs Verloes 2015 cohort/Table 2 (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 3-4, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 35d77931, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 95e3b204, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 87756bb4)
Arched eyebrows HP:0002553 Highly arched eyebrow 35/40 (~88%) overall; ACTG1 6/7; ACTB 29 cases noted Common dysmorphic facial feature Verloes 2015 cohort/Table 2 (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 3-4, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 35d77931, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 95e3b204, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 87756bb4)
Wide, short, upturned nose with broad/flat tip HP:0012805 Broad nose; HP:0000455 Short nose; HP:0000463 Anteverted nares 35/41 (~85%) overall Characteristic facial appearance, present from infancy/childhood Verloes 2015 cohort/Table 2 (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 3-4, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 2-3, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 35d77931, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 95e3b204, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 87756bb4)
Long smooth philtrum HP:0000319 Smooth philtrum; HP:0000343 Long philtrum 32/38 (~84%) overall Common facial feature Verloes 2015 cohort/Table 2 (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 3-4, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 35d77931, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 95e3b204, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 87756bb4)
Metopic ridging / trigonocephaly HP:0000243 Metopic ridging; HP:0000248 Trigonocephaly 26/40 (~65%) overall Congenital cranial abnormality; may contribute to prenatal/early childhood recognition Verloes 2015 cohort/Table 2 (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 2-3, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 35d77931, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 95e3b204, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 87756bb4)
Ocular coloboma (iris and/or retina/choroid) HP:0000589 Coloboma of eye; HP:0000612 Iris coloboma; HP:0000480 Retinal coloboma 11/40 (~28%) overall; ACTG1 3 cases (~38% of ACTG1 subgroup); ACTB 8 cases (~25% of ACTB subgroup) Often congenital; may extend posteriorly and affect vision depending on macular/optic disc involvement Verloes 2015 cohort/Table 2 (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 3-4, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 35d77931, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 95e3b204, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 87756bb4)
Microphthalmia HP:0000568 Microphthalmia 3/31 (~10%) overall Less common ocular manifestation Verloes 2015 cohort/Table 2 (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 3-4, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 35d77931, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 95e3b204, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 87756bb4)
Ear anomalies HP:0000356 Abnormality of the outer ear 30/41 (~73%) overall Structural ear anomalies are common and may co-occur with hearing loss Verloes 2015 cohort/Table 2 (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 35d77931, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 95e3b204, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 87756bb4)
Sensorineural hearing loss / hearing loss HP:0000407 Sensorineural hearing impairment; HP:0000365 Hearing impairment 13/40 (~33%) overall May be progressive; important for longitudinal audiologic follow-up Verloes 2015 cohort/Table 2 (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 35d77931, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 95e3b204, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 87756bb4)
Pachygyria / lissencephaly spectrum (neuronal migration defect) HP:0001302 Pachygyria; HP:0001339 Lissencephaly; HP:0002273 Cortical dysplasia ACTG1 8/9 (~89%); ACTB 17/28–29 (~61%) with pachygyria/lissencephaly reported Core CNS feature; ACTG1-associated disease appears more strongly associated with migration defects Verloes 2015 cohort/Table 2 and text summary (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 1-2, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 35d77931, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 95e3b204, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 87756bb4)
Agenesis of corpus callosum / other midline brain anomalies HP:0001274 Agenesis of the corpus callosum Frequency not clearly extractable from provided counts Part of broader structural brain-malformation spectrum Verloes 2015 cohort summary (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 2-3)
Band heterotopia / neuronal heterotopia HP:0002126 Subcortical band heterotopia; HP:0002282 Heterotopia Frequency not clearly extractable from provided counts Less common than pachygyria but within the cortical malformation spectrum Verloes 2015 cohort summary (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 1-2)
Epilepsy / seizures HP:0001250 Seizure; HP:0002373 Epilepsy ACTG1 7/8 (~88%); ACTB 13/30 (~43%) Mean seizure onset approximately 5-6 years in the cohort summary; severity variable Verloes 2015 cohort/Table 2 (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 35d77931, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 95e3b204, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 87756bb4)
Intellectual disability / developmental delay HP:0001249 Intellectual disability; HP:0001263 Global developmental delay Severity distribution reported: ACTG1 mild/moderate/severe = 2/2/3; ACTB = 7/11/11 Developmental impairment ranges from mild to severe and correlates broadly with CNS involvement Verloes 2015 cohort/Table 2 (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 35d77931, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 95e3b204, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 87756bb4)
Delayed walking HP:0001270 Motor delay Mean age at walking: ~27 months ACTG1; ~31 months ACTB Pediatric onset developmental delay Verloes 2015 cohort (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 3-4, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5)
Delayed first words / speech delay HP:0000750 Delayed speech and language development Mean first words: ~43 months ACTG1; ~54 months ACTB Marked language delay is common Verloes 2015 cohort (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5)
Cleft lip and/or palate / high-arched palate HP:0000204 Cleft upper lip; HP:0000175 Cleft palate; HP:0000218 High palate Cleft lip/palate in 4 patients overall in one summary; subgroup estimate: ACTG1 1/8, ACTB 7/29 reported in another summary; highly arched palate common Congenital; frequency varies across table/text summaries, so use as approximate Verloes 2015 cohort summary/Table 2 (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 3-4, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 35d77931, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 95e3b204, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 87756bb4)
Cardiac defects HP:0001627 Abnormality of the cardiovascular system Uncommon; approximate subgroup counts reported as ACTG1 1 case, ACTB 11 cases in extracted summary Congenital but not universal; phenotype is variable Verloes 2015 cohort summary (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 1-2)
Renal tract anomalies HP:0000077 Abnormality of the kidney; HP:0012210 Abnormality of the urinary system Present in some cases; no stable count extractable from provided evidence Secondary/systemic involvement rather than defining feature Verloes 2015 cohort summary (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 1-2)
Reduced shoulder-girdle muscle bulk / progressive joint stiffness HP:0003551 Muscle atrophy; HP:0001387 Joint stiffness Frequency not clearly extractable from provided counts Can become progressive over time and contribute to disability Verloes 2015 cohort summary (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 1-2)
Microcephaly developing over time HP:0000252 Microcephaly Not consistently present at birth; frequency not clearly extractable May evolve postnatally rather than being congenital in all patients Verloes 2015 cohort summary (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 1-2)

