Baraitser-Winter Cerebrofrontofacial Syndrome
Baraitser-Winter cerebrofrontofacial syndrome is an autosomal dominant developmental actinopathy caused by heterozygous missense variants in ACTB or ACTG1, usually arising de novo. Its variable manifestations include distinctive craniofacial features, ocular coloboma, cortical malformations, developmental impairment, hearing loss, and musculoskeletal, cardiac, renal, or gastrointestinal abnormalities. Functional consequences depend on the allele and experimental system. Human cerebral organoids support a progenitor-division mechanism for microcephaly, while epithelial experiments with ACTB Ser348Leu support a possible pathway to orofacial clefting; these models do not establish one cellular mechanism for every manifestation.
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Subtypes
2
Baraitser-Winter syndrome 1 (ACTB)
MONDO:0009470
ACTB-related disease caused by heterozygous missense variants with dominant effects on actin function. Most cases arise de novo. Severe presentations formerly called Fryns-Aftimos syndrome fall within this spectrum, but severity varies between alleles and between individuals carrying the same allele.
Baraitser-Winter syndrome 2 (ACTG1)
MONDO:0013812
ACTG1-related disease caused by heterozygous missense variants. Cortical malformations are frequent in reported BRWS cohorts, with marked variation in severity. ACTG1-related nonsyndromic hearing loss DFNA20/26 is an allelic condition and should not be counted as BRWS solely because the same gene is involved.
Mechanistic Hypotheses
2Altered progenitor division and microcephaly
Evidence balance
2 support
Patient-derived ACTB Thr120Ile and ACTG1 Thr203Met cerebral organoids, supported by engineered ACTB Thr120Ile organoids, link abnormal progenitor division orientation to reduced ventricular-zone progenitor abundance. Delamination and long-term neuronal-output effects are inferred, and the upstream contribution of individual cytoskeletal abnormalities remains unresolved.
Pathograph links
Variant-Dependent Actin Cytoskeletal Dysregulation
->
Apical Progenitor Cytoskeletal Irregularities
ACTB Thr120Ile and ACTG1 Thr203Met organoids display apical structural abnormalities; the lymphoblastoid drug response is not itself the demonstrated intermediate.
Apical Progenitor Cytoskeletal Irregularities
->
Actin-Dependent Apical Progenitor Cleavage-Plane Defect
Apical cytoskeletal and morphological abnormalities may alter spindle positioning; the study expressly does not establish their causal relationship.
Actin-Dependent Apical Progenitor Cleavage-Plane Defect
->
Reduced Ventricular-Zone Progenitor Abundance
The orientation shift is proposed to increase delamination and basal progenitor output at the expense of the apical progenitor pool.
Reduced Ventricular-Zone Progenitor Abundance
->
Microcephaly
An early reduction in the primary progenitor pool may limit later neuronal output and brain growth. This explanation is supported by smaller organoids and microcephaly in the donors, not direct measurement of fetal patient progenitor dynamics.
Show evidence (2 references)
"We found that in contrast to the predominantly vertical cleavage plane orientation of mitotic APs in control cerebral organoids, mitotic APs of BWCFF-S cerebral organoids exhibited a nearly randomized or majoritarian horizontal cleavage plane orientation"
This is the directly observed division-orientation phenotype in ACTB Thr120Ile and ACTG1 Thr203Met patient-derived organoids.
"the VZ progenitor pool in BWCFF-S cerebral organoids is diminished, likely due to the shift in cleavage plane orientation of mitotic anaphase APs, which increases the probability of progenitor delamination and thereby promotes BP generation at the expense of the primary progenitor type, the AP."
The authors infer the orientation-to-delamination mechanism from static division angles and increased basal progenitor abundance; daughter-cell fate was not directly traced.
ACTB Ser348Leu epithelial dysfunction and clefting
Evidence balance
1 support
Reduced PFN1 association, impaired junctional localization, and slower migration in overexpression models suggest an epithelial contribution to clefting with ACTB Ser348Leu. Partial PFN1 rescue concerns localization in cultured cells. The frog indel phenotype and failure of mutant ACTB to rescue it do not reproduce the exact human heterozygous genotype.
Pathograph links
Dominant ACTB or ACTG1 Missense Actinopathy
->
Reduced ACTB-PFN1 Association
The Ser348Leu allele reduces PFN1 association in an overexpression assay; this branch is variant-specific.
Reduced ACTB-PFN1 Association
->
Impaired Junctional ACTB Localization
PFN1 coexpression partially restores mutant junctional localization, supporting a contribution of the impaired interaction.
Impaired Junctional ACTB Localization
->
Reduced Epithelial Cell Migration
Defective junctional localization and slower gap closure occur in the same mutant overexpression system; their causal sequence is proposed rather than isolated experimentally.
Reduced Epithelial Cell Migration
->
Orofacial Cleft
Impaired epithelial behavior is proposed to contribute to clefting for ACTB Ser348Leu; the cell assay does not directly demonstrate human palatal fusion.
Show evidence (1 reference)
url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
SUPPORT
INDIRECT
PRIMARY RESULT
In Vitro
"The limited ability of ACTB(p .S348L) to localize to cell -cell junctions in epithelial cells observed in this study may reflect a defect in actin polymerization, consequently impairing surface epithelial cell adhesion and palatal shelf convergence in the affected individual ... contributing to..."
Tsujimoto et al. propose a link from the epithelial findings to clefting. The separate frog experiment used mosaic indels near Ser348, not a patient-allele knock-in.
Discussions and Knowledge Gaps
1How 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?
Attached to
The published organoid study establishes altered progenitor orientation and abundance, including replication in engineered ACTB Thr120Ile organoids. It does not show that this mechanism reproduces the complete human cortical migration pattern, anteroposterior gradient, or variant-specific severity. Patient-variant correction, ACTG1 isogenic comparisons, and later cortical organization remain useful tests.
Proposed experiments
ACTB/ACTG1 isogenic cerebral organoid cortical-gradient panel
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.
Perturbations
ACTB/ACTG1 variant correction and knock-in
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
Quantify VZ thickness, apical cytoskeletal architecture, cleavage-plane orientation, radial glial scaffolding, neuronal migration distance, cortical-plate-like organization and region-patterning markers.
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.
Show evidence (2 references)
"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."
The cohort documents the anatomical cortical-malformation pattern. It does not directly measure neuronal migration, laminar connectivity, or the origin of the anteroposterior gradient.
"We found that in contrast to the predominantly vertical cleavage plane orientation of mitotic APs in control cerebral organoids, mitotic APs of BWCFF-S cerebral organoids exhibited a nearly randomized or majoritarian horizontal cleavage plane orientation"
This is the directly observed division-orientation phenotype in ACTB Thr120Ile and ACTG1 Thr203Met patient-derived organoids.
Pathophysiology
9Dominant ACTB or ACTG1 Missense Actinopathy
Heterozygous ACTB or ACTG1 missense variants alter cytoplasmic actin function. Dominant-negative or gain-of-function effects are supported; a uniform increase in actin stability and simple haploinsufficiency are not established mechanisms for classic BRWS.
Downstream
Missense variants alter actin organization and dynamics in patient-derived cells.
The genetic actinopathy causes a variable cortical-malformation spectrum, but the cellular intermediates and regional gradient are not fully resolved.
The Ser348Leu allele reduces PFN1 association in an overexpression assay; this branch is variant-specific.
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not established.
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not established.
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not established.
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not established.
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not established.
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not established.
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not established.
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not established.
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not established.
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not established.
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not established.
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not established.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain unresolved.
This manifestation is reported in the genetic syndrome; its specific cellular intermediates remain unresolved.
This manifestation is reported in the genetic syndrome; its specific cellular intermediates remain unresolved.
This manifestation is reported in the genetic syndrome; its specific cellular intermediates remain unresolved.
This manifestation is reported in the genetic syndrome; its specific cellular intermediates remain unresolved.
This manifestation is reported in the genetic syndrome; its specific cellular intermediates remain unresolved.
A reported clinical manifestation whose specific cellular intermediates remain unresolved.
A reported clinical manifestation whose specific cellular intermediates remain unresolved.
A reported clinical manifestation whose specific cellular intermediates remain unresolved.
A reported clinical manifestation whose specific cellular intermediates remain unresolved.
A reported clinical manifestation whose specific cellular intermediates remain unresolved.
A reported clinical manifestation whose specific cellular intermediates remain unresolved.
A reported clinical manifestation whose specific cellular intermediates remain unresolved.
A reported clinical manifestation whose specific cellular intermediates remain unresolved.
A reported clinical manifestation whose specific cellular intermediates remain unresolved.
A reported clinical manifestation with unresolved cellular intermediates.
A reported clinical manifestation with unresolved cellular intermediates.
A reported clinical manifestation with unresolved cellular intermediates.
A reported clinical manifestation with unresolved cellular intermediates.
A clinical manifestation with unresolved cellular intermediates.
A clinical manifestation with unresolved cellular intermediates.
A clinical manifestation with unresolved cellular intermediates.
A clinical manifestation with unresolved cellular intermediates.
A clinical manifestation with unresolved cellular intermediates.
Show evidence (3 references)
"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.
"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)."
The founding study found an ACTB or ACTG1 missense variant in each of 18 selected probands; this is a cohort finding, not proof of universal de novo inheritance.
"Several observations support a dominant-negative or gain-of-function mechanism for the disease-causing mutations."
The founding study supports an altered-function dominant mechanism rather than simple haploinsufficiency, without resolving one universal biochemical direction.
Variant-Dependent Actin Cytoskeletal Dysregulation
Patient lymphoblastoid cells show mutation-specific F-actin accumulation and abnormal morphology. ACTB Arg196His confers relative latrunculin resistance whereas ACTG1 Ser155Phe increases sensitivity. Other variants and tissues can show different biochemical behavior; organoids do not show a corresponding uniform increase in actin abundance.
Experimental models
Animal models
Downstream
ACTB Thr120Ile and ACTG1 Thr203Met organoids display apical structural abnormalities; the lymphoblastoid drug response is not itself the demonstrated intermediate.
Show evidence (1 reference)
"We observed an increased resistance to latrunculin A in β-actin p.Arg196His mutant cells, which is consistent with the previously reported p.Arg183Trp mutation34, whereas the γ-actin p.Ser155Phe mutant displayed increased sensitivity to the treatment"
Patient-derived lymphoblastoid cells show opposite drug sensitivities for these two alleles; increased filament stability is not a uniform consequence of BRWS variants.
Apical Progenitor Cytoskeletal Irregularities
Patient-derived cerebral organoids show variable apical cell shape, intercellular protrusions, and increased apical microtubule bundles. The adherens-junction belt is largely preserved and astral microtubule counts are unchanged. These observations are candidate contributors to altered spindle positioning rather than proven individual causes.
Experimental models
Downstream
Apical cytoskeletal and morphological abnormalities may alter spindle positioning; the study expressly does not establish their causal relationship.
Show evidence (1 reference)
"we observed a higher density of microtubule bundles at the apical cell cortex that appeared to be anchored to the apical adherens junction belt rather than being nucleated at the basal body of the primary cilium"
Electron microscopy identifies abnormal apical cytoskeletal organization in the patient-derived organoids. The authors did not quantify these ultrastructural changes or establish their causal relation to spindle orientation.
Actin-Dependent Apical Progenitor Cleavage-Plane Defect
ACTB Thr120Ile and ACTG1 Thr203Met patient-derived cerebral organoids show a shift away from predominantly vertical apical-progenitor cleavage planes. Engineered heterozygous ACTB Thr120Ile organoids reproduce this finding. Cleavage angle constrains possible division modes but does not by itself determine daughter-cell fate.
Experimental models
Downstream
The orientation shift is proposed to increase delamination and basal progenitor output at the expense of the apical progenitor pool.
Show evidence (1 reference)
"We found that in contrast to the predominantly vertical cleavage plane orientation of mitotic APs in control cerebral organoids, mitotic APs of BWCFF-S cerebral organoids exhibited a nearly randomized or majoritarian horizontal cleavage plane orientation"
This is the directly observed division-orientation phenotype in ACTB Thr120Ile and ACTG1 Thr203Met patient-derived organoids.
Reduced Ventricular-Zone Progenitor Abundance
The organoid ventricular zone contains fewer progenitors per ventricle-like structure and is thinner. The basal-progenitor-to-radial-glia ratio is increased; greater basal progenitor production is inferred from these observations. Apoptotic cells remain rare and the proportions of Ki-67- and PH3-positive cells are not significantly different, so progenitor depletion should not be equated with a general cell-cycle arrest.
Experimental models
Downstream
An early reduction in the primary progenitor pool may limit later neuronal output and brain growth. This explanation is supported by smaller organoids and microcephaly in the donors, not direct measurement of fetal patient progenitor dynamics.
Show evidence (1 reference)
"quantification of the DAPI-stained nuclei revealed a substantial decrease of the number of VZ progenitors per ventricle-like structure in the BWCFF-S organoids as compared to control organoids"
Direct cell counting documents a smaller ventricular-zone progenitor pool; unchanged Ki-67 and PH3 proportions do not establish a general block in cell cycling.
Cortical Developmental Malformation
Human imaging shows anterior-predominant pachygyria, with less frequent lissencephaly, heterotopia, and corpus-callosum abnormalities. These findings are compatible with disturbed cortical development but do not directly demonstrate a specific neuronal migration, axonal wiring, or regional-timing mechanism. Some affected individuals have no detectable cortical malformation.
Downstream
Pachygyria is a structural manifestation of the cortical developmental disorder.
Cortical malformations contribute to neurological impairment, but intellectual disability also occurs with apparently normal MRI.
Cortical structural abnormalities can contribute to epilepsy; the precise circuit mechanisms are not established by the clinical cohort.
Show evidence (2 references)
"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."
The cohort documents the anatomical cortical-malformation pattern. It does not directly measure neuronal migration, laminar connectivity, or the origin of the anteroposterior gradient.
"Intellectual disability and epilepsy are variable in severity and largely correlate with CNS anomalies."
The association between neurological severity and CNS malformations supports a contribution of cortical pathology, without establishing a specific circuit mechanism or excluding disability with normal MRI.
Reduced ACTB-PFN1 Association
ACTB Ser348Leu shows reduced association with exogenous PFN1 in GFP-pulldown experiments from transfected MDCK cells. This allele-specific result suggests altered interactions with an actin-polymerization factor; an equilibrium affinity constant was not measured.
Experimental models
Downstream
PFN1 coexpression partially restores mutant junctional localization, supporting a contribution of the impaired interaction.
Show evidence (1 reference)
url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
SUPPORT
PRIMARY RESULT
In Vitro
"We detected similar expression levels between the mutant (p.S348L) ... while the signal of PFN1 was noticeably reduced in the sample with mutant ACTB (p.S348L)"
Tsujimoto et al. (2024), Compromised actin dynamics underlie the orofacial cleft in Baraitser-Winter Cerebrofrontofacial Syndrome with a variant in ACTB: GFP pulldown from MDCK extracts mixed with exogenous PFN1 shows reduced association. This is not a measured binding constant.
Impaired Junctional ACTB Localization
Overexpressed ACTB Ser348Leu has reduced localization at epithelial cell junctions in MDCK cells and live Xenopus animal-cap epithelium. Diffuse mutant protein does not behave like endogenous filamentous actin during latrunculin treatment. Impaired incorporation is favored, but detailed polymerization effects remain unresolved.
Experimental models
Animal models
Downstream
Defective junctional localization and slower gap closure occur in the same mutant overexpression system; their causal sequence is proposed rather than isolated experimentally.
Show evidence (1 reference)
url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
SUPPORT
PRIMARY RESULT
In Vitro
"In contrast, the mutant ACTB (p.S348L) did not show an intense signal at the cell junction but rather showed uniform expression in the cytoplasm"
This result is specifically from MDCK cells overexpressing GFP-tagged ACTB.
Reduced Epithelial Cell Migration
MDCK cells overexpressing ACTB Ser348Leu close a defined cell-free gap more slowly than cells overexpressing wild-type ACTB. This experimental behavior supports a candidate epithelial contribution to clefting rather than a directly observed patient palatal-fusion defect.
Experimental models
Downstream
Impaired epithelial behavior is proposed to contribute to clefting for ACTB Ser348Leu; the cell assay does not directly demonstrate human palatal fusion.
Show evidence (1 reference)
url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
SUPPORT
PRIMARY RESULT
In Vitro
"We observed that the mutant ACTB (p.S348L) -overexpressing cells displayed slower migration over time than the wild-type ACTB-overexpressing cells"
The MDCK assay measures closure of a defined cell-free gap after removal of a silicone insert. It is a surrogate for epithelial behavior, not direct measurement of patient palatal fusion.
Pathograph
Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Phenotypes
73Cardiovascular 4
Congenital Heart Defects
FREQUENT
Abnormal heart morphology
HP:0001627
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Moderate short stature (44%) ... Cardiovascular abnormality (38%)"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter reports 38% cardiovascular abnormality; the 2015 cohort independently reports congenital heart defects in 12 of 36 evaluated patients.
Ventricular Septal Defect
HP:0001629
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Ventricular septal defect (HP:0001629). HP:0001629 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Cardiovascular malformations such as patent ductus arteriosus, ventricular or atrial septal defects"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This identifies a specific congenital cardiac lesion.
Atrial Septal Defect
HP:0001631
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Cardiovascular malformations such as patent ductus arteriosus, ventricular or atrial septal defects"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The same list distinguishes the atrial lesion.
Patent Ductus Arteriosus
HP:0001643
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Patent ductus arteriosus (HP:0001643). HP:0001643 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Cardiovascular malformations such as patent ductus arteriosus, ventricular or atrial septal defects"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The source explicitly lists this lesion.
Digestive 6
Gastrointestinal Dysfunction
FREQUENT
Abnormality of the gastrointestinal tract
HP:0011024
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Abnormality of the gastrointestinal tract (HP:0011024). HP:0011024 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Gastrointestinal dysfunction (41%) ... Frequent chronic constipation (requiring daily medication) & reflux disease"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The frequency applies to the broad gastrointestinal spectrum, not to every component.
Constipation
HP:0002019
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Constipation (HP:0002019). HP:0002019 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Constipation (either chronic or occasional) is the most frequently observed GI finding."
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The source identifies the most common gastrointestinal manifestation without a separate population denominator.
Gastroesophageal Reflux
HP:0002020
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Gastroesophageal reflux (HP:0002020). HP:0002020 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Frequent vomiting and gastroesophageal reflux disease have been reported occasionally in newborns and small children."
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The age context and variable occurrence are retained.
Feeding Difficulties
HP:0011968
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Severe feeding difficulties requiring nasogastric tube feeding with subsequent feeding tube have been reported in several children."
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This supports clinically significant feeding impairment.
Intestinal Malrotation
HP:0002566
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Intestinal malrotation (HP:0002566). HP:0002566 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Structural malformations include duodenal atresia and intestinal malrotation"
GeneReviews (March 2022 revision): The specific structural findings are recorded alongside the broad gastrointestinal category.
Duodenal Atresia
HP:0002247
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Duodenal atresia (HP:0002247). HP:0002247 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Structural malformations include duodenal atresia and intestinal malrotation"
GeneReviews (March 2022 revision): The named obstructive lesion is distinct from functional constipation or reflux.
Ear 4
Sensorineural Hearing Loss
Sensorineural hearing impairment
HP:0000407
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Sensorineural hearing loss, annotated with Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Sensorineural hearing loss of variable degree may be present and can be progressive and require hearing aids."
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This specifically supports sensorineural impairment and variable course, without importing frequencies from nonsyndromic ACTG1 deafness.
Small Ears
Microtia
HP:0008551
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Microtia (HP:0008551). HP:0008551 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Ears are often small with increased posterior angulation, sometimes anteverted pinnae, with an overfolded, thick helix and an underdeveloped antihelix."
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The source groups size and several shape findings; no composite percentage is assigned to size alone.
Posteriorly Rotated Ears
HP:0000358
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Posteriorly rotated ears (HP:0000358). HP:0000358 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Ears are often small with increased posterior angulation"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The feature is separate from ear size.
Conductive Hearing Loss
Conductive hearing impairment
HP:0000405
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Conductive hearing impairment (HP:0000405). HP:0000405 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Several individuals have frequent otitis media resulting in conductive hearing loss especially in early childhood."
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This separates a middle-ear mechanism from sensorineural impairment.
Eye 7
Iris Coloboma
HP:0000612
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Iris coloboma (HP:0000612). HP:0000612 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Uni- or bilateral ocular coloboma that may extend from the iris to the macula, sometimes with microphthalmia"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This supports iris involvement without assigning the combined ocular-coloboma frequency to iris coloboma alone.
Congenital Ptosis
VERY_FREQUENT
HP:0000508
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Congenital ptosis, annotated with Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Bilateral ptosis (90%) ... Highly arched eyebrows (90%)"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter gives a specific bilateral-ptosis frequency.
Hypertelorism
VERY_FREQUENT
HP:0000316
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Widely spaced eyes (95%) ... Bilateral ptosis (90%)"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The frequency concerns widely spaced eyes directly.
Retinal Coloboma
HP:0000480
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Retinal coloboma (HP:0000480). HP:0000480 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Iris and retinal coloboma and microphthalmia may severely impair vision."
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The posterior-segment finding is distinct from iris coloboma.
Microphthalmia
HP:0000568
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Microphthalmia (HP:0000568). HP:0000568 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Uni- or bilateral ocular coloboma that may extend from the iris to the macula, sometimes with microphthalmia"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This documents a distinct eye-size abnormality.
Amblyopia
HP:0000646
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Amblyopia (HP:0000646). HP:0000646 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"For amblyopia treatment, glasses were prescribed for full correction, and occlusion therapy was started for the left eye."
A molecularly confirmed ACTG1 Gly168Cys case supports this manifestation and its management.
Astigmatism
HP:0000483
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Astigmatism (HP:0000483). HP:0000483 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"Cycloplegic refraction revealed compound hyperopic astigmatism that was more severe in the right eye than in the left eye."
The observation is patient-specific rather than a frequency estimate.
