Bohring-Opitz syndrome

Mendelian MONDO:0011510 Pathograph 22 Show in embeddings browser hereditary disease

Bohring-Opitz syndrome is a severe de novo ASXL1-related developmental disorder characterized by severe intellectual disability, growth failure, distinctive facial features, feeding difficulty, hypertrichosis, and congenital anomalies. The disorder is best understood as a chromatin regulatory syndrome with downstream effects on developmental gene expression and Wnt signaling. Childhood Wilms tumor surveillance is recommended, although the magnitude of tumor risk remains uncertain because published estimates derive from very small, potentially biased case series.

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1
Mappings
1
Inheritance
2
Pathophys.
15
Phenotypes
3
Gaps
22
Pathograph
1
Genes
6
Medical Actions
4
Differentials
1
Datasets
2
Trials
4
References
1
Deep Research
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Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE
🔗

Mappings

MONDO
MONDO:0011510 Bohring-Opitz syndrome
skos:exactMatch MONDO
Primary MONDO identifier for Bohring-Opitz syndrome.
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
Bohring-Opitz syndrome is typically caused by a de novo constitutional heterozygous pathogenic variant in ASXL1.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:29446906 SUPPORT Other
"GENETIC COUNSELING: Bohring-Opitz syndrome (BOS) is typically the result of a de novo pathogenic variant in ASXL1."
This directly supports the usual de novo autosomal-dominant inheritance pattern for BOS.
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Discussions and Knowledge Gaps

3
Do late ASXL1 truncating variants cause BOS mainly through loss of full-length repressive function, a dominant-negative effect, gain of function by a truncated protein, or a combination of these mechanisms?
KNOWLEDGE GAP OPEN bos_truncation_molecular_consequence
Attached to
pathophysiology#ASXL1 truncation disrupts epigenetic regulation of developmental gene expression
The causal gene-disease relationship and the cross-tissue epigenomic disturbance are strong, but the variants should not be reduced to simple gene under-expression. The pathophysiology graph therefore records abnormal ASXL1 function and leaves the precise molecular consequence open.
Show evidence (1 reference)
PMID:37053013 SUPPORT In Vitro
"Our data show that regardless of cell type, ASXL1 mutations drive strong cross-tissue effects that disrupt multiple layers of the epigenome."
Patient-derived cells establish a broad epigenomic consequence without resolving one exclusive dosage or protein-effect mechanism.
Does Wnt and VANGL2 dysregulation measured in postnatal blood and skin fibroblasts directly cause BOS craniofacial and organ-patterning phenotypes during embryogenesis?
HUMAN MODEL MISMATCH OPEN bos_wnt_developmental_translation
Attached to
pathophysiology#ASXL1 truncation dysregulates Wnt signaling and tissue patterning
Cross-tissue multi-omics and protein data support Wnt-pathway dysregulation, but the disease-defining malformations arise in embryonic cell populations that were not assayed. The graph therefore marks the Wnt node provisional and its phenotype links as indirect with unknown intermediates.
Show evidence (1 reference)
PMID:37053013 SUPPORT In Vitro
"We used primary cells from individuals with BOS (n = 18) and controls (n = 49) to dissect gene regulatory changes caused by ASXL1 mutations using comprehensive multiomics assays for chromatin accessibility (ATAC-seq), DNA methylation, histone methylation binding, and transcriptome in peripheral..."
The assayed patient-derived specimens are blood and skin fibroblasts, not the embryonic progenitors in which the malformations originate.
What is the age-specific absolute risk of Wilms tumor in molecularly confirmed BOS, and does it justify the same surveillance intensity for all affected children?
KNOWLEDGE GAP OPEN bos_wilms_tumor_risk_precision
Attached to
phenotypes#Nephroblastoma (Wilms tumor) treatments#Wilms tumor renal-ultrasound surveillance
Current surveillance is clinically actionable, but the published numerator comes from a tiny, selected literature cohort. A prospective molecularly confirmed registry with person-time denominators is needed to estimate absolute and age-specific risk.
Show evidence (2 references)
PMID:25921057 SUPPORT Human Clinical
"Including the patients discussed herein, there are 43 published patients with BOS of which two had Wilms tumor and one had bilateral nephroblastomatosis in infancy, making the incidence of a renal neoplastic process 7% among published patients, although this may be inflated due to biased ascertainment."
The original surveillance series explicitly identifies its small denominator and potential ascertainment inflation.
PMID:29446906 SUPPORT Other
"Isolated case reports suggest that individuals with BOS are at greater risk for Wilms tumor than the general population, but large-scale epidemiologic studies have not been conducted."
GeneReviews confirms that population-scale risk data are absent.
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Pathophysiology