Table: This table summarizes major clinical features of Baraitser–Winter cerebrofrontofacial syndrome using approximate frequencies from the 42-case Verloes et al. 2015 cohort, with suggested HPO mappings. It is useful for structured phenotype curation and for comparing ACTB- versus ACTG1-associated presentations.

3.1 Additional phenotype notes (quality of life / functional impact)

  • Neurologic morbidity is driven by cortical malformations and epilepsy, with severity ranging from mild learning issues to severe intellectual disability and refractory epilepsy. (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 1-2)
  • Progressive musculoskeletal limitations (joint stiffness, contractures) can impair mobility and may require assistive devices; one early report describes progression “Despite physical therapy, contractures progressed…” and wheelchair use in some. (riviere2012denovomutations pages 5-9)

Formal QoL instruments (EQ-5D/SF-36/PROMIS): Not identified in the retrieved literature.

4. Genetic / molecular information

4.1 Causal genes

  • ACTB (β-actin; locus reported as 7p22.1 in cohort descriptions). (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 2-3)
  • ACTG1 (γ-actin; locus reported as 17q25.3). (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 2-3)

4.2 Variant spectrum and classes

  • In a foundational cohort, all affected individuals had single amino-acid substitutions, and the authors stated “no subjects with truncating mutations or deletions of either gene have been reported” (in the Baraitser–Winter syndrome context at that time). (riviere2012denovomutations pages 9-12)
  • Recurrent/hotspot variants exist; in the 42-case delineation, “Amino acid 196 in ACTB is a hotspot with 14 affected patients: eight with an ACTB p.Arg196His and six with p.Arg196Cys.” (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 8-9)

4.3 Genotype–phenotype correlations

  • Severity and system involvement can differ by gene. A key genotype–phenotype conclusion is that “mutations in ACTB cause a distinctly more severe phenotype than ACTG1 mutations” (Donato et al., EJHG, 2014; DOI: https://doi.org/10.1038/ejhg.2013.130). (donato2014severeformsof pages 1-3)
  • Neuronal migration defects may be more consistent in ACTG1 in some analyses; the 42-case study reports high pachygyria/lissencephaly burden in ACTG1 and substantial but lower burden in ACTB. (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5)

4.4 Population frequency

Case reports note absence from population databases for specific variants (e.g., an ACTB variant reported “not present in the ExAC database”). (aiyar2019prenatalpresentationin pages 2-3)

4.5 Somatic vs germline

Evidence in the retrieved corpus concerns germline constitutional variants (often de novo). (brown2017theclinicalmanifestations pages 4-4)

4.6 Modifier genes / epigenetics / chromosomal abnormalities

  • Modifier genes / epigenetic signatures: Not identified in the retrieved evidence.
  • CNVs: Early work discussed larger 7p22 or 17q25.3 CNVs including ACTB/ACTG1 in some individuals, often with non-classical phenotypes and apparently de novo origin in tested cases. (riviere2012denovomutations pages 9-12)

5. Environmental information

No validated environmental, lifestyle, occupational, or infectious contributors were identified in the retrieved literature.

6. Mechanism / pathophysiology

6.1 Current mechanistic model (causal chain)

Upstream trigger: heterozygous ACTB/ACTG1 missense variant → altered actin polymerization and/or filament stability and altered actin-binding protein interactions → impaired cell shape, adhesion, and migration (epithelial morphogenesis; neuronal migration; progenitor dynamics) → craniofacial malformations (including clefting in some), cortical malformations (pachygyria/lissencephaly), and downstream neurodevelopmental sequelae (ID, epilepsy), plus sensory deficits (hearing/vision) due to cytoskeletal requirements in specialized tissues. (tsujimoto2024compromisedactindynamics pages 10-14, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 8-9, niehaus2025cerebralorganoidsexpressing pages 15-18)

6.2 Recent developments (prioritize 2023–2024)

(A) Epithelial junction / craniofacial cleft mechanism (2024 preprint): A 2024 mechanistic study of an ACTB BWCFF clefting case reports that mutant ACTB had “compromised capacity… to localize at the epithelial junction” and “exhibited an impaired ability to bind PROFILIN1,” supporting a mechanism where impaired PFN1-mediated actin polymerization disrupts epithelial adhesion/migration critical for palatal fusion. (Tsujimoto et al., bioRxiv, 2024-04; DOI: https://doi.org/10.1101/2024.04.04.587685) (tsujimoto2024compromisedactindynamics pages 1-6)

(B) Actin hotspot/filament dynamics perspective (cohort mechanistic synthesis): The 42-case delineation and associated experimental discussion emphasizes mutation-specific effects on actin dynamics and actin–binding protein interactions (including cofilin resistance for particular variants), consistent with the clinical heterogeneity. (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 8-9)

6.3 Mechanism ontology suggestions

GO Biological Process (examples): - Actin filament organization; regulation of actin polymerization/depolymerization; cell migration; epithelial cell–cell adhesion; neuroblast migration / neuronal migration; mitotic spindle orientation; apical junction assembly.

