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Classifications

Harrison's Part

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Autosomal recessive inheritance. Recurrence is 25% per pregnancy when both parents carry the relevant pathogenic alleles; parental testing establishes phase and permits genotype-specific counseling. Apparent homozygosity may require evaluation for a deletion or uniparental disomy. Prenatal and preimplantation testing are possible once the familial variants are identified.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:27413799 SUPPORT REVIEW SYNTHESIS Human Clinical

"TXNL4A-related craniofacial disorders are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance inheriting neither of the familial TXNL4A pathogenic variants."

GeneReviews states the mode of inheritance and the recurrence risk.

PMID:32187816 SUPPORT BACKGROUND Human Clinical

"Homozygosity or compound heterozygosity of promoter deletions and null variants in TXNL4A are known to cause most cases of BMKS."

Documents both the compound-heterozygous and homozygous promoter-deletion genotypes.

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Discussions and Knowledge Gaps

3

Why does reduced dosage of TXNL4A, a ubiquitously expressed core spliceosome protein, produce a malformation restricted to craniofacial structures rather than a generalised phenotype?

KNOWLEDGE GAP OPEN bmks_spliceosome_tissue_specificity

Attached to

pathophysiology#Selective Pre-mRNA Mis-Splicing

Selective splicing changes, a candidate TCF7L2/WNT route, and an experimental Mdm2-p53/metabolic route offer partial explanations for tissue specificity. Txnl4a-specific stress-response evidence now exists in mouse embryonic stem cells, but patient neural crest validation is lacking. Patient cells did not show increased apoptosis, unlike the frog knockdown model. Perturbation strength, cell state, genetic background and developmental stage may all affect the phenotype.

Proposed experiments

Test the P53/MDM2-MDM4 stress axis in BMKS patient iNCCs

bmks_p53_axis_in_patient_incc

Assay MDM2 and MDM4 regulatory-exon skipping, p53 stabilization and apoptosis in multiple BMKS patient-derived neural crest lines with isogenic and unaffected controls, and test whether controlled p53 perturbation changes differentiation and EMT. The unaffected mother is a carrier control, not an isogenic comparator.

Decision criterion

Concordant molecular changes and rescue across multiple patient lines with isogenic controls would strengthen a causal role. Absent rescue would limit that intervention under the tested conditions, not by itself exclude all p53-dependent or independent contributions.

TCF7L2 isoform rescue in BMKS neural crest

bmks_tcf7l2_rescue

Express the correctly spliced TCF7L2 isoform in BMKS patient iNCCs and test whether WNT responsiveness, EMT timing and differentiation are restored.

Decision criterion

Isoform-specific rescue with appropriate expression and timing controls would strengthen mediation of the WNT/EMT defect. Failure could reflect incomplete rescue, timing or parallel pathways and would not alone prove that TCF7L2 is only a marker.

Show evidence (3 references)

PMID:32735620 SUPPORT INDIRECT BACKGROUND In Vitro

"However, it is unclear how reduced expression of this ubiquitously expressed spliceosome protein results in craniofacial defects during development."

States the knowledge gap explicitly for TXNL4A/BMKS.

PMID:32315467 SUPPORT REVIEW SYNTHESIS Other

"We speculate that mutations in a subset of core splicing factors lead to disrupted splicing in neural crest cells because these cells have increased sensitivity to inefficient splicing."

The review explicitly proposes heightened neural crest sensitivity to splicing inefficiency. It does not establish a particular stress-response mechanism in BMKS patient neural crest cells.

PMID:38426258 SUPPORT DIRECT PRIMARY RESULT In Vitro

"specific KD of any the above splicing factors also resulted in increased presence of the Exon 3-skipping Mdm2 transcript"

Txnl4a-specific cell-culture evidence updates the earlier hypothesis; the patient neural crest question remains open.

Does increased apoptosis mediate all BMKS developmental defects?

INTERPRETATION OPEN bmks-model-apoptosis-differences

Attached to

pathophysiology#Increased Embryonic Ectodermal Apoptosis

The Xenopus study found increased ectodermal TUNEL staining but incorrectly described the earlier patient-iPSC study as showing increased apoptosis. The original patient-cell data found no significant apoptosis difference in either iPSCs or induced neural crest cells. The frog paper also describes TXNL4A haploinsufficiency, which should not replace the established recessive human inheritance model.

Show evidence (1 reference)

PMID:32735620 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Annexin-V staining revealed no significant differences in apoptosis between the patient iNCCs and the mother and unrelated control iNCCs"

Primary human-cell result takes precedence over the later summary.

Which uncommon findings belong to the TXNL4A phenotype?

KNOWLEDGE GAP OPEN bmks-atypical-finding-attribution

A reported infant with a dicentric X chromosome and homozygous TXNL4A promoter deletion had a blended diagnostic context. A separate autopsy case described an incidental hepatocellular adenoma in an infant with BMKS. These reports warrant careful phenotype attribution; they do not establish a recurrent cancer predisposition, justify tumor surveillance, or assign every additional finding to TXNL4A. Older TXNL4A-negative BMKS-like cases also should not define the molecularly confirmed phenotype.

Show evidence (2 references)

PMID:39695270 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Whole exome sequencing was pursued at 3 months of life, revealing homozygosity for likely pathogenic variants in TXNL4A, causing Burn-McKeown syndrome."

The full case also has a variant Turner-syndrome karyotype.

PMID:36262073 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Here we present an autopsy case of a 9-month-old girl with Burn-McKeown syndrome with an incidental liver nodule in the right lobe measuring 1.5 cm in greatest dimension."

One incidental hepatocellular adenoma is an association, not evidence of a syndrome-wide predisposition.

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Pathophysiology

14

Recurrent TXNL4A Promoter Deletion

The recurrent type 1 and type 2 alleles are distinct, partially overlapping 34-bp deletions in the TXNL4A promoter. They disrupt a region containing two 22-bp repeats separated by a 12-bp spacer; there is no single 56-bp pathogenic deletion. These regulatory alterations are distinct from coding, splice-site and copy-number loss on the other allele. Most BMKS genotypes combine a type 1 deletion with a loss-of-function allele; homozygous promoter deletions also occur.

TXNL4A hgnc:30551

Downstream

Reduced TXNL4A Promoter Activity Deletion of promoter sequence reduces regulatory activity in reporter assays.

Show evidence (1 reference)

PMID:25434003 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In 8 families, affected individuals carried a rare loss-of-function mutation (nonsense, frameshift, or microdeletion) on one allele and a low-frequency 34 bp deletion (allele frequency 0.76%) in the core promoter region on the other allele."

Defines the recurrent regulatory-plus-loss-of-function architecture, not a single dominant allele.

Reduced TXNL4A Promoter Activity

HEK293 reporter assays found type 1 and type 2 promoter activity reduced by 59% and 72%, respectively. A later deletion-mapping assay identified the repeated 22-bp motifs as important for promoter activity. Predicted transcription-factor motifs are not evidence that a particular factor binds the endogenous locus in neural crest cells.

Experimental models

TXNL4A promoter reporter assays CELL LINE Type 1 and type 2 constructs show reduced activity.

Downstream

Reduced Functional TXNL4A Dosage Reduced transcription from the promoter-deletion allele lowers the supply of functional TXNL4A; the second allele determines the remaining functional dosage.

Show evidence (2 references)

PMID:25434003 SUPPORT DIRECT PRIMARY RESULT In Vitro

"promoter activity of constructs containing the type 1 Δ (del1) and type 2 Δ (del2) was reduced by 59% and 72%, respectively, compared to the wild-type construct."

Reporter output measures reduced promoter activity in HEK293 cells.

PMID:34713892 SUPPORT DIRECT PRIMARY RESULT In Vitro

"use dual luciferase assays to identify a 22 bp repeated motif essential for TXNL4A expression within this promoter region."

Functional promoter mapping supports sequence dependence without identifying a proven endogenous transcription-factor interaction.

Reduced Functional TXNL4A Dosage

A hypomorphic promoter allele combined with a coding, splice or copy-number loss-of-function allele reduces functional TXNL4A dosage. Patient-derived iPSCs and neural crest cells have reduced TXNL4A RNA. Total RNA is not equivalent to functional protein: several coding-mutant transcripts escape nonsense-mediated decay, and the unaffected mother carrying a frameshift had unchanged total RNA. Complete human biallelic null lethality is hypothesized from conserved model-organism function, not demonstrated in humans.

TXNL4A hgnc:30551

Experimental models

TXNL4A splice-acceptor minigene assays OTHER Loss of normal terminal-exon inclusion provides functional support for the splice-site alleles.

Downstream

Reduced U4/U6.U5 Tri-snRNP Assembly The yeast ortholog depletion experiment supports a conserved assembly defect; direct tri-snRNP quantification in patient neural crest cells remains lacking.

Increased Embryonic Ectodermal Apoptosis Experimental Txnl4a knockdown increases embryonic ectodermal apoptosis in Xenopus; the intermediates and applicability to patient cells are unresolved.

MDM2 Exon 3 Skipping after Experimental Txnl4a Depletion Experimental Txnl4a knockdown in mouse embryonic stem cells increases the exon-3-skipped Mdm2 isoform; human neural crest relevance remains provisional.

Show evidence (3 references)

PMID:32735620 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The expression of TXNL4A was significantly lower in patient iPSCs"

Reduced RNA in the patient lines; this is not a quantitative protein assay.

PMID:25434003 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"these mutant transcripts escaped nonsense-mediated mRNA decay (NMD)"

Observed persistence of coding-mutant transcripts limits a generic NMD explanation.

PMID:34713892 SUPPORT DIRECT PRIMARY RESULT In Vitro

"cause skipping of the final exon of TXNL4A in a minigene splicing assay."

The c.258-3C>G and c.258-2A>G splice variants were functionally tested in a minigene, distinct from promoter regulation.

Reduced U4/U6.U5 Tri-snRNP Assembly

Conditional depletion of yeast Dib1, the TXNL4A ortholog, reduces U4/U6.U5 tri-snRNP assembly. This is a conserved molecular model for reduced spliceosome availability in BMKS, rather than a direct measurement of assembly in affected human tissue.

spliceosomal snRNP assembly GO:0000387 ↓ DECREASED

Experimental models

Conditional yeast Dib1 depletion OTHER Dib1 depletion reduces tri-snRNP assembly.

Downstream

Selective Pre-mRNA Mis-Splicing Reduced spliceosome availability is a candidate explanation for the selective splicing defects measured in patient cells.

Show evidence (1 reference)

PMID:25434003 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Turning off DIB1 expression resulted in reduced assembly of the U4/U6⋅U5 tri-snRNP complex"

Conditional yeast-culture experiment establishes the assembly effect in the ortholog system.

Selective Pre-mRNA Mis-Splicing

Patient-derived iPSCs and induced neural crest cells show selective alternative-splicing abnormalities. At 120 hours of neural crest induction, 2,991 differential events affected 2,029 genes; exon skipping predominated. Vulnerable exons had weaker splice sites and altered intron/exon architecture. These signatures may include indirect regulatory effects and differences in differentiation state; they do not establish that every transcript is directly affected by TXNL4A.

neural crest cell CL:0011012

mRNA splicing, via spliceosome GO:0000398 ⚠ ABNORMAL

Experimental models

BMKS patient-derived iPSC induced neural crest cells IPSC DERIVED MODEL RNA-seq shows selective splicing abnormalities at pluripotent and neural crest stages.

Downstream

Increased TCF7L2 Exon 4 Inclusion TCF7L2 exon 4 is one neural-crest-stage splicing event within the broader transcriptomic phenotype.

Impaired Neural Crest Specification Other altered developmental transcripts may impair specification independently of the TCF7L2 candidate route; the decisive targets remain unresolved.

Show evidence (2 references)

PMID:32735620 SUPPORT DIRECT PRIMARY RESULT In Vitro

"rMATS identified 2991 differential splicing events in 2029 different genes"

Neural crest RNA-seq measures widespread but selective changes.

PMID:32735620 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"One of the difficulties in interpreting the differential gene expression and differential splicing in the RNA-Seq data is determining direct effects"

The authors distinguish primary spliceosome effects from downstream regulatory and cell-state effects.

Increased TCF7L2 Exon 4 Inclusion

Patient induced neural crest cells show increased inclusion of TCF7L2 exon 4, validated by qPCR, without a change in total TCF7L2 expression. The event was not detected in the patient iPSC comparison. It is a downstream RNA-processing change, not a germline TCF7L2 variant or a proven sole cause of BMKS.

Downstream

Dampened WNT Response The exon-4-containing isoform is a candidate contributor to reduced WNT responsiveness; isoform-specific rescue in patient cells has not established causality.

Show evidence (1 reference)

PMID:32735620 SUPPORT DIRECT PRIMARY RESULT In Vitro

"A significant SE event was identified in TCF7L2 with increased inclusion of TCF7L2 exon 4 in the patient iNCCs, although there was no change in overall TCF7L2 gene expression"

Defines the measured isoform change and its distinction from gene-expression abundance.

Dampened WNT Response

Mechanism confidence: Provisional

Patient neural crest cells respond less strongly to the WNT-activating differentiation protocol, including lower AXIN2 expression. TCF7L2 splicing is a proposed contributor. Because the protocol activates WNT downstream of GSK3, its results do not identify every potentially affected step of endogenous WNT signaling.

canonical Wnt signaling pathway GO:0060070 ↓ DECREASED

Experimental models

BMKS patient-derived iPSC induced neural crest cells IPSC DERIVED MODEL AXIN2 response is reduced under GSK3-inhibiting induction.

Downstream

Delayed Neural Crest Epithelial-to-Mesenchymal Transition Reduced WNT response is proposed to impair the differentiation program and the epithelial-to-mesenchymal transition required for neural crest development.

Show evidence (2 references)

PMID:32735620 SUPPORT DIRECT PRIMARY RESULT In Vitro

"AXIN2 expression was significantly lower (p = 0.0004) in patient iNCCs compared to pooled control iNCCs"

A measured response marker supports impaired WNT induction in this in-vitro model.

PMID:32735620 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"our iNCC induction protocol activated WNT signalling by inhibiting GSK3"

Protocol context limits localization of the defect.

Delayed Neural Crest Epithelial-to-Mesenchymal Transition

At 120 hours, patient cells retain epithelial markers and isoforms and express fewer mesenchymal markers. Their EMT score was -5 versus +5 for maternal and +8 for unrelated controls; extending induction to 168 hours did not normalize the phenotype. A delay, incomplete differentiation, or differentiation of only a subset of cells cannot yet be distinguished. Patient-cell migration itself was proposed for future study, not directly established as impaired.

neural crest cell CL:0011012

epithelial to mesenchymal transition GO:0001837 ↓ DECREASED

Experimental models

BMKS patient-derived iPSC induced neural crest cells IPSC DERIVED MODEL Transcript and isoform markers remain more epithelial after induction.

Downstream

Impaired Neural Crest Specification Failure to complete the epithelial-to-mesenchymal program can limit acquisition of a differentiated neural crest state.

Show evidence (2 references)

PMID:32735620 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The patient iNCCs had a score of -5, while the mother iNCCs had an EMT score of +5 and the unrelated controls had an EMT score of +8"

Transcriptomic EMT scores quantify the difference between these lines.

PMID:32735620 SUPPORT DIRECT PRIMARY RESULT In Vitro

"extending the iNCC differentiation protocol time to 168h in the patient iNCCs did not allow the patient iNCCs to ‘catch up’"

A longer induction interval did not resolve the observed delay.

Increased Embryonic Ectodermal Apoptosis

Mechanism confidence: Provisional

Unilateral Txnl4a morpholino knockdown increases TUNEL-positive cells in the dorsal ectoderm of Xenopus neurulae. This result does not establish p53 dependence, which was not assayed, or universal apoptosis in BMKS: patient-derived iPSCs and induced neural crest cells showed no significant increase in apoptosis.

apoptotic process GO:0006915 ↑ INCREASED

Animal models

Xenopus Txnl4a morpholino model Xenopus laevis partially recapitulates TUNEL-positive dorsal ectodermal cells increase; this contrasts with the patient-cell model.

Downstream

Impaired Neural Crest Specification Loss of embryonic progenitors may contribute to reduced neural crest marker expression in the frog model; lineage-specific mediation was not directly tested.

Show evidence (2 references)

PMID:35893124 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In all cases we observed a significant increase in the number of TUNEL-positive cells as a result of the three MOs’ injection"

The experiment includes Txnl4a, Eftud2 and Snrpb knockdowns; the measured tissue is dorsal ectoderm.

PMID:32735620 REFUTE DIRECT PRIMARY RESULT In Vitro

"Annexin-V staining revealed no significant differences in apoptosis between the patient iNCCs and the mother and unrelated control iNCCs"

The human-cell result refutes a uniform increase across models.

Impaired Neural Crest Specification

Patient-derived cells acquire neural crest identity inefficiently, while Txnl4a-depleted Xenopus embryos show reduced neural crest marker expression. In frogs, morpholino-resistant Txnl4a partly restores normal sox10 expression. The human cell and frog models support a developmental vulnerability but differ in perturbation, dosage, stage and cell-death response.

neural crest cell CL:0011012

neural crest cell development GO:0014032 ⚠ ABNORMAL

Animal models

Xenopus Txnl4a morpholino model Xenopus laevis partially recapitulates Knockdown reduces sox10 expression and resistant Txnl4a partly rescues it.

Downstream

Craniofacial Developmental Malformation Impaired neural crest development is a supported route to craniofacial malformation, although the precise intermediates leading to each human anatomical feature remain unresolved.

Show evidence (2 references)

PMID:32735620 SUPPORT DIRECT PRIMARY RESULT In Vitro

"three out of four of the later neural crest identity markers examined here had significantly lower expression"

Patient cells acquire neural crest identity less efficiently at the sampled time.

PMID:35893124 SUPPORT DIRECT PRIMARY RESULT Model Organism

"a modified version of Xenopus Txnl4a restored this proportion from 14% to 62%"

Partial rescue of normal sox10 expression supports specificity of the morpholino phenotype.

MDM2 Exon 3 Skipping after Experimental Txnl4a Depletion

Mechanism confidence: Provisional

Txnl4a knockdown in mouse embryonic stem cells increases the Mdm2 exon-3-skipped transcript. This provides gene-specific experimental support for an alternative stress-response route; it has not been demonstrated in BMKS patient neural crest cells.

Experimental models

Mouse embryonic stem-cell Txnl4a knockdown CELL LINE An alternative Mdm2 transcript is increased after experimental depletion.

Downstream

p53 Accumulation after Experimental Txnl4a Depletion The study implicates a p53-stabilizing Mdm2 isoform across splicing perturbations; Txnl4a-specific isoform rescue was not demonstrated.

Show evidence (1 reference)

PMID:38426258 SUPPORT DIRECT PRIMARY RESULT In Vitro

"specific KD of any the above splicing factors also resulted in increased presence of the Exon 3-skipping Mdm2 transcript"

The preceding experiment names Txnl4a, Prpf8 and Sf3b4; the result is from mouse cell culture, not an animal disease model.

p53 Accumulation after Experimental Txnl4a Depletion

Mechanism confidence: Provisional

p53 protein accumulates after Txnl4a knockdown in mouse embryonic stem cells. This finding does not establish p53 activation or a p53-dependent craniofacial phenotype in human BMKS.

Downstream

Reduced Glycolytic Gene Expression after Experimental Txnl4a Depletion A p53-mediated metabolic response is proposed; rescue in p53-null cells was tested for Eftud2 and Sf3b4 depletion and splicing inhibition, rather than directly for Txnl4a depletion.

Show evidence (1 reference)

PMID:38426258 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We also observed the expected increase in p53 levels when any of the above splicing factors was knocked down with shRNA"

Western blots include Txnl4a knockdown alongside other splicing factors.

Reduced Glycolytic Gene Expression after Experimental Txnl4a Depletion

Mechanism confidence: Provisional

Txnl4a knockdown reduces selected glycolytic transcripts and lactate levels in mouse embryonic stem cells. The authors propose that persistent metabolic changes could alter vulnerable developmental cell states. This remains an indirect hypothesis for human craniofacial disease, not a demonstrated BMKS metabolic biomarker or treatment target.

Experimental models

Mouse embryonic stem-cell Txnl4a knockdown CELL LINE Targeted assays found reduced glycolytic transcripts and lactate.

Downstream

Impaired Neural Crest Specification Altered metabolic state is a proposed contributor to developmental vulnerability; mediation of a Txnl4a-dependent neural crest defect remains untested.

Show evidence (2 references)

PMID:38426258 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We found that KD of any of the above splicing factors always resulted in downregulation of glycolytic transcripts"

qPCR after Txnl4a, Prpf8 or Sf3b4 knockdown measured Hk1, Pfkfb3 and Pfkm transcripts.

PMID:38426258 SUPPORT DIRECT PRIMARY RESULT In Vitro

"we measured lactate levels in mESCs expressing shRNAs targeting Txnl4a, Prpf8 or Sf3b4. We found that all these splicing factor KDs reduce lactate levels"

Gene-specific perturbations were tested in cultured mouse embryonic stem cells.

Craniofacial Developmental Malformation

Congenital malformations include choanal obstruction, lower eyelid defects, altered facial proportions, ear anomalies and clefting. Impaired neural crest development provides a shared developmental explanation, but neither one embryologic lesion nor a symmetric zygoma-maxilla-mandible bundle has been established for every person. Micrognathia and maxillary hypoplasia do occur.

face morphogenesis GO:0060325 ⚠ ABNORMAL

Downstream

Choanal Atresia The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.

Lower Eyelid Coloboma The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.

Hearing Loss The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.

Conductive Hearing Impairment The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.

Sensorineural Hearing Impairment The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.

Prominent Ears The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.

Short Palpebral Fissures The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.

Hypertelorism The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.

Prominent Nasal Bridge The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.

Short Philtrum The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.

Thin Upper Lip Vermilion The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.

Cleft Lip The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.

Cleft Palate The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.

Preauricular Skin Tag The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.

Micrognathia Altered craniofacial development produces this reported anatomical manifestation; the specific developmental intermediates remain unresolved.

Maxillary Hypoplasia Altered craniofacial development produces this reported anatomical manifestation; the specific developmental intermediates remain unresolved.

Narrow Mouth Altered craniofacial development produces this reported anatomical manifestation; the specific developmental intermediates remain unresolved.

Thick Lower Lip Vermilion Altered craniofacial development produces this reported anatomical manifestation; the specific developmental intermediates remain unresolved.