2
ASXL1 truncation disrupts epigenetic regulation of developmental gene expression
Late protein-truncating ASXL1 variants disrupt the protein's chromatin regulatory function and alter developmental transcriptional programs across tissues. The variants should not be represented as simple ASXL1 depletion: available patient-cell data support escape from nonsense-mediated decay, while the relative contributions of lost full-length function, dominant-negative activity, and gain of function remain unresolved.
ASXL1 hgnc:18318 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves abnormal ASXL1 (hgnc:18318). hgnc:18318 is a gene from the HUGO Gene Nomenclature Committee. ⚠ ABNORMAL
epigenetic regulation of gene expression GO:0040029 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal epigenetic regulation of gene expression (GO:0040029). GO:0040029 is a biological process from the Gene Ontology. ⚠ ABNORMAL chromatin remodeling GO:0006338 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chromatin remodeling (GO:0006338). GO:0006338 is a biological process from the Gene Ontology. ⚠ ABNORMAL regulation of transcription by RNA polymerase II GO:0006357 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of transcription by RNA polymerase II (GO:0006357). GO:0006357 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Severe intellectual disability Disrupted developmental gene expression contributes to profound neurodevelopmental impairment.
Global developmental delay Disrupted developmental gene expression contributes to broad developmental delay across motor, language, and adaptive domains.
Seizures ASXL1-related developmental dysregulation is associated with recurrent seizures, but the intervening neural-circuit mechanism is not established.
Recurrent infections Recurrent infection is part of the early-life BOS phenotype, although a specific immune mechanism has not been established.
Obstructive sleep apnea Craniofacial and upper-airway abnormalities contribute to obstructive sleep apnea, but the path from ASXL1 dysregulation remains incompletely specified.
High myopia Severe myopia is a recurrent ocular manifestation of the ASXL1-related syndrome; its intervening developmental mechanism is not established.
Intrauterine growth restriction Prenatal growth restriction is a common early manifestation, although the specific downstream growth pathway is not known.
Failure to thrive Growth failure follows the developmental and feeding phenotype of BOS.
Feeding difficulties Disrupted development and hypotonia contribute to feeding intolerance and poor oral intake.
Hypertrichosis ASXL1-related developmental gene-expression disruption is associated with the characteristic BOS hypertrichosis phenotype.
Characteristic BOS posture The typical flexed elbow, wrist, and metacarpophalangeal posture is part of the ASXL1-related developmental syndrome.
Nephroblastoma (Wilms tumor) Constitutional ASXL1 truncation is associated with increased Wilms tumor surveillance concern in BOS, although the intervening tumor mechanism is not fully specified.
Show evidence (2 references)
PMID:21706002 SUPPORT Human Clinical
"We sequenced the exomes of three individuals with Bohring-Opitz syndrome and in each identified heterozygous de novo nonsense mutations in ASXL1, which is required for maintenance of both activation and silencing of Hox genes."
This is the core molecular evidence linking BOS to de novo ASXL1 loss-of-function and disrupted developmental gene regulation.
PMID:37053013 SUPPORT In Vitro
"ASXL1 (additional sex combs-like 1) plays key roles in epigenetic regulation of early developmental gene expression."
This supports the broader epigenetic mechanism of BOS in patient-derived cell models.
ASXL1 truncation dysregulates Wnt signaling and tissue patterning
Multiomics studies in patient-derived cells show canonical and noncanonical Wnt pathway perturbation, including broad activation of canonical Wnt signaling and increased VANGL2 expression. The cell-level signal is replicated across blood and fibroblast assays, but its causal translation to embryonic craniofacial and organ phenotypes remains provisional because the study examined differentiated postnatal cells.
ASXL1 hgnc:18318 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves abnormal ASXL1 (hgnc:18318). hgnc:18318 is a gene from the HUGO Gene Nomenclature Committee. ⚠ ABNORMAL
Wnt signaling pathway GO:0016055 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Wnt signaling pathway (GO:0016055). GO:0016055 is a biological process from the Gene Ontology. ⚠ ABNORMAL canonical Wnt signaling pathway GO:0060070 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal canonical Wnt signaling pathway (GO:0060070). GO:0060070 is a biological process from the Gene Ontology. ⚠ ABNORMAL Wnt signaling pathway, planar cell polarity pathway GO:0060071 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Wnt signaling pathway, planar cell polarity pathway (GO:0060071). GO:0060071 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Trigonocephaly Disturbed craniofacial patterning contributes to abnormal skull shape and metopic ridge prominence.
Micrognathia Disturbed craniofacial development contributes to the characteristic small jaw phenotype.
Nevus flammeus Disturbed tissue patterning in BOS is associated with the glabellar and eyelid nevus flammeus component of the craniofacial gestalt.
Show evidence (1 reference)
PMID:37053013 SUPPORT In Vitro
"The data showed a broad activation of canonical Wnt signaling at the transcriptional and protein levels and upregulation of VANGL2, which encodes a planar cell polarity pathway protein that acts through noncanonical Wnt signaling to direct tissue patterning and cell migration."
This directly supports Wnt pathway dysregulation and altered tissue-patterning mechanisms in BOS patient-derived cells.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Bohring-Opitz syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