GO Cellular Component (examples): - Actin cytoskeleton; adherens junction; cortical actin; leading edge; apical junction complex.

Cell Ontology (CL) cell types (examples): - Neural progenitor cell / apical radial glia (ventricular-zone progenitors); migrating cortical neurons; epithelial cells of palatal shelves / midline epithelial seam.

7. Anatomical structures affected

Primary systems/organs: - Brain / CNS (cortical malformations: pachygyria/lissencephaly; corpus callosum anomalies). (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 2-3) - Eye (iris/retinal coloboma; ptosis). (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 3-4, kim2024ocularfindingsin pages 1-2) - Craniofacial skeleton/soft tissues (hypertelorism, metopic ridging/trigonocephaly, characteristic nose). (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 3-4, verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 2-3) - Auditory system (sensorineural hearing loss; possibly progressive). (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5, ghiselli2024hearinglossin pages 1-2)

Secondary involvement (variable): congenital heart defects, renal tract anomalies, GI involvement, and musculoskeletal involvement (joint stiffness/contractures). (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 1-2, riviere2012denovomutations pages 5-9)

UBERON suggestions (examples): cerebral cortex; corpus callosum; eye; retina; iris; inner ear; palatal shelf; heart; kidney.

8. Temporal development

Onset: largely congenital/early childhood (ptosis, hypertelorism, coloboma, cranial shape anomalies, congenital brain malformations). (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 1-2)

Progression: variable; seizures may begin in childhood (cohort summary notes mean seizure onset ~5–6 years), hearing loss may be progressive in some, and musculoskeletal stiffness/contractures can progress. (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5, riviere2012denovomutations pages 5-9)

9. Inheritance and population

Inheritance pattern: autosomal dominant; commonly de novo. (brown2017theclinicalmanifestations pages 4-4)

Variable expressivity: marked inter-individual variability; even within ACTG1-related disease, “hypervariable penetrance” of developmental traits and hearing loss is discussed. (dawidziuk2022denovoactg1 pages 1-2)

Epidemiology: robust prevalence/incidence estimates were not located in the retrieved sources. A 2022 paper states “approximately 100 cases have been reported,” consistent with a very rare disorder. (nie2022identificationofa pages 1-2)

10. Diagnostics

10.1 Clinical recognition

Core clues: congenital ptosis + hypertelorism + arched eyebrows + broad nasal tip + ocular coloboma + cortical malformation (pachygyria) ± hearing loss and seizures. (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5, kim2024ocularfindingsin pages 1-2)

10.2 Imaging

Brain MRI commonly shows pachygyria/cortical malformations (example: “Brain magnetic resonance imaging revealed a congenital cortical malformation with pachygyria”). (Kim et al., BMC Ophthalmology, 2024-12; DOI: https://doi.org/10.1186/s12886-024-03791-1) (kim2024ocularfindingsin pages 1-2)

10.3 Genetic testing (real-world implementation)

  • Trio-based sequencing (WES/WGS) is repeatedly highlighted as effective for sporadic developmental disorders and helps differentiate overlapping syndromes. (riviere2012denovomutations pages 5-9, brown2017theclinicalmanifestations pages 4-4)
  • Real-world cases use WES to establish diagnosis: “Whole-exome sequencing revealed a heterozygous, de novo, and likely pathogenic variant… in ACTG1.” (kim2024ocularfindingsin pages 1-2)
  • Prenatal diagnostic workflows may include NIPT → invasive testing (karyotype, SNP microarray) → postnatal gene panels/WES when chromosomal tests are unrevealing. (aiyar2019prenatalpresentationin pages 2-3)

10.4 Functional assessments

  • Audiology: OAE/ABR/tympanometry/PTA and longitudinal follow-up are implemented in reported cases; early amplification is common. (ghiselli2024hearinglossin pages 2-4, ghiselli2024hearinglossin pages 4-6)
  • Ophthalmology: detailed anterior/fundus exams and OCT are used; coloboma extent and macular/optic disc involvement guides prognosis. (kim2024ocularfindingsin pages 1-2)

10.5 Differential diagnosis (examples)

  • Noonan-spectrum disorders are repeatedly discussed as confounders in prenatal/clinical settings; other neurodevelopmental syndromes with coloboma and cortical malformations should be considered. (aiyar2019prenatalpresentationin pages 2-3, brown2017theclinicalmanifestations pages 4-4)

11. Outcome / prognosis

Prognosis is heterogeneous and depends strongly on the severity of cortical malformation and epilepsy, as well as sensory deficits and progressive musculoskeletal involvement. (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5, riviere2012denovomutations pages 5-9)

Formal survival/life-expectancy statistics were not found in the retrieved sources.

12. Treatment

12.1 Current clinical management (supportive / symptomatic)

No disease-modifying therapy is established in the retrieved evidence. Care is multidisciplinary.