Genitourinary 6
Renal Malformations
OCCASIONAL
Abnormal renal morphology
HP:0012210
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Abnormal renal morphology (HP:0012210). HP:0012210 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Structural renal malformation (10%) ... Micropenis, cryptorchidism, & hypospadias (rare)"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The table distinguishes structural renal malformations from the broader genitourinary category.
Hydronephrosis
OCCASIONAL
HP:0000126
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Hydronephrosis (HP:0000126). HP:0000126 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Hydronephrosis (23%) ... Structural renal malformation (10%)"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The table gives a hydronephrosis-specific percentage.
Horseshoe Kidney
HP:0000085
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Horseshoe kidney (HP:0000085). HP:0000085 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Genitourinary abnormalities can include hydronephrosis, horseshoe or ectopic kidneys, renal duplication, and hypospadias."
GeneReviews (March 2022 revision): Specific renal forms are recorded beside the heterogeneous structural category.
Ectopic Kidney
HP:0000086
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Ectopic kidney (HP:0000086). HP:0000086 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Genitourinary abnormalities can include hydronephrosis, horseshoe or ectopic kidneys, renal duplication, and hypospadias."
GeneReviews (March 2022 revision): The source directly identifies abnormal renal position.
Cryptorchidism
HP:0000028
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Genitourinary abnormality (41%) ... Micropenis, cryptorchidism, & hypospadias (rare)"
GeneReviews (March 2022 revision): The table explicitly lists the finding without a separate numeric estimate.
Hypospadias
HP:0000047
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Hypospadias (HP:0000047). HP:0000047 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Genitourinary abnormality (41%) ... Micropenis, cryptorchidism, & hypospadias (rare)"
GeneReviews (March 2022 revision): The same table identifies this specific genital malformation.
Head and Neck 23
Microcephaly
FREQUENT
HP:0000252
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Microcephaly (~50%) Microcephaly may be of prenatal onset, usually mild, but may be severe w/lissencephaly"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter reports approximately half of affected individuals and explicitly includes prenatal onset.
Trigonocephaly
HP:0000243
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Trigonocephaly (HP:0000243). HP:0000243 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Prominent metopic ridging or trigonocephaly (65%)"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The source groups the two findings; their frequencies cannot be separated.
Wide Nasal Bridge
HP:0000431
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Wide nasal bridge (HP:0000431). HP:0000431 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows."
The cohort describes a broad nose and prominent root; the 2014 severe-case series explicitly describes a broad nasal bridge. No compound nose frequency is assigned to this individual feature.
"broad nasal bridge, broad nasal tip and columella, anteverted nostrils"
The severe-case series documents the bridge and tip separately.
Highly Arched Eyebrows
VERY_FREQUENT
HP:0002553
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Highly arched eyebrow (HP:0002553). HP:0002553 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Bilateral ptosis (90%) ... Highly arched eyebrows (90%)"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The table estimates this feature at 90%.
Prominent Metopic Ridge
HP:0005487
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Prominent metopic ridge (HP:0005487). HP:0005487 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Prominent metopic ridging or trigonocephaly (65%)"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The combined frequency cannot be assigned to metopic ridging alone.
Broad Nasal Tip
HP:0000455
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Broad nasal tip (HP:0000455). HP:0000455 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Wide, short, thick, and upturned nose, with a large, flat tip"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter describes tip morphology separately from the nasal bridge.
Short Nose
HP:0003196
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Short nose (HP:0003196). HP:0003196 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Wide, short, thick, and upturned nose, with a large, flat tip"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This supports nasal shortening without assigning the composite nasal-feature percentage.
Anteverted Nares
HP:0000463
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Anteverted nares (HP:0000463). HP:0000463 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"a thick columella, anteverted, thick nares"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter explicitly identifies nostril orientation.
Long Philtrum
HP:0000343
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Long philtrum (HP:0000343). HP:0000343 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Long and smooth philtrum and thin vermilion border of the upper lip"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This separates philtral length from smoothness.
Smooth Philtrum
HP:0000319
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Smooth philtrum (HP:0000319). HP:0000319 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Long and smooth philtrum and thin vermilion border of the upper lip"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This describes philtral surface morphology.
Thin Upper Lip Vermilion
HP:0000219
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Thin upper lip vermilion (HP:0000219). HP:0000219 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Long and smooth philtrum and thin vermilion border of the upper lip"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter identifies this lip feature explicitly.
Wide Mouth
HP:0000154
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Wide mouth (HP:0000154). HP:0000154 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Wide mouth with downturned corners, everted vermilion of the lower lip"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This supports mouth width without treating the entire composite frequency as a separate width estimate.
Everted Lower Lip Vermilion
HP:0000232
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Everted lower lip vermilion (HP:0000232). HP:0000232 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Wide mouth with downturned corners, everted vermilion of the lower lip"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This identifies a separate lower-lip manifestation.
Downslanted Palpebral Fissures
HP:0000494
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Downslanted palpebral fissures (HP:0000494). HP:0000494 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Long, often downslanted palpebral fissures (with or without epicanthal folds or epicanthus inversus)"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter explicitly documents fissure orientation.
Retrognathia
HP:0000278
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Retrognathia (HP:0000278). HP:0000278 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"a flat malar region and retrognathia with a pointed chin"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This supports retrusion rather than assuming a small mandible.
Orofacial Cleft
OCCASIONAL
HP:0000202
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Orofacial cleft (HP:0000202). HP:0000202 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Cleft lip & palate (10%) ... Some persons may have rather mild craniofacial features"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter reports 10% for the combined cleft phenotype.
Webbed Neck
HP:0000465
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Webbed neck (HP:0000465). HP:0000465 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"note bifid nose, narrow shoulder girdle with hypoplastic muscles webbed neck and severe scoliosis"
The figure description documents webbing independently of the combined short-neck/pterygium table category.
Short Neck
HP:0000470
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Short neck (HP:0000470). HP:0000470 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"prominent full and wide cheeks, large mouth, thin upper lip, thick lower lip and short neck"
The ACTB-related second case explicitly documents a short neck.
High Palate
HP:0000218
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is High palate (HP:0000218). HP:0000218 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"The palate is highly arched. Four patients had cleft lip and palate."
The first sentence supports high palate; the adjacent cleft statement concerns a separate manifestation.
Pointed Chin
HP:0000307
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Pointed chin (HP:0000307). HP:0000307 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"There is retrognathia, a pointed chin, a wide mouth with downturned corners and an everted lower lip"
The facial description names the pointed chin; no combined-feature percentage is assigned to it.
Long Palpebral Fissures
HP:0000637
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Long palpebral fissure (HP:0000637). HP:0000637 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Long, often downslanted palpebral fissures (with or without epicanthal folds or epicanthus inversus)"
The chapter describes both length and orientation. They are recorded separately without assigning a compound frequency to either.
Full Cheeks
HP:0000293
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Full cheeks (HP:0000293). HP:0000293 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"prominent full and wide cheeks, large mouth, thin upper lip, thick lower lip and short neck"
The second case documents cheek fullness. No frequency is inferred from this individual.
Prominent Nasal Bridge
HP:0000426
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Prominent nasal bridge (HP:0000426). HP:0000426 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"With time, the nasal root becomes even more prominent, but remains flat in its middle part."
The primary cohort describes profile prominence and its evolution.
Integument 2
Axillary Pterygium
HP:0001060
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Axillary pterygium (HP:0001060). HP:0001060 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Axillary and popliteal pterygia may be present at birth."
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter distinguishes congenital webbing from later contractures.
Popliteal Pterygium
HP:0009756
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Popliteal pterygium (HP:0009756). HP:0009756 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Axillary and popliteal pterygia may be present at birth."
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The same sentence explicitly identifies the popliteal location.
Limbs 3
Shoulder Girdle Muscle Atrophy
HP:0003724
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Shoulder girdle muscle atrophy (HP:0003724). HP:0003724 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"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.
Broad Hallux
HP:0010055
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Broad hallux (HP:0010055). HP:0010055 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Musculoskeletal features include broad thumbs and hallux"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This names a specific skeletal manifestation.
Broad Thumb
HP:0011304
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Broad thumb (HP:0011304). HP:0011304 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Musculoskeletal features include broad thumbs and hallux"
GeneReviews (March 2022 revision): The source names thumb breadth explicitly.
Musculoskeletal 6
Hypotonia
FREQUENT
HP:0001252
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Variable muscular hypotonia, particularly of the upper body, is frequent"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter explicitly identifies hypotonia as frequent.
Flexion Contractures
HP:0001371
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Flexion contracture (HP:0001371). HP:0001371 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"slightly flexed elbows and knees, which may be associated with limited joint movement"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This describes restricted extension as a manifestation of the musculoskeletal disorder.
Scoliosis
HP:0002650
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"progressive, generalized muscle weakness. Some adults may become dependent on a wheelchair for mobility and develop late-onset spinal deformity (kyphosis, scoliosis)."
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter describes progression in some adults; this is not a universal trajectory.
Kyphosis
HP:0002808
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Kyphosis (HP:0002808). HP:0002808 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Many affected individuals, especially teenagers and adults, have a peculiar stance with kyphosis"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The manifestation is explicitly age contextualized.
Pectus Excavatum
HP:0000767
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Pectus excavatum (HP:0000767). HP:0000767 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"Patient B34: preaxial polydactyly of feet – Patient B6: pectus excavatum"
The figure caption identifies pectus excavatum in patient B6; the neighboring finding belongs to a different patient.
Lower Limb Spasticity
HP:0002061
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Lower limb spasticity (HP:0002061). HP:0002061 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"Spasticity of lower limbs ... 7 ... 14"
The ACTB row records seven present and fourteen absent; the ACTG1 fields are NA. The body associates spasticity with severe cases.
Nervous System 11
Pachygyria
FREQUENT
HP:0001302
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Pachygyria (HP:0001302). HP:0001302 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"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.
Intellectual Disability
HP:0001249
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"In children with normal brain structure, motor delay is common, but otherwise development is only mildly to moderately delayed. ID is usually mild. Rare individuals with normal intelligence have also been reported."
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The phenotype is common but not obligatory; the combined developmental-delay/intellectual-disability percentage is not assigned to each component independently.
Seizures
FREQUENT
HP:0001250
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Seizures, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Epilepsy, of no specific type and of variable severity, is present in 50% of individuals, often in conjunction with structural cerebral anomalies."
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter supplies a patient frequency and explicitly variable severity.
Global Developmental Delay
HP:0001263
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Developmental delay (DD) / intellectual disability (ID) is highly variable: ... In children with normal brain structure, motor delay is common"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter distinguishes developmental function from visible brain malformation; its combined DD/ID frequency does not establish an isolated global-delay denominator.
Subcortical Band Heterotopia
HP:0032409
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Subcortical band heterotopia (HP:0032409). HP:0032409 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Subcortical band and/or periventricular heterotopias;"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The combined pachygyria/heterotopia frequency does not give a band-specific estimate.
Agenesis of Corpus Callosum
HP:0001274
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Agenesis of corpus callosum (HP:0001274). HP:0001274 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Short, thick, or absent corpus callosum"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This supports agenesis without applying the overall callosal-abnormality frequency to it.
Lissencephaly
HP:0001339
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Lissencephaly (HP:0001339). HP:0001339 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Frontal or predominantly central pachygyria; more rarely, severe lissencephaly or microlissencephaly"
GeneReviews (March 2022 revision): This supports a rare severe cortical presentation rather than a general feature of one gene subtype.
Periventricular Nodular Heterotopia
HP:0032388
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Periventricular nodular heterotopia (HP:0032388). HP:0032388 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"Patient B22 also had a number of periventricular nodular heterotopia"
This is an individual imaging finding, not a pooled frequency.
Delayed Walking
Delayed ability to walk
HP:0031936
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Delayed ability to walk (HP:0031936). HP:0031936 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"Age at walking (months) ... 27 ... 31"
Table 2 places ACTG1 before ACTB. These are cohort summary ages, not penetrance estimates.
Delayed Speech and Language Development
HP:0000750
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"Age first words (months) ... 54 ... 43"
The table order is ACTG1 then ACTB; the deep-research summary reverses these gene-specific ages.
Ventriculomegaly
HP:0002119
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Ventriculomegaly (HP:0002119). HP:0002119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"The lateral ventricles may be mildly enlarged."
The cohort reports ventricular enlargement without establishing raised intracranial pressure.
Growth 1
Short Stature
FREQUENT
HP:0004322
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Moderate short stature (44%) ... Cardiovascular abnormality (38%)"
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The table assigns 44% specifically to moderate short stature.
Genetic Associations
2
ACTB pathogenic missense variants
(Heterozygous missense variants with dominant effects on actin function)
Show evidence (3 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Most individuals with BWCFF syndrome reported to date have the disorder as the result of a de novo ACTB or ACTG1 pathogenic variant."
GeneReviews (March 2022 revision): Most does not mean all; the following counseling section describes inherited and mosaic cases.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"In rare families, individuals diagnosed with BWCFF syndrome have the disorder as the result of a pathogenic variant inherited from a parent with germline mosaicism"
GeneReviews (March 2022 revision): Parental germline mosaicism provides a documented recurrence mechanism.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"The penetrance of BWCFF syndrome appears to be complete, but no single clinical manifestation is constant."
GeneReviews (March 2022 revision): The chapter separates syndrome penetrance from feature-specific expressivity.
ACTG1 pathogenic missense variants
(Heterozygous missense variants with dominant effects on actin function)
Show evidence (3 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Most individuals with BWCFF syndrome reported to date have the disorder as the result of a de novo ACTB or ACTG1 pathogenic variant."
GeneReviews (March 2022 revision): Most does not mean all; the following counseling section describes inherited and mosaic cases.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"In rare families, individuals diagnosed with BWCFF syndrome have the disorder as the result of a pathogenic variant inherited from a parent with germline mosaicism"
GeneReviews (March 2022 revision): Parental germline mosaicism provides a documented recurrence mechanism.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"The penetrance of BWCFF syndrome appears to be complete, but no single clinical manifestation is constant."
GeneReviews (March 2022 revision): The chapter separates syndrome penetrance from feature-specific expressivity.
Variants
7
ACTB p.Arg196His
A recurrent variant in the founding cohort, reported as NM_001101.2:c.587G>A. Patient-derived cells showed increased F-actin and resistance to latrunculin A.
Show evidence (2 references)
"Strikingly, 8 patients (44%) carried a mutation disrupting Arg196 of β-actin, including 7 with the same nucleotide change (c.587G>A, p.Arg196His)."
This is recurrence within the 18-person discovery cohort, not a population frequency.
"We observed an increased resistance to latrunculin A in β-actin p.Arg196His mutant cells ... whereas the γ-actin p.Ser155Phe mutant displayed increased sensitivity to the treatment"
Opposite responses to actin-monomer sequestration demonstrate variant-dependent actin dynamics.
ACTG1 p.Ser155Phe
A recurrent variant in the founding cohort, reported as NM_001614.2:c.464C>T. Patient-derived cells showed increased F-actin but increased sensitivity to latrunculin A.
Show evidence (2 references)
"including two recurrent de novo alterations (ACTB, encoding p.Arg196His, and ACTG1, encoding p.Ser155Phe)."
The founding report identifies this recurrent disease-associated variant.
"We observed an increased resistance to latrunculin A in β-actin p.Arg196His mutant cells ... whereas the γ-actin p.Ser155Phe mutant displayed increased sensitivity to the treatment"
Opposite responses to actin-monomer sequestration demonstrate variant-dependent actin dynamics.
ACTB p.Thr120Ile
NM_001101.5:c.359C>T; an allele modeled in patient-derived cerebral organoids and two heterozygous engineered control-line clones.
Show evidence (2 references)
"the BWCFF-S patient with the actin variant NM_001101.5 (ACTB):c.359 C > T p.Thr120Ile"
The paper documents the clinical donor variant used for the organoid model.
"heterozygous single-cell clones were identified by Sanger Sequencing of the target region ... Two such clones, referred to as CRTDi011-A–mutACTB-1 and CRTDi011-A–mutACTB-2, were used for the generation of cerebral organoids"
The engineered ACTB comparison uses two heterozygous clones in a control background; there is no analogous engineered ACTG1 comparison in this study.
ACTG1 p.Thr203Met
NM_001614.5:c.608C>T; an allele modeled in patient-derived cerebral organoids. No matched ACTG1 knock-in or corrected-patient comparison was reported.
Show evidence (2 references)
"the BWCFF-S patient with the actin variant NM_001614.5(ACTG1):c.608 C > T p.Thr203Met"
The paper identifies the second patient donor allele.
"We generated cerebral organoids from two clones of each patient-derived iPSC line."
Two clones came from each of two patients, one carrying ACTB Thr120Ile and the other ACTG1 Thr203Met; clones are not independent patients.
ACTB p.Ser348Leu
Likely Pathogenic
NM_001101.5:c.1043C>T. Reported in BRWS with variable clefting and hearing impairment; epithelial and Xenopus assays demonstrate altered function. The 2024 hearing case classified the allele as likely pathogenic.
Show evidence (3 references)
url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
SUPPORT
PRIMARY RESULT
In Vitro
"The nucleotide sequence s encoding ACTB, its mutated form ... ACTB(NM_001101.5):c.1043C>T (p.Ser348Leu) GRCh37 Chr7:5567464) and PFN1 were amplified and cloned"
The methods specify the transcript and variant used to construct the mutant protein expression vector.
url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
SUPPORT
PRIMARY RESULT
In Vitro
"In contrast, the mutant ACTB (p.S348L) did not show an intense signal at the cell junction but rather showed uniform expression in the cytoplasm"
This result is specifically from MDCK cells overexpressing GFP-tagged ACTB.
"a missense variant c.1043C > T (p.Ser348lEU) was found in the ACTB gene compatible with BRWS1 diagnosis. ... can be classified as likely pathogenic (class 4) according to ACMG guidelines"
The second case reports de novo heterozygosity and a likely pathogenic classification; the source uses unusual capitalization for Leu.
ACTG1 p.Gly168Cys
Likely Pathogenic
NM_001614.5:c.502G>T; a de novo likely pathogenic variant in a child with iris/retinal colobomata, pachygyria, hearing loss, and mild intellectual disability.
Show evidence (1 reference)
"Whole-exome sequencing revealed a heterozygous, de novo, and likely pathogenic variant (c.502G > T; p.Gly168Cys) in actin gamma 1 (ACTG1)"
The case report explicitly calls the allele likely pathogenic.
ACTB p.Arg196Cys
A recurrent ACTB hotspot allele reported in six of the 42 patients in the 2015 cohort, with clinical variability even among carriers of the same substitution.
Show evidence (1 reference)
"Amino acid 196 in ACTB is a hotspot with 14 affected patients in our cohort: eight with an ACTB p.Arg196His and six with p.Arg196Cys mutation."
The counts apply to the ascertained clinical cohort, not to population allele frequency.
Medical Actions
14
Antiseizure Therapy
Epilepsy is treated with standard antiseizure medication selected by an experienced neurologist. Response is variable, and no medication has demonstrated efficacy specifically for this syndrome.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Many ASMs may be effective; none has been demonstrated effective specifically for this disorder."
GeneReviews (March 2022 revision): The treatment table supports standard antiseizure management rather than a claim of uniformly refractory epilepsy.
Physical Therapy
Regular physical therapy supports mobility and may slow joint ankylosis and scoliosis; orthopedic follow-up remains necessary.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"PT may be helpful to slow progressive joint ankyloses & scoliosis."
GeneReviews (March 2022 revision): The recommendation is supportive and does not establish reversal of the underlying actinopathy.
Occupational Therapy
Occupational therapy addresses fine-motor difficulties affecting everyday activities.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing."
GeneReviews (March 2022 revision): This is function-directed supportive care.
Speech and Communication Support
Speech-language assessment and therapy, including augmentative or alternative communication when appropriate, support communication needs.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties."
GeneReviews (March 2022 revision): Communication support is tailored to the individual.
Feeding Support
Assess swallowing safety and provide feeding therapy for oral-motor dysfunction. Severe impairment may require nasogastric or gastrostomy feeding.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues."
GeneReviews (March 2022 revision): Therapy is appropriate when oral feeding is safe.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"When feeding dysfunction is severe, an NG-tube or G-tube may be necessary."
GeneReviews (March 2022 revision): Tube feeding is reserved for severe dysfunction.
Hearing Aids
Hearing aids may improve access to sound; device selection and follow-up depend on audiologic findings.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Hearing aids may be helpful; per otolaryngologist."
GeneReviews (March 2022 revision): The chapter supports hearing amplification.
Cochlear Implantation
A child with ACTB Ser348Leu-related BRWS received a right cochlear implant after limited hearing-aid benefit. Combined implant and contralateral hearing aid improved aided thresholds and tested speech perception; spontaneous speech remained difficult to understand. Evidence is a single case, not a comparative trial.
Show evidence (3 references)
"At the age of 2, she was implanted with a Medel Flex 28 CI model."
This is the ACTB-related second case; the first ACTG1 case was diagnosed with DFNA20/26 and is not used as BRWS treatment evidence.
"Speech perception with right CI and left HA: 100% of intelligibility at 50 dB"
This is an aided speech-perception result, not complete normalization of language.
"intelligibility of spontaneous production remains poor."
Residual functional communication limitation remained.
Refractive Correction and Amblyopia Treatment
In a child with ACTG1 Gly168Cys, glasses and occlusion therapy improved visual acuity from 20/100 right and 20/50 left to 25/25 in both eyes over three years. The maculae were spared by the colobomata, limiting generalization to other ocular anatomy.
Show evidence (1 reference)
"For amblyopia treatment, glasses were prescribed for full correction, and occlusion therapy was started for the left eye. After 3 years of regular follow-up after the initial diagnosis, the patient’s visual acuity had improved to 25/25 in both eyes."
A single case demonstrates a treatable refractive/amblyopic component of poor vision.
Ptosis Surgery
Ptosis may require ophthalmologic surgery according to its functional impact.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Standard treatment(s) per ophthalmologist if coloboma &/or micropthalmia is present & → poor vision Ptosis may require surgery."