15
Digestive 1
Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29446906 SUPPORT Other
"Feeding difficulties in early childhood, including cyclic vomiting, have a significant impact on overall health; feeding tends to improve with age."
This directly supports feeding difficulties as a major BOS feature.
Eye 1
High myopia HP:0011003 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High myopia (HP:0011003). HP:0011003 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25921057 SUPPORT Human Clinical
"Bohring-Opitz syndrome is a rare genetic condition characterized by distinctive facial features, variable microcephaly, hypertrichosis, nevus flammeus, severe myopia, unusual posture (flexion at the elbows with ulnar deviation, and flexion of the wrists and metacarpophalangeal joints), severe..."
The clinical series explicitly lists severe myopia among the characteristic manifestations.
Genitourinary 1
Nephroblastoma (Wilms tumor) HP:0002667 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephroblastoma (HP:0002667). HP:0002667 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25921057 SUPPORT Human Clinical
"Including the patients discussed herein, there are 43 published patients with BOS of which two had Wilms tumor and one had bilateral nephroblastomatosis in infancy, making the incidence of a renal neoplastic process 7% among published patients, although this may be inflated due to biased ascertainment."
This provides human clinical evidence for elevated Wilms tumor risk in BOS.
Head and Neck 1
Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29446906 SUPPORT Other
"The facial features may include microcephaly or trigonocephaly / prominent (but not fused) metopic ridge, hypotonic facies with full cheeks, synophrys, glabellar and eyelid nevus flammeus (simplex), prominent globes, widely set eyes, palate anomalies, and micrognathia."
This directly supports micrognathia as part of the BOS facial phenotype.
Immune 1
Recurrent infections HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29446906 SUPPORT Other
"Affected individuals may experience recurrent infections, which also tend to improve with age."
GeneReviews directly supports recurrent infections and their age-related improvement.
Integument 1
Hypertrichosis HP:0000998 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrichosis (HP:0000998). HP:0000998 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25921057 SUPPORT Human Clinical
"Bohring-Opitz syndrome is a rare genetic condition characterized by distinctive facial features, variable microcephaly, hypertrichosis, nevus flammeus, severe myopia, unusual posture (flexion at the elbows with ulnar deviation, and flexion of the wrists and metacarpophalangeal joints), severe..."
This directly supports hypertrichosis as a BOS phenotype.
Musculoskeletal 1
Characteristic BOS posture Limitation of joint mobility HP:0001376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Characteristic BOS posture, annotated with Limitation of joint mobility (HP:0001376). HP:0001376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25921057 SUPPORT Human Clinical
"Bohring-Opitz syndrome is a rare genetic condition characterized by distinctive facial features, variable microcephaly, hypertrichosis, nevus flammeus, severe myopia, unusual posture (flexion at the elbows with ulnar deviation, and flexion of the wrists and metacarpophalangeal joints), severe..."
This directly supports the characteristic BOS posture phenotype.
Nervous System 4
Severe intellectual disability HP:0010864 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe intellectual disability (HP:0010864). HP:0010864 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21706002 SUPPORT Human Clinical
"Bohring-Opitz syndrome is characterized by severe intellectual disability, distinctive facial features and multiple congenital malformations."
This explicitly supports severe intellectual disability as a core BOS feature.
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25921057 SUPPORT Human Clinical
"Bohring-Opitz syndrome has previously been associated with high infant mortality (11 out of 43 reported patients (26%), intrauterine growth retardation, feeding difficulties often requiring a feeding tube, failure to thrive, severe to profound developmental delays, recurrent infections,..."
This supports broad developmental delay as a common BOS manifestation.
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29446906 SUPPORT Other
"Seizures are common and typically responsive to standard epileptic medications."
GeneReviews directly supports the seizure phenotype and usual treatment response.
Obstructive sleep apnea HP:0002870 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Obstructive sleep apnea (HP:0002870). HP:0002870 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29446906 SUPPORT Other
"Due to the prevalence of obstructive sleep apnea, polysomnography should be considered."
GeneReviews directly supports obstructive sleep apnea as a clinically important BOS complication.
Growth 2
Intrauterine growth restriction Intrauterine growth retardation HP:0001511 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intrauterine growth retardation (HP:0001511). HP:0001511 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25921057 SUPPORT Human Clinical
"Bohring-Opitz syndrome has previously been associated with high infant mortality (11 out of 43 reported patients (26%), intrauterine growth retardation, feeding difficulties often requiring a feeding tube, failure to thrive, severe to profound developmental delays, recurrent infections,..."
The clinical series directly supports prenatal growth restriction as a BOS feature.
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29446906 SUPPORT Other
"Feeding difficulties in early childhood, including cyclic vomiting, have a significant impact on overall health; feeding tends to improve with age."
This supports the feeding-related mechanism that drives failure to thrive in BOS.
Other 2
Trigonocephaly HP:0000243 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Trigonocephaly (HP:0000243). HP:0000243 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29446906 SUPPORT Other
"The facial features may include microcephaly or trigonocephaly / prominent (but not fused) metopic ridge, hypotonic facies with full cheeks, synophrys, glabellar and eyelid nevus flammeus (simplex), prominent globes, widely set eyes, palate anomalies, and micrognathia."
This directly supports trigonocephaly as a BOS craniofacial feature.
Nevus flammeus HP:0001052 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Port-wine stain, annotated with Nevus flammeus (HP:0001052). HP:0001052 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29446906 SUPPORT Other
"The facial features may include microcephaly or trigonocephaly / prominent (but not fused) metopic ridge, hypotonic facies with full cheeks, synophrys, glabellar and eyelid nevus flammeus (simplex), prominent globes, widely set eyes, palate anomalies, and micrognathia."
This directly supports nevus flammeus as a BOS craniofacial feature.
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Genetic Associations