Seizures (MAXO suggestions): anticonvulsant therapy (e.g., valproate reported in an early case: “Seizures… transiently treated with valproic acid”). (riviere2012denovomutations pages 5-9)

Hearing loss (MAXO suggestions): - Hearing aids in infancy/childhood; longitudinal reassessment. (ghiselli2024hearinglossin pages 2-4, dawidziuk2022denovoactg1 pages 4-7) - Cochlear implantation in severe cases, with reported marked functional benefit (speech intelligibility improvement with CI+HA). (ghiselli2024hearinglossin pages 4-6)

Ophthalmology (MAXO suggestions): refractive correction and amblyopia therapy can yield favorable outcomes when macula/optic disc are spared; one 2024 case reports glasses + occlusion therapy improving acuity to 25/25. (kim2024ocularfindingsin pages 1-2)

Rehabilitation / motor (MAXO suggestions): physical therapy for contractures/joint stiffness; outcomes can be limited in progressive cases. (riviere2012denovomutations pages 5-9)

12.2 Experimental/translation-relevant directions

Mechanistic studies suggest actin-polymerization/stabilization pathways as potential future targets (e.g., rescue of polymerization deficits in cell models), but these are not clinical therapies for BWCFF at present in the retrieved literature. (tsujimoto2024compromisedactindynamics pages 10-14)

12.3 Clinical trials

No BWCFF-targeted interventional trials were identified in the retrieved ClinicalTrials.gov search results; the only clearly relevant registry-type study encountered was a broad rare-variant neurodevelopmental cohort (Simons Searchlight), not BWCFF-specific. (ghiselli2024hearinglossin pages 2-4)

13. Prevention

Primary prevention is not currently feasible for de novo dominant disorders, but recurrence risk reduction and early detection are possible.

Genetic counseling (MAXO suggestion: genetic counseling): autosomal dominant inheritance with frequent de novo occurrence; counseling depends on whether a variant is de novo vs inherited and on parental mosaicism considerations (not quantified in retrieved sources). (brown2017theclinicalmanifestations pages 4-4)

Prenatal/preimplantation options: suggested by general Mendelian practice; specific BWCFF guidelines were not found in the retrieved sources.

14. Other species / natural disease

No naturally occurring veterinary analogs were identified in the retrieved sources.

15. Model organisms

Recent and relevant models include: - Xenopus laevis CRISPR-based actb perturbation producing craniofacial deformities including clefts; and epithelial cell models (MDCK, Xenopus animal cap) demonstrating epithelial junction localization defects for mutant ACTB. (tsujimoto2024compromisedactindynamics pages 10-14, tsujimoto2024compromisedactindynamics pages 6-10) - Human iPSC-derived cerebral organoids (patient-derived and CRISPR-engineered ACTB Thr120Ile) showing apical cytoskeletal irregularities in ventricular-zone progenitors, altered spindle orientation, increased delamination, and reduced ventricular zone size consistent with microcephaly mechanisms. (niehaus2025cerebralorganoidsexpressing pages 15-18) - Mouse genetic evidence summarized in the 42-case mechanistic discussion: β-actin knockout embryonic lethality vs γ-actin knockout viability with muscle pathology supports isoform-specific developmental roles. (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 8-9)

Notes on evidence gaps and recommended curation follow-ups

  • MONDO, Orphanet, ICD, MeSH identifiers were not present in the retrieved full-text evidence and should be added using those databases directly.
  • Prevalence/incidence estimates were not found; Orphanet and registry-based natural history studies may contain better epidemiologic estimates.
  • Formal QoL and long-term survival outcomes were not found in the retrieved evidence.

Key recent references (2023–2024 prioritized)

  • Tsujimoto T et al. bioRxiv (2024-04-04). “Compromised actin dynamics underlie the orofacial cleft in Baraitser-Winter Cerebrofrontofacial Syndrome with a variant in ACTB.” https://doi.org/10.1101/2024.04.04.587685 (tsujimoto2024compromisedactindynamics pages 1-6)
  • Ghiselli S et al. Journal of Clinical Medicine (2024-03). “Hearing Loss in Baraitser–Winter Syndrome: Case Reports and Review of the Literature.” https://doi.org/10.3390/jcm13051500 (ghiselli2024hearinglossin pages 1-2, ghiselli2024hearinglossin pages 4-6)
  • Kim JW et al. BMC Ophthalmology (2024-12). “Ocular findings in Baraitser–Winter syndrome with a de novo mutation in the ACTG1 gene: a case report.” https://doi.org/10.1186/s12886-024-03791-1 (kim2024ocularfindingsin pages 1-2)

Foundational cohort/discovery references: - Verloes A et al. European Journal of Human Genetics (2015-07). “Baraitser–Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.” https://doi.org/10.1038/ejhg.2014.95 (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 1-2, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 35d77931, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 95e3b204, verloes2015baraitser–wintercerebrofrontofacialsyndrome media 87756bb4) - Rivière J-B et al. Nature Genetics (2012-02). “De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome.” https://doi.org/10.1038/ng.1091 (riviere2012denovomutations pages 5-9, riviere2012denovomutations pages 9-12)

References

  1. (nie2022identificationofa pages 1-2): Kailai Nie, Junting Huang, Longqian Liu, Hongbin Lv, Danian Chen, and Wei Fan. Identification of a de novo heterozygous missense actb variant in baraitser–winter cerebrofrontofacial syndrome. Frontiers in Genetics, Mar 2022. URL: https://doi.org/10.3389/fgene.2022.828120, doi:10.3389/fgene.2022.828120. This article has 10 citations and is from a peer-reviewed journal.

  2. (riviere2012denovomutations pages 9-12): Jean-Baptiste Rivière, Bregje W M van Bon, Alexander Hoischen, Stanislav S Kholmanskikh, Brian J O'Roak, Christian Gilissen, Sabine Gijsen, Christopher T Sullivan, Susan L Christian, Omar A Abdul-Rahman, Joan F Atkin, Nicolas Chassaing, Valerie Drouin-Garraud, Andrew E Fry, Jean-Pierre Fryns, Karen W Gripp, Marlies Kempers, Tjitske Kleefstra, Grazia M S Mancini, Małgorzata J M Nowaczyk, Conny M A van Ravenswaaij-Arts, Tony Roscioli, Michael Marble, Jill A Rosenfeld, Victoria M Siu, Bert B A de Vries, Jay Shendure, Alain Verloes, Joris A Veltman, Han G Brunner, M Elizabeth Ross, Daniela T Pilz, and William B Dobyns. De novo mutations in the actin genes actb and actg1 cause baraitser-winter syndrome. Nature genetics, 44:440-S2, Feb 2012. URL: https://doi.org/10.1038/ng.1091, doi:10.1038/ng.1091. This article has 351 citations and is from a highest quality peer-reviewed journal.