Hypomimic Face Part of the clinical craniofacial spectrum; the specific cellular intermediates remain unresolved.

Show evidence (1 reference)

PMID:27413799 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears)."

Clinical synthesis defines the malformation spectrum.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

27

Cardiovascular 5

Structural Cardiac Abnormality Abnormal heart morphology HP:0001627

Coarse binding: variable spectrum

Show evidence (3 references)

PMID:27413799 SUPPORT REVIEW SYNTHESIS Human Clinical

"Hearing loss is common and cardiac defects and short stature have been reported."

GeneReviews identifies cardiac defects; the full table supplies the assessed denominator.

PMID:28905882 SUPPORT BACKGROUND Human Clinical

"structural cardiac abnormalities, conductive and sensorineural hearing loss, and cleft lip"

Lists structural cardiac abnormalities among the characterising features of BMKS.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"# of Persons w/Feature / # Assessed ... Cardiac defect ... 5/16"

Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.

Patent Ductus Arteriosus HP:0001643

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Cardiac defects ... include persistent ductus arteriosus and patent foramen ovale."

Documents this manifestation in the stated clinical context.

Patent Foramen Ovale HP:0001655

Show evidence (1 reference)

PMID:25434003 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The affected girl of family BMKS004 originates from Vietnam. She had bilateral choanal atresia and a patent foramen ovale, which closed spontaneously"

Documents this manifestation in the stated clinical context.

Atrial Septal Defect HP:0001631

Show evidence (1 reference)

PMID:28905882 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Cardiac defect | N | Asymptomatic ASD and VSD"

Documents this manifestation in the stated clinical context.

Ventricular Septal Defect HP:0001629

Show evidence (1 reference)

PMID:28905882 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Cardiac defect | N | Asymptomatic ASD and VSD"

Documents this manifestation in the stated clinical context.

Ear 4

Prominent Ears Protruding ear HP:0000411

Show evidence (3 references)

PMID:27413799 SUPPORT REVIEW SYNTHESIS Human Clinical

"Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears)."

GeneReviews lists prominent ears among the typical craniofacial features.

PMID:28905882 SUPPORT BACKGROUND Human Clinical

"Burn-McKeown syndrome (BMKS) is a rare syndrome characterized by choanal atresia, prominent ears, abnormalities of the outer third of the lower eyelid, structural cardiac abnormalities, conductive and sensorineural hearing loss, and cleft lip."

The paper summarizes prominent ears as a characteristic feature.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"# of Persons w/Feature / # Assessed ... Prominent ears ... 13/17"

Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.

Hearing Loss Hearing impairment HP:0000365

Show evidence (3 references)

PMID:27413799 SUPPORT REVIEW SYNTHESIS Human Clinical

"Hearing loss is common and cardiac defects and short stature have been reported."

GeneReviews describes hearing loss as common; the full table supplies the assessed denominator.

PMID:28905882 SUPPORT BACKGROUND Human Clinical

"conductive and sensorineural hearing loss"

Documents that both conductive and sensorineural components occur.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"# of Persons w/Feature / # Assessed ... Hearing loss ... 12/19"

Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.

Conductive Hearing Impairment HP:0000405

Show evidence (1 reference)

PMID:28905882 SUPPORT BACKGROUND Human Clinical

"conductive and sensorineural hearing loss"

Explicitly lists conductive hearing loss among the characterising features.

Sensorineural Hearing Impairment HP:0000407

Show evidence (1 reference)

PMID:28905882 SUPPORT BACKGROUND Human Clinical

"conductive and sensorineural hearing loss"

Explicitly lists sensorineural hearing loss among the characterising features.

Eye 1

Hypertelorism HP:0000316

Show evidence (3 references)

PMID:27413799 SUPPORT REVIEW SYNTHESIS Human Clinical

"Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears)."

GeneReviews lists widely spaced eyes among the typical craniofacial features.

PMID:14564154 SUPPORT PRIMARY RESULT Human Clinical

"a characteristic pattern of facial dysmorphic features consisting of hypertelorism, lower lid coloboma, narrow palpebral fissures"

The two-brother report documents hypertelorism; this family was subsequently included in the 2014 molecular series.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"# of Persons w/Feature / # Assessed ... Hypertelorism ... 12/17"

Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.

Genitourinary 1

Renal Hypoplasia HP:0000089

Show evidence (1 reference)

PMID:14564154 SUPPORT PRIMARY RESULT Human Clinical

"median cleft palate with oronasal fistula, preauricular tag, hypomimic face, and hypoplastic unilateral kidney"

Documents unilateral renal hypoplasia in the reported sibship, without a disease-wide frequency estimate.

Head and Neck 14

Choanal Atresia OBLIGATE HP:0000453

All 20 persons in the pooled GeneReviews table had choanal stenosis/atresia, including the three isolated-choanal-atresia cases; therefore all 17 syndromic cases also had it. This describes the ascertained series, not a population penetrance estimate.

Show evidence (3 references)

PMID:27413799 SUPPORT REVIEW SYNTHESIS Human Clinical

"Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears)."

GeneReviews places bilateral choanal atresia/stenosis first among the typical craniofacial features of BMKS.

PMID:27413799 SUPPORT REVIEW SYNTHESIS Other

"Neonates with airway compromise at delivery may require intubation or surgical correction of choanal stenosis/atresia."

Documents the clinical consequence that makes choanal atresia the presenting and most urgent feature.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Bilateral choanal stenosis/atresia ... 20/20 ... 3 persons have had isolated choanal atresia"

Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.

Lower Eyelid Coloboma HP:0000652

Show evidence (3 references)

PMID:27413799 SUPPORT REVIEW SYNTHESIS Human Clinical

"Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears)."

GeneReviews lists lower eyelid coloboma among the typical craniofacial features.

PMID:27413799 SUPPORT REVIEW SYNTHESIS Other

"Defects of the lower eyelids that can result in corneal exposure require care by an ophthalmologist to reduce the risk of corneal scarring."

Documents the corneal-exposure complication that makes the eyelid defect clinically actionable.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"# of Persons w/Feature / # Assessed ... Defects of lower eyelids ... 12/20"

Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.

Short Palpebral Fissures HP:0012745

Show evidence (2 references)

PMID:27413799 SUPPORT REVIEW SYNTHESIS Human Clinical

"Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears)."

GeneReviews lists short palpebral fissures among the typical craniofacial features.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"# of Persons w/Feature / # Assessed ... Short palpebral fissures ... 11/19"

Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.

Prominent Nasal Bridge VERY_FREQUENT HP:0000426

The pooled 17/18 proportion implies a syndromic-only frequency of at least 14/15 (93%) even if all three isolated-choanal-atresia cases with available data had this feature. The exact syndromic denominator is not supplied; this is not a penetrance estimate.

Show evidence (2 references)

PMID:27413799 SUPPORT REVIEW SYNTHESIS Human Clinical

"Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears)."

GeneReviews lists the prominent nasal bridge among the typical craniofacial features.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"# of Persons w/Feature / # Assessed ... Prominent nasal bridge ... 17/18"

Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.

Short Philtrum HP:0000322

Show evidence (2 references)

PMID:27413799 SUPPORT REVIEW SYNTHESIS Human Clinical

"Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears)."

GeneReviews lists the short philtrum among the typical craniofacial features.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"# of Persons w/Feature / # Assessed ... Short philtrum ... 14/17"

Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.

Thin Upper Lip Vermilion HP:0000219

Show evidence (2 references)

PMID:27413799 SUPPORT REVIEW SYNTHESIS Human Clinical

"Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears)."

GeneReviews lists a thin upper lip vermilion among the typical craniofacial features.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Thin vermilion of the upper lip ... 10/17"

Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.

Cleft Lip Cleft upper lip HP:0000204

Show evidence (3 references)

PMID:28905882 SUPPORT BACKGROUND Human Clinical

"structural cardiac abnormalities, conductive and sensorineural hearing loss, and cleft lip"

Lists cleft lip among the characterising features.

PMID:27413799 SUPPORT REVIEW SYNTHESIS Other

"Treatment of craniofacial manifestations (e.g., cleft lip and/or palate, preauricular tags, prominent ears) is individualized and managed by a multidisciplinary team."

GeneReviews management section confirms cleft lip and/or palate occurs and requires multidisciplinary care.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Submucous cleft palate or cleft lip/palate ... 10/20"

Combined clefting category; no separate lip/palate frequency is inferred.

Cleft Palate HP:0000175

Show evidence (4 references)

PMID:25434003 SUPPORT BACKGROUND Human Clinical

"This rare condition is characterized by bilateral choanal atresia, hearing loss, cleft lip and/or palate, and other craniofacial dysmorphisms."

The introductory clinical characterization includes cleft lip and/or palate without establishing their separate frequencies.

PMID:27413799 SUPPORT REVIEW SYNTHESIS Other

"Treatment of craniofacial manifestations (e.g., cleft lip and/or palate, preauricular tags, prominent ears) is individualized and managed by a multidisciplinary team."

GeneReviews lists cleft palate among the craniofacial manifestations routinely managed in BMKS.

PMID:14564154 SUPPORT PRIMARY RESULT Human Clinical

"These brothers show some additional features that were not previously reported in patients with this syndrome including median cleft palate with oronasal fistula, preauricular tag, hypomimic face, and hypoplastic unilateral kidney, thus indicating that the clinical spectrum of this entity is broader."

Documents the specific median cleft palate with oronasal fistula variant as an expansion of the BMKS phenotypic spectrum.

+ 1 more reference

Preauricular Skin Tag HP:0000384

Show evidence (2 references)

PMID:27413799 SUPPORT REVIEW SYNTHESIS Other

"cleft lip and/or palate, preauricular tags, prominent ears"

GeneReviews lists preauricular tags among the craniofacial manifestations requiring management.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"# of Persons w/Feature / # Assessed ... Preauricular tags ... 10/16"

Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.

Micrognathia HP:0000347

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"# of Persons w/Feature / # Assessed ... Micrognathia ... 12/19"

Documents this manifestation in the stated clinical context.

Maxillary Hypoplasia Hypoplasia of the maxilla HP:0000327

Show evidence (1 reference)

PMID:28905882 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Maxillary hypoplasia was also seen in the same three individuals, and micrognathia was seen in two out of them."

Documents this manifestation in the stated clinical context.

Narrow Mouth HP:0000160

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Short philtrum, thin vermilion of the upper lip, thick vermilion of the lower lip, and reduced opening of the mouth"

Documents this manifestation in the stated clinical context.

Thick Lower Lip Vermilion HP:0000179

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Short philtrum, thin vermilion of the upper lip, thick vermilion of the lower lip, and reduced opening of the mouth"

Documents this manifestation in the stated clinical context.

Hypomimic Face HP:0000338

Show evidence (1 reference)

PMID:14564154 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"including median cleft palate with oronasal fistula, preauricular tag, hypomimic face, and hypoplastic unilateral kidney"

Documents this manifestation in the stated clinical context.

Nervous System 1

Intellectual Disability HP:0001249

GeneReviews reports normal intellect in 16/18 assessed individuals across the TXNL4A spectrum. The severe-ID individual was also the single patient donor in the published iPSC study; that study is not an independent clinical replication.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"One female had mild learning disabilities and another had severe intellectual disability"

Full clinical chapter documents both exceptions to usually normal intellectual development.

Growth 1

Short Stature HP:0004322

Show evidence (2 references)

PMID:27413799 SUPPORT REVIEW SYNTHESIS Human Clinical

"cardiac defects and short stature have been reported"

GeneReviews includes short stature; its full clinical table reports the assessed denominator.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"# of Persons w/Feature / # Assessed ... Short stature ... 3/17"

Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.

🧬

Genetic Associations

1

TXNL4A (Causal - biallelic loss-of-function and promoter-deletion variants)

Gene: TXNL4A hgnc:30551 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (6 references)

PMID:27413799 SUPPORT REVIEW SYNTHESIS Human Clinical

"The diagnosis of a TXNL4A-related craniofacial disorder is established in a proband with suggestive findings and biallelic pathogenic variants in TXNL4A identified by molecular genetic testing. All probands described to date have had at least one copy of one of the two partially overlapping..."

GeneReviews states the biallelic requirement and the near-universal presence of a 34-bp promoter deletion allele.

PMID:25434003 SUPPORT PRIMARY RESULT Human Clinical

"a rare loss-of-function mutation (nonsense, frameshift, or microdeletion) on one allele"

Enumerates the second-allele variant classes, including microdeletion, which is why copy-number analysis is required in addition to promoter sequencing.

PMID:25434003 SUPPORT PRIMARY RESULT Human Clinical

"Mutations were found in 9 of 11 affected families."

Quantifies the diagnostic yield of TXNL4A testing in a clinically ascertained BMKS cohort.

+ 3 more references

💊

Medical Actions

8

Neonatal Airway Management and Choanal Atresia Repair

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Assess and stabilize neonatal airway obstruction; intubation may be required, with surgical correction of choanal atresia or stenosis according to anatomy and clinical need.

Mechanism Target:

BYPASSES Choanal Atresia — Airway stabilization and repair relieve the anatomical obstruction.

Target Phenotypes: Choanal atresia HP:0000453

Show evidence (1 reference)

PMID:27413799 SUPPORT REVIEW SYNTHESIS Other

"Neonates with airway compromise at delivery may require intubation or surgical correction of choanal stenosis/atresia."

GeneReviews states the acute airway management and definitive surgical treatment for the cardinal feature.

Ophthalmological Care for Lower Eyelid Defects

Action: Ophthalmological Care for Lower Eyelid Defects Ontology label: Therapeutic Procedure NCIT:C49236

Platform: Other

Lower eyelid defects can cause corneal exposure. Ophthalmological care is required to reduce the risk of corneal scarring, and monitoring by an ophthalmologist is part of recommended surveillance.

Mechanism Target:

MODULATES Lower Eyelid Coloboma — Care protects the exposed ocular surface and reduces secondary corneal injury.

Target Phenotypes: Lower eyelid coloboma HP:0000652

Show evidence (1 reference)

PMID:27413799 SUPPORT REVIEW SYNTHESIS Other

"Defects of the lower eyelids that can result in corneal exposure require care by an ophthalmologist to reduce the risk of corneal scarring."

GeneReviews specifies ophthalmological care for the eyelid defect and its rationale.

Hearing Loss Management

Action: Hearing rehabilitation Ontology label: Therapeutic Procedure NCIT:C49236

Platform: Device

Treatment of hearing loss is individualised and may involve hearing aids, with audiological monitoring as part of surveillance.

Mechanism Target:

BYPASSES Hearing Loss — Hearing devices provide individualized auditory rehabilitation.

Target Phenotypes: Hearing impairment HP:0000365

Show evidence (1 reference)

PMID:27413799 SUPPORT REVIEW SYNTHESIS Other

"Treatment of hearing loss is individualized and may involve hearing aids."

GeneReviews states the management approach for hearing loss.

Multidisciplinary Craniofacial Care

Action: Multidisciplinary Craniofacial Care Ontology label: Therapeutic Procedure NCIT:C49236

Platform: Other

Individualized craniofacial care can involve maxillofacial and plastic surgeons, ENT, dentistry and orthodontics, and speech-language therapy. Management follows the specific cleft, ear and facial findings and their functional effects.

Show evidence (2 references)

PMID:27413799 SUPPORT REVIEW SYNTHESIS Other

"Treatment of craniofacial manifestations (e.g., cleft lip and/or palate, preauricular tags, prominent ears) is individualized and managed by a multidisciplinary team."

GeneReviews defines multidisciplinary craniofacial management.

PMID:27413799 SUPPORT REVIEW SYNTHESIS Other

"Monitoring by an ophthalmologist, audiologist, and craniofacial team is recommended."

States the recommended surveillance regimen.

Cardiac Management

Action: Cardiac Management Ontology label: Therapeutic Procedure NCIT:C49236

Platform: Other

Cardiac defects are managed in a routine manner, without disorder-specific modification.

Mechanism Target:

MODULATES Structural Cardiac Abnormality — Cardiology care addresses the specific structural lesion and its consequences.

Target Phenotypes: Structural cardiac abnormality HP:0001627

Show evidence (1 reference)

PMID:27413799 SUPPORT REVIEW SYNTHESIS Other

"Cardiac defects are managed in a routine manner."

GeneReviews states that cardiac management is standard rather than disorder-specific.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Discuss genotype-specific autosomal recessive recurrence, parental and family testing, reproductive options, and prenatal or preimplantation testing once the familial alleles are known. A 25% recurrence risk assumes both parents carry the relevant pathogenic alleles; UPD and other unusual configurations require individualized assessment.

Show evidence (1 reference)

PMID:27413799 SUPPORT REVIEW SYNTHESIS Other

"Once the TXNL4A pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible."

GeneReviews states the reproductive testing options that counselling addresses.

Ophthalmic, Hearing and Craniofacial Surveillance

Action: Therapeutic Procedure NCIT:C49236

Platform: Other

Monitor the cornea under ophthalmology guidance; assess hearing shortly after birth and thereafter as directed by audiology; arrange regular craniofacial-team review. Follow-up schedules are individualized rather than supported by BMKS-specific comparative trials.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Other

"Monitoring by an ophthalmologist, audiologist, and craniofacial team is recommended."

Expert surveillance recommendation.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Other

"Hearing assessment ... Shortly after birth ... then per audiologist"

Hearing surveillance timing from Table 6.

Family Support

Action: Therapeutic Procedure NCIT:C49236

Platform: Other

Assess needs for family resources, social work and home nursing alongside specialist care.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Other

"Social work involvement for parental support"

Recommended support assessment after diagnosis.

🔬

Diagnosis

3

Clinical and Multisystem Assessment

Evaluate airway patency promptly in newborns, examine the craniofacial pattern and palate, assess the ocular surface and hearing, and obtain cardiology assessment including echocardiography. Normal intellect or a negative family history does not exclude BMKS.

Physical Examination NCIT:C20989

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Other

"Airway assessment for evidence of upper-airway obstruction"

Initial evaluation explicitly prioritizes airway obstruction.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Other

"Evaluation ... Cardiology assessment ... Incl echocardiography"

Initial evaluation includes echocardiography.

TXNL4A Promoter and Second-Allele Testing

Confirm biallelic pathogenic or likely pathogenic TXNL4A variants in a clinically consistent individual. Test recurrent promoter deletions explicitly, then coding/splice variants and exon or whole-gene copy-number loss as appropriate. Panels and genome analyses must include the noncoding promoter; exome coverage and standard genome filters can miss it. A pair of VUS, or one pathogenic variant plus a VUS, does not establish or rule out the diagnosis.

Genetic Testing NCIT:C15709

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Other

"Targeted assay to detect the type 1 and type 2 promoter deletions"

The targeted promoter assay is part of the chapter testing strategy.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Other

"does not establish or rule out a diagnosis of this disorder."

The surrounding diagnostic paragraph refers specifically to biallelic VUS or one pathogenic allele plus one VUS.

Parental Phase and Copy-Number Assessment

Test parents to confirm the alleles are in trans and refine recurrence risk. Evaluate apparent homozygosity for a hidden deletion or uniparental isodisomy where appropriate; chromosome 18 uniparental disomy was reported with a homozygous type 1 promoter deletion in isolated choanal atresia.

Genetic Testing NCIT:C15709

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Other

"Molecular genetic testing is recommended for the parents of a proband"

Parental testing supports phase and recurrence-risk assessment.

PMID:28905882 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"had a uniparental disomy of chromosome 18p11.32q23, leading to homozygosity for the type 1Δ deletion."

The reported UPD case had isolated choanal atresia, not the full BMKS phenotype.

📊

Prevalence

1

Published families worldwide

Cases In Literature Ultra Rare

Fifteen families were reported in the cited 2020 publication; this is a historical literature count, not a current population prevalence. The 2022 GeneReviews synthesis included 20 individuals across the wider TXNL4A spectrum. Additional reports and overlapping families preclude a reliable current BMKS-only denominator.

Show evidence (1 reference)

PMID:32187816 SUPPORT BACKGROUND Human Clinical

"Till date, 15 families have been described with BMKS."

Quantifies the total published caseload as of 2020, supporting an ultra-rare classification.

🔀

Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from Burn-McKeown Syndrome:

CHARGE Syndrome (CHD7) MONDO:0008965

Overlapping Features Choanal atresia, hearing and cardiac anomalies overlap. GeneReviews distinguishes CHD7-related CHARGE by its intraocular coloboma, genital anomalies and characteristic ear findings; the TXNL4A-associated coloboma described there involves the eyelid rather than intraocular structures. Clinical pattern and molecular testing guide distinction.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"CHARGE syndrome phenotype comprises clinical findings (intraocular coloboma, genital anomalies, ... specific ear anomalies) not seen in ... -related craniofacial disorders. ... The coloboma assoc w/ ... -related craniofacial disorders involves the eyelid only ... not intraocular structures."

GeneReviews states the distinguishing intraocular, genital and ear features and the eyelid-only coloboma in TXNL4A-related disorders.

Treacher Collins Syndrome MONDO:0002457

Overlapping Features The craniofacial phenotype overlaps, including micrognathia and ear or eyelid abnormalities. BMKS does not lack mandibular or maxillary hypoplasia. The overall pattern, extra-craniofacial features and biallelic TXNL4A testing distinguish it from TCOF1/POLR1-associated Treacher Collins syndrome.

Show evidence (1 reference)

PMID:32187816 SUPPORT DIRECT BACKGROUND Human Clinical

"BMKS has overlapping clinical features with Treacher Collins syndrome."

Describes clinical overlap or distinguishing features; molecular assessment resolves uncertain cases.

Mandibulofacial Dysostosis with Microcephaly MONDO:0012516

Overlapping Features EFTUD2-related disease shares a U5 spliceosomal mechanism but more characteristically has microcephaly and moderate-to-severe developmental impairment. Normal intellect is common in BMKS but is not required.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"severe microcephaly ... moderate ID in MFDM"

Describes clinical overlap or distinguishing features; molecular assessment resolves uncertain cases.

Nager Syndrome MONDO:0007943

Overlapping Features SF3B4-related acrofacial dysostosis overlaps craniofacially but typically adds preaxial upper-limb anomalies.

Show evidence (1 reference)

PMID:41081049 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Nager syndrome (OMIM #154400) is a type of acrofacial dysostosis characterized by midface retrusion, micrognathia, absence of thumbs, and radial hypoplasia"

Describes clinical overlap or distinguishing features; molecular assessment resolves uncertain cases.