The treatment table gives conditional ophthalmic interventions.
Osmotic Laxatives
Osmotic laxatives are used for constipation, with gastrointestinal review of long-term medication.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Osmotic laxatives were reported effective in majority of persons w/constipation."
GeneReviews (March 2022 revision): The chapter summarizes reported response without specifying a controlled trial.
Structural Malformation Management
Cardiac and urinary-tract malformations and oral clefts receive standard management tailored to the anatomical defect.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Malformations of the heart, urinary tract, and oral clefts are treated using standard procedures."
GeneReviews (March 2022 revision): This supports conventional lesion-specific management.
Genetic Counseling
Offer parental testing and counseling about autosomal dominant inheritance. Most cases are de novo, but parental germline mosaicism can cause recurrence despite negative parental blood testing. Each child of an affected individual has a 50% chance of inheriting the variant. Prenatal and preimplantation testing are possible once the familial variant is known.
Show evidence (4 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment."
GeneReviews (March 2022 revision): Parental testing informs recurrence counseling.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only."
GeneReviews (March 2022 revision): A negative blood test does not exclude germline mosaicism.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Each child of an individual with BWCFF syndrome has a 50% chance of inheriting the ACTB or ACTG1 pathogenic variant."
GeneReviews (March 2022 revision): The 50% risk applies to offspring of an affected heterozygote.
+ 1 more reference
Developmental and Organ Surveillance
Monitor development and educational needs at each visit. Follow seizures as clinically indicated. Provide at least annual ophthalmology with glaucoma screening when coloboma or microphthalmia is present, annual assessment of hearing-loss progression, and at least annual review of feeding/GI dysfunction and scoliosis. Orthopedic review increases to every six months during growth spurts and adolescence; cardiac and renal follow-up depend on existing anomalies.
Show evidence (5 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Development Monitor developmental progress & educational needs. At each visit"
GeneReviews (March 2022 revision): The table specifies routine developmental monitoring.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"If coloboma or microphthalmia present, ophthalmologic follow up w/ screening for intraocular hypertension & glaucoma (a known complication of colobomatous microphthalmia) At least annually"
GeneReviews (March 2022 revision): Eye surveillance is conditional on ocular malformation.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Hearing loss Evaluate for progression. Annually"
GeneReviews (March 2022 revision): Hearing-loss progression is assessed annually.
+ 2 more references
Assessment of Unexplained Deterioration
Hematologic malignancies have been reported, but an increased syndrome-specific risk is unestablished. GeneReviews recommends evaluation for malignancy when physical deterioration or unexplained chronic fever occurs, and does not recommend regular cancer surveillance.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"The risk of malignancies is not established for BWCFF syndrome, and thus no regular surveillance is recommended. However, screening for hematologic malignancies must be considered in case of physical deterioration or unexplained chronic fever."
GeneReviews (March 2022 revision): This distinguishes symptom-triggered assessment from an unsupported routine screening program.
Diagnosis
3
Molecular Diagnosis
Suggestive clinical findings plus a heterozygous pathogenic or likely pathogenic missense variant in ACTB or ACTG1 establish the diagnosis. Use a relevant multigene panel or exome/genome sequencing according to the presentation. A variant of uncertain significance is not diagnostic; gene deletions or duplications cause different phenotypes.
Genetic Testing
NCIT:C15709
NCI Thesaurus (NCIT)
Show evidence (4 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"The diagnosis of BWCFF syndrome is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) missense variant in either ACTB or ACTG1 identified by molecular genetic testing"
GeneReviews (March 2022 revision): This is the molecular diagnostic criterion.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Identification of a heterozygous variant of uncertain significance does not establish or rule out the diagnosis."
GeneReviews (March 2022 revision): Uncertain variants must not be treated as confirmed diagnoses.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype."
GeneReviews (March 2022 revision): Testing strategy depends on clinical specificity.
+ 1 more reference
Brain MRI and Neurologic Evaluation
Brain MRI characterizes cortical and callosal malformations. Consider EEG when MRI is abnormal or seizures are present.
Magnetic Resonance Imaging
NCIT:C16809
NCI Thesaurus (NCIT)
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"To incl brain MRI ... Consider EEG if brain MRI anomaly &/or seizures present."
GeneReviews (March 2022 revision): The initial-evaluation table makes EEG conditional.
Baseline Multisystem Evaluation
Assess development, vision including fundoscopy, hearing, cardiac anatomy by echocardiography, and renal/ureteral anatomy by ultrasound. Evaluate feeding and gastrointestinal function. The chapter recommends a baseline blood and platelet count, while noting that thrombocytopenia suggests a distinct ACTB-related disorder.
Show evidence (5 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Eyes Ophthalmologic eval incl fundoscopy"
GeneReviews (March 2022 revision): Baseline eye assessment includes the fundus.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Hearing Audiologic eval Assess for hearing loss"
GeneReviews (March 2022 revision): Baseline audiology is recommended.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Cardiovascular Echocardiogram Assess for congenital heart defects. Genitourinary Renal ultrasound Evaluate for malformation of kidneys &/or ureters"
GeneReviews (March 2022 revision): The evaluation table specifies cardiac and renal imaging.
+ 2 more references
Differential Diagnoses
5Conditions with similar clinical presentations that must be differentiated from Baraitser-Winter Cerebrofrontofacial Syndrome:
ACTB Loss-of-Function Developmental Disorder
Overlapping Features
ACTB loss-of-function alleles cause a distinct developmental disorder with overlapping organ malformations.
Distinguishing Features
- Loss-of-function variants and a different facial pattern should not be treated as the classic BRWS missense mechanism.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Described in ~40 persons w/DD, ID, internal organ malformations (incl CHDs & renal tract anomalies), growth restriction, & facial dysmorphism distinct from BWCFF syndrome"
GeneReviews separates this condition from classic BWCFF syndrome.
ACTB Arg183Trp Dystonia-Deafness Syndrome
Overlapping Features
Historically included in some broad actinopathy series, this allele produces a distinct dystonia-deafness presentation.
Distinguishing Features
- Drug-nonresponsive dystonia and early-onset sensorineural deafness are characteristic; pooled historical cohorts can distort BRWS natural-history estimates.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Dystonia-deafness syndrome. Drug-nonresponsive dystonia & early-onset sensorineural deafness"
GeneReviews separates this condition from classic BWCFF syndrome.
Overlapping Features
Ptosis, hypertelorism, chest deformity, and neck webbing can resemble mild BRWS in infancy.
Distinguishing Features
- Coloboma and pachygyria favor BRWS; coloboma is rare in Noonan syndrome and pachygyria is not a typical feature.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
SUPPORT
REVIEW SYNTHESIS
Human Clinical
"Coloboma is rarely observed in NS & NS is not assoc w/pachygyria or muscle involvement."
GeneReviews separates this condition from classic BWCFF syndrome.
Related Datasets
2GHGA dataset GHGAD98802067102801 belongs to published study GHGAS92787677252496. It contains single-cell RNA-seq from patient-derived, control, and engineered ACTB cerebral organoids at days 30 and 50. The public metadata list 43 sample records; the paper analyzes 260,880 cells across organoids, which is not a patient count.
Controlled access requires an approved research project. Sample_count represents repository sample records, not donors, cells, or individual organoids.
Show evidence (3 references)
url:https://data.ghga.de/api/metldata/artifacts/embedded_public/classes/EmbeddedDataset/resources/GHGAD98802067102801
SUPPORT
PRIMARY RESULT
In Vitro
"This dataset contains scRNA-seq data from patient-derived and control organoids, collected at 30 and 50 days of culture."
The GHGA record verifies the dataset identity and model/time-point context.
url:https://data.ghga.de/api/metldata/artifacts/embedded_public/classes/EmbeddedDataset/resources/GHGAD98802067102801
SUPPORT
PRIMARY RESULT
Other
"Access to this dataset is restricted to researchers with approved projects. Data may only be used for health/medical/biomedical research purposes."
The repository access policy qualifies the publication’s broad data-availability statement.
"Data consists of 260,880 single cells of 80 control, 44 BWCFF-S ACTB Thr120Ile, 41 BWCFF-S ACTG1 Thr203Met, and 20 cr. ACTB Thr120Ile 30 and 50 days-old cerebral organoids"
The paper distinguishes cells from organoids and includes engineered ACTB material.
Figure-level source data include bright-field and fluorescence images, electron microscopy volumes, organoid and ventricular-zone measurements, cleavage-plane angles, and single-cell composition summaries. These files complement the separately archived GHGA sequencing data.
Show evidence (2 references)
url:https://www.ebi.ac.uk/biostudies/api/v1/studies/S-SCDT-10_1038-S44319-025-00647-7
SUPPORT
PRIMARY RESULT
In Vitro
"These organoids were reduced in size, showing a thinner ventricular zone (VZ) due to reduced VZ progenitor abundance."
The matching BioStudies record describes the organoid study and lists source images and measurement spreadsheets.
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC12852704/fullTextXML
SUPPORT
PRIMARY RESULT
In Vitro
"The source data of this paper are collected in the following database record: ... biostudies:S-SCDT-10_1038-S44319-025-00647-7"
The publication explicitly associates this BioStudies accession with its source data.
Experimental Models
4
Patient-Derived Lymphoblastoid Cell Lines
CELL_LINE
The founding study tested actin protein abundance, F-actin organization, morphology, and latrunculin A response. ACTB Arg196His and ACTG1 Ser155Phe cells showed increased F-actin but opposite drug responses; actin protein abundance was unchanged. These non-neural cells do not directly establish cortical developmental mechanisms.
Organism
Homo sapiens
NCBITaxon:9606
NCBI Taxonomy (NCBITaxon)
Relation: this experimental model is built in this organism
This experimental model is built in Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
EBV-immortalized peripheral-blood lymphoblastoid lines from six patients and two controls
Publication
Pathograph links
Variant-Dependent Actin Cytoskeletal Dysregulation
Show evidence (1 reference)
"We observed an increased resistance to latrunculin A in β-actin p.Arg196His mutant cells ... whereas the γ-actin p.Ser155Phe mutant displayed increased sensitivity to the treatment"
Opposite responses to actin-monomer sequestration demonstrate variant-dependent actin dynamics.
Show evidence (2 references)
"Epstein-Barr virus immortalized lymphoblastoid cell lines were established from peripheral blood samples of six affected individuals (LR04-173, LP98-096, LR09-079, LP98-085, LR04-298 and LR06-241) and two control individuals (09.1359 and 07.0841) using standard procedures."
The model comprises patient-derived immortalized cells, not neurons or an animal infection model.
"We observed an increased resistance to latrunculin A in β-actin p.Arg196His mutant cells ... whereas the γ-actin p.Ser155Phe mutant displayed increased sensitivity to the treatment"
Opposite responses to actin-monomer sequestration demonstrate variant-dependent actin dynamics.
Patient-Derived Cerebral Organoids
ORGANOID
Patient organoids were compared with SC102A-1 and CRTDi011-A control lines. Mutant organoids were smaller, with altered apical progenitor cleavage orientation and reduced ventricular-zone progenitor abundance. Cytoskeletal abnormalities were observed, but their causal relation to altered division orientation was not established. No patient-variant correction or direct cell-fate tracing was reported.
Organism
Homo sapiens
NCBITaxon:9606
NCBI Taxonomy (NCBITaxon)
Relation: this experimental model is built in this organism
This experimental model is built in Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Two iPSC clones from each of two female patients carrying ACTB Thr120Ile or ACTG1 Thr203Met
Culture
Three-dimensional cerebral organoids studied at culture days 30 and 50
Publication
Pathograph links
Apical Progenitor Cytoskeletal Irregularities
Show evidence (1 reference)
"we observed a higher density of microtubule bundles at the apical cell cortex that appeared to be anchored to the apical adherens junction belt rather than being nucleated at the basal body of the primary cilium"
Electron microscopy identifies abnormal apical cytoskeletal organization in the patient-derived organoids. The authors did not quantify these ultrastructural changes or establish their causal relation to spindle orientation.
Actin-Dependent Apical Progenitor Cleavage-Plane Defect
Show evidence (1 reference)
"We found that in contrast to the predominantly vertical cleavage plane orientation of mitotic APs in control cerebral organoids, mitotic APs of BWCFF-S cerebral organoids exhibited a nearly randomized or majoritarian horizontal cleavage plane orientation"
This is the directly observed division-orientation phenotype in ACTB Thr120Ile and ACTG1 Thr203Met patient-derived organoids.
Reduced Ventricular-Zone Progenitor Abundance
Show evidence (1 reference)
"quantification of the DAPI-stained nuclei revealed a substantial decrease of the number of VZ progenitors per ventricle-like structure in the BWCFF-S organoids as compared to control organoids"
Direct cell counting documents a smaller ventricular-zone progenitor pool; unchanged Ki-67 and PH3 proportions do not establish a general block in cell cycling.
Show evidence (1 reference)
"We generated cerebral organoids from two clones of each patient-derived iPSC line."
Two clones came from each of two patients, one carrying ACTB Thr120Ile and the other ACTG1 Thr203Met; clones are not independent patients.
Engineered ACTB Thr120Ile Cerebral Organoids
ORGANOID
Engineered ACTB Thr120Ile organoids provide a comparison in a matched control background and reproduce altered progenitor division orientation and reduced progenitor abundance. These results concern this ACTB allele; an ACTG1 isogenic model and rescue by patient-variant correction were not tested. The number of ventricle-like structures did not differ significantly from controls, unlike the patient-derived comparison.
Organism
Homo sapiens
NCBITaxon:9606
NCBI Taxonomy (NCBITaxon)
Relation: this experimental model is built in this organism
This experimental model is built in Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Two heterozygous CRISPR-edited CRTDi011-A clones
Publication
Pathograph links
Actin-Dependent Apical Progenitor Cleavage-Plane Defect
Limitations: The engineered comparison tests ACTB Thr120Ile in one parental line; it does not establish all-allele or all-gene generality.
Show evidence (1 reference)
"anaphase AP cleavage plane angles ... revealed essentially the same phenotypes—with exception of the number of ventricle-like structures ... in the 30 days-old cr. ACTB Thr120Ile organoids as observed in the BWCFF-S ACTB Thr120Ile patient-derived organoids"
The results compare engineered and patient-derived ACTB Thr120Ile organoids. The ventricle-number phenotype did not reproduce, and the comparison is not an ACTG1 isogenic experiment.
Reduced Ventricular-Zone Progenitor Abundance
Show evidence (1 reference)
"anaphase AP cleavage plane angles ... revealed essentially the same phenotypes—with exception of the number of ventricle-like structures ... in the 30 days-old cr. ACTB Thr120Ile organoids as observed in the BWCFF-S ACTB Thr120Ile patient-derived organoids"
The results compare engineered and patient-derived ACTB Thr120Ile organoids. The ventricle-number phenotype did not reproduce, and the comparison is not an ACTG1 isogenic experiment.
Show evidence (2 references)
"heterozygous single-cell clones were identified by Sanger Sequencing of the target region ... Two such clones, referred to as CRTDi011-A–mutACTB-1 and CRTDi011-A–mutACTB-2, were used for the generation of cerebral organoids"
The engineered ACTB comparison uses two heterozygous clones in a control background; there is no analogous engineered ACTG1 comparison in this study.
"anaphase AP cleavage plane angles ... revealed essentially the same phenotypes—with exception of the number of ventricle-like structures ... in the 30 days-old cr. ACTB Thr120Ile organoids as observed in the BWCFF-S ACTB Thr120Ile patient-derived organoids"
The results compare engineered and patient-derived ACTB Thr120Ile organoids. The ventricle-number phenotype did not reproduce, and the comparison is not an ACTG1 isogenic experiment.
ACTB Ser348Leu MDCK Epithelial Model
CELL_LINE
Mutant ACTB showed reduced junctional localization and slower gap closure. A GFP pull-down from cell lysate mixed with exogenous PFN1 showed reduced association; this was not an equilibrium binding-affinity measurement. PFN1 coexpression partially restored junctional localization. Transient overexpression in canine kidney epithelium does not directly measure human palatal morphogenesis.
Organism
Canis lupus familiaris
NCBITaxon:9615
NCBI Taxonomy (NCBITaxon)
Relation: this experimental model is built in this organism
This experimental model is built in Canis lupus familiaris (NCBITaxon:9615). NCBITaxon:9615 is an organism from the NCBI Taxonomy.
Cell source
MDCK IFO50071 cells transiently expressing GFP-tagged wild-type or Ser348Leu human ACTB
Culture
Epithelial monolayers with a silicone-insert cell-free gap for migration assays
Publication
Pathograph links
Reduced ACTB-PFN1 Association
Show evidence (1 reference)
url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
SUPPORT
PRIMARY RESULT
In Vitro
"We detected similar expression levels between the mutant (p.S348L) ... while the signal of PFN1 was noticeably reduced in the sample with mutant ACTB (p.S348L)"
Tsujimoto et al. (2024), Compromised actin dynamics underlie the orofacial cleft in Baraitser-Winter Cerebrofrontofacial Syndrome with a variant in ACTB: GFP pulldown from MDCK extracts mixed with exogenous PFN1 shows reduced association. This is not a measured binding constant.
Impaired Junctional ACTB Localization
Show evidence (1 reference)
url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
SUPPORT
PRIMARY RESULT
In Vitro
"In contrast, the mutant ACTB (p.S348L) did not show an intense signal at the cell junction but rather showed uniform expression in the cytoplasm"
This result is specifically from MDCK cells overexpressing GFP-tagged ACTB.
Reduced Epithelial Cell Migration
Show evidence (1 reference)
url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
SUPPORT
PRIMARY RESULT
In Vitro
"We observed that the mutant ACTB (p.S348L) -overexpressing cells displayed slower migration over time than the wild-type ACTB-overexpressing cells"
The MDCK assay measures closure of a defined cell-free gap after removal of a silicone insert. It is a surrogate for epithelial behavior, not direct measurement of patient palatal fusion.
Show evidence (2 references)
url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
SUPPORT
PRIMARY RESULT
In Vitro
"MDCK cells (JCRB cell bank: IFO50071) were cultured in αMEM with nucleosides (Gibco) and 10% FBS (Gibco) under standard conditions."
The epithelial system is an established canine kidney cell line with transfected human ACTB constructs.
url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
SUPPORT
PRIMARY RESULT
In Vitro
"In contrast, the mutant ACTB (p.S348L) did not show an intense signal at the cell junction but rather showed uniform expression in the cytoplasm"
This result is specifically from MDCK cells overexpressing GFP-tagged ACTB.
Animal Models
2
ACTB Ser348Leu Overexpression in Xenopus Embryos
Live stage 9–10 embryos were imaged to assess ACTB localization in animal-cap epithelium. This whole-embryo overexpression experiment is distinct from explant culture and from the later F0 indel experiment.
Species
Xenopus laevis
Genotype
Injected mRNA encoding GFP-tagged wild-type or Ser348Leu human ACTB
Publication
Pathograph links
Impaired Junctional ACTB Localization
Show evidence (1 reference)
url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
SUPPORT
PRIMARY RESULT
Model Organism
"the mutant ACTB (p.S348L) in Xenopus leavis animal cap cells failed to localize to the cell-cell junction"
Live embryo animal-cap epithelium supported the junction-localization observation; the source misspells laevis in this passage.
Show evidence (1 reference)
url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
SUPPORT
PRIMARY RESULT
Model Organism
"the mutant ACTB (p.S348L) in Xenopus leavis animal cap cells failed to localize to the cell-cell junction"
Live embryo animal-cap epithelium supported the junction-localization observation; the source misspells laevis in this passage.
Xenopus actb.L/S F0 Crispants
Crispants showed reduced mouth width and intercanthal distance with upper-jaw notching. Wild-type human ACTB supplementation improved these measurements whereas Ser348Leu did not. The model perturbs actin function but does not recreate a heterozygous human missense allele; epithelial migration and PFN1 binding were not measured in these crispants.
Species
Xenopus laevis
Genotype
Mosaic CRISPR-generated indels near the Ser348-equivalent region of actb.L and actb.S
Publication
Pathograph links
Variant-Dependent Actin Cytoskeletal Dysregulation
Limitations: Mosaic indels and mRNA complementation test actin function rather than the dominant human Ser348Leu genotype or its specific molecular intermediates.
Show evidence (2 references)
url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
SUPPORT
PRIMARY RESULT
Model Organism
"Sequencing of the targeted region was performed in F0 crispant embryos, and the results showed that more than 90% of the cells exhibited indel mutations"
The perturbation consists of mosaic indels near Ser348 in actb.L/S, not a patient-allele knock-in.
+ 1 more reference
Show evidence (2 references)
url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
SUPPORT
PRIMARY RESULT
Model Organism
"Sequencing of the targeted region was performed in F0 crispant embryos, and the results showed that more than 90% of the cells exhibited indel mutations"
The perturbation consists of mosaic indels near Ser348 in actb.L/S, not a patient-allele knock-in.
url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
SUPPORT
PRIMARY RESULT
Model Organism
"supplementation with wild-type ACTB ameliorated the intercanthal distance and mouth width phenotypes of crispants, whereas mutated ACTB (p.S348L) did not"
A functional complementation comparison supports altered activity of Ser348Leu, without proving the same molecular route produces a human cleft.
Source YAML
click to showname: Baraitser-Winter Cerebrofrontofacial Syndrome
creation_date: '2026-06-05T00:00:00Z'
description: >-
Baraitser-Winter cerebrofrontofacial syndrome is an autosomal dominant developmental actinopathy caused by
heterozygous missense variants in ACTB or ACTG1, usually arising de novo. Its variable manifestations include
distinctive craniofacial features, ocular coloboma, cortical malformations, developmental impairment, hearing
loss, and musculoskeletal, cardiac, renal, or gastrointestinal abnormalities. Functional consequences depend
on the allele and experimental system. Human cerebral organoids support a progenitor-division mechanism for
microcephaly, while epithelial experiments with ACTB Ser348Leu support a possible pathway to orofacial clefting;
these models do not establish one cellular mechanism for every manifestation.