1
ASXL1 (Heterozygous protein-truncating pathogenic variants)
Gene: ASXL1 hgnc:18318 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ASXL1 (hgnc:18318). hgnc:18318 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: DE_NOVO
Show evidence (3 references)
CGGV:assertion_31e0ce4d-aeb7-4983-9ec2-85178d7f40f0-2021-07-30T160000.000Z SUPPORT Other
"ASXL1 | HGNC:18318 | Bohring-Opitz syndrome | MONDO:0011510 | AD | Definitive"
ClinGen classifies the ASXL1-Bohring-Opitz syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
PMID:21706002 SUPPORT Human Clinical
"We sequenced the exomes of three individuals with Bohring-Opitz syndrome and in each identified heterozygous de novo nonsense mutations in ASXL1, which is required for maintenance of both activation and silencing of Hox genes."
The discovery series directly supports heterozygous de novo truncating ASXL1 variants as causal.
PMID:37053013 SUPPORT Human Clinical
"These BOS-causing ASXL1 variants are also high-prevalence somatic driver mutations in acute myeloid leukemia."
The overlap with somatic myeloid driver variants supports explicitly requiring a constitutional diagnostic interpretation.
💊

Medical Actions

6
Enteral feeding support
Category: Therapeutic Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Gastrostomy or gastrojejunal tube feeding is commonly used when oral intake is inadequate because of severe feeding difficulty and cyclic emesis.
Target Phenotypes: Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25921057 SUPPORT Human Clinical
"All eight patients struggled with adequate caloric intake by mouth, and Patients 2 and 5 had significant episodes of cyclic emesis."
This supports feeding support as a central management need in BOS.
PMID:25921057 SUPPORT Human Clinical
"Patients 2–6 required gastrostomy tubes due to aspiration and/or an inability to take adequate calories orally."
This directly supports gastrostomy-based enteral feeding support in BOS.
Cyclic vomiting prevention and early abortive treatment
Category: Therapeutic Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Identify and avoid individual emesis triggers, consider daily preventive medication, and use an early abortive antiemetic plan. Controlling severe vomiting can reduce dehydration, aspiration, hospitalization, and infectious exposure.
Target Phenotypes: Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29446906 SUPPORT Other
"Cyclic vomiting may be managed by identification and avoidance of triggers, daily maintenance medication, and early abortive treatment; G-tubes or GJ-tubes may decrease aspiration and improve nutrition."
GeneReviews directly supports trigger avoidance, maintenance therapy, and early abortive management of cyclic vomiting.
Standard antiseizure management
Category: Therapeutic Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Treat seizures with standard syndrome-appropriate antiseizure medication and neurologic follow-up; no BOS-specific antiseizure regimen has been established.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29446906 SUPPORT Other
"Standard management is indicated for seizures, congenital heart defects, intellectual disability, myopia, urinary tract infections, urinary retention, and kidney stones."
GeneReviews recommends standard management rather than a BOS-specific seizure regimen.
Wilms tumor renal-ultrasound surveillance
Category: Screening Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Perform renal ultrasound every three months from birth through age eight years. The recommendation is precautionary: it is based on isolated reports and a small case series rather than a population-level risk estimate.
Show evidence (2 references)
PMID:29446906 SUPPORT Other
"Surveillance: Renal ultrasound every three months from birth to age eight to screen for the development of Wilms tumor"
GeneReviews directly states the surveillance interval and age range.
PMID:25921057 SUPPORT Human Clinical
"Including the patients discussed herein, there are 43 published patients with BOS of which two had Wilms tumor and one had bilateral nephroblastomatosis in infancy, making the incidence of a renal neoplastic process 7% among published patients, although this may be inflated due to biased ascertainment."
The source supports surveillance concern while explicitly warning that the observed proportion may be inflated by ascertainment bias.
Growth, feeding, development, and vision follow-up
Category: Monitoring Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Provide frequent growth and developmental monitoring, specialist follow-up for feeding intolerance, and regular ophthalmologic care to optimize vision.
Show evidence (1 reference)
PMID:29446906 SUPPORT Other
"frequent monitoring of growth and development; close monitoring of feeding intolerance with a gastroenterology specialist; regular follow up for vision optimization."
GeneReviews directly states these longitudinal monitoring needs.
🔬