Cerebrocostomandibular Syndrome MONDO:0007301

Overlapping Features SNRPB-related disease features the combination of mandibular/oropharyngeal abnormalities and posterior rib gaps.

Show evidence (1 reference)

PMID:41081049 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Mutations in SNRPB cause cerebro-costo-mandibular syndrome (CCMS; OMIM #117650), which is a disorder that includes micrognathia, glossoptosis, cleft palate, and posterior rib gaps"

Describes clinical overlap or distinguishing features; molecular assessment resolves uncertain cases.

🧫

Experimental Models

5

BMKS patient-derived iPSC induced neural crest cells IPSC_DERIVED_MODEL

Two patient and two maternal iPSC clones plus two unrelated control lines were examined. The patient carried type 1 promoter deletion in trans with c.131delT; the mother carried only the frameshift. Comparisons are not isogenic and include sex and genetic-background differences. The patient had atypical severe intellectual disability. MTT showed reduced iPSC proliferation, but neither iPSCs nor induced neural crest cells had significantly increased apoptosis. RNA-seq and differentiation findings require replication in additional families.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Blood mononuclear cells from one affected 11-year-old girl and her unaffected frameshift-carrier mother, with two unrelated male control donors

Culture

iPSC reprogramming followed by directed differentiation to induced neural crest cells (iNCCs)

Publication

PMID:32735620

Pathograph links

Selective Pre-mRNA Mis-Splicing partially recapitulates fidelity: moderate RNA-seq shows selective splicing abnormalities at pluripotent and neural crest stages.

Show evidence (1 reference)

PMID:32735620 SUPPORT DIRECT PRIMARY RESULT In Vitro

"rMATS identified 2991 differential splicing events in 2029 different genes"

Neural crest-stage result.

Delayed Neural Crest Epithelial-to-Mesenchymal Transition partially recapitulates fidelity: moderate Transcript and isoform markers remain more epithelial after induction.

Show evidence (1 reference)

PMID:32735620 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The patient iNCCs had a score of -5, while the mother iNCCs had an EMT score of +5 and the unrelated controls had an EMT score of +8"

EMT state differs among these lines.

Dampened WNT Response partially recapitulates fidelity: moderate AXIN2 response is reduced under GSK3-inhibiting induction.

Show evidence (1 reference)

PMID:32735620 SUPPORT DIRECT PRIMARY RESULT In Vitro

"AXIN2 expression was significantly lower (p = 0.0004) in patient iNCCs compared to pooled control iNCCs"

Measured response in the induction protocol.

Findings

BMKS patient iPSCs proliferate more slowly than maternal and unrelated control lines and show significant differences in gene expression and alternative splicing.

"BMKS patient-derived iPSCs proliferated more slowly than both mother- and unrelated control-derived iPSCs, and RNA-Seq analysis revealed significant differences in gene expression and alternative splicing."

Differentiation to induced neural crest cells is defective, with a delay in undergoing the epithelial-to-mesenchymal transition.

"Patient iPSCs displayed defective differentiation into iNCCs compared to maternal and unrelated control iPSCs, in particular a delay in undergoing an epithelial-to-mesenchymal transition (EMT)."

Show evidence (1 reference)

PMID:32735620 SUPPORT PRIMARY RESULT In Vitro

"Here we reprogrammed peripheral mononuclear blood cells from a BMKS patient and her unaffected mother into induced pluripotent stem cells (iPSCs) and differentiated the iPSCs into induced neural crest cells (iNCCs), the key cell type required for correct craniofacial development."

Describes the patient-derived cellular model and its maternal control, the principal experimental system for BMKS mechanism.

Conditional yeast Dib1 depletion OTHER

A haploid yeast strain with DIB1 under GAL1 promoter control models reduced conserved spliceosomal protein supply. Whole-cell extracts were fractionated to assess snRNP assembly. This molecular culture model has no neural crest or craniofacial anatomy.

Organism

Saccharomyces cerevisiae NCBITaxon:4932

Publication

PMID:25434003

Pathograph links

Reduced U4/U6.U5 Tri-snRNP Assembly partially recapitulates fidelity: moderate Dib1 depletion reduces tri-snRNP assembly.

Show evidence (1 reference)

PMID:25434003 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Turning off DIB1 expression resulted in reduced assembly of the U4/U6⋅U5 tri-snRNP complex"

Conditional yeast-culture result.

TXNL4A promoter reporter assays CELL_LINE

Wild-type and deletion-containing TXNL4A promoter constructs were compared by dual luciferase assay. Episomal reporter activity supports a regulatory effect but does not reproduce endogenous chromatin or neural crest differentiation.

Organism

Homo sapiens NCBITaxon:9606

Cell source

HEK293 cells

Publication

PMID:25434003

Pathograph links

Reduced TXNL4A Promoter Activity partially recapitulates fidelity: moderate Type 1 and type 2 constructs show reduced activity.

Show evidence (1 reference)

PMID:25434003 SUPPORT DIRECT PRIMARY RESULT In Vitro

"promoter activity of constructs containing the type 1 Δ (del1) and type 2 Δ (del2) was reduced by 59% and 72%, respectively, compared to the wild-type construct."

Reporter activity relative to wild type.

TXNL4A splice-acceptor minigene assays OTHER

Minigene assays for c.258-3C>G and c.258-2A>G demonstrate final-exon skipping. These assays define a splice consequence, not a promoter-expression mechanism or a direct measure of patient tissue splicing.

Publication

PMID:34713892

Pathograph links

Reduced Functional TXNL4A Dosage partially recapitulates fidelity: moderate Loss of normal terminal-exon inclusion provides functional support for the splice-site alleles.

Show evidence (1 reference)

PMID:34713892 SUPPORT DIRECT PRIMARY RESULT In Vitro

"cause skipping of the final exon of TXNL4A in a minigene splicing assay."

Functional splice assay.

Mouse embryonic stem-cell Txnl4a knockdown CELL_LINE

Lentiviral shRNA depletion of Txnl4a in cultured mouse embryonic stem cells increases Mdm2 exon 3 skipping and p53 protein and reduces selected glycolytic transcripts and lactate. This is not a BMKS mouse or patient-neural-crest model. Direct p53-null rescue after Txnl4a knockdown was not reported; corresponding rescue experiments used other splicing perturbations.

Organism

Mus musculus NCBITaxon:10090

Publication

PMID:38426258

Pathograph links

MDM2 Exon 3 Skipping after Experimental Txnl4a Depletion partially recapitulates fidelity: moderate An alternative Mdm2 transcript is increased after experimental depletion.

Show evidence (1 reference)

PMID:38426258 SUPPORT DIRECT PRIMARY RESULT In Vitro

"specific KD of any the above splicing factors also resulted in increased presence of the Exon 3-skipping Mdm2 transcript"

The tested factors include Txnl4a.

Reduced Glycolytic Gene Expression after Experimental Txnl4a Depletion partially recapitulates fidelity: moderate Targeted assays found reduced glycolytic transcripts and lactate.

Show evidence (1 reference)

PMID:38426258 SUPPORT DIRECT PRIMARY RESULT In Vitro

"we measured lactate levels in mESCs expressing shRNAs targeting Txnl4a, Prpf8 or Sf3b4. We found that all these splicing factor KDs reduce lactate levels"

Measured cellular metabolic output, not a human disease biomarker.

🐁

Animal Models

1

Xenopus Txnl4a morpholino model

Unilateral translation-blocking morpholino injection at the two-cell stage reduces neural crest markers, increases dorsal ectodermal apoptosis at neurula stage 15, and produces cranial cartilage defects in 38% of stage-45 tadpoles. A resistant Txnl4a construct partly rescues sox10 expression. This transient knockdown does not reproduce the human promoter-plus-loss-of-function genotype and does not establish dominant inheritance or p53 dependence.

Species

Xenopus laevis

Genotype

Txnl4a morpholino knockdown

Genes

TXNL4A hgnc:30551

Publication

PMID:35893124

Pathograph links

Impaired Neural Crest Specification partially recapitulates fidelity: moderate Knockdown reduces sox10 expression and resistant Txnl4a partly rescues it.

Show evidence (1 reference)

PMID:35893124 SUPPORT DIRECT PRIMARY RESULT Model Organism

"a modified version of Xenopus Txnl4a restored this proportion from 14% to 62%"

Specificity rescue of the marker phenotype.

Increased Embryonic Ectodermal Apoptosis partially recapitulates fidelity: moderate TUNEL-positive dorsal ectodermal cells increase; this contrasts with the patient-cell model.

Show evidence (1 reference)

PMID:35893124 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In all cases we observed a significant increase in the number of TUNEL-positive cells as a result of the three MOs’ injection"

Measured in the frog embryos.

Show evidence (1 reference)

PMID:35893124 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Snrpb and Txnl4a knockdown produced cartilage defects at a lower frequency, in 29% and 38% of morphant tadpoles, respectively"

The Txnl4a cartilage-defect proportion is 38%; the 29% belongs to Snrpb.