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: >-
ACTB-related disease caused by heterozygous missense variants with dominant effects on actin function.
Most cases arise de novo. Severe presentations formerly called Fryns-Aftimos syndrome fall within this
spectrum, but severity varies between alleles and between individuals carrying the same allele.
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: >-
ACTG1-related disease caused by heterozygous missense variants. Cortical malformations are frequent in
reported BRWS cohorts, with marked variation in severity. ACTG1-related nonsyndromic hearing loss DFNA20/26
is an allelic condition and should not be counted as BRWS solely because the same gene is involved.
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: Dominant ACTB or ACTG1 Missense Actinopathy
biological_scale: MOLECULAR
genes:
- preferred_term: ACTB
term:
id: hgnc:132
label: ACTB
- preferred_term: ACTG1
term:
id: hgnc:144
label: ACTG1
description: >-
Heterozygous ACTB or ACTG1 missense variants alter cytoplasmic actin function. Dominant-negative or gain-of-function
effects are supported; a uniform increase in actin stability and simple haploinsufficiency are not established
mechanisms for classic BRWS.
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.
quote_role: PRIMARY_RESULT
- 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: >-
The founding study found an ACTB or ACTG1 missense variant in each of 18 selected probands; this is a
cohort finding, not proof of universal de novo inheritance.
quote_role: PRIMARY_RESULT
- reference: PMID:22366783
reference_title: De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
Several observations support a dominant-negative or gain-of-function mechanism for the disease-causing
mutations.
explanation: >-
The founding study supports an altered-function dominant mechanism rather than simple haploinsufficiency,
without resolving one universal biochemical direction.
downstream:
- target: Variant-Dependent Actin Cytoskeletal Dysregulation
causal_link_type: DIRECT
description: >-
Missense variants alter actin organization and dynamics in patient-derived cells.
evidence:
- reference: PMID:22366783
reference_title: De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
We observed an increased resistance to latrunculin A in β-actin p.Arg196His mutant cells, which is
consistent with the previously reported p.Arg183Trp mutation34, whereas the γ-actin p.Ser155Phe mutant
displayed increased sensitivity to the treatment
explanation: >-
Patient-derived lymphoblastoid cells show opposite drug sensitivities for these two alleles; increased
filament stability is not a uniform consequence of BRWS variants.
- target: Cortical Developmental Malformation
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The genetic actinopathy causes a variable cortical-malformation spectrum, but the cellular intermediates
and regional gradient are not fully resolved.
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: >-
The cohort documents the anatomical cortical-malformation pattern. It does not directly measure neuronal
migration, laminar connectivity, or the origin of the anteroposterior gradient.
quote_role: PRIMARY_RESULT
- target: Reduced ACTB-PFN1 Association
causal_link_type: DIRECT
description: >-
The Ser348Leu allele reduces PFN1 association in an overexpression assay; this branch is variant-specific.
evidence:
- reference: url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
reference_title: https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
We detected similar expression levels between the mutant (p.S348L) ... while the signal of PFN1 was
noticeably reduced in the sample with mutant ACTB (p.S348L)
explanation: >-
Tsujimoto et al. (2024), Compromised actin dynamics underlie the orofacial cleft in Baraitser-Winter
Cerebrofrontofacial Syndrome with a variant in ACTB: GFP pulldown from MDCK extracts mixed with exogenous
PFN1 shows reduced association. This is not a measured binding constant.
hypothesis_groups:
- ser348leu_epithelial_clefting
- target: Iris Coloboma
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not
established.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Uni- or bilateral ocular coloboma that may extend from the iris to the macula, sometimes with microphthalmia
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This supports iris
involvement without assigning the combined ocular-coloboma frequency to iris coloboma alone.
- target: Congenital Ptosis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not
established.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Bilateral ptosis (90%) ... Highly arched eyebrows (90%)
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter gives
a specific bilateral-ptosis frequency.
- target: Hypertelorism
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not
established.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Widely spaced eyes (95%) ... Bilateral ptosis (90%)
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The frequency concerns
widely spaced eyes directly.
- target: Trigonocephaly
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not
established.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Prominent metopic ridging or trigonocephaly (65%)
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The source groups
the two findings; their frequencies cannot be separated.
- target: Wide Nasal Bridge
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not
established.
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: >-
The cohort describes a broad nose and prominent root; the 2014 severe-case series explicitly describes
a broad nasal bridge. No compound nose frequency is assigned to this individual feature.
- target: Short Stature
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not
established.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Moderate short stature (44%) ... Cardiovascular abnormality (38%)
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The table assigns
44% specifically to moderate short stature.
- target: Shoulder Girdle Muscle Atrophy
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not
established.
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.
- target: Sensorineural Hearing Loss
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not
established.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Sensorineural hearing loss of variable degree may be present and can be progressive and require hearing
aids.
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This specifically
supports sensorineural impairment and variable course, without importing frequencies from nonsyndromic
ACTG1 deafness.
- target: Congenital Heart Defects
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not
established.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Moderate short stature (44%) ... Cardiovascular abnormality (38%)
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter reports
38% cardiovascular abnormality; the 2015 cohort independently reports congenital heart defects in 12
of 36 evaluated patients.
- target: Renal Malformations
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not
established.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Structural renal malformation (10%) ... Micropenis, cryptorchidism, & hypospadias (rare)
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The table distinguishes
structural renal malformations from the broader genitourinary category.
- target: Gastrointestinal Dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not
established.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Gastrointestinal dysfunction (41%) ... Frequent chronic constipation (requiring daily medication) &
reflux disease
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The frequency applies
to the broad gastrointestinal spectrum, not to every component.
- target: Global Developmental Delay
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This manifestation is associated with the genetic syndrome; its specific cellular intermediates are not
established.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Developmental delay (DD) / intellectual disability (ID) is highly variable: ... In children with normal
brain structure, motor delay is common
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter distinguishes
developmental function from visible brain malformation; its combined DD/ID frequency does not establish
an isolated global-delay denominator.
- target: Retinal Coloboma
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Iris and retinal coloboma and microphthalmia may severely impair vision.
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The posterior-segment
finding is distinct from iris coloboma.
- target: Microphthalmia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Uni- or bilateral ocular coloboma that may extend from the iris to the macula, sometimes with microphthalmia
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This documents a
distinct eye-size abnormality.
- target: Highly Arched Eyebrows
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Bilateral ptosis (90%) ... Highly arched eyebrows (90%)
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The table estimates
this feature at 90%.
- target: Prominent Metopic Ridge
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Prominent metopic ridging or trigonocephaly (65%)
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The combined frequency
cannot be assigned to metopic ridging alone.
- target: Broad Nasal Tip
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Wide, short, thick, and upturned nose, with a large, flat tip
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter describes
tip morphology separately from the nasal bridge.
- target: Short Nose
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Wide, short, thick, and upturned nose, with a large, flat tip
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This supports nasal
shortening without assigning the composite nasal-feature percentage.
- target: Anteverted Nares
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
a thick columella, anteverted, thick nares
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter explicitly
identifies nostril orientation.
- target: Long Philtrum
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Long and smooth philtrum and thin vermilion border of the upper lip
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This separates philtral
length from smoothness.
- target: Smooth Philtrum
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Long and smooth philtrum and thin vermilion border of the upper lip
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This describes philtral
surface morphology.
- target: Thin Upper Lip Vermilion
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Long and smooth philtrum and thin vermilion border of the upper lip
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter identifies
this lip feature explicitly.
- target: Wide Mouth
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Wide mouth with downturned corners, everted vermilion of the lower lip
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This supports mouth
width without treating the entire composite frequency as a separate width estimate.
- target: Everted Lower Lip Vermilion
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Wide mouth with downturned corners, everted vermilion of the lower lip
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This identifies a
separate lower-lip manifestation.
- target: Small Ears
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Ears are often small with increased posterior angulation, sometimes anteverted pinnae, with an overfolded,
thick helix and an underdeveloped antihelix.
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The source groups
size and several shape findings; no composite percentage is assigned to size alone.
- target: Posteriorly Rotated Ears
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Ears are often small with increased posterior angulation
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The feature is separate
from ear size.
- target: Downslanted Palpebral Fissures
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Long, often downslanted palpebral fissures (with or without epicanthal folds or epicanthus inversus)
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter explicitly
documents fissure orientation.
- target: Retrognathia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
a flat malar region and retrognathia with a pointed chin
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This supports retrusion
rather than assuming a small mandible.
- target: Orofacial Cleft
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Cleft lip & palate (10%) ... Some persons may have rather mild craniofacial features
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter reports
10% for the combined cleft phenotype.
- target: Subcortical Band Heterotopia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Subcortical band and/or periventricular heterotopias;
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The combined pachygyria/heterotopia
frequency does not give a band-specific estimate.
- target: Agenesis of Corpus Callosum
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Short, thick, or absent corpus callosum
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This supports agenesis
without applying the overall callosal-abnormality frequency to it.
- target: Hypotonia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Variable muscular hypotonia, particularly of the upper body, is frequent
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter explicitly
identifies hypotonia as frequent.
- target: Flexion Contractures
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
slightly flexed elbows and knees, which may be associated with limited joint movement
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This describes restricted
extension as a manifestation of the musculoskeletal disorder.
- target: Axillary Pterygium
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Axillary and popliteal pterygia may be present at birth.
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter distinguishes
congenital webbing from later contractures.
- target: Popliteal Pterygium
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Axillary and popliteal pterygia may be present at birth.
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The same sentence
explicitly identifies the popliteal location.
- target: Scoliosis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
progressive, generalized muscle weakness. Some adults may become dependent on a wheelchair for mobility
and develop late-onset spinal deformity (kyphosis, scoliosis).
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter describes
progression in some adults; this is not a universal trajectory.
- target: Kyphosis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Many affected individuals, especially teenagers and adults, have a peculiar stance with kyphosis
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The manifestation
is explicitly age contextualized.
- target: Hydronephrosis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Hydronephrosis (23%) ... Structural renal malformation (10%)
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The table gives a
hydronephrosis-specific percentage.
- target: Constipation
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Constipation (either chronic or occasional) is the most frequently observed GI finding.
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The source identifies
the most common gastrointestinal manifestation without a separate population denominator.
- target: Gastroesophageal Reflux
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Frequent vomiting and gastroesophageal reflux disease have been reported occasionally in newborns and
small children.
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The age context and
variable occurrence are retained.
- target: Feeding Difficulties
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Severe feeding difficulties requiring nasogastric tube feeding with subsequent feeding tube have been
reported in several children.
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This supports clinically
significant feeding impairment.
- target: Broad Hallux
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Musculoskeletal features include broad thumbs and hallux
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This names a specific
skeletal manifestation.
- target: Ventricular Septal Defect
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Cardiovascular malformations such as patent ductus arteriosus, ventricular or atrial septal defects
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This identifies a
specific congenital cardiac lesion.
- target: Atrial Septal Defect
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Cardiovascular malformations such as patent ductus arteriosus, ventricular or atrial septal defects
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The same list distinguishes
the atrial lesion.
- target: Patent Ductus Arteriosus
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Cardiovascular malformations such as patent ductus arteriosus, ventricular or atrial septal defects
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The source explicitly
lists this lesion.
- target: Conductive Hearing Loss
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This clinical manifestation is reported in the genetic syndrome; specific cellular intermediates remain
unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Several individuals have frequent otitis media resulting in conductive hearing loss especially in early
childhood.
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This separates a
middle-ear mechanism from sensorineural impairment.
- target: Lissencephaly
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This manifestation is reported in the genetic syndrome; its specific cellular intermediates remain unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Frontal or predominantly central pachygyria; more rarely, severe lissencephaly or microlissencephaly
explanation: >-
GeneReviews (March 2022 revision): This supports a rare severe cortical presentation rather than a
general feature of one gene subtype.
- target: Intestinal Malrotation
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This manifestation is reported in the genetic syndrome; its specific cellular intermediates remain unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Structural malformations include duodenal atresia and intestinal malrotation
explanation: >-
GeneReviews (March 2022 revision): The specific structural findings are recorded alongside the broad
gastrointestinal category.
- target: Duodenal Atresia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This manifestation is reported in the genetic syndrome; its specific cellular intermediates remain unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Structural malformations include duodenal atresia and intestinal malrotation
explanation: >-
GeneReviews (March 2022 revision): The named obstructive lesion is distinct from functional constipation
or reflux.
- target: Horseshoe Kidney
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This manifestation is reported in the genetic syndrome; its specific cellular intermediates remain unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Genitourinary abnormalities can include hydronephrosis, horseshoe or ectopic kidneys, renal duplication,
and hypospadias.
explanation: >-
GeneReviews (March 2022 revision): Specific renal forms are recorded beside the heterogeneous structural
category.
- target: Ectopic Kidney
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
This manifestation is reported in the genetic syndrome; its specific cellular intermediates remain unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Genitourinary abnormalities can include hydronephrosis, horseshoe or ectopic kidneys, renal duplication,
and hypospadias.
explanation: >-
GeneReviews (March 2022 revision): The source directly identifies abnormal renal position.
- target: Webbed Neck
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
A reported clinical manifestation whose specific cellular intermediates remain unresolved.
evidence:
- reference: PMID:25052316
reference_title: 'Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
note bifid nose, narrow shoulder girdle with hypoplastic muscles webbed neck and severe scoliosis
explanation: >-
The figure description documents webbing independently of the combined short-neck/pterygium table category.
- target: Short Neck
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
A reported clinical manifestation whose specific cellular intermediates remain unresolved.
evidence:
- reference: PMID:38592426
reference_title: 'Hearing Loss in Baraitser-Winter Syndrome: Case Reports and Review of the Literature.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
prominent full and wide cheeks, large mouth, thin upper lip, thick lower lip and short neck
explanation: >-
The ACTB-related second case explicitly documents a short neck.
- target: Pectus Excavatum
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
A reported clinical manifestation whose specific cellular intermediates remain unresolved.
evidence:
- reference: PMID:25052316
reference_title: 'Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
Patient B34: preaxial polydactyly of feet – Patient B6: pectus excavatum
explanation: >-
The figure caption identifies pectus excavatum in patient B6; the neighboring finding belongs to a
different patient.
- target: Broad Thumb
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
A reported clinical manifestation whose specific cellular intermediates remain unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Musculoskeletal features include broad thumbs and hallux
explanation: >-
GeneReviews (March 2022 revision): The source names thumb breadth explicitly.
- target: Periventricular Nodular Heterotopia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
A reported clinical manifestation whose specific cellular intermediates remain unresolved.
evidence:
- reference: PMID:25052316
reference_title: 'Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
Patient B22 also had a number of periventricular nodular heterotopia
explanation: >-
This is an individual imaging finding, not a pooled frequency.
- target: Cryptorchidism
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
A reported clinical manifestation whose specific cellular intermediates remain unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Genitourinary abnormality (41%) ... Micropenis, cryptorchidism, & hypospadias (rare)
explanation: >-
GeneReviews (March 2022 revision): The table explicitly lists the finding without a separate numeric
estimate.
- target: Hypospadias
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
A reported clinical manifestation whose specific cellular intermediates remain unresolved.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Genitourinary abnormality (41%) ... Micropenis, cryptorchidism, & hypospadias (rare)
explanation: >-
GeneReviews (March 2022 revision): The same table identifies this specific genital malformation.
- target: Amblyopia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
A reported clinical manifestation whose specific cellular intermediates remain unresolved.
evidence:
- reference: PMID:39639254
reference_title: 'Ocular findings in Baraitser-Winter syndrome with a de novo mutation in the ACTG1 gene: a case report.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
For amblyopia treatment, glasses were prescribed for full correction, and occlusion therapy was started
for the left eye.
explanation: >-
A molecularly confirmed ACTG1 Gly168Cys case supports this manifestation and its management.
- target: Astigmatism
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
A reported clinical manifestation whose specific cellular intermediates remain unresolved.
evidence:
- reference: PMID:39639254
reference_title: 'Ocular findings in Baraitser-Winter syndrome with a de novo mutation in the ACTG1 gene: a case report.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
Cycloplegic refraction revealed compound hyperopic astigmatism that was more severe in the right eye
than in the left eye.
explanation: >-
The observation is patient-specific rather than a frequency estimate.
- target: High Palate
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
A reported clinical manifestation with unresolved cellular intermediates.
evidence:
- reference: PMID:25052316
reference_title: 'Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
The palate is highly arched. Four patients had cleft lip and palate.
explanation: >-
The first sentence supports high palate; the adjacent cleft statement concerns a separate manifestation.
- target: Pointed Chin
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
A reported clinical manifestation with unresolved cellular intermediates.
evidence:
- reference: PMID:25052316
reference_title: 'Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
There is retrognathia, a pointed chin, a wide mouth with downturned corners and an everted lower lip
explanation: >-
The facial description names the pointed chin; no combined-feature percentage is assigned to it.
- target: Delayed Walking
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
A reported clinical manifestation with unresolved cellular intermediates.
evidence:
- reference: url:https://www.nature.com/articles/ejhg201495/tables/2
reference_title: Table 2 Clinical manifestations of ACTB and ACTG1 mutations | European Journal of Human Genetics
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
Age at walking (months) ... 27 ... 31
explanation: >-
Table 2 places ACTG1 before ACTB. These are cohort summary ages, not penetrance estimates.
- target: Delayed Speech and Language Development
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
A reported clinical manifestation with unresolved cellular intermediates.
evidence:
- reference: url:https://www.nature.com/articles/ejhg201495/tables/2
reference_title: Table 2 Clinical manifestations of ACTB and ACTG1 mutations | European Journal of Human Genetics
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
Age first words (months) ... 54 ... 43
explanation: >-
The table order is ACTG1 then ACTB; the deep-research summary reverses these gene-specific ages.
- target: Long Palpebral Fissures
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
A clinical manifestation with unresolved cellular intermediates.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Long, often downslanted palpebral fissures (with or without epicanthal folds or epicanthus inversus)
explanation: >-
The chapter describes both length and orientation. They are recorded separately without assigning a
compound frequency to either.
- target: Full Cheeks
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
A clinical manifestation with unresolved cellular intermediates.
evidence:
- reference: PMID:38592426
reference_title: 'Hearing Loss in Baraitser-Winter Syndrome: Case Reports and Review of the Literature.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
prominent full and wide cheeks, large mouth, thin upper lip, thick lower lip and short neck
explanation: >-
The second case documents cheek fullness. No frequency is inferred from this individual.
- target: Prominent Nasal Bridge
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
A clinical manifestation with unresolved cellular intermediates.
evidence:
- reference: PMID:25052316
reference_title: 'Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
With time, the nasal root becomes even more prominent, but remains flat in its middle part.
explanation: >-
The primary cohort describes profile prominence and its evolution.
- target: Ventriculomegaly
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
A clinical manifestation with unresolved cellular intermediates.
evidence:
- reference: PMID:25052316
reference_title: 'Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
The lateral ventricles may be mildly enlarged.
explanation: >-
The cohort reports ventricular enlargement without establishing raised intracranial pressure.
- target: Lower Limb Spasticity
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
A clinical manifestation with unresolved cellular intermediates.
evidence:
- reference: url:https://www.nature.com/articles/ejhg201495/tables/2
reference_title: Table 2 Clinical manifestations of ACTB and ACTG1 mutations | European Journal of Human Genetics
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
Spasticity of lower limbs ... 7 ... 14
explanation: >-
The ACTB row records seven present and fourteen absent; the ACTG1 fields are NA. The body associates
spasticity with severe cases.
- name: Variant-Dependent Actin Cytoskeletal Dysregulation
biological_scale: CELLULAR
biological_processes:
- preferred_term: actin cytoskeleton organization
term:
id: GO:0030036
label: actin cytoskeleton organization
description: >-
Patient lymphoblastoid cells show mutation-specific F-actin accumulation and abnormal morphology. ACTB
Arg196His confers relative latrunculin resistance whereas ACTG1 Ser155Phe increases sensitivity. Other
variants and tissues can show different biochemical behavior; organoids do not show a corresponding uniform
increase in actin abundance.
evidence:
- reference: PMID:22366783
reference_title: De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
We observed an increased resistance to latrunculin A in β-actin p.Arg196His mutant cells, which is consistent
with the previously reported p.Arg183Trp mutation34, whereas the γ-actin p.Ser155Phe mutant displayed
increased sensitivity to the treatment
explanation: >-
Patient-derived lymphoblastoid cells show opposite drug sensitivities for these two alleles; increased
filament stability is not a uniform consequence of BRWS variants.
downstream:
- target: Apical Progenitor Cytoskeletal Irregularities
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
ACTB Thr120Ile and ACTG1 Thr203Met organoids display apical structural abnormalities; the lymphoblastoid
drug response is not itself the demonstrated intermediate.
evidence:
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
we observed a higher density of microtubule bundles at the apical cell cortex that appeared to be anchored
to the apical adherens junction belt rather than being nucleated at the basal body of the primary cilium
explanation: >-
Electron microscopy identifies abnormal apical cytoskeletal organization in the patient-derived organoids.
The authors did not quantify these ultrastructural changes or establish their causal relation to spindle
orientation.
hypothesis_groups:
- organoid_progenitor_depletion
- name: Apical Progenitor Cytoskeletal Irregularities
biological_scale: CELLULAR
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
description: >-
Patient-derived cerebral organoids show variable apical cell shape, intercellular protrusions, and increased
apical microtubule bundles. The adherens-junction belt is largely preserved and astral microtubule counts
are unchanged. These observations are candidate contributors to altered spindle positioning rather than
proven individual causes.
evidence:
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
we observed a higher density of microtubule bundles at the apical cell cortex that appeared to be anchored
to the apical adherens junction belt rather than being nucleated at the basal body of the primary cilium
explanation: >-
Electron microscopy identifies abnormal apical cytoskeletal organization in the patient-derived organoids.