  3. (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 4-5): Alain Verloes, Nataliya Di Donato, Julien Masliah-Planchon, Marjolijn Jongmans, Omar A Abdul-Raman, Beate Albrecht, Judith Allanson, Han Brunner, Debora Bertola, Nicolas Chassaing, Albert David, Koen Devriendt, Pirayeh Eftekhari, Valérie Drouin-Garraud, Francesca Faravelli, Laurence Faivre, Fabienne Giuliano, Leina Guion Almeida, Jorge Juncos, Marlies Kempers, Hatice Koçak Eker, Didier Lacombe, Angela Lin, Grazia Mancini, Daniela Melis, Charles Marques Lourenço, Victoria Mok Siu, Gilles Morin, Marjan Nezarati, Malgorzata J M Nowaczyk, Jeanette C Ramer, Sara Osimani, Nicole Philip, Mary Ella Pierpont, Vincent Procaccio, Zeichi-Seide Roseli, Massimiliano Rossi, Cristina Rusu, Yves Sznajer, Ludivine Templin, Vera Uliana, Mirjam Klaus, Bregje Van Bon, Conny Van Ravenswaaij, Bruce Wainer, Andrew E Fry, Andreas Rump, Alexander Hoischen, Séverine Drunat, Jean-Baptiste Rivière, William B Dobyns, and Daniela T Pilz. Baraitser–winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. European Journal of Human Genetics, 23:292-301, Jul 2015. URL: https://doi.org/10.1038/ejhg.2014.95, doi:10.1038/ejhg.2014.95. This article has 189 citations and is from a domain leading peer-reviewed journal.

  4. (riviere2012denovomutations pages 5-9): Jean-Baptiste Rivière, Bregje W M van Bon, Alexander Hoischen, Stanislav S Kholmanskikh, Brian J O'Roak, Christian Gilissen, Sabine Gijsen, Christopher T Sullivan, Susan L Christian, Omar A Abdul-Rahman, Joan F Atkin, Nicolas Chassaing, Valerie Drouin-Garraud, Andrew E Fry, Jean-Pierre Fryns, Karen W Gripp, Marlies Kempers, Tjitske Kleefstra, Grazia M S Mancini, Małgorzata J M Nowaczyk, Conny M A van Ravenswaaij-Arts, Tony Roscioli, Michael Marble, Jill A Rosenfeld, Victoria M Siu, Bert B A de Vries, Jay Shendure, Alain Verloes, Joris A Veltman, Han G Brunner, M Elizabeth Ross, Daniela T Pilz, and William B Dobyns. De novo mutations in the actin genes actb and actg1 cause baraitser-winter syndrome. Nature genetics, 44:440-S2, Feb 2012. URL: https://doi.org/10.1038/ng.1091, doi:10.1038/ng.1091. This article has 351 citations and is from a highest quality peer-reviewed journal.

  5. (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 3-4): Alain Verloes, Nataliya Di Donato, Julien Masliah-Planchon, Marjolijn Jongmans, Omar A Abdul-Raman, Beate Albrecht, Judith Allanson, Han Brunner, Debora Bertola, Nicolas Chassaing, Albert David, Koen Devriendt, Pirayeh Eftekhari, Valérie Drouin-Garraud, Francesca Faravelli, Laurence Faivre, Fabienne Giuliano, Leina Guion Almeida, Jorge Juncos, Marlies Kempers, Hatice Koçak Eker, Didier Lacombe, Angela Lin, Grazia Mancini, Daniela Melis, Charles Marques Lourenço, Victoria Mok Siu, Gilles Morin, Marjan Nezarati, Malgorzata J M Nowaczyk, Jeanette C Ramer, Sara Osimani, Nicole Philip, Mary Ella Pierpont, Vincent Procaccio, Zeichi-Seide Roseli, Massimiliano Rossi, Cristina Rusu, Yves Sznajer, Ludivine Templin, Vera Uliana, Mirjam Klaus, Bregje Van Bon, Conny Van Ravenswaaij, Bruce Wainer, Andrew E Fry, Andreas Rump, Alexander Hoischen, Séverine Drunat, Jean-Baptiste Rivière, William B Dobyns, and Daniela T Pilz. Baraitser–winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. European Journal of Human Genetics, 23:292-301, Jul 2015. URL: https://doi.org/10.1038/ejhg.2014.95, doi:10.1038/ejhg.2014.95. This article has 189 citations and is from a domain leading peer-reviewed journal.

  6. (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 1-2): Alain Verloes, Nataliya Di Donato, Julien Masliah-Planchon, Marjolijn Jongmans, Omar A Abdul-Raman, Beate Albrecht, Judith Allanson, Han Brunner, Debora Bertola, Nicolas Chassaing, Albert David, Koen Devriendt, Pirayeh Eftekhari, Valérie Drouin-Garraud, Francesca Faravelli, Laurence Faivre, Fabienne Giuliano, Leina Guion Almeida, Jorge Juncos, Marlies Kempers, Hatice Koçak Eker, Didier Lacombe, Angela Lin, Grazia Mancini, Daniela Melis, Charles Marques Lourenço, Victoria Mok Siu, Gilles Morin, Marjan Nezarati, Malgorzata J M Nowaczyk, Jeanette C Ramer, Sara Osimani, Nicole Philip, Mary Ella Pierpont, Vincent Procaccio, Zeichi-Seide Roseli, Massimiliano Rossi, Cristina Rusu, Yves Sznajer, Ludivine Templin, Vera Uliana, Mirjam Klaus, Bregje Van Bon, Conny Van Ravenswaaij, Bruce Wainer, Andrew E Fry, Andreas Rump, Alexander Hoischen, Séverine Drunat, Jean-Baptiste Rivière, William B Dobyns, and Daniela T Pilz. Baraitser–winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. European Journal of Human Genetics, 23:292-301, Jul 2015. URL: https://doi.org/10.1038/ejhg.2014.95, doi:10.1038/ejhg.2014.95. This article has 189 citations and is from a domain leading peer-reviewed journal.