{ }

Source YAML

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name: Burn-McKeown Syndrome
creation_date: "2026-07-31T00:00:00Z"
description: >-
  Burn-McKeown syndrome is a rare autosomal recessive craniofacial disorder caused by biallelic TXNL4A variants.
  Bilateral choanal atresia or stenosis occurs with a recognizable facial pattern, lower eyelid defects, hearing
  impairment, variable clefting and micrognathia, and occasional cardiac or other anomalies. Intellectual development
  is usually normal but exceptions occur. Most genotypes combine a hypomorphic 34-bp promoter deletion with
  a coding, splice or copy-number loss-of-function allele; homozygous promoter deletions also occur. Human-cell
  and experimental models support selective splicing defects and impaired neural crest development, with tissue
  specificity and individual downstream routes incompletely resolved. BMKS is the syndromic part of a broader
  TXNL4A spectrum that also includes isolated choanal atresia.
category: Mendelian
parents:
- Craniofacial Malformation Syndrome
- Spliceosomopathy
notes: >-
  This entry covers Burn-McKeown syndrome, not every TXNL4A-related choanal-atresia presentation. GeneReviews
  phenotype counts pool the wider TXNL4A spectrum and are identified as such below. TXNL4A is distinct from
  EFTUD2, SF3B4 and SNRPB craniofacial disorders. Conformance to the first two pharyngeal-arch/neural-crest
  module nodes reflects a shared developmental route; the third module node asserts a symmetric multi-element
  skeletal bundle not established across BMKS. This does not imply absence of micrognathia, maxillary hypoplasia
  or malar abnormalities in BMKS. Expression biomarkers in unrelated cancers do not establish a BMKS cancer
  predisposition.
disease_term:
  preferred_term: Burn-McKeown syndrome
  term:
    id: MONDO:0012064
    label: choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome
synonyms:
- BMKS
- Burn-McKeown syndrome
- choanal atresia-deafness-cardiac defects-dysmorphism syndrome
- TXNL4A-related craniofacial disorder
- oculootofacial dysplasia
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
references:
- reference: PMID:32187816
  title: Burn-McKeown syndrome with biallelic promoter type 2 deletion in TXNL4A in two siblings.
- reference: PMID:27413799
  title: "TXNL4A-Related Craniofacial Disorders."
  tags:
  - GeneReviews
- reference: PMID:25434003
  title: Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome.
- reference: PMID:34713892
  title: Expanding the genotypic spectrum of TXNL4A variants in Burn-McKeown syndrome.
- reference: PMID:32735620
  title: Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells.
- reference: PMID:35893124
  title: "The Core Splicing Factors EFTUD2, SNRPB and TXNL4A Are Essential for Neural Crest and Craniofacial Development."
- reference: PMID:38426258
  title: A common cellular response to broad splicing perturbations is characterized by metabolic transcript downregulation driven by the Mdm2-p53 axis.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
  title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
- reference: PMID:14564154
  title: Two brothers with Burn-McKeown syndrome.
- reference: PMID:28905882
  title: Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia.
- reference: PMID:41081049
  title: "Modeling craniofacial spliceosomopathies: a pathway toward deciphering disease mechanisms."
- reference: PMID:32315467
  title: "Spliceosomopathies and neurocristopathies: Two sides of the same coin?"
- reference: PMID:39695270
  title: Ultra-rare monogenic disorders frequently detected among sex chromosome aneuploidy patients with atypical findings.
- reference: PMID:36262073
  title: "Hepatocellular Adenoma in an Infant With Burn-McKeown Syndrome: Report of a Case."
prevalence:
- population: Published families worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Fifteen families were reported in the cited 2020 publication; this is a historical literature count, not
    a current population prevalence. The 2022 GeneReviews synthesis included 20 individuals across the wider
    TXNL4A spectrum. Additional reports and overlapping families preclude a reliable current BMKS-only denominator.
  evidence:
  - reference: PMID:32187816
    reference_title: "Burn-McKeown syndrome with biallelic promoter type 2 deletion in TXNL4A in two siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Till date, 15 families have been described with BMKS."
    explanation: Quantifies the total published caseload as of 2020, supporting an ultra-rare classification.
    quote_role: BACKGROUND
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Autosomal recessive inheritance. Recurrence is 25% per pregnancy when both parents carry the relevant pathogenic
    alleles; parental testing establishes phase and permits genotype-specific counseling. Apparent homozygosity
    may require evaluation for a deletion or uniparental disomy. Prenatal and preimplantation testing are possible
    once the familial variants are identified.
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TXNL4A-related craniofacial disorders are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance inheriting neither of the familial TXNL4A pathogenic variants."
    explanation: GeneReviews states the mode of inheritance and the recurrence risk.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:32187816
    reference_title: "Burn-McKeown syndrome with biallelic promoter type 2 deletion in TXNL4A in two siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygosity or compound heterozygosity of promoter deletions and null variants in TXNL4A are known to cause most cases of BMKS."
    explanation: Documents both the compound-heterozygous and homozygous promoter-deletion genotypes.
    quote_role: BACKGROUND
pathophysiology:
- name: Recurrent TXNL4A Promoter Deletion
  description: The recurrent type 1 and type 2 alleles are distinct, partially overlapping 34-bp deletions in the TXNL4A promoter. They disrupt a region containing two 22-bp repeats separated by a 12-bp spacer; there is no single 56-bp pathogenic deletion. These regulatory alterations are distinct from coding, splice-site and copy-number loss on the other allele. Most BMKS genotypes combine a type 1 deletion with a loss-of-function allele; homozygous promoter deletions also occur.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:25434003
    reference_title: Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In 8 families, affected individuals carried a rare loss-of-function mutation (nonsense, frameshift, or microdeletion) on one allele and a low-frequency 34 bp deletion (allele frequency 0.76%) in the core promoter region on the other allele.
    explanation: Defines the recurrent regulatory-plus-loss-of-function architecture, not a single dominant allele.
  genes:
  - &id001
    preferred_term: TXNL4A
    term:
      id: hgnc:30551
      label: TXNL4A
  downstream:
  - target: Reduced TXNL4A Promoter Activity
    description: Deletion of promoter sequence reduces regulatory activity in reporter assays.
    causal_link_type: DIRECT
- name: Reduced TXNL4A Promoter Activity
  description: HEK293 reporter assays found type 1 and type 2 promoter activity reduced by 59% and 72%, respectively. A later deletion-mapping assay identified the repeated 22-bp motifs as important for promoter activity. Predicted transcription-factor motifs are not evidence that a particular factor binds the endogenous locus in neural crest cells.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:25434003
    reference_title: Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: promoter activity of constructs containing the type 1 Δ (del1) and type 2 Δ (del2) was reduced by 59% and 72%, respectively, compared to the wild-type construct.
    explanation: Reporter output measures reduced promoter activity in HEK293 cells.
  - reference: PMID:34713892
    reference_title: Expanding the genotypic spectrum of TXNL4A variants in Burn-McKeown syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: use dual luciferase assays to identify a 22 bp repeated motif essential for TXNL4A expression within this promoter region.
    explanation: Functional promoter mapping supports sequence dependence without identifying a proven endogenous transcription-factor interaction.
  downstream:
  - target: Reduced Functional TXNL4A Dosage
    description: Reduced transcription from the promoter-deletion allele lowers the supply of functional TXNL4A; the second allele determines the remaining functional dosage.
    causal_link_type: DIRECT
- name: Reduced Functional TXNL4A Dosage
  description: 'A hypomorphic promoter allele combined with a coding, splice or copy-number loss-of-function allele reduces functional TXNL4A dosage. Patient-derived iPSCs and neural crest cells have reduced TXNL4A RNA. Total RNA is not equivalent to functional protein: several coding-mutant transcripts escape nonsense-mediated decay, and the unaffected mother carrying a frameshift had unchanged total RNA. Complete human biallelic null lethality is hypothesized from conserved model-organism function, not demonstrated in humans.'
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:32735620
    reference_title: Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The expression of TXNL4A was significantly lower in patient iPSCs
    explanation: Reduced RNA in the patient lines; this is not a quantitative protein assay.
  - reference: PMID:25434003
    reference_title: Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: these mutant transcripts escaped nonsense-mediated mRNA decay (NMD)
    explanation: Observed persistence of coding-mutant transcripts limits a generic NMD explanation.
  - reference: PMID:34713892
    reference_title: Expanding the genotypic spectrum of TXNL4A variants in Burn-McKeown syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: cause skipping of the final exon of TXNL4A in a minigene splicing assay.
    explanation: The c.258-3C>G and c.258-2A>G splice variants were functionally tested in a minigene, distinct from promoter regulation.
  genes:
  - *id001
  downstream:
  - target: Reduced U4/U6.U5 Tri-snRNP Assembly
    description: The yeast ortholog depletion experiment supports a conserved assembly defect; direct tri-snRNP quantification in patient neural crest cells remains lacking.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Increased Embryonic Ectodermal Apoptosis
    description: Experimental Txnl4a knockdown increases embryonic ectodermal apoptosis in Xenopus; the intermediates and applicability to patient cells are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: MDM2 Exon 3 Skipping after Experimental Txnl4a Depletion
    description: Experimental Txnl4a knockdown in mouse embryonic stem cells increases the exon-3-skipped Mdm2 isoform; human neural crest relevance remains provisional.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Reduced U4/U6.U5 Tri-snRNP Assembly
  description: Conditional depletion of yeast Dib1, the TXNL4A ortholog, reduces U4/U6.U5 tri-snRNP assembly. This is a conserved molecular model for reduced spliceosome availability in BMKS, rather than a direct measurement of assembly in affected human tissue.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:25434003
    reference_title: Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Turning off DIB1 expression resulted in reduced assembly of the U4/U6⋅U5 tri-snRNP complex
    explanation: Conditional yeast-culture experiment establishes the assembly effect in the ortholog system.
  biological_processes:
  - preferred_term: spliceosomal snRNP assembly
    term:
      id: GO:0000387
      label: spliceosomal snRNP assembly
    modifier: DECREASED
  conforms_to: pharyngeal_arch_patterning_serial_homology#Cranial Neural Crest and Pharyngeal Arch Program Perturbation
  downstream:
  - target: Selective Pre-mRNA Mis-Splicing
    description: Reduced spliceosome availability is a candidate explanation for the selective splicing defects measured in patient cells.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Selective Pre-mRNA Mis-Splicing
  description: Patient-derived iPSCs and induced neural crest cells show selective alternative-splicing abnormalities. At 120 hours of neural crest induction, 2,991 differential events affected 2,029 genes; exon skipping predominated. Vulnerable exons had weaker splice sites and altered intron/exon architecture. These signatures may include indirect regulatory effects and differences in differentiation state; they do not establish that every transcript is directly affected by TXNL4A.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:32735620
    reference_title: Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: rMATS identified 2991 differential splicing events in 2029 different genes
    explanation: Neural crest RNA-seq measures widespread but selective changes.
  - reference: PMID:32735620
    reference_title: Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: One of the difficulties in interpreting the differential gene expression and differential splicing in the RNA-Seq data is determining direct effects
    explanation: The authors distinguish primary spliceosome effects from downstream regulatory and cell-state effects.
  cell_types:
  - &id002
    preferred_term: neural crest cell
    term:
      id: CL:0011012
      label: neural crest cell
  biological_processes:
  - preferred_term: mRNA splicing, via spliceosome
    term:
      id: GO:0000398
      label: mRNA splicing, via spliceosome
    modifier: ABNORMAL
  downstream:
  - target: Increased TCF7L2 Exon 4 Inclusion
    description: TCF7L2 exon 4 is one neural-crest-stage splicing event within the broader transcriptomic phenotype.
    causal_link_type: DIRECT
  - target: Impaired Neural Crest Specification
    description: Other altered developmental transcripts may impair specification independently of the TCF7L2 candidate route; the decisive targets remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Increased TCF7L2 Exon 4 Inclusion
  description: Patient induced neural crest cells show increased inclusion of TCF7L2 exon 4, validated by qPCR, without a change in total TCF7L2 expression. The event was not detected in the patient iPSC comparison. It is a downstream RNA-processing change, not a germline TCF7L2 variant or a proven sole cause of BMKS.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:32735620
    reference_title: Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: A significant SE event was identified in TCF7L2 with increased inclusion of TCF7L2 exon 4 in the patient iNCCs, although there was no change in overall TCF7L2 gene expression
    explanation: Defines the measured isoform change and its distinction from gene-expression abundance.
  downstream:
  - target: Dampened WNT Response
    description: The exon-4-containing isoform is a candidate contributor to reduced WNT responsiveness; isoform-specific rescue in patient cells has not established causality.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Dampened WNT Response
  description: Patient neural crest cells respond less strongly to the WNT-activating differentiation protocol, including lower AXIN2 expression. TCF7L2 splicing is a proposed contributor. Because the protocol activates WNT downstream of GSK3, its results do not identify every potentially affected step of endogenous WNT signaling.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:32735620
    reference_title: Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: AXIN2 expression was significantly lower (p = 0.0004) in patient iNCCs compared to pooled control iNCCs
    explanation: A measured response marker supports impaired WNT induction in this in-vitro model.
  - reference: PMID:32735620
    reference_title: Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: our iNCC induction protocol activated WNT signalling by inhibiting GSK3
    explanation: Protocol context limits localization of the defect.
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
    modifier: DECREASED
  downstream:
  - target: Delayed Neural Crest Epithelial-to-Mesenchymal Transition
    description: Reduced WNT response is proposed to impair the differentiation program and the epithelial-to-mesenchymal transition required for neural crest development.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Delayed Neural Crest Epithelial-to-Mesenchymal Transition
  description: At 120 hours, patient cells retain epithelial markers and isoforms and express fewer mesenchymal markers. Their EMT score was -5 versus +5 for maternal and +8 for unrelated controls; extending induction to 168 hours did not normalize the phenotype. A delay, incomplete differentiation, or differentiation of only a subset of cells cannot yet be distinguished. Patient-cell migration itself was proposed for future study, not directly established as impaired.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:32735620
    reference_title: Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The patient iNCCs had a score of -5, while the mother iNCCs had an EMT score of +5 and the unrelated controls had an EMT score of +8
    explanation: Transcriptomic EMT scores quantify the difference between these lines.
  - reference: PMID:32735620
    reference_title: Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: extending the iNCC differentiation protocol time to 168h in the patient iNCCs did not allow the patient iNCCs to ‘catch up’
    explanation: A longer induction interval did not resolve the observed delay.
  cell_types:
  - *id002
  biological_processes:
  - preferred_term: epithelial to mesenchymal transition
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
    modifier: DECREASED
  downstream:
  - target: Impaired Neural Crest Specification
    description: Failure to complete the epithelial-to-mesenchymal program can limit acquisition of a differentiated neural crest state.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Increased Embryonic Ectodermal Apoptosis
  description: 'Unilateral Txnl4a morpholino knockdown increases TUNEL-positive cells in the dorsal ectoderm of Xenopus neurulae. This result does not establish p53 dependence, which was not assayed, or universal apoptosis in BMKS: patient-derived iPSCs and induced neural crest cells showed no significant increase in apoptosis.'
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:35893124
    reference_title: "The Core Splicing Factors EFTUD2, SNRPB and TXNL4A Are Essential for Neural Crest and Craniofacial Development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In all cases we observed a significant increase in the number of TUNEL-positive cells as a result of the three MOs’ injection
    explanation: The experiment includes Txnl4a, Eftud2 and Snrpb knockdowns; the measured tissue is dorsal ectoderm.
  - reference: PMID:32735620
    reference_title: Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells.
    supports: REFUTE
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Annexin-V staining revealed no significant differences in apoptosis between the patient iNCCs and the mother and unrelated control iNCCs
    explanation: The human-cell result refutes a uniform increase across models.
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  downstream:
  - target: Impaired Neural Crest Specification
    description: Loss of embryonic progenitors may contribute to reduced neural crest marker expression in the frog model; lineage-specific mediation was not directly tested.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Neural Crest Specification
  description: Patient-derived cells acquire neural crest identity inefficiently, while Txnl4a-depleted Xenopus embryos show reduced neural crest marker expression. In frogs, morpholino-resistant Txnl4a partly restores normal sox10 expression. The human cell and frog models support a developmental vulnerability but differ in perturbation, dosage, stage and cell-death response.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:32735620
    reference_title: Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: three out of four of the later neural crest identity markers examined here had significantly lower expression
    explanation: Patient cells acquire neural crest identity less efficiently at the sampled time.
  - reference: PMID:35893124
    reference_title: "The Core Splicing Factors EFTUD2, SNRPB and TXNL4A Are Essential for Neural Crest and Craniofacial Development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: a modified version of Xenopus Txnl4a restored this proportion from 14% to 62%
    explanation: Partial rescue of normal sox10 expression supports specificity of the morpholino phenotype.
  cell_types:
  - *id002
  biological_processes:
  - preferred_term: neural crest cell development
    term:
      id: GO:0014032
      label: neural crest cell development
    modifier: ABNORMAL
  conforms_to: pharyngeal_arch_patterning_serial_homology#Disrupted Pharyngeal-Arch Patterning and Neural-Crest Skeletogenesis
  downstream:
  - target: Craniofacial Developmental Malformation
    description: Impaired neural crest development is a supported route to craniofacial malformation, although the precise intermediates leading to each human anatomical feature remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: MDM2 Exon 3 Skipping after Experimental Txnl4a Depletion
  description: Txnl4a knockdown in mouse embryonic stem cells increases the Mdm2 exon-3-skipped transcript. This provides gene-specific experimental support for an alternative stress-response route; it has not been demonstrated in BMKS patient neural crest cells.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:38426258
    reference_title: A common cellular response to broad splicing perturbations is characterized by metabolic transcript downregulation driven by the Mdm2-p53 axis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: specific KD of any the above splicing factors also resulted in increased presence of the Exon 3-skipping Mdm2 transcript
    explanation: The preceding experiment names Txnl4a, Prpf8 and Sf3b4; the result is from mouse cell culture, not an animal disease model.
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: p53 Accumulation after Experimental Txnl4a Depletion
    description: The study implicates a p53-stabilizing Mdm2 isoform across splicing perturbations; Txnl4a-specific isoform rescue was not demonstrated.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: p53 Accumulation after Experimental Txnl4a Depletion
  description: p53 protein accumulates after Txnl4a knockdown in mouse embryonic stem cells. This finding does not establish p53 activation or a p53-dependent craniofacial phenotype in human BMKS.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:38426258
    reference_title: A common cellular response to broad splicing perturbations is characterized by metabolic transcript downregulation driven by the Mdm2-p53 axis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We also observed the expected increase in p53 levels when any of the above splicing factors was knocked down with shRNA
    explanation: Western blots include Txnl4a knockdown alongside other splicing factors.
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Reduced Glycolytic Gene Expression after Experimental Txnl4a Depletion
    description: A p53-mediated metabolic response is proposed; rescue in p53-null cells was tested for Eftud2 and Sf3b4 depletion and splicing inhibition, rather than directly for Txnl4a depletion.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Reduced Glycolytic Gene Expression after Experimental Txnl4a Depletion
  description: Txnl4a knockdown reduces selected glycolytic transcripts and lactate levels in mouse embryonic stem cells. The authors propose that persistent metabolic changes could alter vulnerable developmental cell states. This remains an indirect hypothesis for human craniofacial disease, not a demonstrated BMKS metabolic biomarker or treatment target.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:38426258
    reference_title: A common cellular response to broad splicing perturbations is characterized by metabolic transcript downregulation driven by the Mdm2-p53 axis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We found that KD of any of the above splicing factors always resulted in downregulation of glycolytic transcripts
    explanation: qPCR after Txnl4a, Prpf8 or Sf3b4 knockdown measured Hk1, Pfkfb3 and Pfkm transcripts.
  - reference: PMID:38426258
    reference_title: A common cellular response to broad splicing perturbations is characterized by metabolic transcript downregulation driven by the Mdm2-p53 axis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: we measured lactate levels in mESCs expressing shRNAs targeting Txnl4a, Prpf8 or Sf3b4. We found that all these splicing factor KDs reduce lactate levels
    explanation: Gene-specific perturbations were tested in cultured mouse embryonic stem cells.
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Impaired Neural Crest Specification
    description: Altered metabolic state is a proposed contributor to developmental vulnerability; mediation of a Txnl4a-dependent neural crest defect remains untested.
    causal_link_type: UNKNOWN
- name: Craniofacial Developmental Malformation
  description: Congenital malformations include choanal obstruction, lower eyelid defects, altered facial proportions, ear anomalies and clefting. Impaired neural crest development provides a shared developmental explanation, but neither one embryologic lesion nor a symmetric zygoma-maxilla-mandible bundle has been established for every person. Micrognathia and maxillary hypoplasia do occur.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:27413799
    reference_title: TXNL4A-Related Craniofacial Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears).
    explanation: Clinical synthesis defines the malformation spectrum.
  biological_processes:
  - preferred_term: face morphogenesis
    term:
      id: GO:0060325
      label: face morphogenesis
    modifier: ABNORMAL
  downstream:
  - target: Choanal Atresia
    description: The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Lower Eyelid Coloboma
    description: The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hearing Loss
    description: The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Conductive Hearing Impairment
    description: The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Sensorineural Hearing Impairment
    description: The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Prominent Ears
    description: The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Short Palpebral Fissures
    description: The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypertelorism
    description: The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Prominent Nasal Bridge
    description: The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Short Philtrum
    description: The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Thin Upper Lip Vermilion
    description: The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cleft Lip
    description: The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cleft Palate
    description: The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Preauricular Skin Tag
    description: The craniofacial developmental disorder includes this manifestation; its specific cellular and anatomical intermediates remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Micrognathia
    description: Altered craniofacial development produces this reported anatomical manifestation; the specific developmental intermediates remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Maxillary Hypoplasia
    description: Altered craniofacial development produces this reported anatomical manifestation; the specific developmental intermediates remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Narrow Mouth
    description: Altered craniofacial development produces this reported anatomical manifestation; the specific developmental intermediates remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Thick Lower Lip Vermilion
    description: Altered craniofacial development produces this reported anatomical manifestation; the specific developmental intermediates remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypomimic Face
    description: Part of the clinical craniofacial spectrum; the specific cellular intermediates remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Craniofacial
  name: Choanal Atresia
  description: >-
    Bilateral choanal atresia or stenosis is the cardinal presenting feature in reported BMKS series and can
    cause life-threatening neonatal airway obstruction. The cited clinical studies do not establish a single
    embryologic mechanism for the obstruction.
  diagnostic: true
  phenotype_term:
    preferred_term: Choanal atresia
    term:
      id: HP:0000453
      label: Choanal atresia
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears)."
    explanation: GeneReviews places bilateral choanal atresia/stenosis first among the typical craniofacial features of BMKS.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Neonates with airway compromise at delivery may require intubation or surgical correction of choanal stenosis/atresia."
    explanation: Documents the clinical consequence that makes choanal atresia the presenting and most urgent feature.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Bilateral choanal stenosis/atresia ... 20/20 ... 3 persons have had isolated choanal atresia
    explanation: Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.
  frequency: OBLIGATE
  notes: All 20 persons in the pooled GeneReviews table had choanal stenosis/atresia, including the three isolated-choanal-atresia cases; therefore all 17 syndromic cases also had it. This describes the ascertained series, not a population penetrance estimate.
- category: Ophthalmological
  name: Lower Eyelid Coloboma
  description: >-
    Coloboma of the outer third of the lower eyelid, characteristically with
    eyelashes present medial to the defect, is a highly distinctive feature and
    can cause corneal exposure.
  diagnostic: true
  phenotype_term:
    preferred_term: Lower eyelid coloboma
    term:
      id: HP:0000652
      label: Lower eyelid coloboma
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears)."
    explanation: GeneReviews lists lower eyelid coloboma among the typical craniofacial features.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Defects of the lower eyelids that can result in corneal exposure require care by an ophthalmologist to reduce the risk of corneal scarring."
    explanation: Documents the corneal-exposure complication that makes the eyelid defect clinically actionable.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: '# of Persons w/Feature / # Assessed ... Defects of lower eyelids ... 12/20'
    explanation: Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.
  review_notes: The 2022 GeneReviews table reports 12/20 for lower eyelid defects collectively, not coloboma alone. Its denominator pools the wider TXNL4A spectrum, including isolated choanal atresia, so it is not assigned as a BMKS-only frequency band.
- category: Craniofacial
  name: Short Palpebral Fissures
  description: >-
    Short (narrow) palpebral fissures are part of the recognisable facial gestalt.
  diagnostic: true
  phenotype_term:
    preferred_term: Short palpebral fissure
    term:
      id: HP:0012745
      label: Short palpebral fissure
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears)."
    explanation: GeneReviews lists short palpebral fissures among the typical craniofacial features.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: '# of Persons w/Feature / # Assessed ... Short palpebral fissures ... 11/19'
    explanation: Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.
  review_notes: The 2022 GeneReviews table reports 11/19. Its denominator pools the wider TXNL4A spectrum, including isolated choanal atresia, so it is not assigned as a BMKS-only frequency band.
- category: Craniofacial
  name: Hypertelorism
  description: >-
    Widely spaced eyes accompany the prominent nasal bridge.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears)."
    explanation: GeneReviews lists widely spaced eyes among the typical craniofacial features.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:14564154
    reference_title: "Two brothers with Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a characteristic pattern of facial dysmorphic features consisting of hypertelorism, lower lid coloboma, narrow palpebral fissures"
    explanation: The two-brother report documents hypertelorism; this family was subsequently included in the 2014 molecular series.
    quote_role: PRIMARY_RESULT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: '# of Persons w/Feature / # Assessed ... Hypertelorism ... 12/17'
    explanation: Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.
  review_notes: The 2022 GeneReviews table reports 12/17. Its denominator pools the wider TXNL4A spectrum, including isolated choanal atresia, so it is not assigned as a BMKS-only frequency band.
- category: Craniofacial
  name: Prominent Nasal Bridge
  description: >-
    A prominent nasal bridge with widely spaced eyes is a consistent component of
    the facial gestalt.
  phenotype_term:
    preferred_term: Prominent nasal bridge
    term:
      id: HP:0000426
      label: Prominent nasal bridge
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears)."
    explanation: GeneReviews lists the prominent nasal bridge among the typical craniofacial features.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: '# of Persons w/Feature / # Assessed ... Prominent nasal bridge ... 17/18'
    explanation: Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.
  frequency: VERY_FREQUENT
  notes: The pooled 17/18 proportion implies a syndromic-only frequency of at least 14/15 (93%) even if all three isolated-choanal-atresia cases with available data had this feature. The exact syndromic denominator is not supplied; this is not a penetrance estimate.
- category: Craniofacial
  name: Short Philtrum
  description: >-
    A short philtrum is part of the facial gestalt.
  phenotype_term:
    preferred_term: Short philtrum
    term:
      id: HP:0000322
      label: Short philtrum
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears)."
    explanation: GeneReviews lists the short philtrum among the typical craniofacial features.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: '# of Persons w/Feature / # Assessed ... Short philtrum ... 14/17'
    explanation: Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.
  review_notes: The 2022 GeneReviews table reports 14/17. Its denominator pools the wider TXNL4A spectrum, including isolated choanal atresia, so it is not assigned as a BMKS-only frequency band.
- category: Craniofacial
  name: Thin Upper Lip Vermilion
  description: >-
    A thin upper lip vermilion, often with a small mouth, is part of the facial
    gestalt.
  phenotype_term:
    preferred_term: Thin upper lip vermilion
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears)."
    explanation: GeneReviews lists a thin upper lip vermilion among the typical craniofacial features.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Thin vermilion of the upper lip ... 10/17
    explanation: Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.
  review_notes: The 2022 GeneReviews table reports 10/17. Its denominator pools the wider TXNL4A spectrum, including isolated choanal atresia, so it is not assigned as a BMKS-only frequency band.
- category: Craniofacial
  name: Prominent Ears
  description: >-
    Prominent or protruding ears are a consistent external feature.
  diagnostic: true
  phenotype_term:
    preferred_term: Protruding ear
    term:
      id: HP:0000411
      label: Protruding ear
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears)."
    explanation: GeneReviews lists prominent ears among the typical craniofacial features.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:28905882
    reference_title: "Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Burn-McKeown syndrome (BMKS) is a rare syndrome characterized by choanal atresia, prominent ears, abnormalities of the outer third of the lower eyelid, structural cardiac abnormalities, conductive and sensorineural hearing loss, and cleft lip."
    explanation: The paper summarizes prominent ears as a characteristic feature.
    quote_role: BACKGROUND
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: '# of Persons w/Feature / # Assessed ... Prominent ears ... 13/17'
    explanation: Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.
  review_notes: The 2022 GeneReviews table reports 13/17. Its denominator pools the wider TXNL4A spectrum, including isolated choanal atresia, so it is not assigned as a BMKS-only frequency band.
- category: Auditory
  name: Hearing Loss
  description: >-
    Hearing impairment is common in reported BMKS cases; conductive, sensorineural and mixed components occur.
    Disease-wide severity, onset and progression are not well quantified.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hearing loss is common and cardiac defects and short stature have been reported."
    explanation: GeneReviews describes hearing loss as common; the full table supplies the assessed denominator.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:28905882
    reference_title: "Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "conductive and sensorineural hearing loss"
    explanation: Documents that both conductive and sensorineural components occur.
    quote_role: BACKGROUND
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: '# of Persons w/Feature / # Assessed ... Hearing loss ... 12/19'
    explanation: Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.
  review_notes: The 2022 GeneReviews table reports 12/19. Its denominator pools the wider TXNL4A spectrum, including isolated choanal atresia, so it is not assigned as a BMKS-only frequency band.
- category: Auditory
  name: Conductive Hearing Impairment
  description: >-
    Conductive hearing impairment can occur alone or together with a sensorineural component. Audiological
    assessment distinguishes these components; their separate frequencies and anatomical causes are incompletely
    characterized.
  phenotype_term:
    preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:28905882
    reference_title: "Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "conductive and sensorineural hearing loss"
    explanation: Explicitly lists conductive hearing loss among the characterising features.
    quote_role: BACKGROUND
- category: Auditory
  name: Sensorineural Hearing Impairment
  description: >-
    A sensorineural component can occur alone or with conductive impairment. Audiological assessment distinguishes
    these components; their separate frequencies are incompletely characterized.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:28905882
    reference_title: "Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "conductive and sensorineural hearing loss"
    explanation: Explicitly lists sensorineural hearing loss among the characterising features.
    quote_role: BACKGROUND
- category: Cardiovascular
  name: Structural Cardiac Abnormality
  description: >-
    Congenital cardiac lesions vary. Patent ductus arteriosus and patent foramen ovale are described in GeneReviews;
    atrial and ventricular septal defects were reported in a molecularly confirmed individual.
  phenotype_term:
    preferred_term: Structural cardiac abnormality
    term:
      id: HP:0001627
      label: Abnormal heart morphology
    coarse_binding_basis: VARIABLE_SPECTRUM
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hearing loss is common and cardiac defects and short stature have been reported."
    explanation: GeneReviews identifies cardiac defects; the full table supplies the assessed denominator.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:28905882
    reference_title: "Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "structural cardiac abnormalities, conductive and sensorineural hearing loss, and cleft lip"
    explanation: Lists structural cardiac abnormalities among the characterising features of BMKS.
    quote_role: BACKGROUND
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: '# of Persons w/Feature / # Assessed ... Cardiac defect ... 5/16'
    explanation: Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.
  review_notes: The 2022 GeneReviews table reports 5/16. Its denominator pools the wider TXNL4A spectrum, including isolated choanal atresia, so it is not assigned as a BMKS-only frequency band.
- category: Craniofacial
  name: Cleft Lip
  description: >-
    Unilateral or bilateral cleft lip, with or without palatal involvement, is a variable manifestation.
  phenotype_term:
    preferred_term: Cleft upper lip
    term:
      id: HP:0000204
      label: Cleft upper lip
  evidence:
  - reference: PMID:28905882
    reference_title: "Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "structural cardiac abnormalities, conductive and sensorineural hearing loss, and cleft lip"
    explanation: Lists cleft lip among the characterising features.
    quote_role: BACKGROUND
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Treatment of craniofacial manifestations (e.g., cleft lip and/or palate, preauricular tags, prominent ears) is individualized and managed by a multidisciplinary team."
    explanation: GeneReviews management section confirms cleft lip and/or palate occurs and requires multidisciplinary care.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Submucous cleft palate or cleft lip/palate ... 10/20
    explanation: Combined clefting category; no separate lip/palate frequency is inferred.
  review_notes: The GeneReviews combined category of submucous cleft palate or cleft lip/palate was present in 10/20 across the TXNL4A spectrum. This cannot be assigned as a separate frequency for cleft lip or cleft palate.
- category: Craniofacial
  name: Cleft Palate
  description: >-
    Palatal involvement includes overt or submucous clefting. A median cleft palate with oronasal fistula was
    reported in the two brothers subsequently included in the molecular discovery series.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:25434003
    reference_title: "Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This rare condition is characterized by bilateral choanal atresia, hearing loss, cleft lip and/or palate, and other craniofacial dysmorphisms."
    explanation: The introductory clinical characterization includes cleft lip and/or palate without establishing their separate frequencies.
    quote_role: BACKGROUND
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Treatment of craniofacial manifestations (e.g., cleft lip and/or palate, preauricular tags, prominent ears) is individualized and managed by a multidisciplinary team."
    explanation: GeneReviews lists cleft palate among the craniofacial manifestations routinely managed in BMKS.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:14564154
    reference_title: "Two brothers with Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These brothers show some additional features that were not previously reported in patients with this syndrome including median cleft palate with oronasal fistula, preauricular tag, hypomimic face, and hypoplastic unilateral kidney, thus indicating that the clinical spectrum of this entity is broader."