The authors did not quantify these ultrastructural changes or establish their causal relation to spindle
orientation.
downstream:
- target: Actin-Dependent Apical Progenitor Cleavage-Plane Defect
causal_link_type: UNKNOWN
description: >-
Apical cytoskeletal and morphological abnormalities may alter spindle positioning; the study expressly
does not establish their causal relationship.
evidence:
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
While these findings do not establish a causal relationship, they provide reproducible observations
explanation: >-
The authors limit the causal interpretation of the ultrastructural findings.
directness: INDIRECT
hypothesis_groups:
- organoid_progenitor_depletion
- name: Actin-Dependent Apical Progenitor Cleavage-Plane Defect
biological_scale: CELLULAR
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
description: >-
ACTB Thr120Ile and ACTG1 Thr203Met patient-derived cerebral organoids show a shift away from predominantly
vertical apical-progenitor cleavage planes. Engineered heterozygous ACTB Thr120Ile organoids reproduce
this finding. Cleavage angle constrains possible division modes but does not by itself determine daughter-cell
fate.
evidence:
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
We found that in contrast to the predominantly vertical cleavage plane orientation of mitotic APs in
control cerebral organoids, mitotic APs of BWCFF-S cerebral organoids exhibited a nearly randomized or
majoritarian horizontal cleavage plane orientation
explanation: >-
This is the directly observed division-orientation phenotype in ACTB Thr120Ile and ACTG1 Thr203Met patient-derived
organoids.
downstream:
- target: Reduced Ventricular-Zone Progenitor Abundance
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
The orientation shift is proposed to increase delamination and basal progenitor output at the expense
of the apical progenitor pool.
evidence:
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
the VZ progenitor pool in BWCFF-S cerebral organoids is diminished, likely due to the shift in cleavage
plane orientation of mitotic anaphase APs, which increases the probability of progenitor delamination
and thereby promotes BP generation at the expense of the primary progenitor type, the AP.
explanation: >-
The authors infer the orientation-to-delamination mechanism from static division angles and increased
basal progenitor abundance; daughter-cell fate was not directly traced.
directness: INDIRECT
hypothesis_groups:
- organoid_progenitor_depletion
- name: Reduced Ventricular-Zone Progenitor Abundance
biological_scale: CELLULAR
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
description: >-
The organoid ventricular zone contains fewer progenitors per ventricle-like structure and is thinner. The
basal-progenitor-to-radial-glia ratio is increased; greater basal progenitor production is inferred from
these observations. Apoptotic cells remain rare and the proportions of Ki-67- and PH3-positive cells are
not significantly different, so progenitor depletion should not be equated with a general cell-cycle arrest.
evidence:
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
quantification of the DAPI-stained nuclei revealed a substantial decrease of the number of VZ progenitors
per ventricle-like structure in the BWCFF-S organoids as compared to control organoids
explanation: >-
Direct cell counting documents a smaller ventricular-zone progenitor pool; unchanged Ki-67 and PH3 proportions
do not establish a general block in cell cycling.
downstream:
- target: Microcephaly
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
An early reduction in the primary progenitor pool may limit later neuronal output and brain growth. This
explanation is supported by smaller organoids and microcephaly in the donors, not direct measurement
of fetal patient progenitor dynamics.
evidence:
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
In the long run, such a reduction in the AP pool could limit the source from which BPs are generated,
potentially decreasing neuronal output—one mechanism that would be consistent with microcephaly.
explanation: >-
The authors explicitly present reduced later neuronal output as a possible consequence of progenitor
depletion.
directness: INDIRECT
hypothesis_groups:
- organoid_progenitor_depletion
- name: Cortical Developmental Malformation
biological_scale: TISSUE
description: >-
Human imaging shows anterior-predominant pachygyria, with less frequent lissencephaly, heterotopia, and
corpus-callosum abnormalities. These findings are compatible with disturbed cortical development but do
not directly demonstrate a specific neuronal migration, axonal wiring, or regional-timing mechanism. Some
affected individuals have no detectable cortical malformation.
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: >-
The cohort documents the anatomical cortical-malformation pattern. It does not directly measure neuronal
migration, laminar connectivity, or the origin of the anteroposterior gradient.
quote_role: PRIMARY_RESULT
- 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: >-
The association between neurological severity and CNS malformations supports a contribution of cortical
pathology, without establishing a specific circuit mechanism or excluding disability with normal MRI.
quote_role: PRIMARY_RESULT
downstream:
- target: Pachygyria
causal_link_type: DIRECT
description: >-
Pachygyria is a structural manifestation of the cortical developmental disorder.
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: >-
The cohort documents the anatomical cortical-malformation pattern. It does not directly measure neuronal
migration, laminar connectivity, or the origin of the anteroposterior gradient.
quote_role: PRIMARY_RESULT
- target: Intellectual Disability
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Cortical malformations contribute to neurological impairment, but intellectual disability also occurs
with apparently normal MRI.
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: >-
The association between neurological severity and CNS malformations supports a contribution of cortical
pathology, without establishing a specific circuit mechanism or excluding disability with normal MRI.
quote_role: PRIMARY_RESULT
- target: Seizures
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Cortical structural abnormalities can contribute to epilepsy; the precise circuit mechanisms are not
established by the clinical cohort.
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: >-
The association between neurological severity and CNS malformations supports a contribution of cortical
pathology, without establishing a specific circuit mechanism or excluding disability with normal MRI.
quote_role: PRIMARY_RESULT
- name: Reduced ACTB-PFN1 Association
biological_scale: MOLECULAR
description: >-
ACTB Ser348Leu shows reduced association with exogenous PFN1 in GFP-pulldown experiments from transfected
MDCK cells. This allele-specific result suggests altered interactions with an actin-polymerization factor;
an equilibrium affinity constant was not measured.
evidence:
- reference: url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
reference_title: https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
We detected similar expression levels between the mutant (p.S348L) ... while the signal of PFN1 was noticeably
reduced in the sample with mutant ACTB (p.S348L)
explanation: >-
Tsujimoto et al. (2024), Compromised actin dynamics underlie the orofacial cleft in Baraitser-Winter
Cerebrofrontofacial Syndrome with a variant in ACTB: GFP pulldown from MDCK extracts mixed with exogenous
PFN1 shows reduced association. This is not a measured binding constant.
downstream:
- target: Impaired Junctional ACTB Localization
causal_link_type: DIRECT
description: >-
PFN1 coexpression partially restores mutant junctional localization, supporting a contribution of the
impaired interaction.
evidence:
- reference: url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
reference_title: https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
PFN1 overexpression partially restored the localization of mutated ACTB (p.S348L) to the cell junction
explanation: >-
Partial localization rescue supports the proposed interaction-to-localization link in MDCK cells.
hypothesis_groups:
- ser348leu_epithelial_clefting
- name: Impaired Junctional ACTB Localization
biological_scale: CELLULAR
description: >-
Overexpressed ACTB Ser348Leu has reduced localization at epithelial cell junctions in MDCK cells and live
Xenopus animal-cap epithelium. Diffuse mutant protein does not behave like endogenous filamentous actin
during latrunculin treatment. Impaired incorporation is favored, but detailed polymerization effects remain
unresolved.
evidence:
- reference: url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
reference_title: https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
In contrast, the mutant ACTB (p.S348L) did not show an intense signal at the cell junction but rather
showed uniform expression in the cytoplasm
explanation: >-
This result is specifically from MDCK cells overexpressing GFP-tagged ACTB.
downstream:
- target: Reduced Epithelial Cell Migration
causal_link_type: UNKNOWN
description: >-
Defective junctional localization and slower gap closure occur in the same mutant overexpression system;
their causal sequence is proposed rather than isolated experimentally.
evidence:
- reference: url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
reference_title: https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
We observed that the mutant ACTB (p.S348L) -overexpressing cells displayed slower migration over time
than the wild-type ACTB-overexpressing cells
explanation: >-
The MDCK assay measures closure of a defined cell-free gap after removal of a silicone insert. It is
a surrogate for epithelial behavior, not direct measurement of patient palatal fusion.
hypothesis_groups:
- ser348leu_epithelial_clefting
- name: Reduced Epithelial Cell Migration
biological_scale: CELLULAR
description: >-
MDCK cells overexpressing ACTB Ser348Leu close a defined cell-free gap more slowly than cells overexpressing
wild-type ACTB. This experimental behavior supports a candidate epithelial contribution to clefting rather
than a directly observed patient palatal-fusion defect.
evidence:
- reference: url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
reference_title: https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
We observed that the mutant ACTB (p.S348L) -overexpressing cells displayed slower migration over time
than the wild-type ACTB-overexpressing cells
explanation: >-
The MDCK assay measures closure of a defined cell-free gap after removal of a silicone insert. It is
a surrogate for epithelial behavior, not direct measurement of patient palatal fusion.
downstream:
- target: Orofacial Cleft
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
hypothesis_groups:
- ser348leu_epithelial_clefting
description: >-
Impaired epithelial behavior is proposed to contribute to clefting for ACTB Ser348Leu; the cell assay
does not directly demonstrate human palatal fusion.
evidence:
- reference: url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
reference_title: https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
The limited ability of ACTB(p .S348L) to localize to cell -cell junctions in epithelial cells observed
in this study may reflect a defect in actin polymerization, consequently impairing surface epithelial
cell adhesion and palatal shelf convergence in the affected individual ... contributing to the orofacial
clefting phenotype.
explanation: >-
Tsujimoto et al. propose a link from the epithelial findings to clefting. The separate frog experiment
used mosaic indels near Ser348, not a patient-allele knock-in.
directness: INDIRECT
phenotypes:
- name: Pachygyria
description: >-
Pachygyria is often anterior predominant. The 2015 clinically ascertained cohort reported it in nearly
all ACTG1 cases and approximately 60% of ACTB cases; these selected-cohort proportions should not be treated
as invariant gene-specific penetrance.
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: >-
Microcephaly may be prenatal or develop postnatally. Severity varies, with severe cases accompanying lissencephaly;
it is not exclusively a secondary postnatal process.
category: Neurological
phenotype_term:
preferred_term: Microcephaly
term:
id: HP:0000252
label: Microcephaly
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Microcephaly (~50%) Microcephaly may be of prenatal onset, usually mild, but may be severe w/lissencephaly
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter reports
approximately half of affected individuals and explicitly includes prenatal onset.
frequency: FREQUENT
- name: Intellectual Disability
description: >-
Intellectual disability ranges from mild to profound. Structural brain abnormalities influence severity,
but impairment also occurs with apparently normal brain structure; rare individuals have normal intelligence.
category: Neurological
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
In children with normal brain structure, motor delay is common, but otherwise development is only mildly
to moderately delayed. ID is usually mild. Rare individuals with normal intelligence have also been reported.
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The phenotype is common
but not obligatory; the combined developmental-delay/intellectual-disability percentage is not assigned
to each component independently.
- name: Seizures
description: >-
Epilepsy affects approximately half of reported individuals and varies in type and severity. Onset is age
dependent, ranging from the first months of life into adulthood. Some seizures are difficult to control,
but refractoriness is not universal.
category: Neurological
phenotype_term:
preferred_term: Seizures
term:
id: HP:0001250
label: Seizure
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Epilepsy, of no specific type and of variable severity, is present in 50% of individuals, often in conjunction
with structural cerebral anomalies.
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter supplies
a patient frequency and explicitly variable severity.
frequency: FREQUENT
- name: Global Developmental Delay
description: >-
Developmental delay varies markedly. Motor and language development may be delayed even when no cortical
malformation is visible on imaging.
category: Neurological
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Developmental delay (DD) / intellectual disability (ID) is highly variable: ... In children with normal
brain structure, motor delay is common
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter distinguishes
developmental function from visible brain malformation; its combined DD/ID frequency does not establish
an isolated global-delay denominator.
- name: Iris Coloboma
description: >-
Unilateral or bilateral iris coloboma may occur, sometimes extending into the posterior segment. The roughly
30% frequency for all ocular coloboma is not an iris-specific estimate.
category: Ophthalmological
phenotype_term:
preferred_term: Iris coloboma
term:
id: HP:0000612
label: Iris coloboma
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Uni- or bilateral ocular coloboma that may extend from the iris to the macula, sometimes with microphthalmia
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This supports iris
involvement without assigning the combined ocular-coloboma frequency to iris coloboma alone.
- name: Congenital Ptosis
description: >-
Bilateral congenital non-myopathic ptosis is a characteristic feature and can require surgery. A specific
levator-muscle or neural-crest mechanism has not been established by the clinical evidence.
category: Ophthalmological
phenotype_term:
preferred_term: Congenital ptosis
term:
id: HP:0000508
label: Ptosis
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Bilateral ptosis (90%) ... Highly arched eyebrows (90%)
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter gives a
specific bilateral-ptosis frequency.
frequency: VERY_FREQUENT
- name: Hypertelorism
description: >-
Widely spaced eyes are a highly frequent craniofacial manifestation.
category: Craniofacial
phenotype_term:
preferred_term: Hypertelorism
term:
id: HP:0000316
label: Hypertelorism
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Widely spaced eyes (95%) ... Bilateral ptosis (90%)
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The frequency concerns
widely spaced eyes directly.
frequency: VERY_FREQUENT
- name: Trigonocephaly
description: >-
Trigonocephaly and a prominent metopic ridge are related but distinct findings. The reported 65% combines
both and is not a trigonocephaly-specific estimate.
category: Craniofacial
phenotype_term:
preferred_term: Trigonocephaly
term:
id: HP:0000243
label: Trigonocephaly
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Prominent metopic ridging or trigonocephaly (65%)
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The source groups the
two findings; their frequencies cannot be separated.
- name: Wide Nasal Bridge
description: >-
A broad nasal bridge may accompany a broad nose and large tip; these dimensions are recorded separately.
category: Craniofacial
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: >-
The cohort describes a broad nose and prominent root; the 2014 severe-case series explicitly describes
a broad nasal bridge. No compound nose frequency is assigned to this individual feature.
- 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
quote_role: PRIMARY_RESULT
snippet: broad nasal bridge, broad nasal tip and columella, anteverted nostrils
explanation: >-
The severe-case series documents the bridge and tip separately.
- name: Short Stature
description: >-
Moderate short stature is common, with variable prenatal growth.
category: Growth
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Moderate short stature (44%) ... Cardiovascular abnormality (38%)
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The table assigns 44%
specifically to moderate short stature.
frequency: FREQUENT
- name: Shoulder Girdle Muscle Atrophy
description: >-
Reduced shoulder-girdle muscle bulk and progressive muscle wasting occur in some individuals. Congenital
muscle hypoplasia and later atrophy are not interchangeable, and the aggregate neuromuscular frequency
is not a shoulder-specific estimate.
category: Musculoskeletal
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 may be progressive and require amplification. Conductive hearing loss
also occurs, so the combined 35% hearing-loss frequency is not applied to this subtype.
category: Auditory
phenotype_term:
preferred_term: Sensorineural hearing loss
term:
id: HP:0000407
label: Sensorineural hearing impairment
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Sensorineural hearing loss of variable degree may be present and can be progressive and require hearing
aids.
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This specifically supports
sensorineural impairment and variable course, without importing frequencies from nonsyndromic ACTG1 deafness.
- name: Congenital Heart Defects
description: >-
Congenital cardiac malformations include septal defects, patent ductus arteriosus, and valve abnormalities.
category: Cardiovascular
phenotype_term:
preferred_term: Abnormal heart morphology
term:
id: HP:0001627
label: Abnormal heart morphology
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Moderate short stature (44%) ... Cardiovascular abnormality (38%)
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter reports
38% cardiovascular abnormality; the 2015 cohort independently reports congenital heart defects in 12
of 36 evaluated patients.
frequency: FREQUENT
- name: Renal Malformations
description: >-
Structural renal anomalies include horseshoe or ectopic kidneys and duplication. Hydronephrosis is recorded
separately.
category: Renal
phenotype_term:
preferred_term: Abnormal renal morphology
term:
id: HP:0012210
label: Abnormal renal morphology
coarse_binding_basis: VARIABLE_SPECTRUM
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Structural renal malformation (10%) ... Micropenis, cryptorchidism, & hypospadias (rare)
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The table distinguishes
structural renal malformations from the broader genitourinary category.
frequency: OCCASIONAL
- name: Gastrointestinal Dysfunction
description: >-
Gastrointestinal manifestations include constipation, reflux, feeding difficulties and occasional structural
anomalies, with different mechanisms and management needs.
category: Gastrointestinal
phenotype_term:
preferred_term: Abnormality of the gastrointestinal tract
term:
id: HP:0011024
label: Abnormality of the gastrointestinal tract
coarse_binding_basis: VARIABLE_SPECTRUM
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Gastrointestinal dysfunction (41%) ... Frequent chronic constipation (requiring daily medication) & reflux
disease
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The frequency applies
to the broad gastrointestinal spectrum, not to every component.
frequency: FREQUENT
- name: Retinal Coloboma
category: Ophthalmological
description: >-
Retinal coloboma varies in extent; visual prognosis depends partly on macular and optic-disc involvement.
phenotype_term:
preferred_term: Retinal coloboma
term:
id: HP:0000480
label: Retinal coloboma
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Iris and retinal coloboma and microphthalmia may severely impair vision.
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The posterior-segment
finding is distinct from iris coloboma.
- name: Microphthalmia
category: Ophthalmological
description: >-
Microphthalmia can accompany ocular coloboma.
phenotype_term:
preferred_term: Microphthalmia
term:
id: HP:0000568
label: Microphthalmia
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Uni- or bilateral ocular coloboma that may extend from the iris to the macula, sometimes with microphthalmia
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This documents a distinct
eye-size abnormality.
- name: Highly Arched Eyebrows
category: Craniofacial
description: >-
Highly arched eyebrows are a characteristic facial feature.
phenotype_term:
preferred_term: Highly arched eyebrow
term:
id: HP:0002553
label: Highly arched eyebrow
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Bilateral ptosis (90%) ... Highly arched eyebrows (90%)
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The table estimates
this feature at 90%.
frequency: VERY_FREQUENT
- name: Prominent Metopic Ridge
category: Craniofacial
description: >-
A palpable or visible midline metopic ridge can occur without assuming trigonocephaly or proven craniosynostosis.
phenotype_term:
preferred_term: Prominent metopic ridge
term:
id: HP:0005487
label: Prominent metopic ridge
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Prominent metopic ridging or trigonocephaly (65%)
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The combined frequency
cannot be assigned to metopic ridging alone.
- name: Broad Nasal Tip
category: Craniofacial
description: >-
A large broad nasal tip contributes to the characteristic nasal appearance.
phenotype_term:
preferred_term: Broad nasal tip
term:
id: HP:0000455
label: Broad nasal tip
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Wide, short, thick, and upturned nose, with a large, flat tip
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter describes
tip morphology separately from the nasal bridge.
- name: Short Nose
category: Craniofacial
description: >-
The nose may be short and upturned.
phenotype_term:
preferred_term: Short nose
term:
id: HP:0003196
label: Short nose
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Wide, short, thick, and upturned nose, with a large, flat tip
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This supports nasal
shortening without assigning the composite nasal-feature percentage.
- name: Anteverted Nares
category: Craniofacial
description: >-
Anteverted nares may accompany the upturned nose.
phenotype_term:
preferred_term: Anteverted nares
term:
id: HP:0000463
label: Anteverted nares
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
a thick columella, anteverted, thick nares
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter explicitly
identifies nostril orientation.
- name: Long Philtrum
category: Craniofacial
description: >-
The philtrum is often long.
phenotype_term:
preferred_term: Long philtrum
term:
id: HP:0000343
label: Long philtrum
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Long and smooth philtrum and thin vermilion border of the upper lip
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This separates philtral
length from smoothness.
- name: Smooth Philtrum
category: Craniofacial
description: >-
Reduced philtral definition can accompany a long philtrum.
phenotype_term:
preferred_term: Smooth philtrum
term:
id: HP:0000319
label: Smooth philtrum
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Long and smooth philtrum and thin vermilion border of the upper lip
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This describes philtral
surface morphology.
- name: Thin Upper Lip Vermilion
category: Craniofacial
description: >-
The upper-lip vermilion may be thin.
phenotype_term:
preferred_term: Thin upper lip vermilion
term:
id: HP:0000219
label: Thin upper lip vermilion
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Long and smooth philtrum and thin vermilion border of the upper lip
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter identifies
this lip feature explicitly.
- name: Wide Mouth
category: Craniofacial
description: >-
A wide mouth may have downturned corners.
phenotype_term:
preferred_term: Wide mouth
term:
id: HP:0000154
label: Wide mouth
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Wide mouth with downturned corners, everted vermilion of the lower lip
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This supports mouth
width without treating the entire composite frequency as a separate width estimate.
- name: Everted Lower Lip Vermilion
category: Craniofacial
description: >-
The lower-lip vermilion can be everted.
phenotype_term:
preferred_term: Everted lower lip vermilion
term:
id: HP:0000232
label: Everted lower lip vermilion
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Wide mouth with downturned corners, everted vermilion of the lower lip
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This identifies a separate
lower-lip manifestation.
- name: Small Ears
category: Craniofacial
description: >-
Ears are often small, with variable helix and antihelix morphology.
phenotype_term:
preferred_term: Microtia
term:
id: HP:0008551
label: Microtia
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Ears are often small with increased posterior angulation, sometimes anteverted pinnae, with an overfolded,
thick helix and an underdeveloped antihelix.
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The source groups size
and several shape findings; no composite percentage is assigned to size alone.
- name: Posteriorly Rotated Ears
category: Craniofacial
description: >-
Increased posterior ear angulation is reported.
phenotype_term:
preferred_term: Posteriorly rotated ears
term:
id: HP:0000358
label: Posteriorly rotated ears
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Ears are often small with increased posterior angulation
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The feature is separate
from ear size.
- name: Downslanted Palpebral Fissures
category: Ophthalmological
description: >-
Long palpebral fissures may be downslanted.
phenotype_term:
preferred_term: Downslanted palpebral fissures
term:
id: HP:0000494
label: Downslanted palpebral fissures
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Long, often downslanted palpebral fissures (with or without epicanthal folds or epicanthus inversus)
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter explicitly
documents fissure orientation.
- name: Retrognathia
category: Craniofacial
description: >-
A retruded mandible and pointed chin can contribute to the facial appearance.
phenotype_term:
preferred_term: Retrognathia
term:
id: HP:0000278
label: Retrognathia
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
a flat malar region and retrognathia with a pointed chin
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This supports retrusion
rather than assuming a small mandible.