Diagnosis

1
ASXL1 molecular genetic testing (Identification of a constitutional heterozygous pathogenic ASXL1 variant establishes the diagnosis.)
Molecular testing for a constitutional heterozygous pathogenic ASXL1 variant confirms the diagnosis in a proband with suggestive clinical features.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:29446906 SUPPORT Other
"DIAGNOSIS/TESTING: The diagnosis of Bohring-Opitz syndrome (BOS) is established in a proband with suggestive clinical features and/or the identification of a constitutional heterozygous pathogenic variant in ASXL1 by molecular genetic testing."
This directly supports ASXL1 molecular testing as the confirmatory diagnostic approach.
📈

Progression

3
Prenatal and neonatal presentation
Age: Prenatal period to birth
Intrauterine growth restriction and congenital anomalies may be evident before or at birth; dysmorphic features, hypotonia, and early feeding or respiratory difficulty commonly bring the disorder to attention.
Show evidence (1 reference)
PMID:25921057 SUPPORT Human Clinical
"Bohring-Opitz syndrome has previously been associated with high infant mortality (11 out of 43 reported patients (26%), intrauterine growth retardation, feeding difficulties often requiring a feeding tube, failure to thrive, severe to profound developmental delays, recurrent infections,..."
The published clinical series documents prenatal growth restriction and the major early-life manifestations.
High-burden infancy and early childhood
Age: Infancy through early childhood
Severe feeding intolerance, cyclic vomiting, aspiration, recurrent respiratory infections, growth failure, and profound developmental delay can drive repeated hospitalizations. Historical published cases included substantial infant mortality, but that estimate is vulnerable to reporting and ascertainment bias.
Show evidence (1 reference)
PMID:25921057 SUPPORT Human Clinical
"Bohring-Opitz syndrome has previously been associated with high infant mortality (11 out of 43 reported patients (26%), intrauterine growth retardation, feeding difficulties often requiring a feeding tube, failure to thrive, severe to profound developmental delays, recurrent infections,..."
This small published cohort supports a severe early-life course while also motivating caution about generalizing its mortality estimate.
Partial improvement with persistent neurodevelopmental disability
Age: Later childhood onward
Feeding difficulty, recurrent infection, and the characteristic BOS posture often become less prominent with age. Severe intellectual and adaptive disability generally persists, so improving medical stability does not imply resolution of the underlying developmental disorder.
Show evidence (2 references)
PMID:29446906 SUPPORT Other
"The BOS posture, which is most striking in early childhood and often becomes less apparent with age, is characterized by flexion at the elbows with ulnar deviation and flexion of the wrists and metacarpophalangeal joints. Feeding difficulties in early childhood, including cyclic vomiting, have a..."
GeneReviews documents age-related improvement of posture and feeding difficulty.
PMID:29446906 SUPPORT Other
"Affected individuals may experience recurrent infections, which also tend to improve with age."
GeneReviews also documents improvement of recurrent infections.
⚖️

Clinical Burden

High
BOS combines profound lifelong neurodevelopmental disability with growth failure, feeding and aspiration risk, cyclic vomiting, respiratory morbidity, seizures, sleep-disordered breathing, repeated procedures or hospitalizations, and a childhood tumor-surveillance burden. Some medical complications improve with age, but early morbidity and care intensity can be substantial.
Show evidence (1 reference)
PMID:25921057 SUPPORT Human Clinical
"Bohring-Opitz syndrome has previously been associated with high infant mortality (11 out of 43 reported patients (26%), intrauterine growth retardation, feeding difficulties often requiring a feeding tube, failure to thrive, severe to profound developmental delays, recurrent infections,..."
The reported early mortality, feeding-tube dependence, growth failure, and severe developmental impairment support a high disease-level burden.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Bohring-Opitz syndrome:

Cornelia de Lange syndrome MONDO:0016033
Overlapping Features Cornelia de Lange syndrome overlaps with BOS through growth restriction and hypertrichosis, but the shared presentation should be resolved by BOS-typical ASXL1 testing and the broader BOS facial/postural pattern.
Distinguishing Features
  • BOS typically shows ASXL1 truncating variants rather than cohesin-pathway defects.
  • BOS posture and the characteristic facial gestalt help separate BOS from CdLS.
Show evidence (1 reference)
PMID:25921057 SUPPORT Human Clinical
"The differential is broad for these patients with hypertrichosis and IUGR resembling Cornelia de Lange syndrome, coarse facial features resembling a storage disease or RASopathy, and micrognathia resembling Treacher Collins syndrome."
This explicitly names Cornelia de Lange syndrome as a BOS mimic.
Treacher Collins syndrome MONDO:0007944
Overlapping Features Treacher Collins syndrome is a craniofacial differential because BOS can present with micrognathia and facial dysmorphism, but BOS has more global neurodevelopmental involvement and hypertrichosis.
Distinguishing Features
  • BOS usually has profound developmental delay and hypertrichosis, which are not defining features of Treacher Collins syndrome.
  • BOS facial pattern is broader than isolated mandibulofacial dysostosis.
Show evidence (1 reference)
PMID:25921057 SUPPORT Human Clinical
"The differential is broad for these patients with hypertrichosis and IUGR resembling Cornelia de Lange syndrome, coarse facial features resembling a storage disease or RASopathy, and micrognathia resembling Treacher Collins syndrome."
This explicitly names Treacher Collins syndrome as a BOS mimic.
RASopathy Not Yet Curated MONDO:0021060
Overlapping Features RASopathy is a useful broad differential for BOS because coarse facial features may resemble a RAS/MAPK syndrome, but BOS is driven by ASXL1 truncation and has the BOS posture and neurodevelopmental profile.
Distinguishing Features
  • BOS has ASXL1-related chromatin dysregulation rather than RAS/MAPK pathway activation.
  • BOS usually has marked feeding issues, hypertrichosis, and a characteristic posture.
Show evidence (1 reference)
PMID:25921057 SUPPORT Human Clinical
"The differential is broad for these patients with hypertrichosis and IUGR resembling Cornelia de Lange syndrome, coarse facial features resembling a storage disease or RASopathy, and micrognathia resembling Treacher Collins syndrome."
This explicitly names RASopathy as a BOS mimic.
Lysosomal storage disease Not Yet Curated MONDO:0002561
Overlapping Features Lysosomal storage disease can resemble BOS when coarse facial features are prominent, but BOS lacks the enzyme-deficiency and biochemical storage signature of a true lysosomal disorder.
Distinguishing Features
  • BOS is molecularly confirmed by ASXL1 testing rather than by lysosomal enzyme analysis.
  • BOS typically shows early developmental delay and hypertrichosis rather than a storage biochemistry profile.
Show evidence (1 reference)
PMID:25921057 SUPPORT Human Clinical
"The differential is broad for these patients with hypertrichosis and IUGR resembling Cornelia de Lange syndrome, coarse facial features resembling a storage disease or RASopathy, and micrognathia resembling Treacher Collins syndrome."
This explicitly names storage disease as a BOS mimic.
📊

Related Datasets

1
Multiomics of Bohring-Opitz syndrome truncating ASXL1 mutations geo:GSE230696
Human primary-cell multi-omics dataset from Bohring-Opitz syndrome patients and controls, including peripheral blood and skin fibroblast assays used to study epigenomic dysregulation and Wnt signaling.
human MULTI OMICS PERTURBATION n=67
peripheral blood UBERON:0000178 Uberon multi-species anatomy ontology (UBERON) Relation: this dataset samples this sample type This dataset samples peripheral blood, annotated with blood (UBERON:0000178). UBERON:0000178 is a sample type from the Uberon multi-species anatomy ontology. skin fibroblast CL:0002620 Cell Ontology (CL) Relation: this dataset samples this sample type This dataset samples skin fibroblast (CL:0002620). CL:0002620 is a sample type from the Cell Ontology.
Conditions: Bohring-Opitz syndrome control
Findings
Patient-derived primary cells from BOS and controls reveal cross-tissue epigenomic disruption and Wnt signaling dysregulation.
Show evidence (2 references)
PMID:37053013 SUPPORT In Vitro
"We used primary cells from individuals with BOS (n = 18) and controls (n = 49) to dissect gene regulatory changes caused by ASXL1 mutations using comprehensive multiomics assays for chromatin accessibility (ATAC-seq), DNA methylation, histone methylation binding, and transcriptome in peripheral..."
This supports the dataset as a human primary-cell BOS resource for mechanistic epigenomic analysis.
PMID:37053013 SUPPORT In Vitro
"Our data show that regardless of cell type, ASXL1 mutations drive strong cross-tissue effects that disrupt multiple layers of the epigenome."
This supports the dataset as a primary-cell BOS resource for multi-omics epigenomic analysis.
PMID:37053013
The reported total comprises 18 individuals with BOS and 49 controls; assay-specific sample sizes differ, and only four affected individuals contributed both blood and fibroblast specimens.
Show evidence (1 reference)
PMID:37053013 SUPPORT In Vitro
"We used primary cells from individuals with BOS (n = 18) and controls (n = 49) to dissect gene regulatory changes caused by ASXL1 mutations using comprehensive multiomics assays for chromatin accessibility (ATAC-seq), DNA methylation, histone methylation binding, and transcriptome in peripheral..."
This directly supports the cohort size, specimen types, and multi-omics content represented by GSE230696.
🔬