    explanation: Documents the specific median cleft palate with oronasal fistula variant as an expansion of the BMKS phenotypic spectrum.
    quote_role: PRIMARY_RESULT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Submucous cleft palate or cleft lip/palate ... 10/20
    explanation: Combined clefting category; no separate lip/palate frequency is inferred.
  review_notes: The GeneReviews combined category of submucous cleft palate or cleft lip/palate was present in 10/20 across the TXNL4A spectrum. This cannot be assigned as a separate frequency for cleft lip or cleft palate.
- category: Craniofacial
  name: Preauricular Skin Tag
  description: >-
    Preauricular tags are part of the variable craniofacial phenotype; the pooled GeneReviews series recorded
    them in 10 of 16 assessed individuals.
  phenotype_term:
    preferred_term: Preauricular skin tag
    term:
      id: HP:0000384
      label: Preauricular skin tag
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "cleft lip and/or palate, preauricular tags, prominent ears"
    explanation: GeneReviews lists preauricular tags among the craniofacial manifestations requiring management.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: '# of Persons w/Feature / # Assessed ... Preauricular tags ... 10/16'
    explanation: Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.
  review_notes: The 2022 GeneReviews table reports 10/16. Its denominator pools the wider TXNL4A spectrum, including isolated choanal atresia, so it is not assigned as a BMKS-only frequency band.
- category: Growth
  name: Short Stature
  description: >-
    Short stature is reported in a minority and is described as mild and proportionate in GeneReviews.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiac defects and short stature have been reported"
    explanation: GeneReviews includes short stature; its full clinical table reports the assessed denominator.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: '# of Persons w/Feature / # Assessed ... Short stature ... 3/17'
    explanation: Table 2 reports the phenotype and assessed denominator across the wider TXNL4A spectrum.
  review_notes: The 2022 GeneReviews table reports 3/17. Its denominator pools the wider TXNL4A spectrum, including isolated choanal atresia, so it is not assigned as a BMKS-only frequency band.
- category: Renal
  name: Renal Hypoplasia
  description: >-
    Unilateral renal hypoplasia was described in the 2003 sibship later included as BMKS001 in the molecularly
    confirmed 2014 series. Its population frequency and broader renal natural history are unknown.
  phenotype_term:
    preferred_term: Renal hypoplasia
    term:
      id: HP:0000089
      label: Renal hypoplasia
  evidence:
  - reference: PMID:14564154
    reference_title: "Two brothers with Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "median cleft palate with oronasal fistula, preauricular tag, hypomimic face, and hypoplastic unilateral kidney"
    explanation: Documents unilateral renal hypoplasia in the reported sibship, without a disease-wide frequency estimate.
    quote_role: PRIMARY_RESULT
- category: Cognitive
  name: Intellectual Disability
  description: >-
    Intellect is usually normal, but mild learning disability and severe intellectual disability have been
    reported. Developmental impairment does not exclude BMKS and may also warrant assessment for an additional
    diagnosis.
  notes: >-
    GeneReviews reports normal intellect in 16/18 assessed individuals across the TXNL4A spectrum. The severe-ID
    individual was also the single patient donor in the published iPSC study; that study is not an independent
    clinical replication.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: One female had mild learning disabilities and another had severe intellectual disability
    explanation: Full clinical chapter documents both exceptions to usually normal intellectual development.
- name: Micrognathia
  category: Craniofacial
  description: Micrognathia is a recognized BMKS feature; its presence cannot be used to distinguish BMKS from Treacher Collins syndrome. GeneReviews reports 12/19 in the pooled TXNL4A spectrum.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: '# of Persons w/Feature / # Assessed ... Micrognathia ... 12/19'
    explanation: Documents this manifestation in the stated clinical context.
  review_notes: Pooled spectrum count, not a BMKS-only frequency estimate.
- name: Maxillary Hypoplasia
  category: Craniofacial
  description: Maxillary hypoplasia was reported in the 2017 molecularly confirmed series, including unilateral involvement in a BMKS proband. A uniform symmetric skeletal pattern is not established.
  phenotype_term:
    preferred_term: Hypoplasia of the maxilla
    term:
      id: HP:0000327
      label: Hypoplasia of the maxilla
  evidence:
  - reference: PMID:28905882
    reference_title: Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Maxillary hypoplasia was also seen in the same three individuals, and micrognathia was seen in two out of them.
    explanation: Documents this manifestation in the stated clinical context.
- name: Narrow Mouth
  category: Craniofacial
  description: Reduced mouth opening or a small mouth contributes to the characteristic facial appearance.
  phenotype_term:
    preferred_term: Narrow mouth
    term:
      id: HP:0000160
      label: Narrow mouth
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Short philtrum, thin vermilion of the upper lip, thick vermilion of the lower lip, and reduced opening of the mouth
    explanation: Documents this manifestation in the stated clinical context.
- name: Thick Lower Lip Vermilion
  category: Craniofacial
  description: Thick lower lip vermilion can accompany thin upper lip vermilion and a short philtrum.
  phenotype_term:
    preferred_term: Thick lower lip vermilion
    term:
      id: HP:0000179
      label: Thick lower lip vermilion
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Short philtrum, thin vermilion of the upper lip, thick vermilion of the lower lip, and reduced opening of the mouth
    explanation: Documents this manifestation in the stated clinical context.
- name: Patent Ductus Arteriosus
  category: Cardiovascular
  description: Persistent ductus arteriosus is one reported cardiac lesion.
  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/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Cardiac defects ... include persistent ductus arteriosus and patent foramen ovale.
    explanation: Documents this manifestation in the stated clinical context.
- name: Patent Foramen Ovale
  category: Cardiovascular
  description: Patent foramen ovale is reported; the 2014 BMKS004 proband had spontaneous closure.
  phenotype_term:
    preferred_term: Patent foramen ovale
    term:
      id: HP:0001655
      label: Patent foramen ovale
  evidence:
  - reference: PMID:25434003
    reference_title: Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The affected girl of family BMKS004 originates from Vietnam. She had bilateral choanal atresia and a patent foramen ovale, which closed spontaneously
    explanation: Documents this manifestation in the stated clinical context.
- name: Atrial Septal Defect
  category: Cardiovascular
  description: An asymptomatic septal defect was reported in the molecularly confirmed BMKS proband of family 2 in the 2017 series; no disease-wide frequency is inferred.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: PMID:28905882
    reference_title: Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Cardiac defect | N | Asymptomatic ASD and VSD
    explanation: Documents this manifestation in the stated clinical context.
- name: Ventricular Septal Defect
  category: Cardiovascular
  description: An asymptomatic septal defect was reported in the molecularly confirmed BMKS proband of family 2 in the 2017 series; no disease-wide frequency is inferred.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:28905882
    reference_title: Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Cardiac defect | N | Asymptomatic ASD and VSD
    explanation: Documents this manifestation in the stated clinical context.
- name: Hypomimic Face
  category: Craniofacial
  description: Reduced facial expression was described in the two-brother report later molecularly linked to TXNL4A.
  phenotype_term:
    preferred_term: Hypomimic face
    term:
      id: HP:0000338
      label: Hypomimic face
  evidence:
  - reference: PMID:14564154
    reference_title: Two brothers with Burn-McKeown syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: including median cleft palate with oronasal fistula, preauricular tag, hypomimic face, and hypoplastic unilateral kidney
    explanation: Documents this manifestation in the stated clinical context.
genetic:
- name: TXNL4A
  gene_term:
    preferred_term: TXNL4A
    term:
      id: hgnc:30551
      label: TXNL4A
  association: Causal - biallelic loss-of-function and promoter-deletion variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: Positive
  notes: >-
    TXNL4A at 18q23 encodes a U5 snRNP component. The type 1 and type 2 promoter alleles delete 34 bp at GRCh37
    chr18:g.77748581_77748614del and chr18:g.77748604_77748637del, respectively. These are hypomorphic regulatory
    alleles; coding, splice and exon/whole-gene losses constitute distinct second-allele classes. The reported
    0.76% German control allele frequency is neither carrier frequency nor disease prevalence; control craniofacial
    phenotypes were unavailable. Promoter alleles occurred on different haplotypes, supporting recurrence rather
    than a single founder. Homozygous promoter deletions can produce milder choanal-atresia phenotypes, but
    no deterministic genotype-phenotype correlation is established. Promoter deletions can be missed by coding-only
    assays and by default genome-analysis filters.
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of a TXNL4A-related craniofacial disorder is established in a proband with suggestive findings and biallelic pathogenic variants in TXNL4A identified by molecular genetic testing. All probands described to date have had at least one copy of one of the two partially overlapping 34-bp deletions in the TXNL4A promoter."
    explanation: GeneReviews states the biallelic requirement and the near-universal presence of a 34-bp promoter deletion allele.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:25434003
    reference_title: "Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a rare loss-of-function mutation (nonsense, frameshift, or microdeletion) on one allele"
    explanation: Enumerates the second-allele variant classes, including microdeletion, which is why copy-number analysis is required in addition to promoter sequencing.
    quote_role: PRIMARY_RESULT
  - reference: PMID:25434003
    reference_title: "Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations were found in 9 of 11 affected families."
    explanation: Quantifies the diagnostic yield of TXNL4A testing in a clinically ascertained BMKS cohort.
    quote_role: PRIMARY_RESULT
  - reference: PMID:28905882
    reference_title: "Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hence, we identified causative recessive variants in TXNL4A in two individuals with BMKS as well as in three individuals (from two families) with isolated choanal atresia."
    explanation: Establishes the allelic spectrum in which the same gene causes both BMKS and isolated choanal atresia.
    quote_role: PRIMARY_RESULT
  - reference: PMID:34713892
    reference_title: "Expanding the genotypic spectrum of TXNL4A variants in Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients have a loss-of-function variant in trans with a 34-base pair (bp) deletion (type 1 Δ34) in the promoter region."
    explanation: Confirms the canonical compound-heterozygous architecture.
    quote_role: BACKGROUND
  - reference: PMID:34713892
    reference_title: "Expanding the genotypic spectrum of TXNL4A variants in Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Finally, our data emphasises the need to analyse the non-coding sequence in individuals where a single likely pathogenic coding variant is identified in an autosomal recessive disorder consistent with the clinical presentation."
    explanation: States the diagnostic implication that the promoter (non-coding) allele will be missed unless specifically sought.
    quote_role: PRIMARY_RESULT
diagnosis:
- name: Clinical and Multisystem Assessment
  description: Evaluate airway patency promptly in newborns, examine the craniofacial pattern and palate, assess the ocular surface and hearing, and obtain cardiology assessment including echocardiography. Normal intellect or a negative family history does not exclude BMKS.
  diagnosis_term:
    preferred_term: Physical Examination
    term:
      id: NCIT:C20989
      label: Physical Examination
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Airway assessment for evidence of upper-airway obstruction
    explanation: Initial evaluation explicitly prioritizes airway obstruction.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Evaluation ... Cardiology assessment ... Incl echocardiography
    explanation: Initial evaluation includes echocardiography.
- name: TXNL4A Promoter and Second-Allele Testing
  description: Confirm biallelic pathogenic or likely pathogenic TXNL4A variants in a clinically consistent individual. Test recurrent promoter deletions explicitly, then coding/splice variants and exon or whole-gene copy-number loss as appropriate. Panels and genome analyses must include the noncoding promoter; exome coverage and standard genome filters can miss it. A pair of VUS, or one pathogenic variant plus a VUS, does not establish or rule out the diagnosis.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Targeted assay to detect the type 1 and type 2 promoter deletions
    explanation: The targeted promoter assay is part of the chapter testing strategy.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: does not establish or rule out a diagnosis of this disorder.
    explanation: The surrounding diagnostic paragraph refers specifically to biallelic VUS or one pathogenic allele plus one VUS.
- name: Parental Phase and Copy-Number Assessment
  description: Test parents to confirm the alleles are in trans and refine recurrence risk. Evaluate apparent homozygosity for a hidden deletion or uniparental isodisomy where appropriate; chromosome 18 uniparental disomy was reported with a homozygous type 1 promoter deletion in isolated choanal atresia.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Molecular genetic testing is recommended for the parents of a proband
    explanation: Parental testing supports phase and recurrence-risk assessment.
  - reference: PMID:28905882
    reference_title: Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: had a uniparental disomy of chromosome 18p11.32q23, leading to homozygosity for the type 1Δ deletion.
    explanation: The reported UPD case had isolated choanal atresia, not the full BMKS phenotype.
differential_diagnoses:
- name: CHARGE Syndrome (CHD7)
  description: Choanal atresia, hearing and cardiac anomalies overlap. GeneReviews distinguishes CHD7-related CHARGE by its intraocular coloboma, genital anomalies and characteristic ear findings; the TXNL4A-associated coloboma described there involves the eyelid rather than intraocular structures. Clinical pattern and molecular testing guide distinction.
  disease_term:
    preferred_term: CHARGE syndrome
    term:
      id: MONDO:0008965
      label: CHARGE syndrome
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: CHARGE syndrome phenotype comprises clinical findings (intraocular coloboma, genital anomalies, ... specific ear anomalies) not seen in ... -related craniofacial disorders. ... The coloboma assoc w/ ... -related craniofacial disorders involves the eyelid only ... not intraocular structures.
    explanation: GeneReviews states the distinguishing intraocular, genital and ear features and the eyelid-only coloboma in TXNL4A-related disorders.
- name: Treacher Collins Syndrome
  description: The craniofacial phenotype overlaps, including micrognathia and ear or eyelid abnormalities. BMKS does not lack mandibular or maxillary hypoplasia. The overall pattern, extra-craniofacial features and biallelic TXNL4A testing distinguish it from TCOF1/POLR1-associated Treacher Collins syndrome.
  disease_term:
    preferred_term: Treacher-Collins syndrome
    term:
      id: MONDO:0002457
      label: Treacher-Collins syndrome
  evidence:
  - reference: PMID:32187816
    reference_title: Burn-McKeown syndrome with biallelic promoter type 2 deletion in TXNL4A in two siblings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: BMKS has overlapping clinical features with Treacher Collins syndrome.
    explanation: Describes clinical overlap or distinguishing features; molecular assessment resolves uncertain cases.
- name: Mandibulofacial Dysostosis with Microcephaly
  description: EFTUD2-related disease shares a U5 spliceosomal mechanism but more characteristically has microcephaly and moderate-to-severe developmental impairment. Normal intellect is common in BMKS but is not required.
  disease_term:
    preferred_term: mandibulofacial dysostosis-microcephaly syndrome
    term:
      id: MONDO:0012516
      label: mandibulofacial dysostosis-microcephaly syndrome
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: severe microcephaly ... moderate ID in MFDM
    explanation: Describes clinical overlap or distinguishing features; molecular assessment resolves uncertain cases.
- name: Nager Syndrome
  description: SF3B4-related acrofacial dysostosis overlaps craniofacially but typically adds preaxial upper-limb anomalies.
  disease_term:
    preferred_term: Nager acrofacial dysostosis
    term:
      id: MONDO:0007943
      label: Nager acrofacial dysostosis
  evidence:
  - reference: PMID:41081049
    reference_title: "Modeling craniofacial spliceosomopathies: a pathway toward deciphering disease mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: 'Nager syndrome (OMIM #154400) is a type of acrofacial dysostosis characterized by midface retrusion, micrognathia, absence of thumbs, and radial hypoplasia'
    explanation: Describes clinical overlap or distinguishing features; molecular assessment resolves uncertain cases.
- name: Cerebrocostomandibular Syndrome
  description: SNRPB-related disease features the combination of mandibular/oropharyngeal abnormalities and posterior rib gaps.
  disease_term:
    preferred_term: cerebrocostomandibular syndrome
    term:
      id: MONDO:0007301
      label: cerebrocostomandibular syndrome
  evidence:
  - reference: PMID:41081049
    reference_title: "Modeling craniofacial spliceosomopathies: a pathway toward deciphering disease mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: 'Mutations in SNRPB cause cerebro-costo-mandibular syndrome (CCMS; OMIM #117650), which is a disorder that includes micrognathia, glossoptosis, cleft palate, and posterior rib gaps'
    explanation: Describes clinical overlap or distinguishing features; molecular assessment resolves uncertain cases.
- name: Isolated TXNL4A-Related Choanal Atresia
  description: Homozygous promoter deletions can occur with isolated choanal atresia or minor anomalies. These are milder allelic presentations, not additional BMKS subtypes with established genotype-based boundaries.
  evidence:
  - reference: PMID:28905882
    reference_title: Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Homozygosity for the type 1Δ deletion was identified in a third individual with isolated choanal atresia.
    explanation: Defines an allelic phenotype outside the full BMKS syndrome.
treatments:
- name: Neonatal Airway Management and Choanal Atresia Repair
  description: >-
    Assess and stabilize neonatal airway obstruction; intubation may be required, with surgical correction
    of choanal atresia or stenosis according to anatomy and clinical need.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: SURGERY
  target_phenotypes:
  - preferred_term: Choanal atresia
    term:
      id: HP:0000453
      label: Choanal atresia
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Neonates with airway compromise at delivery may require intubation or surgical correction of choanal stenosis/atresia."
    explanation: GeneReviews states the acute airway management and definitive surgical treatment for the cardinal feature.
    quote_role: REVIEW_SYNTHESIS
  target_mechanisms:
  - target: Choanal Atresia
    treatment_effect: BYPASSES
    description: Airway stabilization and repair relieve the anatomical obstruction.
- name: Ophthalmological Care for Lower Eyelid Defects
  description: >-
    Lower eyelid defects can cause corneal exposure. Ophthalmological care is required to reduce the risk of
    corneal scarring, and monitoring by an ophthalmologist is part of recommended surveillance.
  treatment_term:
    preferred_term: Ophthalmological Care for Lower Eyelid Defects
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_phenotypes:
  - preferred_term: Lower eyelid coloboma
    term:
      id: HP:0000652
      label: Lower eyelid coloboma
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Defects of the lower eyelids that can result in corneal exposure require care by an ophthalmologist to reduce the risk of corneal scarring."
    explanation: GeneReviews specifies ophthalmological care for the eyelid defect and its rationale.
    quote_role: REVIEW_SYNTHESIS
  therapeutic_modality: OTHER
  target_mechanisms:
  - target: Lower Eyelid Coloboma
    treatment_effect: MODULATES
    description: Care protects the exposed ocular surface and reduces secondary corneal injury.
- name: Hearing Loss Management
  description: >-
    Treatment of hearing loss is individualised and may involve hearing aids, with audiological monitoring
    as part of surveillance.
  treatment_term:
    preferred_term: Hearing rehabilitation
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  therapeutic_modality: DEVICE
  target_phenotypes:
  - preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Treatment of hearing loss is individualized and may involve hearing aids."
    explanation: GeneReviews states the management approach for hearing loss.
    quote_role: REVIEW_SYNTHESIS
  target_mechanisms:
  - target: Hearing Loss
    treatment_effect: BYPASSES
    description: Hearing devices provide individualized auditory rehabilitation.
- name: Multidisciplinary Craniofacial Care
  description: >-
    Individualized craniofacial care can involve maxillofacial and plastic surgeons, ENT, dentistry and orthodontics,
    and speech-language therapy. Management follows the specific cleft, ear and facial findings and their functional
    effects.
  treatment_term:
    preferred_term: Multidisciplinary Craniofacial Care
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Treatment of craniofacial manifestations (e.g., cleft lip and/or palate, preauricular tags, prominent ears) is individualized and managed by a multidisciplinary team."
    explanation: GeneReviews defines multidisciplinary craniofacial management.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Monitoring by an ophthalmologist, audiologist, and craniofacial team is recommended."
    explanation: States the recommended surveillance regimen.
    quote_role: REVIEW_SYNTHESIS
  therapeutic_modality: OTHER
- name: Cardiac Management
  description: >-
    Cardiac defects are managed in a routine manner, without disorder-specific modification.
  treatment_term:
    preferred_term: Cardiac Management
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_phenotypes:
  - preferred_term: Structural cardiac abnormality
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cardiac defects are managed in a routine manner."
    explanation: GeneReviews states that cardiac management is standard rather than disorder-specific.
    quote_role: REVIEW_SYNTHESIS
  therapeutic_modality: OTHER
  target_mechanisms:
  - target: Structural Cardiac Abnormality
    treatment_effect: MODULATES
    description: Cardiology care addresses the specific structural lesion and its consequences.
- name: Genetic Counseling
  description: >-
    Discuss genotype-specific autosomal recessive recurrence, parental and family testing, reproductive options,
    and prenatal or preimplantation testing once the familial alleles are known. A 25% recurrence risk assumes
    both parents carry the relevant pathogenic alleles; UPD and other unusual configurations require individualized
    assessment.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Once the TXNL4A pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible."
    explanation: GeneReviews states the reproductive testing options that counselling addresses.
    quote_role: REVIEW_SYNTHESIS
- name: Ophthalmic, Hearing and Craniofacial Surveillance
  description: Monitor the cornea under ophthalmology guidance; assess hearing shortly after birth and thereafter as directed by audiology; arrange regular craniofacial-team review. Follow-up schedules are individualized rather than supported by BMKS-specific comparative trials.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Therapeutic Procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Monitoring by an ophthalmologist, audiologist, and craniofacial team is recommended.
    explanation: Expert surveillance recommendation.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Hearing assessment ... Shortly after birth  ...  then per audiologist
    explanation: Hearing surveillance timing from Table 6.
- name: Family Support
  description: Assess needs for family resources, social work and home nursing alongside specialist care.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Therapeutic Procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader
    reference_title: "TXNL4A-Related Craniofacial Disorders - GeneReviews&reg; - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Social work involvement for parental support
    explanation: Recommended support assessment after diagnosis.
animal_models:
- species: Xenopus laevis
  genotype: Txnl4a morpholino knockdown
  genes:
  - preferred_term: TXNL4A
    term:
      id: hgnc:30551
      label: TXNL4A
  associated_phenotypes:
  - Reduced neural crest marker expression
  - Cranial cartilage defects
  description: >-
    Unilateral translation-blocking morpholino injection at the two-cell stage reduces neural crest markers,
    increases dorsal ectodermal apoptosis at neurula stage 15, and produces cranial cartilage defects in 38%
    of stage-45 tadpoles. A resistant Txnl4a construct partly rescues sox10 expression. This transient knockdown
    does not reproduce the human promoter-plus-loss-of-function genotype and does not establish dominant inheritance
    or p53 dependence.
  evidence:
  - reference: PMID:35893124
    reference_title: "The Core Splicing Factors EFTUD2, SNRPB and TXNL4A Are Essential for Neural Crest and Craniofacial Development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Snrpb and Txnl4a knockdown produced cartilage defects at a lower frequency, in 29% and 38% of morphant tadpoles, respectively
    explanation: The Txnl4a cartilage-defect proportion is 38%; the 29% belongs to Snrpb.
  name: Xenopus Txnl4a morpholino model
  publication: PMID:35893124
  modeled_mechanisms:
  - target: Impaired Neural Crest Specification
    description: Knockdown reduces sox10 expression and resistant Txnl4a partly rescues it.
    evidence:
    - reference: PMID:35893124
      reference_title: "The Core Splicing Factors EFTUD2, SNRPB and TXNL4A Are Essential for Neural Crest and Craniofacial Development."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: a modified version of Xenopus Txnl4a restored this proportion from 14% to 62%
      explanation: Specificity rescue of the marker phenotype.
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
  - target: Increased Embryonic Ectodermal Apoptosis
    description: TUNEL-positive dorsal ectodermal cells increase; this contrasts with the patient-cell model.
    evidence:
    - reference: PMID:35893124
      reference_title: "The Core Splicing Factors EFTUD2, SNRPB and TXNL4A Are Essential for Neural Crest and Craniofacial Development."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: In all cases we observed a significant increase in the number of TUNEL-positive cells as a result of the three MOs’ injection
      explanation: Measured in the frog embryos.
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
experimental_models:
- name: BMKS patient-derived iPSC induced neural crest cells
  experimental_model_type: IPSC_DERIVED_MODEL
  cell_source: Blood mononuclear cells from one affected 11-year-old girl and her unaffected frameshift-carrier mother, with two unrelated male control donors
  culture_system: iPSC reprogramming followed by directed differentiation to induced neural crest cells (iNCCs)
  publication: PMID:32735620
  cell_types:
  - preferred_term: neural crest cell
    term:
      id: CL:0011012
      label: neural crest cell
  description: >-
    Two patient and two maternal iPSC clones plus two unrelated control lines were examined. The patient carried
    type 1 promoter deletion in trans with c.131delT; the mother carried only the frameshift. Comparisons are
    not isogenic and include sex and genetic-background differences. The patient had atypical severe intellectual
    disability. MTT showed reduced iPSC proliferation, but neither iPSCs nor induced neural crest cells had
    significantly increased apoptosis. RNA-seq and differentiation findings require replication in additional
    families.
  modeled_mechanisms:
  - target: Selective Pre-mRNA Mis-Splicing
    description: RNA-seq shows selective splicing abnormalities at pluripotent and neural crest stages.
    evidence:
    - reference: PMID:32735620
      reference_title: Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: rMATS identified 2991 differential splicing events in 2029 different genes
      explanation: Neural crest-stage result.
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
  - target: Delayed Neural Crest Epithelial-to-Mesenchymal Transition
    description: Transcript and isoform markers remain more epithelial after induction.
    evidence:
    - reference: PMID:32735620
      reference_title: Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The patient iNCCs had a score of -5, while the mother iNCCs had an EMT score of +5 and the unrelated controls had an EMT score of +8
      explanation: EMT state differs among these lines.
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
  - target: Dampened WNT Response
    description: AXIN2 response is reduced under GSK3-inhibiting induction.
    evidence:
    - reference: PMID:32735620
      reference_title: Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: AXIN2 expression was significantly lower (p = 0.0004) in patient iNCCs compared to pooled control iNCCs
      explanation: Measured response in the induction protocol.
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
  findings:
  - statement: >-
      BMKS patient iPSCs proliferate more slowly than maternal and unrelated control lines and show significant
      differences in gene expression and alternative splicing.
    supporting_text: "BMKS patient-derived iPSCs proliferated more slowly than both mother- and unrelated control-derived iPSCs, and RNA-Seq analysis revealed significant differences in gene expression and alternative splicing."
  - statement: >-
      Differentiation to induced neural crest cells is defective, with a delay in undergoing the epithelial-to-mesenchymal
      transition.
    supporting_text: "Patient iPSCs displayed defective differentiation into iNCCs compared to maternal and unrelated control iPSCs, in particular a delay in undergoing an epithelial-to-mesenchymal transition (EMT)."
  evidence:
  - reference: PMID:32735620
    reference_title: "Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here we reprogrammed peripheral mononuclear blood cells from a BMKS patient and her unaffected mother into induced pluripotent stem cells (iPSCs) and differentiated the iPSCs into induced neural crest cells (iNCCs), the key cell type required for correct craniofacial development."
    explanation: Describes the patient-derived cellular model and its maternal control, the principal experimental system for BMKS mechanism.
    quote_role: PRIMARY_RESULT
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
- name: Conditional yeast Dib1 depletion
  experimental_model_type: OTHER
  organism:
    preferred_term: Saccharomyces cerevisiae
    term:
      id: NCBITaxon:4932
      label: Saccharomyces cerevisiae
  publication: PMID:25434003
  description: A haploid yeast strain with DIB1 under GAL1 promoter control models reduced conserved spliceosomal protein supply. Whole-cell extracts were fractionated to assess snRNP assembly. This molecular culture model has no neural crest or craniofacial anatomy.
  modeled_mechanisms:
  - target: Reduced U4/U6.U5 Tri-snRNP Assembly
    description: Dib1 depletion reduces tri-snRNP assembly.
    evidence:
    - reference: PMID:25434003
      reference_title: Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Turning off DIB1 expression resulted in reduced assembly of the U4/U6⋅U5 tri-snRNP complex
      explanation: Conditional yeast-culture result.
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
- name: TXNL4A promoter reporter assays
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:25434003
  cell_source: HEK293 cells
  description: Wild-type and deletion-containing TXNL4A promoter constructs were compared by dual luciferase assay. Episomal reporter activity supports a regulatory effect but does not reproduce endogenous chromatin or neural crest differentiation.
  modeled_mechanisms:
  - target: Reduced TXNL4A Promoter Activity
    description: Type 1 and type 2 constructs show reduced activity.
    evidence:
    - reference: PMID:25434003
      reference_title: Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: promoter activity of constructs containing the type 1 Δ (del1) and type 2 Δ (del2) was reduced by 59% and 72%, respectively, compared to the wild-type construct.
      explanation: Reporter activity relative to wild type.
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
- name: TXNL4A splice-acceptor minigene assays
  experimental_model_type: OTHER
  publication: PMID:34713892
  description: Minigene assays for c.258-3C>G and c.258-2A>G demonstrate final-exon skipping. These assays define a splice consequence, not a promoter-expression mechanism or a direct measure of patient tissue splicing.
  modeled_mechanisms:
  - target: Reduced Functional TXNL4A Dosage
    description: Loss of normal terminal-exon inclusion provides functional support for the splice-site alleles.
    evidence:
    - reference: PMID:34713892
      reference_title: Expanding the genotypic spectrum of TXNL4A variants in Burn-McKeown syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: cause skipping of the final exon of TXNL4A in a minigene splicing assay.
      explanation: Functional splice assay.
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
- name: Mouse embryonic stem-cell Txnl4a knockdown
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Mus musculus
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:38426258
  description: Lentiviral shRNA depletion of Txnl4a in cultured mouse embryonic stem cells increases Mdm2 exon 3 skipping and p53 protein and reduces selected glycolytic transcripts and lactate. This is not a BMKS mouse or patient-neural-crest model. Direct p53-null rescue after Txnl4a knockdown was not reported; corresponding rescue experiments used other splicing perturbations.
  modeled_mechanisms:
  - target: MDM2 Exon 3 Skipping after Experimental Txnl4a Depletion
    description: An alternative Mdm2 transcript is increased after experimental depletion.
    evidence:
    - reference: PMID:38426258
      reference_title: A common cellular response to broad splicing perturbations is characterized by metabolic transcript downregulation driven by the Mdm2-p53 axis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: specific KD of any the above splicing factors also resulted in increased presence of the Exon 3-skipping Mdm2 transcript
      explanation: The tested factors include Txnl4a.
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
  - target: Reduced Glycolytic Gene Expression after Experimental Txnl4a Depletion
    description: Targeted assays found reduced glycolytic transcripts and lactate.
    evidence:
    - reference: PMID:38426258
      reference_title: A common cellular response to broad splicing perturbations is characterized by metabolic transcript downregulation driven by the Mdm2-p53 axis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: we measured lactate levels in mESCs expressing shRNAs targeting Txnl4a, Prpf8 or Sf3b4. We found that all these splicing factor KDs reduce lactate levels
      explanation: Measured cellular metabolic output, not a human disease biomarker.
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
discussions:
- discussion_id: bmks_spliceosome_tissue_specificity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why does reduced dosage of TXNL4A, a ubiquitously expressed core spliceosome protein, produce a malformation
    restricted to craniofacial structures rather than a generalised phenotype?
  attaches_to:
  - pathophysiology#Selective Pre-mRNA Mis-Splicing
  rationale: >-
    Selective splicing changes, a candidate TCF7L2/WNT route, and an experimental Mdm2-p53/metabolic route
    offer partial explanations for tissue specificity. Txnl4a-specific stress-response evidence now exists
    in mouse embryonic stem cells, but patient neural crest validation is lacking. Patient cells did not show
    increased apoptosis, unlike the frog knockdown model. Perturbation strength, cell state, genetic background
    and developmental stage may all affect the phenotype.
  proposed_experiments:
  - experiment_id: bmks_p53_axis_in_patient_incc
    name: Test the P53/MDM2-MDM4 stress axis in BMKS patient iNCCs
    description: >-
      Assay MDM2 and MDM4 regulatory-exon skipping, p53 stabilization and apoptosis in multiple BMKS patient-derived
      neural crest lines with isogenic and unaffected controls, and test whether controlled p53 perturbation
      changes differentiation and EMT. The unaffected mother is a carrier control, not an isogenic comparator.
    decision_criterion: >-
      Concordant molecular changes and rescue across multiple patient lines with isogenic controls would strengthen
      a causal role. Absent rescue would limit that intervention under the tested conditions, not by itself
      exclude all p53-dependent or independent contributions.
  - experiment_id: bmks_tcf7l2_rescue
    name: TCF7L2 isoform rescue in BMKS neural crest
    description: >-
      Express the correctly spliced TCF7L2 isoform in BMKS patient iNCCs and test whether WNT responsiveness,
      EMT timing and differentiation are restored.
    decision_criterion: >-
      Isoform-specific rescue with appropriate expression and timing controls would strengthen mediation of
      the WNT/EMT defect. Failure could reflect incomplete rescue, timing or parallel pathways and would not
      alone prove that TCF7L2 is only a marker.
  evidence:
  - reference: PMID:32735620
    reference_title: "Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, it is unclear how reduced expression of this ubiquitously expressed spliceosome protein results in craniofacial defects during development."
    explanation: States the knowledge gap explicitly for TXNL4A/BMKS.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:32315467
    reference_title: "Spliceosomopathies and neurocristopathies: Two sides of the same coin?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We speculate that mutations in a subset of core splicing factors lead to disrupted splicing in neural crest cells because these cells have increased sensitivity to inefficient splicing."
    explanation: The review explicitly proposes heightened neural crest sensitivity to splicing inefficiency. It does not establish a particular stress-response mechanism in BMKS patient neural crest cells.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:38426258
    reference_title: A common cellular response to broad splicing perturbations is characterized by metabolic transcript downregulation driven by the Mdm2-p53 axis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: specific KD of any the above splicing factors also resulted in increased presence of the Exon 3-skipping Mdm2 transcript
    explanation: Txnl4a-specific cell-culture evidence updates the earlier hypothesis; the patient neural crest question remains open.
- discussion_id: bmks-model-apoptosis-differences
  kind: INTERPRETATION
  status: OPEN
  prompt: Does increased apoptosis mediate all BMKS developmental defects?
  rationale: The Xenopus study found increased ectodermal TUNEL staining but incorrectly described the earlier patient-iPSC study as showing increased apoptosis. The original patient-cell data found no significant apoptosis difference in either iPSCs or induced neural crest cells. The frog paper also describes TXNL4A haploinsufficiency, which should not replace the established recessive human inheritance model.
  attaches_to:
  - pathophysiology#Increased Embryonic Ectodermal Apoptosis
  evidence:
  - reference: PMID:32735620
    reference_title: Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Annexin-V staining revealed no significant differences in apoptosis between the patient iNCCs and the mother and unrelated control iNCCs
    explanation: Primary human-cell result takes precedence over the later summary.
- discussion_id: bmks-atypical-finding-attribution
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Which uncommon findings belong to the TXNL4A phenotype?
  rationale: A reported infant with a dicentric X chromosome and homozygous TXNL4A promoter deletion had a blended diagnostic context. A separate autopsy case described an incidental hepatocellular adenoma in an infant with BMKS. These reports warrant careful phenotype attribution; they do not establish a recurrent cancer predisposition, justify tumor surveillance, or assign every additional finding to TXNL4A. Older TXNL4A-negative BMKS-like cases also should not define the molecularly confirmed phenotype.
  evidence:
  - reference: PMID:39695270
    reference_title: Ultra-rare monogenic disorders frequently detected among sex chromosome aneuploidy patients with atypical findings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Whole exome sequencing was pursued at 3 months of life, revealing homozygosity for likely pathogenic variants in TXNL4A, causing Burn-McKeown syndrome.
    explanation: The full case also has a variant Turner-syndrome karyotype.
  - reference: PMID:36262073
    reference_title: "Hepatocellular Adenoma in an Infant With Burn-McKeown Syndrome: Report of a Case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Here we present an autopsy case of a 9-month-old girl with Burn-McKeown syndrome with an incidental liver nodule in the right lobe measuring 1.5 cm in greatest dimension.
    explanation: One incidental hepatocellular adenoma is an association, not evidence of a syndrome-wide predisposition.