  7. (donato2014severeformsof pages 1-3): N. Donato, A. Rump, R. Koenig, V. M. Kaloustian, F. Halal, K. Sonntag, C. Krause, K. Hackmann, Gabriele Hahn, Evelin Schröck, and A. Verloes. Severe forms of baraitser–winter syndrome are caused by actb mutations rather than actg1 mutations. European Journal of Human Genetics, 22:179-183, Jun 2014. URL: https://doi.org/10.1038/ejhg.2013.130, doi:10.1038/ejhg.2013.130. This article has 114 citations and is from a domain leading peer-reviewed journal.

  8. (aiyar2019prenatalpresentationin pages 2-3): Lila Aiyar, Tammy Stumbaugh, Greigh I. Hirata, Bruce Chen, Helen L. Lau, and Robert J. Wallerstein. Prenatal presentation in a patient with baraitser-winter cerebrofrontofacial syndrome and a novel actb variant. Clinical Dysmorphology, 28:162-164, Jul 2019. URL: https://doi.org/10.1097/mcd.0000000000000266, doi:10.1097/mcd.0000000000000266. This article has 8 citations and is from a peer-reviewed journal.

  9. (dawidziuk2022denovoactg1 pages 1-2): Mateusz Dawidziuk, Anna Kutkowska-Kazmierczak, Ewelina Bukowska-Olech, Marta Jurek, Ewa Kalka, Dorothy Lys Guilbride, Mariusz Ireneusz Furmanek, Monika Bekiesinska-Figatowska, Jerzy Bal, and Pawel Gawlinski. De novo actg1 variant expands the phenotype and genotype of partial deafness and baraitser–winter syndrome. International Journal of Molecular Sciences, 23:692, Jan 2022. URL: https://doi.org/10.3390/ijms23020692, doi:10.3390/ijms23020692. This article has 9 citations.

  10. (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 2-3): Alain Verloes, Nataliya Di Donato, Julien Masliah-Planchon, Marjolijn Jongmans, Omar A Abdul-Raman, Beate Albrecht, Judith Allanson, Han Brunner, Debora Bertola, Nicolas Chassaing, Albert David, Koen Devriendt, Pirayeh Eftekhari, Valérie Drouin-Garraud, Francesca Faravelli, Laurence Faivre, Fabienne Giuliano, Leina Guion Almeida, Jorge Juncos, Marlies Kempers, Hatice Koçak Eker, Didier Lacombe, Angela Lin, Grazia Mancini, Daniela Melis, Charles Marques Lourenço, Victoria Mok Siu, Gilles Morin, Marjan Nezarati, Malgorzata J M Nowaczyk, Jeanette C Ramer, Sara Osimani, Nicole Philip, Mary Ella Pierpont, Vincent Procaccio, Zeichi-Seide Roseli, Massimiliano Rossi, Cristina Rusu, Yves Sznajer, Ludivine Templin, Vera Uliana, Mirjam Klaus, Bregje Van Bon, Conny Van Ravenswaaij, Bruce Wainer, Andrew E Fry, Andreas Rump, Alexander Hoischen, Séverine Drunat, Jean-Baptiste Rivière, William B Dobyns, and Daniela T Pilz. Baraitser–winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. European Journal of Human Genetics, 23:292-301, Jul 2015. URL: https://doi.org/10.1038/ejhg.2014.95, doi:10.1038/ejhg.2014.95. This article has 189 citations and is from a domain leading peer-reviewed journal.

  11. (verloes2015baraitser–wintercerebrofrontofacialsyndrome media 35d77931): Alain Verloes, Nataliya Di Donato, Julien Masliah-Planchon, Marjolijn Jongmans, Omar A Abdul-Raman, Beate Albrecht, Judith Allanson, Han Brunner, Debora Bertola, Nicolas Chassaing, Albert David, Koen Devriendt, Pirayeh Eftekhari, Valérie Drouin-Garraud, Francesca Faravelli, Laurence Faivre, Fabienne Giuliano, Leina Guion Almeida, Jorge Juncos, Marlies Kempers, Hatice Koçak Eker, Didier Lacombe, Angela Lin, Grazia Mancini, Daniela Melis, Charles Marques Lourenço, Victoria Mok Siu, Gilles Morin, Marjan Nezarati, Malgorzata J M Nowaczyk, Jeanette C Ramer, Sara Osimani, Nicole Philip, Mary Ella Pierpont, Vincent Procaccio, Zeichi-Seide Roseli, Massimiliano Rossi, Cristina Rusu, Yves Sznajer, Ludivine Templin, Vera Uliana, Mirjam Klaus, Bregje Van Bon, Conny Van Ravenswaaij, Bruce Wainer, Andrew E Fry, Andreas Rump, Alexander Hoischen, Séverine Drunat, Jean-Baptiste Rivière, William B Dobyns, and Daniela T Pilz. Baraitser–winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. European Journal of Human Genetics, 23:292-301, Jul 2015. URL: https://doi.org/10.1038/ejhg.2014.95, doi:10.1038/ejhg.2014.95. This article has 189 citations and is from a domain leading peer-reviewed journal.