Clinical Trials

2
NCT03303716 RECRUITING
Recruiting observational natural-history registry for ASXL-related disorders, including Bohring-Opitz syndrome, focused on longitudinal natural history, management, and treatment experience. This is not an interventional therapy trial; registry status was checked on 2026-07-24.
Show evidence (1 reference)
clinicaltrials:NCT03303716 SUPPORT Human Clinical
"A registry focused on the natural history, management and treatment of patients with Bohring-Opitz Syndrome (ASXL1), Shashi-Pena Syndrome (ASXL2) and Bainbridge-Ropers Syndrome (ASXL3)."
The ClinicalTrials.gov summary directly supports inclusion of BOS in this ASXL natural-history registry.
NCT01793168 RECRUITING
Recruiting international rare-disease patient registry that lists Bohring-Opitz syndrome among many eligible conditions. It is a broad observational registry rather than a BOS-specific treatment study; registry status was checked on 2026-07-24.
Show evidence (2 references)
clinicaltrials:NCT01793168 SUPPORT Human Clinical
"It provides researchers with a centralized, international patient registry for all rare diseases."
The ClinicalTrials.gov summary supports the registry's broad observational scope.
url:https://clinicaltrials.gov/api/v2/studies/NCT01793168 SUPPORT Human Clinical
"Bohring-Opitz Syndrome"
The current structured registry record specifically lists Bohring-Opitz syndrome as an eligible condition.
{ }