📚

References & Deep Research

References

14

PMID:32187816

Burn-McKeown syndrome with biallelic promoter type 2 deletion in TXNL4A in two siblings.

No top-level findings curated for this source.

PMID:27413799

TXNL4A-Related Craniofacial Disorders.

No top-level findings curated for this source.

PMID:25434003

Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome.

No top-level findings curated for this source.

PMID:34713892

Expanding the genotypic spectrum of TXNL4A variants in Burn-McKeown syndrome.

No top-level findings curated for this source.

PMID:32735620

Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells.

No top-level findings curated for this source.

PMID:35893124

The Core Splicing Factors EFTUD2, SNRPB and TXNL4A Are Essential for Neural Crest and Craniofacial Development.

No top-level findings curated for this source.

PMID:38426258

A common cellular response to broad splicing perturbations is characterized by metabolic transcript downregulation driven by the Mdm2-p53 axis.

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK373577/?report=reader

TXNL4A-Related Craniofacial Disorders - GeneReviews® - NCBI Bookshelf

No top-level findings curated for this source.

PMID:14564154

Two brothers with Burn-McKeown syndrome.

No top-level findings curated for this source.

PMID:28905882

Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia.

No top-level findings curated for this source.

PMID:41081049

Modeling craniofacial spliceosomopathies: a pathway toward deciphering disease mechanisms.

No top-level findings curated for this source.

PMID:32315467

Spliceosomopathies and neurocristopathies: Two sides of the same coin?

No top-level findings curated for this source.

PMID:39695270

Ultra-rare monogenic disorders frequently detected among sex chromosome aneuploidy patients with atypical findings.

No top-level findings curated for this source.

PMID:36262073

Hepatocellular Adenoma in an Infant With Burn-McKeown Syndrome: Report of a Case.

No top-level findings curated for this source.

Deep Research

1

Deep 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.

Evaluations and curation notes (1)

Create: Burn-McKeown_Syndrome · 2026-07-31T18:04:17Z · View source

Created the Burn-McKeown syndrome entry (choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome; MONDO:0012064; OMIM 608572; TXNL4A) for issue #7214. Deep research provider falcon/Edison. NEC preflight passed - MONDO:0012064 carries OMIM:608572 and the TXNL4A gene association, and the falcon report is anchored on TXNL4A/BMKS. Scope was actively policed away from the other craniofacial spliceosomopathies (EFTUD2 mandibulofacial dysostosis with microcephaly, SF3B4 Nager, SNRPB cerebrocostomandibular) and away from the unrelated TXNL4A hepatocellular-carcinoma biomarker literature. GeneReviews chapter PMID:27413799 fetched and tagged, with all four abstract sections mined. Curated 5 pathophysiology nodes, 17 phenotypes with HPO terms, structured prevalence, genetics emphasising the promoter-deletion architecture and its diagnostic consequence, 6 treatments, an experimental_models entry for the patient iPSC-derived neural crest system, one animal model and a KNOWLEDGE_GAP discussion on spliceosomopathy tissue specificity with two proposed experiments. Module conformance was declared against the first two nodes of pharyngeal_arch_patterning_serial_homology and deliberately declined at the third serially-homologous-bundle node, with the reasoning and its caveats documented in notes. Validation: just validate PASS, just validate-terms PASS, programmatic snippet check 66 of 66 exact whitespace-normalised substrings with 0 mismatches, 0 dangling refs and 0 orphan nodes.

Falcon ▸

Burn–McKeown Syndrome: Disease-Characteristics Research Report

Edison Scientific Literature 23 citations 2026-07-31T17:56:14.025744

Burn–McKeown Syndrome: Disease-Characteristics Research Report

Executive summary

Burn–McKeown syndrome (BMKS) is an exceptionally rare, congenital, autosomal-recessive craniofacial spliceosomopathy caused by biallelic variants that reduce TXNL4A function. Bilateral choanal atresia or stenosis is the defining manifestation; hearing loss, cleft lip/palate, lower-eyelid coloboma, short palpebral fissures, a prominent high-bridged nose, short philtrum, large ears, and occasional cardiac or other visceral anomalies form the broader phenotype. Fewer than 20 affected families had been reported by 2020, precluding reliable prevalence, survival, penetrance, or quality-of-life estimates. (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 1-2)

The usual molecular architecture is a hypomorphic 34-bp TXNL4A promoter deletion in trans with a rare loss-of-function allele. Reduced TXNL4A disrupts U4/U6.U5 tri-snRNP assembly and selectively changes pre-mRNA splicing. Patient-derived neural-crest models implicate diminished WNT signaling, abnormal TCF7L2 splicing, delayed epithelial-to-mesenchymal transition (EMT), and reduced proliferation; Xenopus knockdown additionally supports apoptosis-mediated depletion of cranial neural-crest progenitors. (wieczorek2014compoundheterozygosityof pages 7-8, wood2020modellingthedevelopmental pages 37-41, park2022thecoresplicing pages 7-10)

No disease-modifying treatment, validated biomarker, formal clinical guideline, or BMKS-specific interventional trial was identified. Current care is multidisciplinary and directed at airway obstruction, hearing impairment, clefting, cardiac defects, and other individual anomalies.

Table: This table condenses the main disease-level, genetic, mechanistic, diagnostic, and model-system findings for Burn-McKeown syndrome. It highlights established evidence and key quantitative details while preserving citations to the retrieved source contexts.

Evidence scope and currency

The principal human genetic evidence remains the 2014 American Journal of Human Genetics study of 11 families. The most detailed disease-specific mechanistic investigation is a May 2020 bioRxiv patient-iPSC study and should be treated as preprint evidence. The principal organismal BMKS model is a peer-reviewed 2022 Xenopus study. Searches prioritizing 2023–2024 identified no new BMKS-specific clinical cohort, natural-history study, therapeutic trial, or definitive molecular update; recent spliceosomopathy work remains largely contextual rather than BMKS-specific.

1. Disease information

Definition and classification

BMKS is a Mendelian congenital craniofacial developmental disorder, more specifically a U5-snRNP-related craniofacial spliceosomopathy or mandibulofacial dysostosis spectrum disorder. It was clinically recognized before its genetic cause was established; biallelic TXNL4A variants were demonstrated in 2014. (wieczorek2014compoundheterozygosityof pages 1-2)

Identifiers and synonyms

OMIM: 608572.
MONDO: A dedicated MONDO identifier was not verified in the retrieved primary literature; it should be resolved directly against the current MONDO release rather than inferred.
Orphanet: Not verified from the retrieved evidence.
ICD-10/ICD-11: No disease-specific code was identified. Coding generally requires congenital-malformation codes for choanal atresia and associated defects.
MeSH: No dedicated BMKS descriptor was verified.
Synonyms: Burn–McKeown syndrome; Burn-McKeown syndrome; BMKS; occasionally discussed in relation to oculo-oto-facial dysplasia, which may lie within the same phenotypic spectrum. (wieczorek2014compoundheterozygosityof pages 1-2)

The evidence is predominantly aggregated disease-level literature assembled from individually phenotyped families, not population EHR data. The 2014 study evaluated 11 families and found the relevant biallelic TXNL4A genotype in 9. (wieczorek2014compoundheterozygosityof pages 1-2, wieczorek2014compoundheterozygosityof pages 3-4)

Key abstract statement: the discovery report described BMKS as a rare autosomal-recessive condition “characterized by bilateral choanal atresia” with characteristic craniofacial anomalies and identified biallelic TXNL4A mutations. (wieczorek2014compoundheterozygosityof pages 1-2)

2. Etiology

Causal factor

The cause is genetic: insufficient TXNL4A dosage from biallelic germline variants. The common configuration combines a low-frequency promoter deletion with a severe coding or copy-number loss on the other chromosome. Heterozygous relatives can be unaffected, arguing against ordinary monoallelic haploinsufficiency. (wieczorek2014compoundheterozygosityof pages 4-6)

Genetic risk factors

TXNL4A 34-bp promoter deletion D1/type 1: chr18:g.77,748,581_77,748,614del in the reference used by the 2014 report.
D2/type 2: chr18:g.77,748,604_77,748,637del.
Reported loss-of-function examples include c.349G>T, p.(Glu117Ter); c.37C>T, p.(Gln13Ter); and c.131delT, p.(Val44AlafsTer48).
Larger terminal 18q deletions encompassing TXNL4A, ranging from approximately 0.484 to 4.7 Mb in the discovery series, can constitute one allele. (wieczorek2014compoundheterozygosityof pages 3-4, wieczorek2014compoundheterozygosityof pages 4-6)

The type-1 promoter deletion had an estimated allele frequency of 0.76% in the original study. Its predicted homozygous frequency was approximately 1 in 17,300, but homozygosity for that allele was not established as equivalent to classic BMKS; pathogenicity depends on allelic context and residual expression. (wieczorek2014compoundheterozygosityof pages 1-2, wieczorek2014compoundheterozygosityof pages 7-8)

Environmental, infectious, and lifestyle risk factors

No toxin, infection, diet, smoking, occupation, parental age, or lifestyle exposure has been demonstrated to cause or modify BMKS. It is not infectious or multifactorial on present evidence.

Protective factors and gene–environment interaction

No protective allele, environmental protective factor, modifier gene, or reproducible gene–environment interaction has been reported. Avoidance of ordinary environmental exposures cannot prevent the inherited developmental defect.

3. Phenotypes

All manifestations are congenital or developmentally determined. Exact percentages are unavailable for most findings because published cohorts are extremely small and ascertainment is non-uniform.