  12. (verloes2015baraitser–wintercerebrofrontofacialsyndrome media 95e3b204): Alain Verloes, Nataliya Di Donato, Julien Masliah-Planchon, Marjolijn Jongmans, Omar A Abdul-Raman, Beate Albrecht, Judith Allanson, Han Brunner, Debora Bertola, Nicolas Chassaing, Albert David, Koen Devriendt, Pirayeh Eftekhari, Valérie Drouin-Garraud, Francesca Faravelli, Laurence Faivre, Fabienne Giuliano, Leina Guion Almeida, Jorge Juncos, Marlies Kempers, Hatice Koçak Eker, Didier Lacombe, Angela Lin, Grazia Mancini, Daniela Melis, Charles Marques Lourenço, Victoria Mok Siu, Gilles Morin, Marjan Nezarati, Malgorzata J M Nowaczyk, Jeanette C Ramer, Sara Osimani, Nicole Philip, Mary Ella Pierpont, Vincent Procaccio, Zeichi-Seide Roseli, Massimiliano Rossi, Cristina Rusu, Yves Sznajer, Ludivine Templin, Vera Uliana, Mirjam Klaus, Bregje Van Bon, Conny Van Ravenswaaij, Bruce Wainer, Andrew E Fry, Andreas Rump, Alexander Hoischen, Séverine Drunat, Jean-Baptiste Rivière, William B Dobyns, and Daniela T Pilz. Baraitser–winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. European Journal of Human Genetics, 23:292-301, Jul 2015. URL: https://doi.org/10.1038/ejhg.2014.95, doi:10.1038/ejhg.2014.95. This article has 189 citations and is from a domain leading peer-reviewed journal.

  13. (verloes2015baraitser–wintercerebrofrontofacialsyndrome media 87756bb4): Alain Verloes, Nataliya Di Donato, Julien Masliah-Planchon, Marjolijn Jongmans, Omar A Abdul-Raman, Beate Albrecht, Judith Allanson, Han Brunner, Debora Bertola, Nicolas Chassaing, Albert David, Koen Devriendt, Pirayeh Eftekhari, Valérie Drouin-Garraud, Francesca Faravelli, Laurence Faivre, Fabienne Giuliano, Leina Guion Almeida, Jorge Juncos, Marlies Kempers, Hatice Koçak Eker, Didier Lacombe, Angela Lin, Grazia Mancini, Daniela Melis, Charles Marques Lourenço, Victoria Mok Siu, Gilles Morin, Marjan Nezarati, Malgorzata J M Nowaczyk, Jeanette C Ramer, Sara Osimani, Nicole Philip, Mary Ella Pierpont, Vincent Procaccio, Zeichi-Seide Roseli, Massimiliano Rossi, Cristina Rusu, Yves Sznajer, Ludivine Templin, Vera Uliana, Mirjam Klaus, Bregje Van Bon, Conny Van Ravenswaaij, Bruce Wainer, Andrew E Fry, Andreas Rump, Alexander Hoischen, Séverine Drunat, Jean-Baptiste Rivière, William B Dobyns, and Daniela T Pilz. Baraitser–winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. European Journal of Human Genetics, 23:292-301, Jul 2015. URL: https://doi.org/10.1038/ejhg.2014.95, doi:10.1038/ejhg.2014.95. This article has 189 citations and is from a domain leading peer-reviewed journal.

  14. (kim2024ocularfindingsin pages 1-2): Jae Won Kim, Sook-Young Kim, and Donghun Lee. Ocular findings in baraitser–winter syndrome with a de novo mutation in the actg1 gene: a case report. BMC Ophthalmology, Dec 2024. URL: https://doi.org/10.1186/s12886-024-03791-1, doi:10.1186/s12886-024-03791-1. This article has 1 citations and is from a peer-reviewed journal.

  15. (ghiselli2024hearinglossin pages 4-6): Sara Ghiselli, Giulia Parmeggiani, Giulia Zambonini, and Domenico Cuda. Hearing loss in baraitser–winter syndrome: case reports and review of the literature. Journal of Clinical Medicine, 13:1500, Mar 2024. URL: https://doi.org/10.3390/jcm13051500, doi:10.3390/jcm13051500. This article has 3 citations.

  16. (brown2017theclinicalmanifestations pages 4-4): Barry Brown and Tanya Allawh. The clinical manifestations and genetic implications of baraitser–winter syndrome type 2. Journal of Pediatric Genetics, 06:107-110, Nov 2017. URL: https://doi.org/10.1055/s-0036-1593967, doi:10.1055/s-0036-1593967. This article has 7 citations and is from a peer-reviewed journal.

  17. (brown2017theclinicalmanifestations pages 2-3): Barry Brown and Tanya Allawh. The clinical manifestations and genetic implications of baraitser–winter syndrome type 2. Journal of Pediatric Genetics, 06:107-110, Nov 2017. URL: https://doi.org/10.1055/s-0036-1593967, doi:10.1055/s-0036-1593967. This article has 7 citations and is from a peer-reviewed journal.