- name: Orofacial Cleft
category: Craniofacial
description: >-
Cleft lip and/or palate occurs in a minority of individuals, with severity varying between patients carrying
the same allele.
phenotype_term:
preferred_term: Orofacial cleft
term:
id: HP:0000202
label: Orofacial cleft
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Cleft lip & palate (10%) ... Some persons may have rather mild craniofacial features
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter reports
10% for the combined cleft phenotype.
frequency: OCCASIONAL
- name: Subcortical Band Heterotopia
category: Neurological
description: >-
Subcortical heterotopic gray-matter bands may accompany pachygyria.
phenotype_term:
preferred_term: Subcortical band heterotopia
term:
id: HP:0032409
label: Subcortical band heterotopia
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Subcortical band and/or periventricular heterotopias;
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The combined pachygyria/heterotopia
frequency does not give a band-specific estimate.
- name: Agenesis of Corpus Callosum
category: Neurological
description: >-
The corpus callosum may be absent; other patients have different callosal abnormalities.
phenotype_term:
preferred_term: Agenesis of corpus callosum
term:
id: HP:0001274
label: Agenesis of corpus callosum
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Short, thick, or absent corpus callosum
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This supports agenesis
without applying the overall callosal-abnormality frequency to it.
- name: Hypotonia
category: Neurological
description: >-
Muscular hypotonia is variable and can particularly affect the upper body.
phenotype_term:
preferred_term: Hypotonia
term:
id: HP:0001252
label: Hypotonia
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Variable muscular hypotonia, particularly of the upper body, is frequent
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter explicitly
identifies hypotonia as frequent.
frequency: FREQUENT
- name: Flexion Contractures
category: Musculoskeletal
description: >-
Elbows and knees can remain flexed with limited range of motion; contractures may progress.
phenotype_term:
preferred_term: Flexion contracture
term:
id: HP:0001371
label: Flexion contracture
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
slightly flexed elbows and knees, which may be associated with limited joint movement
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This describes restricted
extension as a manifestation of the musculoskeletal disorder.
- name: Axillary Pterygium
category: Musculoskeletal
description: >-
Congenital axillary webbing occurs in some individuals.
phenotype_term:
preferred_term: Axillary pterygium
term:
id: HP:0001060
label: Axillary pterygium
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Axillary and popliteal pterygia may be present at birth.
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter distinguishes
congenital webbing from later contractures.
- name: Popliteal Pterygium
category: Musculoskeletal
description: >-
Congenital popliteal webbing occurs in some individuals.
phenotype_term:
preferred_term: Popliteal pterygium
term:
id: HP:0009756
label: Popliteal pterygium
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Axillary and popliteal pterygia may be present at birth.
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The same sentence explicitly
identifies the popliteal location.
- name: Scoliosis
category: Musculoskeletal
description: >-
Scoliosis may progress with neuromuscular involvement.
phenotype_term:
preferred_term: Scoliosis
term:
id: HP:0002650
label: Scoliosis
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
progressive, generalized muscle weakness. Some adults may become dependent on a wheelchair for mobility
and develop late-onset spinal deformity (kyphosis, scoliosis).
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The chapter describes
progression in some adults; this is not a universal trajectory.
- name: Kyphosis
category: Musculoskeletal
description: >-
Kyphosis contributes to the characteristic stance in some teenagers and adults.
phenotype_term:
preferred_term: Kyphosis
term:
id: HP:0002808
label: Kyphosis
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Many affected individuals, especially teenagers and adults, have a peculiar stance with kyphosis
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The manifestation is
explicitly age contextualized.
- name: Hydronephrosis
category: Renal
description: >-
Dilatation of the renal collecting system is reported in approximately one quarter of affected individuals.
phenotype_term:
preferred_term: Hydronephrosis
term:
id: HP:0000126
label: Hydronephrosis
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Hydronephrosis (23%) ... Structural renal malformation (10%)
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The table gives a hydronephrosis-specific
percentage.
frequency: OCCASIONAL
- name: Constipation
category: Gastrointestinal
description: >-
Constipation can be chronic and require daily treatment.
phenotype_term:
preferred_term: Constipation
term:
id: HP:0002019
label: Constipation
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Constipation (either chronic or occasional) is the most frequently observed GI finding.
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The source identifies
the most common gastrointestinal manifestation without a separate population denominator.
- name: Gastroesophageal Reflux
category: Gastrointestinal
description: >-
Reflux is reported particularly in infants and young children.
phenotype_term:
preferred_term: Gastroesophageal reflux
term:
id: HP:0002020
label: Gastroesophageal reflux
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Frequent vomiting and gastroesophageal reflux disease have been reported occasionally in newborns and
small children.
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The age context and
variable occurrence are retained.
- name: Feeding Difficulties
category: Gastrointestinal
description: >-
Severe feeding difficulties sometimes require nasogastric or longer-term tube feeding.
phenotype_term:
preferred_term: Feeding difficulties
term:
id: HP:0011968
label: Feeding difficulties
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Severe feeding difficulties requiring nasogastric tube feeding with subsequent feeding tube have been
reported in several children.
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This supports clinically
significant feeding impairment.
- name: Broad Hallux
category: Musculoskeletal
description: >-
A broad great toe can occur, distinct from rare duplication.
phenotype_term:
preferred_term: Broad hallux
term:
id: HP:0010055
label: Broad hallux
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Musculoskeletal features include broad thumbs and hallux
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This names a specific
skeletal manifestation.
- name: Ventricular Septal Defect
category: Cardiovascular
description: >-
Ventricular septal defects occur within the cardiac-malformation spectrum.
phenotype_term:
preferred_term: Ventricular septal defect
term:
id: HP:0001629
label: Ventricular septal defect
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Cardiovascular malformations such as patent ductus arteriosus, ventricular or atrial septal defects
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This identifies a specific
congenital cardiac lesion.
- name: Atrial Septal Defect
category: Cardiovascular
description: >-
Atrial septal defects occur within the cardiac-malformation spectrum.
phenotype_term:
preferred_term: Atrial septal defect
term:
id: HP:0001631
label: Atrial septal defect
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Cardiovascular malformations such as patent ductus arteriosus, ventricular or atrial septal defects
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The same list distinguishes
the atrial lesion.
- name: Patent Ductus Arteriosus
category: Cardiovascular
description: >-
Persistence of the ductus arteriosus is reported.
phenotype_term:
preferred_term: Patent ductus arteriosus
term:
id: HP:0001643
label: Patent ductus arteriosus
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Cardiovascular malformations such as patent ductus arteriosus, ventricular or atrial septal defects
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): The source explicitly
lists this lesion.
- name: Conductive Hearing Loss
category: Auditory
description: >-
Conductive hearing loss can accompany recurrent otitis media, especially in early childhood.
phenotype_term:
preferred_term: Conductive hearing impairment
term:
id: HP:0000405
label: Conductive hearing impairment
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Several individuals have frequent otitis media resulting in conductive hearing loss especially in early
childhood.
explanation: >-
GeneReviews, Baraitser-Winter Cerebrofrontofacial Syndrome (March 2022 revision): This separates a middle-ear
mechanism from sensorineural impairment.
- name: Lissencephaly
category: Neurological
description: >-
Severe lissencephaly is less frequent than pachygyria and can accompany profound developmental impairment.
phenotype_term:
preferred_term: Lissencephaly
term:
id: HP:0001339
label: Lissencephaly
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Frontal or predominantly central pachygyria; more rarely, severe lissencephaly or microlissencephaly
explanation: >-
GeneReviews (March 2022 revision): This supports a rare severe cortical presentation rather than a general
feature of one gene subtype.
- name: Intestinal Malrotation
category: Gastrointestinal
description: >-
Malrotation is a rare structural gastrointestinal manifestation.
phenotype_term:
preferred_term: Intestinal malrotation
term:
id: HP:0002566
label: Intestinal malrotation
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Structural malformations include duodenal atresia and intestinal malrotation
explanation: >-
GeneReviews (March 2022 revision): The specific structural findings are recorded alongside the broad
gastrointestinal category.
- name: Duodenal Atresia
category: Gastrointestinal
description: >-
Duodenal atresia is a reported structural gastrointestinal manifestation.
phenotype_term:
preferred_term: Duodenal atresia
term:
id: HP:0002247
label: Duodenal atresia
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Structural malformations include duodenal atresia and intestinal malrotation
explanation: >-
GeneReviews (March 2022 revision): The named obstructive lesion is distinct from functional constipation
or reflux.
- name: Horseshoe Kidney
category: Renal
description: >-
A horseshoe kidney is one reported form of structural renal involvement.
phenotype_term:
preferred_term: Horseshoe kidney
term:
id: HP:0000085
label: Horseshoe kidney
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Genitourinary abnormalities can include hydronephrosis, horseshoe or ectopic kidneys, renal duplication,
and hypospadias.
explanation: >-
GeneReviews (March 2022 revision): Specific renal forms are recorded beside the heterogeneous structural
category.
- name: Ectopic Kidney
category: Renal
description: >-
Renal ectopia is a reported malformation.
phenotype_term:
preferred_term: Ectopic kidney
term:
id: HP:0000086
label: Ectopic kidney
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Genitourinary abnormalities can include hydronephrosis, horseshoe or ectopic kidneys, renal duplication,
and hypospadias.
explanation: >-
GeneReviews (March 2022 revision): The source directly identifies abnormal renal position.
- name: Webbed Neck
category: Musculoskeletal
description: >-
Cervical webbing is reported, including a severe case in the 2015 cohort.
phenotype_term:
preferred_term: Webbed neck
term:
id: HP:0000465
label: Webbed neck
evidence:
- reference: PMID:25052316
reference_title: 'Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
note bifid nose, narrow shoulder girdle with hypoplastic muscles webbed neck and severe scoliosis
explanation: >-
The figure description documents webbing independently of the combined short-neck/pterygium table category.
- name: Short Neck
category: Musculoskeletal
description: >-
A short neck is reported in molecularly confirmed BRWS. The cohort table combines it with pterygium colli,
so a short-neck-specific frequency cannot be inferred.
phenotype_term:
preferred_term: Short neck
term:
id: HP:0000470
label: Short neck
evidence:
- reference: PMID:38592426
reference_title: 'Hearing Loss in Baraitser-Winter Syndrome: Case Reports and Review of the Literature.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
prominent full and wide cheeks, large mouth, thin upper lip, thick lower lip and short neck
explanation: >-
The ACTB-related second case explicitly documents a short neck.
- name: Pectus Excavatum
category: Musculoskeletal
description: >-
Pectus excavatum is one documented chest-wall deformity.
phenotype_term:
preferred_term: Pectus excavatum
term:
id: HP:0000767
label: Pectus excavatum
evidence:
- reference: PMID:25052316
reference_title: 'Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
Patient B34: preaxial polydactyly of feet – Patient B6: pectus excavatum
explanation: >-
The figure caption identifies pectus excavatum in patient B6; the neighboring finding belongs to a different
patient.
- name: Broad Thumb
category: Musculoskeletal
description: >-
Broad thumbs may accompany broad great toes; duplication is uncommon.
phenotype_term:
preferred_term: Broad thumb
term:
id: HP:0011304
label: Broad thumb
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Musculoskeletal features include broad thumbs and hallux
explanation: >-
GeneReviews (March 2022 revision): The source names thumb breadth explicitly.
- name: Periventricular Nodular Heterotopia
category: Neurological
description: >-
Periventricular nodules can occur with cortical malformation.
phenotype_term:
preferred_term: Periventricular nodular heterotopia
term:
id: HP:0032388
label: Periventricular nodular heterotopia
evidence:
- reference: PMID:25052316
reference_title: 'Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
Patient B22 also had a number of periventricular nodular heterotopia
explanation: >-
This is an individual imaging finding, not a pooled frequency.
- name: Cryptorchidism
category: Genitourinary
description: >-
Undescended testes are a rare reported genital manifestation.
phenotype_term:
preferred_term: Cryptorchidism
term:
id: HP:0000028
label: Cryptorchidism
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Genitourinary abnormality (41%) ... Micropenis, cryptorchidism, & hypospadias (rare)
explanation: >-
GeneReviews (March 2022 revision): The table explicitly lists the finding without a separate numeric
estimate.
- name: Hypospadias
category: Genitourinary
description: >-
Hypospadias is a rare reported genital manifestation.
phenotype_term:
preferred_term: Hypospadias
term:
id: HP:0000047
label: Hypospadias
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Genitourinary abnormality (41%) ... Micropenis, cryptorchidism, & hypospadias (rare)
explanation: >-
GeneReviews (March 2022 revision): The same table identifies this specific genital malformation.
- name: Amblyopia
category: Ophthalmological
description: >-
Amblyopia can contribute a treatable component of visual impairment even in a child with large retinal
colobomata.
phenotype_term:
preferred_term: Amblyopia
term:
id: HP:0000646
label: Amblyopia
evidence:
- reference: PMID:39639254
reference_title: 'Ocular findings in Baraitser-Winter syndrome with a de novo mutation in the ACTG1 gene: a case report.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
For amblyopia treatment, glasses were prescribed for full correction, and occlusion therapy was started
for the left eye.
explanation: >-
A molecularly confirmed ACTG1 Gly168Cys case supports this manifestation and its management.
- name: Astigmatism
category: Ophthalmological
description: >-
Hyperopic astigmatism contributed to visual impairment in a reported ACTG1-related case.
phenotype_term:
preferred_term: Astigmatism
term:
id: HP:0000483
label: Astigmatism
evidence:
- reference: PMID:39639254
reference_title: 'Ocular findings in Baraitser-Winter syndrome with a de novo mutation in the ACTG1 gene: a case report.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
Cycloplegic refraction revealed compound hyperopic astigmatism that was more severe in the right eye
than in the left eye.
explanation: >-
The observation is patient-specific rather than a frequency estimate.
- name: High Palate
category: Craniofacial
description: >-
A highly arched palate is described in the clinical cohort.
phenotype_term:
preferred_term: High palate
term:
id: HP:0000218
label: High palate
evidence:
- reference: PMID:25052316
reference_title: 'Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
The palate is highly arched. Four patients had cleft lip and palate.
explanation: >-
The first sentence supports high palate; the adjacent cleft statement concerns a separate manifestation.
- name: Pointed Chin
category: Craniofacial
description: >-
A pointed chin may accompany retrognathia.
phenotype_term:
preferred_term: Pointed chin
term:
id: HP:0000307
label: Pointed chin
evidence:
- reference: PMID:25052316
reference_title: 'Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
There is retrognathia, a pointed chin, a wide mouth with downturned corners and an everted lower lip
explanation: >-
The facial description names the pointed chin; no combined-feature percentage is assigned to it.
- name: Delayed Walking
category: Neurological
description: >-
Walking was delayed in the 2015 cohort, with reported ages of 27 months for ACTG1 and 31 months for ACTB.
phenotype_term:
preferred_term: Delayed ability to walk
term:
id: HP:0031936
label: Delayed ability to walk
evidence:
- reference: url:https://www.nature.com/articles/ejhg201495/tables/2
reference_title: Table 2 Clinical manifestations of ACTB and ACTG1 mutations | European Journal of Human Genetics
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
Age at walking (months) ... 27 ... 31
explanation: >-
Table 2 places ACTG1 before ACTB. These are cohort summary ages, not penetrance estimates.
- name: Delayed Speech and Language Development
category: Neurological
description: >-
The cohort reported first words at 54 months for ACTG1 and 43 months for ACTB, with substantial variation
in developmental impairment.
phenotype_term:
preferred_term: Delayed speech and language development
term:
id: HP:0000750
label: Delayed speech and language development
evidence:
- reference: url:https://www.nature.com/articles/ejhg201495/tables/2
reference_title: Table 2 Clinical manifestations of ACTB and ACTG1 mutations | European Journal of Human Genetics
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
Age first words (months) ... 54 ... 43
explanation: >-
The table order is ACTG1 then ACTB; the deep-research summary reverses these gene-specific ages.
- name: Long Palpebral Fissures
category: Ophthalmological
description: >-
Long palpebral fissures are common; their length is distinct from the downslanting orientation that may
accompany them.
phenotype_term:
preferred_term: Long palpebral fissure
term:
id: HP:0000637
label: Long palpebral fissure
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Long, often downslanted palpebral fissures (with or without epicanthal folds or epicanthus inversus)
explanation: >-
The chapter describes both length and orientation. They are recorded separately without assigning a compound
frequency to either.
- name: Full Cheeks
category: Craniofacial
description: >-
Full cheeks are reported in the cohort and in a molecularly confirmed ACTB case; facial fullness can become
more prominent with age.
phenotype_term:
preferred_term: Full cheeks
term:
id: HP:0000293
label: Full cheeks
evidence:
- reference: PMID:38592426
reference_title: 'Hearing Loss in Baraitser-Winter Syndrome: Case Reports and Review of the Literature.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
prominent full and wide cheeks, large mouth, thin upper lip, thick lower lip and short neck
explanation: >-
The second case documents cheek fullness. No frequency is inferred from this individual.
- name: Prominent Nasal Bridge
category: Craniofacial
description: >-
The nasal root becomes increasingly prominent on profile with age, distinct from nasal width.
phenotype_term:
preferred_term: Prominent nasal bridge
term:
id: HP:0000426
label: Prominent 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
quote_role: PRIMARY_RESULT
snippet: >-
With time, the nasal root becomes even more prominent, but remains flat in its middle part.
explanation: >-
The primary cohort describes profile prominence and its evolution.
- name: Ventriculomegaly
category: Neurological
description: >-
Mild enlargement of the lateral ventricles can accompany the cortical malformation spectrum; it is not
equated with hydrocephalus.
phenotype_term:
preferred_term: Ventriculomegaly
term:
id: HP:0002119
label: Ventriculomegaly
evidence:
- reference: PMID:25052316
reference_title: 'Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
The lateral ventricles may be mildly enlarged.
explanation: >-
The cohort reports ventricular enlargement without establishing raised intracranial pressure.
- name: Lower Limb Spasticity
category: Neurological
description: >-
Lower-limb spasticity was reported in seven of 21 assessed ACTB cases in the 2015 table; ACTG1 status was
not available. These selected-cohort counts are not a general gene-specific penetrance estimate.
phenotype_term:
preferred_term: Lower limb spasticity
term:
id: HP:0002061
label: Lower limb spasticity
evidence:
- reference: url:https://www.nature.com/articles/ejhg201495/tables/2
reference_title: Table 2 Clinical manifestations of ACTB and ACTG1 mutations | European Journal of Human Genetics
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
Spasticity of lower limbs ... 7 ... 14
explanation: >-
The ACTB row records seven present and fourteen absent; the ACTG1 fields are NA. The body associates
spasticity with severe cases.
genetic:
- name: ACTB pathogenic missense variants
gene_term:
preferred_term: ACTB
term:
id: hgnc:132
label: ACTB
association: >-
Heterozygous missense variants with dominant effects on actin function
relationship_type: CAUSATIVE
variant_origin: GERMLINE
subtype: BRWS1
notes: >-
Most affected individuals have a de novo variant, but transmission from an affected parent and parental
germline mosaicism are documented. Penetrance appears complete while no individual clinical feature is
constant. Functional effects and severity are variant dependent; a gene-level rule that ACTB is always
more severe than ACTG1 is not established. ACTB loss-of-function and thrombocytopenia-associated alleles
can cause distinct disorders.
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Most individuals with BWCFF syndrome reported to date have the disorder as the result of a de novo ACTB
or ACTG1 pathogenic variant.
explanation: >-
GeneReviews (March 2022 revision): Most does not mean all; the following counseling section describes
inherited and mosaic cases.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
In rare families, individuals diagnosed with BWCFF syndrome have the disorder as the result of a pathogenic
variant inherited from a parent with germline mosaicism
explanation: >-
GeneReviews (March 2022 revision): Parental germline mosaicism provides a documented recurrence mechanism.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
The penetrance of BWCFF syndrome appears to be complete, but no single clinical manifestation is constant.
explanation: >-
GeneReviews (March 2022 revision): The chapter separates syndrome penetrance from feature-specific expressivity.
- name: ACTG1 pathogenic missense variants
gene_term:
preferred_term: ACTG1
term:
id: hgnc:144
label: ACTG1
association: Heterozygous missense variants with dominant effects on actin function
relationship_type: CAUSATIVE
variant_origin: GERMLINE
subtype: BRWS2
notes: >-
Most affected individuals have a de novo variant, but transmission from an affected parent and parental
germline mosaicism are documented. Penetrance appears complete while no individual clinical feature is
constant. Functional effects and severity are variant dependent; a gene-level rule that ACTB is always
more severe than ACTG1 is not established. ACTG1-related DFNA20/26 nonsyndromic hearing loss is a distinct
allelic condition.