Phenotype	Type, onset, frequency/course	Functional impact	Suggested HPO term
Bilateral choanal atresia/stenosis	Structural sign; neonatal; reported as universal in the 2020 synthesis	Potential neonatal airway emergency; feeding and breathing impairment; surgical burden	Choanal atresia; Bilateral choanal atresia
Hearing loss	Sensorineural and/or conductive impairment; congenital/childhood; recurrent but not quantified	Speech-language, educational, and social effects; severe cases may need implantation	Hearing impairment; Sensorineural hearing impairment; Conductive hearing impairment
Cleft lip/palate, bifid uvula	Congenital structural signs; variable	Feeding, speech, dental, and middle-ear morbidity	Cleft palate; Cleft lip; Bifid uvula
Short palpebral fissures	Congenital dysmorphism; characteristic	Primarily morphological	Short palpebral fissure
Lower-eyelid coloboma	Congenital ocular/adnexal sign; variable	Exposure and ocular-surface risk depending on severity	Coloboma of eyelid
Prominent nose/high nasal bridge	Congenital facial morphology; characteristic	Primarily morphological	Prominent nose; High nasal bridge
Short philtrum, thin lips, small mouth/chin or micrognathia	Congenital; variable	Feeding, dental, airway, and speech consequences can occur	Short philtrum; Thin upper lip vermilion; Microstomia; Micrognathia
Large/protruding ears, preauricular tags	Congenital; variable	Cosmetic and audiological relevance	Large ears; Protruding ear; Preauricular skin tag
Congenital heart defects	Variable: patent foramen ovale, persistent ductus arteriosus and other defects reported	Depends on anatomy and hemodynamic significance	Congenital heart defect; Patent ductus arteriosus
Renal agenesis	Rare reported associated anomaly	Reduced renal reserve when unilateral; severe if bilateral	Renal agenesis
Imperforate anus	Rare congenital anomaly	Neonatal obstruction requiring surgery	Anal atresia
Clinodactyly/hallux valgus	Variable skeletal signs	Usually mild functional effect	Clinodactyly of the fifth finger; Hallux valgus
Short stature	Variable	Growth and psychosocial effects	Short stature
Intellectual disability	Usually absent; one severe case highlighted	Potential major lifelong support need in the exceptional case	Intellectual disability

The clinical series also reported hypertelorism and inguinal hernia. Intellectual development is generally normal, so severe intellectual disability should prompt assessment for a larger deletion, blended diagnosis, complications, or expanded phenotype. (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 3-4, wieczorek2014compoundheterozygosityof pages 2-3)

No BMKS-specific EQ-5D, SF-36, PROMIS, caregiver-burden, or disease-specific quality-of-life data were found. Quality-of-life effects above are clinically plausible consequences of the lesions, not measured BMKS outcomes.

4. Genetic and molecular information

Causal gene

TXNL4A at 18q23, also called DIB1, encodes an essential U5 small nuclear ribonucleoprotein component. A current HGNC identifier and transcript accession should be imported directly from HGNC/NCBI for production annotation because reference-transcript differences affect variant nomenclature.

Variant classes and interpretation

Established disease alleles include promoter deletions, nonsense and frameshift variants, splice-disrupting variants, intragenic/terminal copy-number deletions, and possibly other severe loss-of-function alleles. They are constitutional germline variants, not somatic mutations. The original severe coding variants were absent from 1000 Genomes, dbSNP, and approximately 3,000 control exomes available at the time. (wieczorek2014compoundheterozygosityof pages 4-6)

D1 and D2 reduced promoter activity by 59% and 72%, respectively. Classic BMKS therefore appears to require residual expression: a hypomorphic regulatory allele paired with a null allele, or an appropriate biallelic hypomorphic configuration. Complete biallelic null loss is considered likely incompatible with life because DIB1 is essential in experimental organisms. (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 7-8)

Variant classifications should nevertheless be checked in current ClinVar and assessed using ACMG/AMP rules, including noncoding-variant guidance. A common promoter allele should not be called pathogenic in isolation; phase, second-allele severity, phenotype, segregation, and functional evidence are essential.

Modifiers, epigenetics, and chromosomal abnormalities

No validated modifier gene or BMKS-specific DNA-methylation/chromatin signature is known. Large 18q deletions may broaden the phenotype through contiguous-gene effects. No recurrent aneuploidy, balanced translocation, or inversion defines BMKS. (wieczorek2014compoundheterozygosityof pages 3-4, wieczorek2014compoundheterozygosityof pages 4-6)

5. Environmental information

No environmental toxin, radiation exposure, pollutant, occupational factor, diet, alcohol, smoking behavior, or infectious agent is causally associated with BMKS. Environmental influences may affect general pregnancy or postoperative outcomes but are not established components of disease etiology. CTD-style chemical–disease assertions should therefore not be populated as causal without separate evidence.

6. Mechanism and pathophysiology

Causal chain

Upstream genetic defect: biallelic TXNL4A alleles lower functional protein dosage.
Spliceosomal defect: insufficient TXNL4A/DIB1 compromises U5-snRNP and U4/U6.U5 tri-snRNP assembly and control of spliceosome activation.
Selective RNA-processing vulnerability: transcripts with particular exon/intron architecture and weaker splice sites are disproportionately mis-spliced rather than all transcripts failing uniformly.
Developmental signaling disturbance: neural-crest-relevant expression programs, cell adhesion, WNT/β-catenin signaling, and EMT become abnormal.
Cellular phenotype: reduced proliferation, delayed/failed neural-crest differentiation and EMT, and—in Xenopus—excess dorsal-ectoderm/neural-crest apoptosis deplete or impair cranial neural-crest progenitors.
Tissue phenotype: deficient formation of neural-crest-derived craniofacial cartilage, bone, and nasal/choanal structures produces choanal atresia and facial dysostosis. (wieczorek2014compoundheterozygosityof pages 7-8, wood2020modellingthedevelopmental pages 37-41, park2022thecoresplicing pages 1-2)

Human iPSC/iNCC evidence

Patient iPSCs proliferated 52% more slowly than maternal cells and 65% more slowly than unrelated controls, without increased apoptosis. RNA sequencing identified 1,181 differentially expressed genes and 1,511 alternative-splicing events in 1,096 genes; 1,154 were exon-skipping events. (wood2020modellingthedevelopmental pages 24-27, wood2020modellingthedevelopmental pages 21-24)

After neural-crest differentiation, there were 5,746 differentially expressed genes and 2,991 differential-splicing events in 2,029 genes; 88% of affected splicing events were iNCC-specific. Patient cells retained epithelial markers and had reduced mesenchymal/neural-crest markers, with an EMT score of −5 versus +5 in maternal and +8 in unrelated-control cells. Extending differentiation to 168 hours did not rescue the defect. (wood2020modellingthedevelopmental pages 34-37, wood2020modellingthedevelopmental pages 27-31, wood2020modellingthedevelopmental pages 69-74)

AXIN2 was downregulated (p=0.0004), supporting reduced WNT activation. Abnormal inclusion of TCF7L2 exon 4, which is associated with a dampened WNT response, was proposed as one mechanistic link. This is a leading model, not yet proof that TCF7L2 alone causes the human phenotype. (wood2020modellingthedevelopmental pages 34-37, wood2020modellingthedevelopmental pages 27-31)

Exact abstract excerpt from the 2020 preprint: “Patient iPSCs displayed defective differentiation into iNCCs … in particular a delay in undergoing an epithelial-to-mesenchymal transition (EMT).” The abstract further reports “a dampened response to WNT signalling” and identifies TCF7L2 exon-4 mis-splicing as a potential cause. (wood2020modellingthedevelopmental pages 1-5, wood2020modellingthedevelopmental pages 37-41)

Model-organism evidence

In Xenopus, 30-ng Txnl4a morpholino knockdown reduced sox10 in 85.7% and tfap2e in 32.4% of embryos; morpholino-resistant txnl4a increased normal sox10 expression from 14% to 62%, supporting specificity. TUNEL-positive apoptosis increased in dorsal ectoderm at stage 15 (n=41, p<0.0005), and 38% of stage-45 morphants showed craniofacial cartilage defects (p<0.0001). (park2022thecoresplicing pages 7-10, park2022thecoresplicing pages 4-7)

Ontology suggestions

GO biological process: mRNA splicing via spliceosome; spliceosomal complex assembly; neural crest cell development; epithelial-to-mesenchymal transition; canonical WNT signaling; regulation of apoptotic process; craniofacial morphogenesis; cartilage development.
GO cellular component: spliceosomal complex; U5 snRNP; U4/U6.U5 tri-snRNP; nucleus/nucleoplasm.
Cell Ontology: neural crest cell; cranial neural crest cell; craniofacial chondrocyte; osteoblast progenitor; craniofacial mesenchymal cell. Exact CL identifiers should be ontology-validated before ingestion.

No BMKS-specific proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, epigenomic, organoid, or in-vivo CRISPR-screen dataset was identified. The iPSC experiment is bulk transcriptomic evidence from one family, a major limitation. (wood2020modellingthedevelopmental pages 37-41, wood2020modellingthedevelopmental pages 45-49)

7. Anatomical structures affected

Primary structures

Posterior nasal apertures/choanae and nasal airway.
Craniofacial skeleton and neural-crest-derived cartilage.
Palate and lip.
Eyelids and periocular region.
External/middle/inner auditory system, depending on the basis of hearing loss.

Secondary or variable structures

Heart and great-vessel derivatives, kidney, anus/rectum, digits, feet, and inguinal region can be involved. (wieczorek2014compoundheterozygosityof pages 3-4, wieczorek2014compoundheterozygosityof pages 2-3)

Suggested anatomy terms: choana; nasal cavity; nasopharynx; palate; mandible; eyelid; external ear; middle ear; inner ear; craniofacial skeleton; heart; kidney; anus. Exact UBERON identifiers should be resolved against the active release. Bilateral involvement is characteristic for choanal atresia; other anomalies may be unilateral, bilateral, or asymmetric.

At the subcellular level, the primary compartment is the nuclear spliceosome, especially the U5 and U4/U6.U5 snRNP assemblies.

8. Temporal development

BMKS begins during embryogenesis and is clinically evident at birth. Bilateral choanal atresia can present acutely with neonatal respiratory compromise, whereas hearing, speech, dental, growth, and educational consequences become clearer through childhood.

The underlying malformations are stable congenital lesions rather than relapsing or degenerative disease. Functional morbidity may evolve with growth or after reconstructive procedures. There are no validated disease stages, progression rate, remission pattern, or longitudinal natural-history model. Critical developmental vulnerability probably coincides with cranial neural-crest specification, EMT, migration, and craniofacial morphogenesis; clinically, birth is the critical airway-intervention window. (wood2020modellingthedevelopmental pages 1-5, park2022thecoresplicing pages 7-10)

9. Inheritance and population

Inheritance: autosomal recessive.
Recurrence risk: when both parents carry relevant alleles, each pregnancy conventionally has a 25% probability of an affected child, 50% of a carrier, and 25% of inheriting neither familial allele, subject to confirmation of phase and variant pathogenicity.
Penetrance: apparently high for appropriately damaging biallelic genotypes, but not numerically estimable.
Expressivity: variable for clefting, hearing loss, heart/renal/anal defects, growth, and neurodevelopment.
Anticipation: not expected and not reported.
Germline mosaicism: not established.
Consanguinity: can facilitate homozygosity; one consanguineous family was homozygous for the D2 promoter deletion. (wieczorek2014compoundheterozygosityof pages 1-2)
Founder effect: no confirmed founder population was identified.
Carrier frequency: cannot be equated with the 0.76% D1 allele frequency because multiple alleles and genotype-dependent pathogenicity are involved.

Fewer than 20 families were reported worldwide by 2020. No defensible cases-per-100,000 prevalence, annual incidence, geographic concentration, ethnic enrichment, age distribution, or sex ratio is available. (wood2020modellingthedevelopmental pages 1-5)

10. Diagnostics

Clinical recognition and immediate evaluation

Suspect BMKS in a neonate or child with bilateral choanal atresia/stenosis plus the characteristic oculo-oto-facial pattern, clefting, hearing loss, or congenital heart disease. Immediate priorities are airway patency, feeding, and cardiorespiratory stability.

A reasonable phenotype-directed work-up includes nasal endoscopy and thin-section CT for choanal anatomy; formal audiology; ophthalmologic assessment; cleft/craniofacial examination; echocardiography; renal ultrasonography; assessment for anal patency, feeding, growth, development, and speech. These are anomaly-directed clinical practices; no BMKS-specific consensus protocol was found.

Molecular testing

Preferred: a craniofacial/choanal-atresia panel or genome analysis that includes TXNL4A coding exons, splice regions, the recurrent promoter interval, and copy-number analysis.
WES: can identify coding loss-of-function alleles but may miss the 34-bp promoter deletion and some CNVs.
WGS: potentially best single assay because it can interrogate coding, promoter, and structural alleles, provided the pipeline calls and interprets the repetitive promoter region reliably.
Targeted testing: PCR/fragment analysis or Sanger sequencing for D1/D2 plus sequencing of coding/splice regions in a strongly suggestive case.
CMA/MLPA: useful when a deletion encompassing TXNL4A is suspected; the discovery study used microarray and MLPA.
Karyotype, FISH, mtDNA, and repeat-expansion testing have no routine disease-specific role unless another diagnosis is suspected. (wieczorek2014compoundheterozygosityof pages 3-4, wieczorek2014compoundheterozygosityof pages 4-6)

Confirm trans configuration through parental testing. RNA analysis or promoter functional studies may help resolve unusual splice/regulatory VUS but are not validated routine biomarkers.

Differential diagnosis

Important alternatives include CHARGE syndrome/CHD7 disorder; Treacher Collins syndrome (TCOF1, POLR1D, POLR1C); mandibulofacial dysostosis with microcephaly (EFTUD2); Nager syndrome (SF3B4); cerebro-costo-mandibular syndrome (SNRPB); Miller syndrome (DHODH); craniofacial microsomia; isolated choanal atresia; and 18q deletion syndromes. BMKS is favored by bilateral choanal atresia together with short palpebral fissures, lower-eyelid coloboma, prominent high-bridged nose, short philtrum, large ears, hearing loss, clefting, usually normal intellect, and biallelic TXNL4A variants. Oculo-oto-facial dysplasia may overlap the same spectrum. (wieczorek2014compoundheterozygosityof pages 2-3, wieczorek2014compoundheterozygosityof pages 1-2)

No biochemical, histopathologic, electrophysiologic, circulating, proteomic, metabolomic, or liquid-biopsy marker is established. There are no standardized diagnostic criteria beyond phenotype plus molecular confirmation.

11. Outcome and prognosis

No 5- or 10-year survival estimate, life expectancy, disease-specific mortality rate, disability score, or validated prognostic biomarker exists. The main immediate risk is neonatal airway obstruction from bilateral choanal atresia. Longer-term morbidity is expected to reflect restenosis or repeated airway procedures, hearing and speech impairment, cleft-related feeding/dental problems, and the severity of cardiac, renal, or anorectal anomalies.

Normal intellectual development is typical, but rare severe disability has been reported. Recovery means correction or adaptation to individual malformations; the constitutional molecular defect is lifelong. Prognosis is therefore anatomy-dependent rather than governed by a validated TXNL4A genotype score. (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 2-3)

12. Treatment

There is no approved TXNL4A-directed therapy, pharmacotherapy, gene therapy, RNA therapy, cell therapy, or splice-correcting treatment.

Current clinical management

Bilateral choanal atresia: emergency airway stabilization followed by definitive otolaryngologic repair, generally using an endoscopic transnasal approach according to anatomy and local expertise; monitor for restenosis.
Hearing loss: serial audiology, hearing aids or bone-conduction devices as appropriate, and cochlear-implant assessment for severe sensorineural loss. Cochlear implantation was contemplated in reported BMKS care. (wieczorek2014compoundheterozygosityof pages 2-3)
Cleft lip/palate: multidisciplinary craniofacial repair, feeding support, dental/orthodontic care, and speech-language therapy.
Eyelid coloboma: ocular-surface protection and ophthalmic reconstruction when indicated.
Cardiac, renal, anorectal, and hernia anomalies: standard specialty-specific surveillance and surgery.
Development: early-intervention, educational, occupational, and speech support based on individual assessment.

Suggested NCIT intervention concepts include surgical procedure, reconstructive surgery, airway management, hearing aid, cochlear implantation, speech therapy, genetic counseling, and supportive care; exact NCIT codes should be terminology-validated.

No treatment-response rate, comparative surgical outcome, pharmacogenomic recommendation, or BMKS-specific adverse-event profile was found. The ClinicalTrials.gov search identified no relevant BMKS interventional study or NCT identifier.

The WNT/TCF7L2 and apoptosis findings are mechanistic research leads, not justification for prenatal or postnatal WNT- or apoptosis-targeted therapy. (wood2020modellingthedevelopmental pages 34-37, park2022thecoresplicing pages 7-10)

13. Prevention

Primary lifestyle or vaccine prevention is not applicable. Evidence-based prevention is reproductive and complication-focused:

Offer genetic counseling and parental testing after molecular confirmation.
Provide cascade testing to at-risk adult relatives for the known familial alleles.
For a known familial genotype, discuss prenatal diagnosis by chorionic-villus sampling or amniocentesis and preimplantation genetic testing for monogenic disease.
Ensure assays test both the promoter deletion and the family’s second allele.
Targeted fetal imaging may detect clefting or major associated anomalies but cannot exclude BMKS or reliably establish choanal patency.
Tertiary prevention consists of early airway treatment, newborn/serial hearing assessment, feeding support, cardiac and renal evaluation, and timely craniofacial intervention.

BMKS is not part of standard biochemical newborn screening, and population carrier screening is not established.

14. Other species and natural disease

No naturally occurring veterinary syndrome definitively homologous to human BMKS was identified, and there is no zoonotic or cross-species transmission. TXNL4A/DIB1 function is evolutionarily conserved. Experimental ortholog evidence exists in:

Saccharomyces cerevisiae DIB1: depletion reduces U4/U6.U5 tri-snRNP assembly.
Caenorhabditis elegans: null ortholog loss is reported as lethal in the disease-model literature.
Xenopus laevis: experimentally reduced txnl4a produces neural-crest and craniofacial defects. (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 7-8, park2022thecoresplicing pages 2-4)

These are induced models, not natural animal disease. Exact NCBI Taxonomy and ortholog Gene IDs should be imported from NCBI/Alliance rather than inferred here.

15. Model organisms and experimental systems

Yeast

Conditional DIB1 depletion models the upstream spliceosome defect and demonstrated impaired tri-snRNP assembly. It is powerful for molecular spliceosome biology but cannot model vertebrate neural crest or facial anatomy. (wieczorek2014compoundheterozygosityof pages 7-8)

Patient-derived iPSCs and induced neural-crest cells

Peripheral blood cells from one affected individual and her unaffected carrier mother were reprogrammed and compared with unrelated controls. This system recapitulated reduced proliferation, extensive mis-splicing, diminished WNT response, and delayed EMT during neural-crest differentiation. Its strengths are human genetic context and disease-relevant cell lineage; limitations include one family, a patient with atypical severe intellectual disability, non-isogenic controls, bulk RNA sequencing, and preprint publication status. (wood2020modellingthedevelopmental pages 37-41, wood2020modellingthedevelopmental pages 1-5, wood2020modellingthedevelopmental pages 45-49)

Xenopus

Morpholino knockdown at the two-cell stage reduced neural-crest markers, increased apoptosis, and produced craniofacial-cartilage defects; partial rescue with morpholino-resistant txnl4a supports on-target action. Limitations include transient knockdown, incomplete phenotype penetrance, dosage sensitivity, and absence of the precise human promoter/compound-heterozygous architecture. (park2022thecoresplicing pages 7-10, park2022thecoresplicing pages 2-4)

No published BMKS-specific knock-in mouse, zebrafish germline mutant, patient organoid, or isogenic CRISPR-corrected iPSC model was identified in the retrieved literature. The highest-value next steps are isogenic correction/introduction of D1 and D2 alleles, multiple-patient iPSC cohorts, single-cell time courses of cranial neural-crest differentiation, direct spliceosome-complex proteomics, and animal knock-in models reproducing human residual TXNL4A dosage.

Key publications

Wieczorek et al. “Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome.” American Journal of Human Genetics 95:698–707. Published December 2014. DOI/URL: https://doi.org/10.1016/j.ajhg.2014.10.014. This is the landmark human genetic and functional study. (wieczorek2014compoundheterozygosityof pages 1-2, wieczorek2014compoundheterozygosityof pages 4-6)
Wood et al. “Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells.” bioRxiv preprint, posted May 14, 2020. DOI/URL: https://doi.org/10.1101/2020.05.13.094029. This is the principal patient-derived transcriptomic/mechanistic study but was retrieved as a preprint. (wood2020modellingthedevelopmental pages 1-5, wood2020modellingthedevelopmental pages 37-41)
Park et al. “The Core Splicing Factors EFTUD2, SNRPB and TXNL4A Are Essential for Neural Crest and Craniofacial Development.” Journal of Developmental Biology 10:29. Published July 2022. DOI/URL: https://doi.org/10.3390/jdb10030029. This provides the principal TXNL4A Xenopus knockdown/rescue evidence. (park2022thecoresplicing pages 7-10, park2022thecoresplicing pages 1-2)

PMIDs were not consistently exposed by the retrieved full-text records and have therefore not been guessed. For database ingestion, they should be resolved through PubMed using the exact titles/DOIs above.

Overall evidence assessment

The causal association between biallelic TXNL4A insufficiency and BMKS is strong, based on segregation across multiple human families plus promoter assays and conserved functional evidence. The detailed WNT/TCF7L2–EMT mechanism is biologically coherent but rests principally on one-family, preprint iPSC data and should be represented as supported/provisional, not definitive. Xenopus data independently support neural-crest progenitor loss and craniofacial consequences. Clinical epidemiology, longitudinal outcome, quality of life, genotype–phenotype prediction, standardized management, and disease-modifying treatment remain major evidence gaps.