  18. (verloes2015baraitser–wintercerebrofrontofacialsyndrome pages 8-9): Alain Verloes, Nataliya Di Donato, Julien Masliah-Planchon, Marjolijn Jongmans, Omar A Abdul-Raman, Beate Albrecht, Judith Allanson, Han Brunner, Debora Bertola, Nicolas Chassaing, Albert David, Koen Devriendt, Pirayeh Eftekhari, Valérie Drouin-Garraud, Francesca Faravelli, Laurence Faivre, Fabienne Giuliano, Leina Guion Almeida, Jorge Juncos, Marlies Kempers, Hatice Koçak Eker, Didier Lacombe, Angela Lin, Grazia Mancini, Daniela Melis, Charles Marques Lourenço, Victoria Mok Siu, Gilles Morin, Marjan Nezarati, Malgorzata J M Nowaczyk, Jeanette C Ramer, Sara Osimani, Nicole Philip, Mary Ella Pierpont, Vincent Procaccio, Zeichi-Seide Roseli, Massimiliano Rossi, Cristina Rusu, Yves Sznajer, Ludivine Templin, Vera Uliana, Mirjam Klaus, Bregje Van Bon, Conny Van Ravenswaaij, Bruce Wainer, Andrew E Fry, Andreas Rump, Alexander Hoischen, Séverine Drunat, Jean-Baptiste Rivière, William B Dobyns, and Daniela T Pilz. Baraitser–winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. European Journal of Human Genetics, 23:292-301, Jul 2015. URL: https://doi.org/10.1038/ejhg.2014.95, doi:10.1038/ejhg.2014.95. This article has 189 citations and is from a domain leading peer-reviewed journal.

  19. (tsujimoto2024compromisedactindynamics pages 10-14): Takayuki Tsujimoto, Yushi Ou, Makoto Suzuki, Yuka Murata, Toshihiro Inubushi, Miho Nagata, Yasuki Ishihara, Ayumi Yonei, Yohei Miyashita, Yoshihiro Asano, Norio Sakai, Yasushi Sakata, Hajime Ogino, Takashi Yamashiro, and Hiroshi Kurosaka. Compromised actin dynamics underlie the orofacial cleft in baraitser-winter cerebrofrontofacial syndrome with a variant in actb. bioRxiv, Apr 2024. URL: https://doi.org/10.1101/2024.04.04.587685, doi:10.1101/2024.04.04.587685. This article has 3 citations.

  20. (niehaus2025cerebralorganoidsexpressing pages 15-18): Indra Niehaus, Michaela Wilsch-Bräuninger, Felipe Mora-Bermúdez, Mihaela Bobic-Rasonja, Velena Radosevic, Marija Milkovic-Perisa, Pauline Wimberger, Mariasavina Severino, Alexandra Haase, Ulrich Martin, Karolina Kuenzel, Kaomei Guan, Katrin Neumann, Noreen Walker, Evelin Schröck, Natasa Jovanov-Milosevic, Wieland B. Huttner, Nataliya Di Donato, and Michael Heide. Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly. bioRxiv, Jun 2025. URL: https://doi.org/10.1101/2022.12.07.519435, doi:10.1101/2022.12.07.519435. This article has 11 citations.

  21. (tsujimoto2024compromisedactindynamics pages 1-6): Takayuki Tsujimoto, Yushi Ou, Makoto Suzuki, Yuka Murata, Toshihiro Inubushi, Miho Nagata, Yasuki Ishihara, Ayumi Yonei, Yohei Miyashita, Yoshihiro Asano, Norio Sakai, Yasushi Sakata, Hajime Ogino, Takashi Yamashiro, and Hiroshi Kurosaka. Compromised actin dynamics underlie the orofacial cleft in baraitser-winter cerebrofrontofacial syndrome with a variant in actb. bioRxiv, Apr 2024. URL: https://doi.org/10.1101/2024.04.04.587685, doi:10.1101/2024.04.04.587685. This article has 3 citations.

  22. (ghiselli2024hearinglossin pages 1-2): Sara Ghiselli, Giulia Parmeggiani, Giulia Zambonini, and Domenico Cuda. Hearing loss in baraitser–winter syndrome: case reports and review of the literature. Journal of Clinical Medicine, 13:1500, Mar 2024. URL: https://doi.org/10.3390/jcm13051500, doi:10.3390/jcm13051500. This article has 3 citations.

  23. (ghiselli2024hearinglossin pages 2-4): Sara Ghiselli, Giulia Parmeggiani, Giulia Zambonini, and Domenico Cuda. Hearing loss in baraitser–winter syndrome: case reports and review of the literature. Journal of Clinical Medicine, 13:1500, Mar 2024. URL: https://doi.org/10.3390/jcm13051500, doi:10.3390/jcm13051500. This article has 3 citations.

  24. (dawidziuk2022denovoactg1 pages 4-7): Mateusz Dawidziuk, Anna Kutkowska-Kazmierczak, Ewelina Bukowska-Olech, Marta Jurek, Ewa Kalka, Dorothy Lys Guilbride, Mariusz Ireneusz Furmanek, Monika Bekiesinska-Figatowska, Jerzy Bal, and Pawel Gawlinski. De novo actg1 variant expands the phenotype and genotype of partial deafness and baraitser–winter syndrome. International Journal of Molecular Sciences, 23:692, Jan 2022. URL: https://doi.org/10.3390/ijms23020692, doi:10.3390/ijms23020692. This article has 9 citations.

  25. (tsujimoto2024compromisedactindynamics pages 6-10): Takayuki Tsujimoto, Yushi Ou, Makoto Suzuki, Yuka Murata, Toshihiro Inubushi, Miho Nagata, Yasuki Ishihara, Ayumi Yonei, Yohei Miyashita, Yoshihiro Asano, Norio Sakai, Yasushi Sakata, Hajime Ogino, Takashi Yamashiro, and Hiroshi Kurosaka. Compromised actin dynamics underlie the orofacial cleft in baraitser-winter cerebrofrontofacial syndrome with a variant in actb. bioRxiv, Apr 2024. URL: https://doi.org/10.1101/2024.04.04.587685, doi:10.1101/2024.04.04.587685. This article has 3 citations.

Artifacts