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Most individuals with BWCFF syndrome reported to date have the disorder as the result of a de novo ACTB
or ACTG1 pathogenic variant.
explanation: >-
GeneReviews (March 2022 revision): Most does not mean all; the following counseling section describes
inherited and mosaic cases.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
In rare families, individuals diagnosed with BWCFF syndrome have the disorder as the result of a pathogenic
variant inherited from a parent with germline mosaicism
explanation: >-
GeneReviews (March 2022 revision): Parental germline mosaicism provides a documented recurrence mechanism.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
The penetrance of BWCFF syndrome appears to be complete, but no single clinical manifestation is constant.
explanation: >-
GeneReviews (March 2022 revision): The chapter separates syndrome penetrance from feature-specific expressivity.
treatments:
- name: Antiseizure Therapy
description: >-
Epilepsy is treated with standard antiseizure medication selected by an experienced neurologist. Response
is variable, and no medication has demonstrated efficacy specifically for this syndrome.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
explanation: >-
GeneReviews (March 2022 revision): The treatment table supports standard antiseizure management rather
than a claim of uniformly refractory epilepsy.
therapeutic_modality: SMALL_MOLECULE
action_category: THERAPEUTIC
target_phenotypes:
- preferred_term: Seizures
term:
id: HP:0001250
label: Seizure
- name: Physical Therapy
description: >-
Regular physical therapy supports mobility and may slow joint ankylosis and scoliosis; orthopedic follow-up
remains necessary.
action_category: THERAPEUTIC
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
PT may be helpful to slow progressive joint ankyloses & scoliosis.
explanation: >-
GeneReviews (March 2022 revision): The recommendation is supportive and does not establish reversal of
the underlying actinopathy.
treatment_term:
preferred_term: Physical Therapy
term:
id: NCIT:C15302
label: Physical Therapy
therapeutic_modality: BEHAVIORAL
target_phenotypes:
- preferred_term: Flexion Contractures
term:
id: HP:0001371
label: Flexion contracture
- preferred_term: Scoliosis
term:
id: HP:0002650
label: Scoliosis
- name: Occupational Therapy
description: >-
Occupational therapy addresses fine-motor difficulties affecting everyday activities.
action_category: THERAPEUTIC
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function
such as feeding, grooming, dressing, and writing.
explanation: >-
GeneReviews (March 2022 revision): This is function-directed supportive care.
treatment_term:
preferred_term: Occupational Therapy
term:
id: NCIT:C121351
label: Occupational Therapy
therapeutic_modality: BEHAVIORAL
- name: Speech and Communication Support
description: >-
Speech-language assessment and therapy, including augmentative or alternative communication when appropriate,
support communication needs.
action_category: THERAPEUTIC
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication
[AAC]) for individuals who have expressive language difficulties.
explanation: >-
GeneReviews (March 2022 revision): Communication support is tailored to the individual.
treatment_term:
preferred_term: Speech Language Therapy
term:
id: NCIT:C159273
label: Speech Language Therapy
therapeutic_modality: BEHAVIORAL
- name: Feeding Support
description: >-
Assess swallowing safety and provide feeding therapy for oral-motor dysfunction. Severe impairment may
require nasogastric or gastrostomy feeding.
action_category: THERAPEUTIC
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination
or sensory-related feeding issues.
explanation: >-
GeneReviews (March 2022 revision): Therapy is appropriate when oral feeding is safe.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.
explanation: >-
GeneReviews (March 2022 revision): Tube feeding is reserved for severe dysfunction.
treatment_term:
preferred_term: Nutritional Support
term:
id: NCIT:C15433
label: Nutritional Support
target_phenotypes:
- preferred_term: Feeding Difficulties
term:
id: HP:0011968
label: Feeding difficulties
- name: Hearing Aids
description: >-
Hearing aids may improve access to sound; device selection and follow-up depend on audiologic findings.
action_category: THERAPEUTIC
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Hearing aids may be helpful; per otolaryngologist.
explanation: >-
GeneReviews (March 2022 revision): The chapter supports hearing amplification.
treatment_term:
preferred_term: Hearing amplification
term:
id: NCIT:C15747
label: Supportive Care
therapeutic_modality: DEVICE
target_phenotypes:
- preferred_term: Sensorineural Hearing Loss
term:
id: HP:0000407
label: Sensorineural hearing impairment
- preferred_term: Conductive Hearing Loss
term:
id: HP:0000405
label: Conductive hearing impairment
- name: Cochlear Implantation
description: >-
A child with ACTB Ser348Leu-related BRWS received a right cochlear implant after limited hearing-aid benefit.
Combined implant and contralateral hearing aid improved aided thresholds and tested speech perception;
spontaneous speech remained difficult to understand. Evidence is a single case, not a comparative trial.
action_category: THERAPEUTIC
evidence:
- reference: PMID:38592426
reference_title: 'Hearing Loss in Baraitser-Winter Syndrome: Case Reports and Review of the Literature.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
At the age of 2, she was implanted with a Medel Flex 28 CI model.
explanation: >-
This is the ACTB-related second case; the first ACTG1 case was diagnosed with DFNA20/26 and is not used
as BRWS treatment evidence.
- reference: PMID:38592426
reference_title: 'Hearing Loss in Baraitser-Winter Syndrome: Case Reports and Review of the Literature.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
Speech perception with right CI and left HA: 100% of intelligibility at 50 dB
explanation: >-
This is an aided speech-perception result, not complete normalization of language.
- reference: PMID:38592426
reference_title: 'Hearing Loss in Baraitser-Winter Syndrome: Case Reports and Review of the Literature.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
intelligibility of spontaneous production remains poor.
explanation: >-
Residual functional communication limitation remained.
treatment_term:
preferred_term: Cochlear implantation
term:
id: NCIT:C15329
label: Surgical Procedure
therapeutic_modality: DEVICE
target_phenotypes:
- preferred_term: Sensorineural Hearing Loss
term:
id: HP:0000407
label: Sensorineural hearing impairment
- name: Refractive Correction and Amblyopia Treatment
description: >-
In a child with ACTG1 Gly168Cys, glasses and occlusion therapy improved visual acuity from 20/100 right
and 20/50 left to 25/25 in both eyes over three years. The maculae were spared by the colobomata, limiting
generalization to other ocular anatomy.
action_category: THERAPEUTIC
evidence:
- reference: PMID:39639254
reference_title: 'Ocular findings in Baraitser-Winter syndrome with a de novo mutation in the ACTG1 gene: a case report.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
For amblyopia treatment, glasses were prescribed for full correction, and occlusion therapy was started
for the left eye. After 3 years of regular follow-up after the initial diagnosis, the patient’s visual
acuity had improved to 25/25 in both eyes.
explanation: >-
A single case demonstrates a treatable refractive/amblyopic component of poor vision.
target_phenotypes:
- preferred_term: Amblyopia
term:
id: HP:0000646
label: Amblyopia
- preferred_term: Astigmatism
term:
id: HP:0000483
label: Astigmatism
- name: Ptosis Surgery
description: >-
Ptosis may require ophthalmologic surgery according to its functional impact.
action_category: THERAPEUTIC
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Standard treatment(s) per ophthalmologist if coloboma &/or micropthalmia is present & → poor vision Ptosis
may require surgery.
explanation: >-
The treatment table gives conditional ophthalmic interventions.
treatment_term:
preferred_term: Ophthalmologic Surgical Procedure
term:
id: NCIT:C15331
label: Ophthalmologic Surgical Procedure
therapeutic_modality: SURGERY
target_phenotypes:
- preferred_term: Congenital Ptosis
term:
id: HP:0000508
label: Ptosis
- name: Osmotic Laxatives
description: >-
Osmotic laxatives are used for constipation, with gastrointestinal review of long-term medication.
action_category: THERAPEUTIC
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Osmotic laxatives were reported effective in majority of persons w/constipation.
explanation: >-
GeneReviews (March 2022 revision): The chapter summarizes reported response without specifying a controlled
trial.
treatment_term:
preferred_term: Osmotic laxative therapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_modality: SMALL_MOLECULE
target_phenotypes:
- preferred_term: Constipation
term:
id: HP:0002019
label: Constipation
- name: Structural Malformation Management
description: >-
Cardiac and urinary-tract malformations and oral clefts receive standard management tailored to the anatomical
defect.
action_category: THERAPEUTIC
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Malformations of the heart, urinary tract, and oral clefts are treated using standard procedures.
explanation: >-
GeneReviews (March 2022 revision): This supports conventional lesion-specific management.
treatment_term:
preferred_term: Surgical Procedure
term:
id: NCIT:C15329
label: Surgical Procedure
therapeutic_modality: SURGERY
target_phenotypes:
- preferred_term: Orofacial Cleft
term:
id: HP:0000202
label: Orofacial cleft
- name: Genetic Counseling
description: >-
Offer parental testing and counseling about autosomal dominant inheritance. Most cases are de novo, but
parental germline mosaicism can cause recurrence despite negative parental blood testing. Each child of
an affected individual has a 50% chance of inheriting the variant. Prenatal and preimplantation testing
are possible once the familial variant is known.
action_category: COUNSELING_INFORMATIONAL
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status
and inform recurrence risk assessment.
explanation: >-
GeneReviews (March 2022 revision): Parental testing informs recurrence counseling.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect
a pathogenic variant that is present in the germ cells only.
explanation: >-
GeneReviews (March 2022 revision): A negative blood test does not exclude germline mosaicism.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Each child of an individual with BWCFF syndrome has a 50% chance of inheriting the ACTB or ACTG1 pathogenic
variant.
explanation: >-
GeneReviews (March 2022 revision): The 50% risk applies to offspring of an affected heterozygote.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Once the ACTB or ACTG1 pathogenic variant has been identified in an affected family member, prenatal
and preimplantation genetic testing for BWCFF syndrome are possible.
explanation: >-
GeneReviews (March 2022 revision): Reproductive testing requires identification of the familial variant.
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
- name: Developmental and Organ Surveillance
description: >-
Monitor development and educational needs at each visit. Follow seizures as clinically indicated. Provide
at least annual ophthalmology with glaucoma screening when coloboma or microphthalmia is present, annual
assessment of hearing-loss progression, and at least annual review of feeding/GI dysfunction and scoliosis.
Orthopedic review increases to every six months during growth spurts and adolescence; cardiac and renal
follow-up depend on existing anomalies.
action_category: MONITORING
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Development Monitor developmental progress & educational needs. At each visit
explanation: >-
GeneReviews (March 2022 revision): The table specifies routine developmental monitoring.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
If coloboma or microphthalmia present, ophthalmologic follow up w/ screening for intraocular hypertension
& glaucoma (a known complication of colobomatous microphthalmia) At least annually
explanation: >-
GeneReviews (March 2022 revision): Eye surveillance is conditional on ocular malformation.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Hearing loss Evaluate for progression. Annually
explanation: >-
GeneReviews (March 2022 revision): Hearing-loss progression is assessed annually.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Gastroenterology Monitor those w/feeding difficulties & GI dysfunction. At least annually Orthopedic
Monitor for scoliosis. At least annually; every 6 mos during growth spurts & adolescence
explanation: >-
GeneReviews (March 2022 revision): These are follow-up intervals, not therapeutic efficacy claims.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Cardiovascular Monitor for complications if cardiac malformation present. Per cardiologist Genitourinary
Monitor for renal insufficiency if renal anomaly present. Per nephrologist
explanation: >-
GeneReviews (March 2022 revision): Follow-up is directed by the known lesion.
treatment_term:
preferred_term: Clinical monitoring
- name: Assessment of Unexplained Deterioration
description: >-
Hematologic malignancies have been reported, but an increased syndrome-specific risk is unestablished.
GeneReviews recommends evaluation for malignancy when physical deterioration or unexplained chronic fever
occurs, and does not recommend regular cancer surveillance.
action_category: MONITORING
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
The risk of malignancies is not established for BWCFF syndrome, and thus no regular surveillance is recommended.
However, screening for hematologic malignancies must be considered in case of physical deterioration
or unexplained chronic fever.
explanation: >-
GeneReviews (March 2022 revision): This distinguishes symptom-triggered assessment from an unsupported
routine screening program.
treatment_term:
preferred_term: Clinical monitoring
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#Variant-Dependent Actin Cytoskeletal Dysregulation
- pathophysiology#Cortical Developmental Malformation
- pathophysiology#Actin-Dependent Apical Progenitor Cleavage-Plane Defect
rationale: >-
The published organoid study establishes altered progenitor orientation and abundance, including replication
in engineered ACTB Thr120Ile organoids. It does not show that this mechanism reproduces the complete human
cortical migration pattern, anteroposterior gradient, or variant-specific severity. Patient-variant correction,
ACTG1 isogenic comparisons, and later cortical organization remain useful tests.
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: >-
The cohort documents the anatomical cortical-malformation pattern. It does not directly measure neuronal
migration, laminar connectivity, or the origin of the anteroposterior gradient.
quote_role: PRIMARY_RESULT
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
We found that in contrast to the predominantly vertical cleavage plane orientation of mitotic APs in
control cerebral organoids, mitotic APs of BWCFF-S cerebral organoids exhibited a nearly randomized or
majoritarian horizontal cleavage plane orientation
explanation: >-
This is the directly observed division-orientation phenotype in ACTB Thr120Ile and ACTG1 Thr203Met patient-derived
organoids.
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#Dominant ACTB or ACTG1 Missense Actinopathy
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#Cortical Developmental Malformation
mechanistic_hypotheses:
- hypothesis_group_id: organoid_progenitor_depletion
hypothesis_label: Altered progenitor division and microcephaly
status: EMERGING
description: >-
Patient-derived ACTB Thr120Ile and ACTG1 Thr203Met cerebral organoids, supported by engineered ACTB Thr120Ile
organoids, link abnormal progenitor division orientation to reduced ventricular-zone progenitor abundance.
Delamination and long-term neuronal-output effects are inferred, and the upstream contribution of individual
cytoskeletal abnormalities remains unresolved.
evidence:
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
We found that in contrast to the predominantly vertical cleavage plane orientation of mitotic APs in
control cerebral organoids, mitotic APs of BWCFF-S cerebral organoids exhibited a nearly randomized or
majoritarian horizontal cleavage plane orientation
explanation: >-
This is the directly observed division-orientation phenotype in ACTB Thr120Ile and ACTG1 Thr203Met patient-derived
organoids.
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
the VZ progenitor pool in BWCFF-S cerebral organoids is diminished, likely due to the shift in cleavage
plane orientation of mitotic anaphase APs, which increases the probability of progenitor delamination
and thereby promotes BP generation at the expense of the primary progenitor type, the AP.
explanation: >-
The authors infer the orientation-to-delamination mechanism from static division angles and increased
basal progenitor abundance; daughter-cell fate was not directly traced.
directness: INDIRECT
- hypothesis_group_id: ser348leu_epithelial_clefting
hypothesis_label: ACTB Ser348Leu epithelial dysfunction and clefting
status: EMERGING
description: >-
Reduced PFN1 association, impaired junctional localization, and slower migration in overexpression models
suggest an epithelial contribution to clefting with ACTB Ser348Leu. Partial PFN1 rescue concerns localization
in cultured cells. The frog indel phenotype and failure of mutant ACTB to rescue it do not reproduce the
exact human heterozygous genotype.
evidence:
- reference: url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
reference_title: https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
The limited ability of ACTB(p .S348L) to localize to cell -cell junctions in epithelial cells observed
in this study may reflect a defect in actin polymerization, consequently impairing surface epithelial
cell adhesion and palatal shelf convergence in the affected individual ... contributing to the orofacial
clefting phenotype.
explanation: >-
Tsujimoto et al. propose a link from the epithelial findings to clefting. The separate frog experiment
used mosaic indels near Ser348, not a patient-allele knock-in.
directness: INDIRECT
diagnosis:
- name: Molecular Diagnosis
diagnosis_term:
preferred_term: Genetic Testing
term:
id: NCIT:C15709
label: Genetic Testing
description: >-
Suggestive clinical findings plus a heterozygous pathogenic or likely pathogenic missense variant in ACTB
or ACTG1 establish the diagnosis. Use a relevant multigene panel or exome/genome sequencing according to
the presentation. A variant of uncertain significance is not diagnostic; gene deletions or duplications
cause different phenotypes.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
The diagnosis of BWCFF syndrome is established in a proband with suggestive findings and a heterozygous
pathogenic (or likely pathogenic) missense variant in either ACTB or ACTG1 identified by molecular genetic
testing
explanation: >-
GeneReviews (March 2022 revision): This is the molecular diagnostic criterion.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Identification of a heterozygous variant of uncertain significance does not establish or rule out the
diagnosis.
explanation: >-
GeneReviews (March 2022 revision): Uncertain variants must not be treated as confirmed diagnoses.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel)
and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.
explanation: >-
GeneReviews (March 2022 revision): Testing strategy depends on clinical specificity.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Deletions and duplications of either ACTB or ACTG1 do not result in the BWCFF syndrome phenotype.
explanation: >-
GeneReviews (March 2022 revision): Copy-number disorders should not be conflated with classic missense
actinopathy.
- name: Brain MRI and Neurologic Evaluation
diagnosis_term:
preferred_term: Magnetic Resonance Imaging
term:
id: NCIT:C16809
label: Magnetic Resonance Imaging
description: >-
Brain MRI characterizes cortical and callosal malformations. Consider EEG when MRI is abnormal or seizures
are present.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
To incl brain MRI ... Consider EEG if brain MRI anomaly &/or seizures present.
explanation: >-
GeneReviews (March 2022 revision): The initial-evaluation table makes EEG conditional.
- name: Baseline Multisystem Evaluation
description: >-
Assess development, vision including fundoscopy, hearing, cardiac anatomy by echocardiography, and renal/ureteral
anatomy by ultrasound. Evaluate feeding and gastrointestinal function. The chapter recommends a baseline
blood and platelet count, while noting that thrombocytopenia suggests a distinct ACTB-related disorder.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Eyes Ophthalmologic eval incl fundoscopy
explanation: >-
GeneReviews (March 2022 revision): Baseline eye assessment includes the fundus.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Hearing Audiologic eval Assess for hearing loss
explanation: >-
GeneReviews (March 2022 revision): Baseline audiology is recommended.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Cardiovascular Echocardiogram Assess for congenital heart defects. Genitourinary Renal ultrasound Evaluate
for malformation of kidneys &/or ureters
explanation: >-
GeneReviews (March 2022 revision): The evaluation table specifies cardiac and renal imaging.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Hematology Blood count & platelet count Baseline study given possible ↑ risk for hematologic malignancy
explanation: >-
GeneReviews (March 2022 revision): This supports a baseline evaluation, not an established cancer-risk
estimate or a periodic screening program.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Abdominal ultrasound &, if necessary, assess GI motility. ... Assess for feeding difficulties.
explanation: >-
The initial evaluation includes feeding and gastrointestinal function.
experimental_models:
- name: Patient-Derived Lymphoblastoid Cell Lines
experimental_model_type: CELL_LINE
organism:
preferred_term: Homo sapiens
term:
id: NCBITaxon:9606
label: Homo sapiens
cell_source: EBV-immortalized peripheral-blood lymphoblastoid lines from six patients and two controls
description: >-
The founding study tested actin protein abundance, F-actin organization, morphology, and latrunculin A
response. ACTB Arg196His and ACTG1 Ser155Phe cells showed increased F-actin but opposite drug responses;
actin protein abundance was unchanged. These non-neural cells do not directly establish cortical developmental
mechanisms.
publication: PMID:22366783
evidence:
- reference: PMID:22366783
reference_title: De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
Epstein-Barr virus immortalized lymphoblastoid cell lines were established from peripheral blood samples
of six affected individuals (LR04-173, LP98-096, LR09-079, LP98-085, LR04-298 and LR06-241) and two control
individuals (09.1359 and 07.0841) using standard procedures.
explanation: >-
The model comprises patient-derived immortalized cells, not neurons or an animal infection model.
- reference: PMID:22366783
reference_title: De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
We observed an increased resistance to latrunculin A in β-actin p.Arg196His mutant cells ... whereas
the γ-actin p.Ser155Phe mutant displayed increased sensitivity to the treatment
explanation: >-
Opposite responses to actin-monomer sequestration demonstrate variant-dependent actin dynamics.
modeled_mechanisms:
- target: Variant-Dependent Actin Cytoskeletal Dysregulation
relationship: RECAPITULATES
evidence:
- reference: PMID:22366783
reference_title: De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
We observed an increased resistance to latrunculin A in β-actin p.Arg196His mutant cells ... whereas
the γ-actin p.Ser155Phe mutant displayed increased sensitivity to the treatment
explanation: >-
Opposite responses to actin-monomer sequestration demonstrate variant-dependent actin dynamics.
- name: Patient-Derived Cerebral Organoids
experimental_model_type: ORGANOID
organism:
preferred_term: Homo sapiens
term:
id: NCBITaxon:9606
label: Homo sapiens
cell_source: Two iPSC clones from each of two female patients carrying ACTB Thr120Ile or ACTG1 Thr203Met
culture_system: Three-dimensional cerebral organoids studied at culture days 30 and 50
description: >-
Patient organoids were compared with SC102A-1 and CRTDi011-A control lines. Mutant organoids were smaller,
with altered apical progenitor cleavage orientation and reduced ventricular-zone progenitor abundance.
Cytoskeletal abnormalities were observed, but their causal relation to altered division orientation was
not established. No patient-variant correction or direct cell-fate tracing was reported.
publication: PMID:41372632
evidence:
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
We generated cerebral organoids from two clones of each patient-derived iPSC line.
explanation: >-
Two clones came from each of two patients, one carrying ACTB Thr120Ile and the other ACTG1 Thr203Met;
clones are not independent patients.
modeled_mechanisms:
- target: Apical Progenitor Cytoskeletal Irregularities
relationship: RECAPITULATES
evidence:
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
we observed a higher density of microtubule bundles at the apical cell cortex that appeared to be anchored
to the apical adherens junction belt rather than being nucleated at the basal body of the primary cilium
explanation: >-
Electron microscopy identifies abnormal apical cytoskeletal organization in the patient-derived organoids.
The authors did not quantify these ultrastructural changes or establish their causal relation to spindle
orientation.
- target: Actin-Dependent Apical Progenitor Cleavage-Plane Defect
relationship: RECAPITULATES
evidence:
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
We found that in contrast to the predominantly vertical cleavage plane orientation of mitotic APs in
control cerebral organoids, mitotic APs of BWCFF-S cerebral organoids exhibited a nearly randomized
or
majoritarian horizontal cleavage plane orientation
explanation: >-
This is the directly observed division-orientation phenotype in ACTB Thr120Ile and ACTG1 Thr203Met
patient-derived
organoids.
- target: Reduced Ventricular-Zone Progenitor Abundance
relationship: RECAPITULATES
evidence:
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
quantification of the DAPI-stained nuclei revealed a substantial decrease of the number of VZ progenitors
per ventricle-like structure in the BWCFF-S organoids as compared to control organoids
explanation: >-
Direct cell counting documents a smaller ventricular-zone progenitor pool; unchanged Ki-67 and PH3
proportions
do not establish a general block in cell cycling.