References

(wood2020modellingthedevelopmental pages 1-5): Katherine A. Wood, Charlie F. Rowlands, Huw B. Thomas, Steven Woods, Julieta O’Flaherty, Sofia Douzgou, Susan J. Kimber, William G. Newman, and Raymond T. O’Keefe. Modelling the developmental spliceosomal craniofacial disorder burn-mckeown syndrome using induced pluripotent stem cells. BioRxiv, May 2020. URL: https://doi.org/10.1101/2020.05.13.094029, doi:10.1101/2020.05.13.094029. This article has 30 citations.
(wieczorek2014compoundheterozygosityof pages 1-2): Dagmar Wieczorek, William G. Newman, Thomas Wieland, Tea Berulava, Maria Kaffe, Daniela Falkenstein, Christian Beetz, Elisabeth Graf, Thomas Schwarzmayr, Sofia Douzgou, Jill Clayton-Smith, Sarah B. Daly, Simon G. Williams, Sanjeev S. Bhaskar, Jill E. Urquhart, Beverley Anderson, James O’Sullivan, Odile Boute, Jasmin Gundlach, Johanna Christina Czeschik, Anthonie J. van Essen, Filiz Hazan, Sarah Park, Anne Hing, Alma Kuechler, Dietmar R. Lohmann, Kerstin U. Ludwig, Elisabeth Mangold, Laura Steenpaß, Michael Zeschnigk, Johannes R. Lemke, Charles Marques Lourenco, Ute Hehr, Eva-Christina Prott, Melanie Waldenberger, Anne C. Böhmer, Bernhard Horsthemke, Raymond T. O’Keefe, Thomas Meitinger, John Burn, Hermann-Josef Lüdecke, and Tim M. Strom. Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in txnl4a causes burn-mckeown syndrome. American journal of human genetics, 95 6:698-707, Dec 2014. URL: https://doi.org/10.1016/j.ajhg.2014.10.014, doi:10.1016/j.ajhg.2014.10.014. This article has 78 citations and is from a highest quality peer-reviewed journal.
(wieczorek2014compoundheterozygosityof pages 7-8): Dagmar Wieczorek, William G. Newman, Thomas Wieland, Tea Berulava, Maria Kaffe, Daniela Falkenstein, Christian Beetz, Elisabeth Graf, Thomas Schwarzmayr, Sofia Douzgou, Jill Clayton-Smith, Sarah B. Daly, Simon G. Williams, Sanjeev S. Bhaskar, Jill E. Urquhart, Beverley Anderson, James O’Sullivan, Odile Boute, Jasmin Gundlach, Johanna Christina Czeschik, Anthonie J. van Essen, Filiz Hazan, Sarah Park, Anne Hing, Alma Kuechler, Dietmar R. Lohmann, Kerstin U. Ludwig, Elisabeth Mangold, Laura Steenpaß, Michael Zeschnigk, Johannes R. Lemke, Charles Marques Lourenco, Ute Hehr, Eva-Christina Prott, Melanie Waldenberger, Anne C. Böhmer, Bernhard Horsthemke, Raymond T. O’Keefe, Thomas Meitinger, John Burn, Hermann-Josef Lüdecke, and Tim M. Strom. Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in txnl4a causes burn-mckeown syndrome. American journal of human genetics, 95 6:698-707, Dec 2014. URL: https://doi.org/10.1016/j.ajhg.2014.10.014, doi:10.1016/j.ajhg.2014.10.014. This article has 78 citations and is from a highest quality peer-reviewed journal.
(wood2020modellingthedevelopmental pages 37-41): Katherine A. Wood, Charlie F. Rowlands, Huw B. Thomas, Steven Woods, Julieta O’Flaherty, Sofia Douzgou, Susan J. Kimber, William G. Newman, and Raymond T. O’Keefe. Modelling the developmental spliceosomal craniofacial disorder burn-mckeown syndrome using induced pluripotent stem cells. BioRxiv, May 2020. URL: https://doi.org/10.1101/2020.05.13.094029, doi:10.1101/2020.05.13.094029. This article has 30 citations.
(park2022thecoresplicing pages 7-10): Byung-Yong Park, Melanie Tachi-Duprat, Chibuike Ihewulezi, Arun Devotta, and Jean-Pierre Saint-Jeannet. The core splicing factors eftud2, snrpb and txnl4a are essential for neural crest and craniofacial development. Journal of Developmental Biology, 10:29, Jul 2022. URL: https://doi.org/10.3390/jdb10030029, doi:10.3390/jdb10030029. This article has 27 citations.
(wieczorek2014compoundheterozygosityof pages 4-6): Dagmar Wieczorek, William G. Newman, Thomas Wieland, Tea Berulava, Maria Kaffe, Daniela Falkenstein, Christian Beetz, Elisabeth Graf, Thomas Schwarzmayr, Sofia Douzgou, Jill Clayton-Smith, Sarah B. Daly, Simon G. Williams, Sanjeev S. Bhaskar, Jill E. Urquhart, Beverley Anderson, James O’Sullivan, Odile Boute, Jasmin Gundlach, Johanna Christina Czeschik, Anthonie J. van Essen, Filiz Hazan, Sarah Park, Anne Hing, Alma Kuechler, Dietmar R. Lohmann, Kerstin U. Ludwig, Elisabeth Mangold, Laura Steenpaß, Michael Zeschnigk, Johannes R. Lemke, Charles Marques Lourenco, Ute Hehr, Eva-Christina Prott, Melanie Waldenberger, Anne C. Böhmer, Bernhard Horsthemke, Raymond T. O’Keefe, Thomas Meitinger, John Burn, Hermann-Josef Lüdecke, and Tim M. Strom. Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in txnl4a causes burn-mckeown syndrome. American journal of human genetics, 95 6:698-707, Dec 2014. URL: https://doi.org/10.1016/j.ajhg.2014.10.014, doi:10.1016/j.ajhg.2014.10.014. This article has 78 citations and is from a highest quality peer-reviewed journal.
(wieczorek2014compoundheterozygosityof pages 3-4): Dagmar Wieczorek, William G. Newman, Thomas Wieland, Tea Berulava, Maria Kaffe, Daniela Falkenstein, Christian Beetz, Elisabeth Graf, Thomas Schwarzmayr, Sofia Douzgou, Jill Clayton-Smith, Sarah B. Daly, Simon G. Williams, Sanjeev S. Bhaskar, Jill E. Urquhart, Beverley Anderson, James O’Sullivan, Odile Boute, Jasmin Gundlach, Johanna Christina Czeschik, Anthonie J. van Essen, Filiz Hazan, Sarah Park, Anne Hing, Alma Kuechler, Dietmar R. Lohmann, Kerstin U. Ludwig, Elisabeth Mangold, Laura Steenpaß, Michael Zeschnigk, Johannes R. Lemke, Charles Marques Lourenco, Ute Hehr, Eva-Christina Prott, Melanie Waldenberger, Anne C. Böhmer, Bernhard Horsthemke, Raymond T. O’Keefe, Thomas Meitinger, John Burn, Hermann-Josef Lüdecke, and Tim M. Strom. Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in txnl4a causes burn-mckeown syndrome. American journal of human genetics, 95 6:698-707, Dec 2014. URL: https://doi.org/10.1016/j.ajhg.2014.10.014, doi:10.1016/j.ajhg.2014.10.014. This article has 78 citations and is from a highest quality peer-reviewed journal.
(wieczorek2014compoundheterozygosityof pages 2-3): Dagmar Wieczorek, William G. Newman, Thomas Wieland, Tea Berulava, Maria Kaffe, Daniela Falkenstein, Christian Beetz, Elisabeth Graf, Thomas Schwarzmayr, Sofia Douzgou, Jill Clayton-Smith, Sarah B. Daly, Simon G. Williams, Sanjeev S. Bhaskar, Jill E. Urquhart, Beverley Anderson, James O’Sullivan, Odile Boute, Jasmin Gundlach, Johanna Christina Czeschik, Anthonie J. van Essen, Filiz Hazan, Sarah Park, Anne Hing, Alma Kuechler, Dietmar R. Lohmann, Kerstin U. Ludwig, Elisabeth Mangold, Laura Steenpaß, Michael Zeschnigk, Johannes R. Lemke, Charles Marques Lourenco, Ute Hehr, Eva-Christina Prott, Melanie Waldenberger, Anne C. Böhmer, Bernhard Horsthemke, Raymond T. O’Keefe, Thomas Meitinger, John Burn, Hermann-Josef Lüdecke, and Tim M. Strom. Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in txnl4a causes burn-mckeown syndrome. American journal of human genetics, 95 6:698-707, Dec 2014. URL: https://doi.org/10.1016/j.ajhg.2014.10.014, doi:10.1016/j.ajhg.2014.10.014. This article has 78 citations and is from a highest quality peer-reviewed journal.
(wood2020modellingthedevelopmental pages 24-27): Katherine A. Wood, Charlie F. Rowlands, Huw B. Thomas, Steven Woods, Julieta O’Flaherty, Sofia Douzgou, Susan J. Kimber, William G. Newman, and Raymond T. O’Keefe. Modelling the developmental spliceosomal craniofacial disorder burn-mckeown syndrome using induced pluripotent stem cells. BioRxiv, May 2020. URL: https://doi.org/10.1101/2020.05.13.094029, doi:10.1101/2020.05.13.094029. This article has 30 citations.
(wood2020modellingthedevelopmental pages 27-31): Katherine A. Wood, Charlie F. Rowlands, Huw B. Thomas, Steven Woods, Julieta O’Flaherty, Sofia Douzgou, Susan J. Kimber, William G. Newman, and Raymond T. O’Keefe. Modelling the developmental spliceosomal craniofacial disorder burn-mckeown syndrome using induced pluripotent stem cells. BioRxiv, May 2020. URL: https://doi.org/10.1101/2020.05.13.094029, doi:10.1101/2020.05.13.094029. This article has 30 citations.
(wood2020modellingthedevelopmental pages 69-74): Katherine A. Wood, Charlie F. Rowlands, Huw B. Thomas, Steven Woods, Julieta O’Flaherty, Sofia Douzgou, Susan J. Kimber, William G. Newman, and Raymond T. O’Keefe. Modelling the developmental spliceosomal craniofacial disorder burn-mckeown syndrome using induced pluripotent stem cells. BioRxiv, May 2020. URL: https://doi.org/10.1101/2020.05.13.094029, doi:10.1101/2020.05.13.094029. This article has 30 citations.
(wood2020modellingthedevelopmental pages 34-37): Katherine A. Wood, Charlie F. Rowlands, Huw B. Thomas, Steven Woods, Julieta O’Flaherty, Sofia Douzgou, Susan J. Kimber, William G. Newman, and Raymond T. O’Keefe. Modelling the developmental spliceosomal craniofacial disorder burn-mckeown syndrome using induced pluripotent stem cells. BioRxiv, May 2020. URL: https://doi.org/10.1101/2020.05.13.094029, doi:10.1101/2020.05.13.094029. This article has 30 citations.
(wood2020modellingthedevelopmental pages 21-24): Katherine A. Wood, Charlie F. Rowlands, Huw B. Thomas, Steven Woods, Julieta O’Flaherty, Sofia Douzgou, Susan J. Kimber, William G. Newman, and Raymond T. O’Keefe. Modelling the developmental spliceosomal craniofacial disorder burn-mckeown syndrome using induced pluripotent stem cells. BioRxiv, May 2020. URL: https://doi.org/10.1101/2020.05.13.094029, doi:10.1101/2020.05.13.094029. This article has 30 citations.
(park2022thecoresplicing pages 4-7): Byung-Yong Park, Melanie Tachi-Duprat, Chibuike Ihewulezi, Arun Devotta, and Jean-Pierre Saint-Jeannet. The core splicing factors eftud2, snrpb and txnl4a are essential for neural crest and craniofacial development. Journal of Developmental Biology, 10:29, Jul 2022. URL: https://doi.org/10.3390/jdb10030029, doi:10.3390/jdb10030029. This article has 27 citations.
(park2022thecoresplicing pages 1-2): Byung-Yong Park, Melanie Tachi-Duprat, Chibuike Ihewulezi, Arun Devotta, and Jean-Pierre Saint-Jeannet. The core splicing factors eftud2, snrpb and txnl4a are essential for neural crest and craniofacial development. Journal of Developmental Biology, 10:29, Jul 2022. URL: https://doi.org/10.3390/jdb10030029, doi:10.3390/jdb10030029. This article has 27 citations.
(wood2020modellingthedevelopmental pages 45-49): Katherine A. Wood, Charlie F. Rowlands, Huw B. Thomas, Steven Woods, Julieta O’Flaherty, Sofia Douzgou, Susan J. Kimber, William G. Newman, and Raymond T. O’Keefe. Modelling the developmental spliceosomal craniofacial disorder burn-mckeown syndrome using induced pluripotent stem cells. BioRxiv, May 2020. URL: https://doi.org/10.1101/2020.05.13.094029, doi:10.1101/2020.05.13.094029. This article has 30 citations.
(park2022thecoresplicing pages 2-4): Byung-Yong Park, Melanie Tachi-Duprat, Chibuike Ihewulezi, Arun Devotta, and Jean-Pierre Saint-Jeannet. The core splicing factors eftud2, snrpb and txnl4a are essential for neural crest and craniofacial development. Journal of Developmental Biology, 10:29, Jul 2022. URL: https://doi.org/10.3390/jdb10030029, doi:10.3390/jdb10030029. This article has 27 citations.

Artifacts

Edison artifact artifact-00

domain	established finding	quantitative evidence	suggested ontology terms	evidence type/source
Disease identity	Burn-McKeown syndrome is a rare congenital craniofacial spliceosomopathy; OMIM 608572	Fewer than 20 affected families reported worldwide by 2020 (wood2020modellingthedevelopmental pages 1-5)	OMIM: 608572; congenital disorder; craniofacial developmental disorder	Human disease synthesis and patient-derived model background (wood2020modellingthedevelopmental pages 1-5)
Inheritance	Autosomal recessive disease caused by biallelic TXNL4A variants	9 of 11 families in the discovery study had biallelic TXNL4A mutations (wieczorek2014compoundheterozygosityof pages 1-2, wieczorek2014compoundheterozygosityof pages 7-8)	autosomal recessive inheritance; TXNL4A	Human clinical genetics, AJHG 2014 (wieczorek2014compoundheterozygosityof pages 1-2, wieczorek2014compoundheterozygosityof pages 7-8)
Causal gene/mechanism class	TXNL4A encodes a U5 snRNP/spliceosome component; disease reflects reduced TXNL4A dosage rather than simple heterozygous haploinsufficiency	Unaffected heterozygous relatives carried single variants; disease required biallelic hypomorphic/LoF combinations (wieczorek2014compoundheterozygosityof pages 4-6)	TXNL4A; U5 snRNP; pre-mRNA splicing	Human genetics with functional interpretation (wieczorek2014compoundheterozygosityof pages 4-6)
Pathogenic variant architecture	Typical genotype is compound heterozygosity for a 34-bp promoter deletion on one allele plus a loss-of-function allele on the other; homozygous promoter deletion also reported	Promoter D1: chr18:g.77,748,581_77,748,614del; promoter D2: chr18:g.77,748,604_77,748,637del; LoF examples: c.349G>T p.(Glu117), c.37C>T p.(Gln13), c.131delT p.(Val44Alafs*48); terminal 18q deletions also observed (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 4-6)	TXNL4A; promoter deletion; nonsense variant; frameshift variant; copy-number loss	Human clinical genetics and molecular characterization (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 4-6)
Population genetics	The commonest disease-associated promoter allele is low frequency in the general population, consistent with a rare recessive disorder	Type 1 promoter deletion allele frequency 0.76%; predicted homozygous frequency ~1 in 17,300 (wieczorek2014compoundheterozygosityof pages 1-2, wieczorek2014compoundheterozygosityof pages 7-8)	low-frequency regulatory allele	Human case-control/segregation data (wieczorek2014compoundheterozygosityof pages 1-2, wieczorek2014compoundheterozygosityof pages 7-8)
Core phenotype	Choanal atresia/stenosis is the defining feature; reported synthesis states it was observed in all patients, with associated craniofacial, hearing, and occasional visceral anomalies	Choanal atresia observed in all patients in the 2020 synthesis; common additional features include hearing loss, cleft lip/palate, short palpebral fissures, lower eyelid coloboma, short philtrum, prominent nose/high bridge, large ears; congenital heart defects can occur (wood2020modellingthedevelopmental pages 1-5)	choanal atresia; cleft palate; hearing impairment; eyelid coloboma; short philtrum; prominent nose; congenital heart defect	Human disease synthesis and original family series (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 1-2)
Additional variable features	Reported variable findings extend beyond the canonical craniofacial pattern	Patent foramen ovale, persistent ductus arteriosus, imperforate anus, fifth-finger clinodactyly, hallux valgus, preauricular tags, renal agenesis, inguinal hernia reported across families (wieczorek2014compoundheterozygosityof pages 3-4, wieczorek2014compoundheterozygosityof pages 2-3)	imperforate anus; clinodactyly; renal agenesis; preauricular tag	Human family series (wieczorek2014compoundheterozygosityof pages 3-4, wieczorek2014compoundheterozygosityof pages 2-3)
Neurodevelopment	Intellectual development is usually normal, but severe intellectual disability has been reported rarely	One exceptional severe intellectual disability case noted in the literature/model background (wood2020modellingthedevelopmental pages 1-5, wood2020modellingthedevelopmental pages 37-41)	intellectual disability	Human case-based synthesis and iPSC-study background (wood2020modellingthedevelopmental pages 1-5, wood2020modellingthedevelopmental pages 37-41)
Molecular pathophysiology upstream	Promoter deletions reduce TXNL4A expression; reduced TXNL4A impairs U4/U6.U5 tri-snRNP assembly	Type 1 and type 2 promoter deletions reduced promoter activity by 59% and 72%, respectively; yeast DIB1 depletion impaired tri-snRNP assembly (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 7-8)	TXNL4A; U4/U6.U5 tri-snRNP assembly; mRNA splicing	Human regulatory assay plus yeast functional model (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 7-8)
Molecular pathophysiology downstream	Reduced TXNL4A causes selective mis-splicing and altered gene expression, especially in neural crest-relevant programs	In patient iPSCs: 1,511 alternative splicing events in 1,096 genes and 1,181 DEGs; in iNCCs: 2,991 splicing events in 2,029 genes and 5,746 DEGs, with 88% of differential splicing unique to iNCCs (wood2020modellingthedevelopmental pages 24-27, wood2020modellingthedevelopmental pages 27-31, wood2020modellingthedevelopmental pages 69-74)	alternative splicing; gene expression regulation; neural crest development	Human patient-derived iPSC/iNCC transcriptomics (preprint) (wood2020modellingthedevelopmental pages 24-27, wood2020modellingthedevelopmental pages 27-31, wood2020modellingthedevelopmental pages 69-74)
WNT/neural crest mechanism	A leading mechanistic model links TXNL4A deficiency to dampened WNT signaling via TCF7L2 mis-splicing, delaying neural crest epithelial-to-mesenchymal transition	Patient iNCC EMT score -5 vs +5 (mother) and +8 (controls); AXIN2 downregulated (p=0.0004); TCF7L2 exon 4 mis-splicing validated; patient iPSCs proliferated 52%-65% more slowly than controls/mother (wood2020modellingthedevelopmental pages 34-37, wood2020modellingthedevelopmental pages 27-31, wood2020modellingthedevelopmental pages 21-24)	WNT signaling; TCF7L2; epithelial to mesenchymal transition; neural crest cell	Human patient-derived iPSC/iNCC functional model (preprint) (wood2020modellingthedevelopmental pages 34-37, wood2020modellingthedevelopmental pages 27-31, wood2020modellingthedevelopmental pages 21-24)
Developmental cell biology	Neural crest depletion/dysfunction is supported across models as a proximate cause of craniofacial malformation	Xenopus Txnl4a knockdown increased apoptosis in dorsal ectoderm at stage 15 (n=41, p<0.0005) and produced craniofacial cartilage defects in 38% of tadpoles; sox10 reduction was partially rescued by morpholino-resistant txnl4a (park2022thecoresplicing pages 7-10, park2022thecoresplicing pages 4-7, park2022thecoresplicing pages 1-2)	neural crest cell; apoptosis; craniofacial cartilage development; sox10	Xenopus morpholino/rescue model (park2022thecoresplicing pages 7-10, park2022thecoresplicing pages 4-7, park2022thecoresplicing pages 1-2)
Onset/course	Disease onset is congenital/developmental and non-remitting; manifestations arise from embryonic craniofacial development defects	Choanal atresia and craniofacial anomalies are present from birth; no evidence for episodic course or spontaneous remission (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 1-2)	congenital onset; craniofacial malformation	Human clinical description/synthesis (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 1-2)
Diagnostic strategy	Diagnosis is clinical plus molecular: recognize the choanal-atresia/facial dysostosis pattern, then confirm biallelic TXNL4A variants including regulatory deletion and CNV detection	Discovery study used exome/genome sequencing, microarray, and MLPA; CNVs ranged from 0.484 Mb to 4.7 Mb; promoter deletions would be missed by coding-only analysis if regulatory regions are not interrogated (wieczorek2014compoundheterozygosityof pages 3-4, wieczorek2014compoundheterozygosityof pages 4-6)	facial dysostosis; TXNL4A molecular testing; copy-number analysis; promoter variant analysis	Human genetics workflow evidence (wieczorek2014compoundheterozygosityof pages 3-4, wieczorek2014compoundheterozygosityof pages 4-6)
Management	No disease-modifying BMKS therapy is established; care is supportive and anomaly-directed	No BMKS-specific interventional trials identified; reported care needs include airway management for choanal atresia, hearing support including possible cochlear implantation, and management of cleft/cardiac/other anomalies as indicated (wieczorek2014compoundheterozygosityof pages 2-3)	supportive care; surgical repair; hearing rehabilitation	Human case series plus evidence gap on trials (wieczorek2014compoundheterozygosityof pages 2-3)
Prognosis/evidence gaps	Prognosis is poorly quantified because of the rarity of the condition; survival, QoL, and natural-history metrics are not well defined in the literature retrieved	No robust prevalence, incidence, survival, or treatment-response statistics identified beyond family counts and phenotype summaries (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 1-2)	rare disease epidemiology	Evidence-gap synthesis from available literature (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 1-2)
Model systems	BMKS has mechanistic models in yeast, patient-derived iPSC/iNCC systems, and Xenopus embryos	Yeast DIB1 depletion showed tri-snRNP assembly defects; iPSC/iNCC model demonstrated proliferation, splicing, and EMT/WNT abnormalities; Xenopus knockdown caused neural crest/apoptosis/cartilage phenotypes with partial rescue (wieczorek2014compoundheterozygosityof pages 7-8, wood2020modellingthedevelopmental pages 37-41, park2022thecoresplicing pages 7-10)	Saccharomyces cerevisiae model; induced pluripotent stem cell; induced neural crest cell; Xenopus laevis	Yeast, in vitro human, and amphibian model evidence (wieczorek2014compoundheterozygosityof pages 7-8, wood2020modellingthedevelopmental pages 37-41, park2022thecoresplicing pages 7-10)

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Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

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Burn–McKeown Syndrome: Disease-Characteristics Research Report

Executive summary

Evidence scope and currency

1. Disease information

Definition and classification

Identifiers and synonyms

2. Etiology

Causal factor

Genetic risk factors

Environmental, infectious, and lifestyle risk factors

Protective factors and gene–environment interaction

3. Phenotypes

4. Genetic and molecular information

Causal gene

Variant classes and interpretation

Modifiers, epigenetics, and chromosomal abnormalities

5. Environmental information

6. Mechanism and pathophysiology

Causal chain

Human iPSC/iNCC evidence

Model-organism evidence

Ontology suggestions

7. Anatomical structures affected

Primary structures

Secondary or variable structures

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical recognition and immediate evaluation

Molecular testing

Differential diagnosis

11. Outcome and prognosis

12. Treatment

Current clinical management

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Yeast

Patient-derived iPSCs and induced neural-crest cells

Xenopus

Key publications

Overall evidence assessment

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