- name: Engineered ACTB Thr120Ile Cerebral Organoids
experimental_model_type: ORGANOID
organism:
preferred_term: Homo sapiens
term:
id: NCBITaxon:9606
label: Homo sapiens
cell_source: Two heterozygous CRISPR-edited CRTDi011-A clones
description: >-
Engineered ACTB Thr120Ile organoids provide a comparison in a matched control background and reproduce
altered progenitor division orientation and reduced progenitor abundance. These results concern this ACTB
allele; an ACTG1 isogenic model and rescue by patient-variant correction were not tested. The number of
ventricle-like structures did not differ significantly from controls, unlike the patient-derived comparison.
publication: PMID:41372632
evidence:
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
heterozygous single-cell clones were identified by Sanger Sequencing of the target region ... Two such
clones, referred to as CRTDi011-A–mutACTB-1 and CRTDi011-A–mutACTB-2, were used for the generation of
cerebral organoids
explanation: >-
The engineered ACTB comparison uses two heterozygous clones in a control background; there is no analogous
engineered ACTG1 comparison in this study.
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
anaphase AP cleavage plane angles ... revealed essentially the same phenotypes—with exception of the
number of ventricle-like structures ... in the 30 days-old cr. ACTB Thr120Ile organoids as observed in
the BWCFF-S ACTB Thr120Ile patient-derived organoids
explanation: >-
The results compare engineered and patient-derived ACTB Thr120Ile organoids. The ventricle-number phenotype
did not reproduce, and the comparison is not an ACTG1 isogenic experiment.
modeled_mechanisms:
- target: Actin-Dependent Apical Progenitor Cleavage-Plane Defect
relationship: RECAPITULATES
evidence:
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
anaphase AP cleavage plane angles ... revealed essentially the same phenotypes—with exception of the
number of ventricle-like structures ... in the 30 days-old cr. ACTB Thr120Ile organoids as observed
in the BWCFF-S ACTB Thr120Ile patient-derived organoids
explanation: >-
The results compare engineered and patient-derived ACTB Thr120Ile organoids. The ventricle-number phenotype
did not reproduce, and the comparison is not an ACTG1 isogenic experiment.
limitations: >-
The engineered comparison tests ACTB Thr120Ile in one parental line; it does not establish all-allele
or all-gene generality.
- target: Reduced Ventricular-Zone Progenitor Abundance
relationship: RECAPITULATES
evidence:
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
anaphase AP cleavage plane angles ... revealed essentially the same phenotypes—with exception of the
number of ventricle-like structures ... in the 30 days-old cr. ACTB Thr120Ile organoids as observed
in the BWCFF-S ACTB Thr120Ile patient-derived organoids
explanation: >-
The results compare engineered and patient-derived ACTB Thr120Ile organoids. The ventricle-number phenotype
did not reproduce, and the comparison is not an ACTG1 isogenic experiment.
- name: ACTB Ser348Leu MDCK Epithelial Model
experimental_model_type: CELL_LINE
organism:
preferred_term: Canis lupus familiaris
term:
id: NCBITaxon:9615
label: Canis lupus familiaris
cell_source: MDCK IFO50071 cells transiently expressing GFP-tagged wild-type or Ser348Leu human ACTB
culture_system: Epithelial monolayers with a silicone-insert cell-free gap for migration assays
description: >-
Mutant ACTB showed reduced junctional localization and slower gap closure. A GFP pull-down from cell lysate
mixed with exogenous PFN1 showed reduced association; this was not an equilibrium binding-affinity measurement.
PFN1 coexpression partially restored junctional localization. Transient overexpression in canine kidney
epithelium does not directly measure human palatal morphogenesis.
publication: PMID:39271101
evidence:
- reference: url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
reference_title: https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
MDCK cells (JCRB cell bank: IFO50071) were cultured in αMEM with nucleosides (Gibco) and 10% FBS (Gibco)
under standard conditions.
explanation: >-
The epithelial system is an established canine kidney cell line with transfected human ACTB constructs.
- reference: url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
reference_title: https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
In contrast, the mutant ACTB (p.S348L) did not show an intense signal at the cell junction but rather
showed uniform expression in the cytoplasm
explanation: >-
This result is specifically from MDCK cells overexpressing GFP-tagged ACTB.
modeled_mechanisms:
- target: Reduced ACTB-PFN1 Association
relationship: RECAPITULATES
evidence:
- reference: url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
reference_title: https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
We detected similar expression levels between the mutant (p.S348L) ... while the signal of PFN1 was
noticeably
reduced in the sample with mutant ACTB (p.S348L)
explanation: >-
Tsujimoto et al. (2024), Compromised actin dynamics underlie the orofacial cleft in Baraitser-Winter
Cerebrofrontofacial Syndrome with a variant in ACTB: GFP pulldown from MDCK extracts mixed with exogenous
PFN1 shows reduced association. This is not a measured binding constant.
- target: Impaired Junctional ACTB Localization
relationship: RECAPITULATES
evidence:
- reference: url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
reference_title: https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
In contrast, the mutant ACTB (p.S348L) did not show an intense signal at the cell junction but rather
showed uniform expression in the cytoplasm
explanation: >-
This result is specifically from MDCK cells overexpressing GFP-tagged ACTB.
- target: Reduced Epithelial Cell Migration
relationship: RECAPITULATES
evidence:
- reference: url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
reference_title: https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
We observed that the mutant ACTB (p.S348L) -overexpressing cells displayed slower migration over time
than the wild-type ACTB-overexpressing cells
explanation: >-
The MDCK assay measures closure of a defined cell-free gap after removal of a silicone insert. It is
a surrogate for epithelial behavior, not direct measurement of patient palatal fusion.
animal_models:
- name: ACTB Ser348Leu Overexpression in Xenopus Embryos
species: Xenopus laevis
genotype: Injected mRNA encoding GFP-tagged wild-type or Ser348Leu human ACTB
description: >-
Live stage 9–10 embryos were imaged to assess ACTB localization in animal-cap epithelium. This whole-embryo
overexpression experiment is distinct from explant culture and from the later F0 indel experiment.
publication: PMID:39271101
evidence:
- reference: url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
reference_title: https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: >-
the mutant ACTB (p.S348L) in Xenopus leavis animal cap cells failed to localize to the cell-cell junction
explanation: >-
Live embryo animal-cap epithelium supported the junction-localization observation; the source misspells
laevis in this passage.
modeled_mechanisms:
- target: Impaired Junctional ACTB Localization
relationship: RECAPITULATES
evidence:
- reference: url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
reference_title: https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: >-
the mutant ACTB (p.S348L) in Xenopus leavis animal cap cells failed to localize to the cell-cell junction
explanation: >-
Live embryo animal-cap epithelium supported the junction-localization observation; the source misspells
laevis in this passage.
- name: Xenopus actb.L/S F0 Crispants
species: Xenopus laevis
genotype: Mosaic CRISPR-generated indels near the Ser348-equivalent region of actb.L and actb.S
description: >-
Crispants showed reduced mouth width and intercanthal distance with upper-jaw notching. Wild-type human
ACTB supplementation improved these measurements whereas Ser348Leu did not. The model perturbs actin function
but does not recreate a heterozygous human missense allele; epithelial migration and PFN1 binding were
not measured in these crispants.
publication: PMID:39271101
evidence:
- reference: url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
reference_title: https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: >-
Sequencing of the targeted region was performed in F0 crispant embryos, and the results showed that more
than 90% of the cells exhibited indel mutations
explanation: >-
The perturbation consists of mosaic indels near Ser348 in actb.L/S, not a patient-allele knock-in.
- reference: url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
reference_title: https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: >-
supplementation with wild-type ACTB ameliorated the intercanthal distance and mouth width phenotypes
of crispants, whereas mutated ACTB (p.S348L) did not
explanation: >-
A functional complementation comparison supports altered activity of Ser348Leu, without proving the same
molecular route produces a human cleft.
modeled_mechanisms:
- target: Variant-Dependent Actin Cytoskeletal Dysregulation
relationship: PERTURBS
evidence:
- reference: url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
reference_title: https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: >-
Sequencing of the targeted region was performed in F0 crispant embryos, and the results showed that
more than 90% of the cells exhibited indel mutations
explanation: >-
The perturbation consists of mosaic indels near Ser348 in actb.L/S, not a patient-allele knock-in.
- reference: url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
reference_title: https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: >-
supplementation with wild-type ACTB ameliorated the intercanthal distance and mouth width phenotypes
of crispants, whereas mutated ACTB (p.S348L) did not
explanation: >-
A functional complementation comparison supports altered activity of Ser348Leu, without proving the
same molecular route produces a human cleft.
limitations: >-
Mosaic indels and mRNA complementation test actin function rather than the dominant human Ser348Leu genotype
or its specific molecular intermediates.
variants:
- name: ACTB p.Arg196His
gene:
preferred_term: ACTB
term:
id: hgnc:132
label: ACTB
description: >-
A recurrent variant in the founding cohort, reported as NM_001101.2:c.587G>A. Patient-derived cells showed
increased F-actin and resistance to latrunculin A.
type: Missense
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
quote_role: PRIMARY_RESULT
snippet: >-
Strikingly, 8 patients (44%) carried a mutation disrupting Arg196 of β-actin, including 7 with the same
nucleotide change (c.587G>A, p.Arg196His).
explanation: >-
This is recurrence within the 18-person discovery cohort, not a population frequency.
- reference: PMID:22366783
reference_title: De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
We observed an increased resistance to latrunculin A in β-actin p.Arg196His mutant cells ... whereas
the γ-actin p.Ser155Phe mutant displayed increased sensitivity to the treatment
explanation: >-
Opposite responses to actin-monomer sequestration demonstrate variant-dependent actin dynamics.
- name: ACTG1 p.Ser155Phe
gene:
preferred_term: ACTG1
term:
id: hgnc:144
label: ACTG1
description: >-
A recurrent variant in the founding cohort, reported as NM_001614.2:c.464C>T. Patient-derived cells showed
increased F-actin but increased sensitivity to latrunculin A.
type: Missense
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
quote_role: PRIMARY_RESULT
snippet: >-
including two recurrent de novo alterations (ACTB, encoding p.Arg196His, and ACTG1, encoding p.Ser155Phe).
explanation: >-
The founding report identifies this recurrent disease-associated variant.
- reference: PMID:22366783
reference_title: De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
We observed an increased resistance to latrunculin A in β-actin p.Arg196His mutant cells ... whereas
the γ-actin p.Ser155Phe mutant displayed increased sensitivity to the treatment
explanation: >-
Opposite responses to actin-monomer sequestration demonstrate variant-dependent actin dynamics.
- name: ACTB p.Thr120Ile
gene:
preferred_term: ACTB
term:
id: hgnc:132
label: ACTB
description: >-
NM_001101.5:c.359C>T; an allele modeled in patient-derived cerebral organoids and two heterozygous engineered
control-line clones.
type: Missense
evidence:
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
the BWCFF-S patient with the actin variant NM_001101.5 (ACTB):c.359 C > T p.Thr120Ile
explanation: >-
The paper documents the clinical donor variant used for the organoid model.
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
heterozygous single-cell clones were identified by Sanger Sequencing of the target region ... Two such
clones, referred to as CRTDi011-A–mutACTB-1 and CRTDi011-A–mutACTB-2, were used for the generation of
cerebral organoids
explanation: >-
The engineered ACTB comparison uses two heterozygous clones in a control background; there is no analogous
engineered ACTG1 comparison in this study.
- name: ACTG1 p.Thr203Met
gene:
preferred_term: ACTG1
term:
id: hgnc:144
label: ACTG1
description: >-
NM_001614.5:c.608C>T; an allele modeled in patient-derived cerebral organoids. No matched ACTG1 knock-in
or corrected-patient comparison was reported.
type: Missense
evidence:
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
the BWCFF-S patient with the actin variant NM_001614.5(ACTG1):c.608 C > T p.Thr203Met
explanation: >-
The paper identifies the second patient donor allele.
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
We generated cerebral organoids from two clones of each patient-derived iPSC line.
explanation: >-
Two clones came from each of two patients, one carrying ACTB Thr120Ile and the other ACTG1 Thr203Met;
clones are not independent patients.
- name: ACTB p.Ser348Leu
gene:
preferred_term: ACTB
term:
id: hgnc:132
label: ACTB
description: >-
NM_001101.5:c.1043C>T. Reported in BRWS with variable clefting and hearing impairment; epithelial and Xenopus
assays demonstrate altered function. The 2024 hearing case classified the allele as likely pathogenic.
type: Missense
evidence:
- reference: url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
reference_title: https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
The nucleotide sequence s encoding ACTB, its mutated form ... ACTB(NM_001101.5):c.1043C>T (p.Ser348Leu)
GRCh37 Chr7:5567464) and PFN1 were amplified and cloned
explanation: >-
The methods specify the transcript and variant used to construct the mutant protein expression vector.
- reference: url:https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
reference_title: https://ir.library.osaka-u.ac.jp/repo/ouka/all/103591//HumMolGenet_33_22_1975.pdf
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
In contrast, the mutant ACTB (p.S348L) did not show an intense signal at the cell junction but rather
showed uniform expression in the cytoplasm
explanation: >-
This result is specifically from MDCK cells overexpressing GFP-tagged ACTB.
- reference: PMID:38592426
reference_title: 'Hearing Loss in Baraitser-Winter Syndrome: Case Reports and Review of the Literature.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
a missense variant c.1043C > T (p.Ser348lEU) was found in the ACTB gene compatible with BRWS1 diagnosis.
... can be classified as likely pathogenic (class 4) according to ACMG guidelines
explanation: >-
The second case reports de novo heterozygosity and a likely pathogenic classification; the source uses
unusual capitalization for Leu.
clinical_significance: LIKELY_PATHOGENIC
- name: ACTG1 p.Gly168Cys
gene:
preferred_term: ACTG1
term:
id: hgnc:144
label: ACTG1
description: >-
NM_001614.5:c.502G>T; a de novo likely pathogenic variant in a child with iris/retinal colobomata, pachygyria,
hearing loss, and mild intellectual disability.
type: Missense
evidence:
- reference: PMID:39639254
reference_title: 'Ocular findings in Baraitser-Winter syndrome with a de novo mutation in the ACTG1 gene: a case report.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
Whole-exome sequencing revealed a heterozygous, de novo, and likely pathogenic variant (c.502G > T; p.Gly168Cys)
in actin gamma 1 (ACTG1)
explanation: >-
The case report explicitly calls the allele likely pathogenic.
clinical_significance: LIKELY_PATHOGENIC
- name: ACTB p.Arg196Cys
gene:
preferred_term: ACTB
term:
id: hgnc:132
label: ACTB
type: Missense
description: >-
A recurrent ACTB hotspot allele reported in six of the 42 patients in the 2015 cohort, with clinical variability
even among carriers of the same substitution.
evidence:
- reference: PMID:25052316
reference_title: 'Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: >-
Amino acid 196 in ACTB is a hotspot with 14 affected patients in our cohort: eight with an ACTB p.Arg196His
and six with p.Arg196Cys mutation.
explanation: >-
The counts apply to the ascertained clinical cohort, not to population allele frequency.
differential_diagnoses:
- name: ACTB-Related Syndromic Thrombocytopenia
description: >-
An allelic actinopathy can share developmental delay, microcephaly, facial differences, and malformations.
distinguishing_features:
- >-
Thrombocytopenia with platelet size variability and clustering of ACTB variants in exons 5–6 distinguish
this disorder; thrombocytopenia is not a typical BRWS feature.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Syndromic thrombocytopenia. Mild DD, mild variable dysmorphism, microcephaly, & leukocytosis as well
as thrombocytopenia w/platelet anisotropy
explanation: >-
GeneReviews separates this condition from classic BWCFF syndrome.
- name: ACTB Loss-of-Function Developmental Disorder
description: >-
ACTB loss-of-function alleles cause a distinct developmental disorder with overlapping organ malformations.
distinguishing_features:
- >-
Loss-of-function variants and a different facial pattern should not be treated as the classic BRWS missense
mechanism.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Described in ~40 persons w/DD, ID, internal organ malformations (incl CHDs & renal tract anomalies),
growth restriction, & facial dysmorphism distinct from BWCFF syndrome
explanation: >-
GeneReviews separates this condition from classic BWCFF syndrome.
- name: ACTB Arg183Trp Dystonia-Deafness Syndrome
description: >-
Historically included in some broad actinopathy series, this allele produces a distinct dystonia-deafness
presentation.
distinguishing_features:
- >-
Drug-nonresponsive dystonia and early-onset sensorineural deafness are characteristic; pooled historical
cohorts can distort BRWS natural-history estimates.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Dystonia-deafness syndrome. Drug-nonresponsive dystonia & early-onset sensorineural deafness
explanation: >-
GeneReviews separates this condition from classic BWCFF syndrome.
- name: ACTG1-Related DFNA20/26
description: >-
ACTG1 variants can cause isolated progressive hearing loss without BRWS.
distinguishing_features:
- >-
A variant in the same gene alone does not establish BRWS; assess the allele and syndromic craniofacial,
ocular, and cortical findings.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Autosomal dominant nonsyndromic progressive sensorineural hearing loss (DFNA20/26)
explanation: >-
GeneReviews separates this condition from classic BWCFF syndrome.
- name: Noonan Syndrome
description: >-
Ptosis, hypertelorism, chest deformity, and neck webbing can resemble mild BRWS in infancy.
distinguishing_features:
- >-
Coloboma and pachygyria favor BRWS; coloboma is rare in Noonan syndrome and pachygyria is not a typical
feature.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK327153/pdf/Bookshelf_NBK327153.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Coloboma is rarely observed in NS & NS is not assoc w/pachygyria or muscle involvement.
explanation: >-
GeneReviews separates this condition from classic BWCFF syndrome.
disease_term:
preferred_term: Noonan syndrome
term:
id: MONDO:0018997
label: Noonan syndrome
datasets:
- accession: https://data.ghga.de/dataset/GHGAD98802067102801
description: >-
GHGA dataset GHGAD98802067102801 belongs to published study GHGAS92787677252496. It contains single-cell
RNA-seq from patient-derived, control, and engineered ACTB cerebral organoids at days 30 and 50. The public
metadata list 43 sample records; the paper analyzes 260,880 cells across organoids, which is not a patient
count.
organism:
preferred_term: Homo sapiens
term:
id: NCBITaxon:9606
label: Homo sapiens
data_type: SINGLE_CELL_RNA_SEQ
sample_count: 43
sample_types:
- preferred_term: iPSC-derived cerebral organoids
conditions:
- ACTB Thr120Ile patient-derived organoids
- ACTG1 Thr203Met patient-derived organoids
- Engineered ACTB Thr120Ile organoids
- Control cerebral organoids
platform: 10x Genomics Chromium Single Cell 3-prime v3 chemistry; Illumina NovaSeq 6000
publication: PMID:41372632
notes: >-
Controlled access requires an approved research project. Sample_count represents repository sample records,
not donors, cells, or individual organoids.
evidence:
- reference: url:https://data.ghga.de/api/metldata/artifacts/embedded_public/classes/EmbeddedDataset/resources/GHGAD98802067102801
reference_title: https://data.ghga.de/api/metldata/artifacts/embedded_public/classes/EmbeddedDataset/resources/GHGAD98802067102801
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
This dataset contains scRNA-seq data from patient-derived and control organoids, collected at 30 and
50 days of culture.
explanation: >-
The GHGA record verifies the dataset identity and model/time-point context.
- reference: url:https://data.ghga.de/api/metldata/artifacts/embedded_public/classes/EmbeddedDataset/resources/GHGAD98802067102801
reference_title: https://data.ghga.de/api/metldata/artifacts/embedded_public/classes/EmbeddedDataset/resources/GHGAD98802067102801
supports: SUPPORT
evidence_source: OTHER
quote_role: PRIMARY_RESULT
snippet: >-
Access to this dataset is restricted to researchers with approved projects. Data may only be used for
health/medical/biomedical research purposes.
explanation: >-
The repository access policy qualifies the publication’s broad data-availability statement.
- reference: PMID:41372632
reference_title: Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
Data consists of 260,880 single cells of 80 control, 44 BWCFF-S ACTB Thr120Ile, 41 BWCFF-S ACTG1 Thr203Met,
and 20 cr. ACTB Thr120Ile 30 and 50 days-old cerebral organoids
explanation: >-
The paper distinguishes cells from organoids and includes engineered ACTB material.
- accession: https://www.ebi.ac.uk/biostudies/sourcedata/studies/S-SCDT-10_1038-S44319-025-00647-7
description: >-
Figure-level source data include bright-field and fluorescence images, electron microscopy volumes, organoid
and ventricular-zone measurements, cleavage-plane angles, and single-cell composition summaries. These
files complement the separately archived GHGA sequencing data.
organism:
preferred_term: Homo sapiens
term:
id: NCBITaxon:9606
label: Homo sapiens
data_type: IMAGING
publication: PMID:41372632
evidence:
- reference: url:https://www.ebi.ac.uk/biostudies/api/v1/studies/S-SCDT-10_1038-S44319-025-00647-7
reference_title: https://www.ebi.ac.uk/biostudies/api/v1/studies/S-SCDT-10_1038-S44319-025-00647-7
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
These organoids were reduced in size, showing a thinner ventricular zone (VZ) due to reduced VZ progenitor
abundance.
explanation: >-
The matching BioStudies record describes the organoid study and lists source images and measurement spreadsheets.
- reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC12852704/fullTextXML
reference_title: Abstract
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: >-
The source data of this paper are collected in the following database record: ... biostudies:S-SCDT-10_1038-S44319-025-00647-7
explanation: >-
The publication explicitly associates this BioStudies accession with its source data.
References & Deep Research
References
1Baraitser-Winter Cerebrofrontofacial Syndrome.
No top-level findings curated for this source.
Deep Research
1Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Falcon
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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
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(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.
-
(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.
-
(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.
-
(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.
-
(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.
-
(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.
-
(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.
-
(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.
-
(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.
-
(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.
-
(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.
-
(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.
-
(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.
-
(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.
-
(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.
-
(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.
-
(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.
-
(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.
-
(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.
-
(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.
-
(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.
-
(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.
-
(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.
-
(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.
-
(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.