Source YAML

click to show 
name: Bohring-Opitz syndrome
creation_date: "2026-04-16T18:28:41Z"
category: Mendelian
description: >-
  Bohring-Opitz syndrome is a severe de novo ASXL1-related developmental
  disorder characterized by severe intellectual disability, growth failure,
  distinctive facial features, feeding difficulty, hypertrichosis, and
  congenital anomalies. The disorder is best understood as a chromatin
  regulatory syndrome with downstream effects on developmental gene
  expression and Wnt signaling. Childhood Wilms tumor surveillance is
  recommended, although the magnitude of tumor risk remains uncertain because
  published estimates derive from very small, potentially biased case series.
disease_term:
  preferred_term: Bohring-Opitz syndrome
  term:
    id: MONDO:0011510
    label: Bohring-Opitz syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0011510
      label: Bohring-Opitz syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO identifier for Bohring-Opitz syndrome.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
parents:
- hereditary disease
progression:
- phase: Prenatal and neonatal presentation
  age_range: Prenatal period to birth
  notes: >-
    Intrauterine growth restriction and congenital anomalies may be evident
    before or at birth; dysmorphic features, hypotonia, and early feeding or
    respiratory difficulty commonly bring the disorder to attention.
  evidence:
  - reference: PMID:25921057
    reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bohring-Opitz syndrome has previously been associated with high infant
      mortality (11 out of 43 reported patients (26%), intrauterine growth
      retardation, feeding difficulties often requiring a feeding tube,
      failure to thrive, severe to profound developmental delays, recurrent
      infections, nonspecific brain abnormalities, variable microcephaly,
      distinctive facial features
    explanation: >-
      The published clinical series documents prenatal growth restriction and
      the major early-life manifestations.
- phase: High-burden infancy and early childhood
  age_range: Infancy through early childhood
  notes: >-
    Severe feeding intolerance, cyclic vomiting, aspiration, recurrent
    respiratory infections, growth failure, and profound developmental delay
    can drive repeated hospitalizations. Historical published cases included
    substantial infant mortality, but that estimate is vulnerable to reporting
    and ascertainment bias.
  evidence:
  - reference: PMID:25921057
    reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bohring-Opitz syndrome has previously been associated with high infant
      mortality (11 out of 43 reported patients (26%), intrauterine growth
      retardation, feeding difficulties often requiring a feeding tube,
      failure to thrive, severe to profound developmental delays, recurrent
      infections, nonspecific brain abnormalities, variable microcephaly,
      distinctive facial features
    explanation: >-
      This small published cohort supports a severe early-life course while
      also motivating caution about generalizing its mortality estimate.
- phase: Partial improvement with persistent neurodevelopmental disability
  age_range: Later childhood onward
  notes: >-
    Feeding difficulty, recurrent infection, and the characteristic BOS posture
    often become less prominent with age. Severe intellectual and adaptive
    disability generally persists, so improving medical stability does not
    imply resolution of the underlying developmental disorder.
  evidence:
  - reference: PMID:29446906
    reference_title: Bohring-Opitz Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The BOS posture, which is most striking in early childhood and often
      becomes less apparent with age, is characterized by flexion at the elbows
      with ulnar deviation and flexion of the wrists and metacarpophalangeal
      joints. Feeding difficulties in early childhood, including cyclic
      vomiting, have a significant impact on overall health; feeding tends to
      improve with age.
    explanation: >-
      GeneReviews documents age-related improvement of posture and feeding
      difficulty.
  - reference: PMID:29446906
    reference_title: Bohring-Opitz Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Affected individuals may experience recurrent infections, which also tend
      to improve with age.
    explanation: GeneReviews also documents improvement of recurrent infections.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    BOS combines profound lifelong neurodevelopmental disability with growth
    failure, feeding and aspiration risk, cyclic vomiting, respiratory
    morbidity, seizures, sleep-disordered breathing, repeated procedures or
    hospitalizations, and a childhood tumor-surveillance burden. Some medical
    complications improve with age, but early morbidity and care intensity can
    be substantial.
  evidence:
  - reference: PMID:25921057
    reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bohring-Opitz syndrome has previously been associated with high infant
      mortality (11 out of 43 reported patients (26%), intrauterine growth
      retardation, feeding difficulties often requiring a feeding tube,
      failure to thrive, severe to profound developmental delays, recurrent
      infections, nonspecific brain abnormalities, variable microcephaly,
      distinctive facial features
    explanation: >-
      The reported early mortality, feeding-tube dependence, growth failure, and
      severe developmental impairment support a high disease-level burden.
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    Bohring-Opitz syndrome is typically caused by a de novo constitutional
    heterozygous pathogenic variant in ASXL1.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:29446906
    reference_title: Bohring-Opitz Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      GENETIC COUNSELING: Bohring-Opitz syndrome (BOS) is typically the result
      of a de novo pathogenic variant in ASXL1.
    explanation: This directly supports the usual de novo autosomal-dominant inheritance pattern for BOS.
pathophysiology:
- name: ASXL1 truncation disrupts epigenetic regulation of developmental gene expression
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Late protein-truncating ASXL1 variants disrupt the protein's chromatin
    regulatory function and alter developmental transcriptional programs across
    tissues. The variants should not be represented as simple ASXL1 depletion:
    available patient-cell data support escape from nonsense-mediated decay,
    while the relative contributions of lost full-length function,
    dominant-negative activity, and gain of function remain unresolved.
  genes:
  - preferred_term: ASXL1
    modifier: ABNORMAL
    term:
      id: hgnc:18318
      label: ASXL1
  biological_processes:
  - preferred_term: epigenetic regulation of gene expression
    modifier: ABNORMAL
    term:
      id: GO:0040029
      label: epigenetic regulation of gene expression
  - preferred_term: chromatin remodeling
    modifier: ABNORMAL
    term:
      id: GO:0006338
      label: chromatin remodeling
  - preferred_term: regulation of transcription by RNA polymerase II
    modifier: ABNORMAL
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
  downstream:
  - target: Severe intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Disrupted developmental gene expression contributes to profound neurodevelopmental impairment.
    evidence:
    - reference: PMID:21706002
      reference_title: De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Bohring-Opitz syndrome is characterized by severe intellectual
        disability, distinctive facial features and multiple congenital
        malformations.
      explanation: This supports severe intellectual disability as a core BOS manifestation downstream of ASXL1 disruption.
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Disrupted developmental gene expression contributes to broad developmental delay across motor, language, and adaptive domains.
    evidence:
    - reference: PMID:25921057
      reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Bohring-Opitz syndrome has previously been associated with high infant
        mortality (11 out of 43 reported patients (26%), intrauterine growth
        retardation, feeding difficulties often requiring a feeding tube,
        failure to thrive, severe to profound developmental delays, recurrent
        infections, nonspecific brain abnormalities, variable microcephaly,
        distinctive facial features
      explanation: This supports global developmental delay as a common BOS phenotype linked to the underlying ASXL1-driven disorder.
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      ASXL1-related developmental dysregulation is associated with recurrent
      seizures, but the intervening neural-circuit mechanism is not established.
    evidence:
    - reference: PMID:29446906
      reference_title: Bohring-Opitz Syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Seizures are common and typically responsive to standard epileptic
        medications.
      explanation: GeneReviews supports seizures as a common BOS manifestation.
  - target: Recurrent infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Recurrent infection is part of the early-life BOS phenotype, although a
      specific immune mechanism has not been established.
    evidence:
    - reference: PMID:29446906
      reference_title: Bohring-Opitz Syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Affected individuals may experience recurrent infections, which also
        tend to improve with age.
      explanation: GeneReviews supports recurrent infections as an age-dependent BOS manifestation.
  - target: Obstructive sleep apnea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Craniofacial and upper-airway abnormalities contribute to obstructive
      sleep apnea, but the path from ASXL1 dysregulation remains incompletely
      specified.
    evidence:
    - reference: PMID:29446906
      reference_title: Bohring-Opitz Syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Due to the prevalence of obstructive sleep apnea, polysomnography should
        be considered.
      explanation: GeneReviews supports obstructive sleep apnea as a sufficiently prevalent BOS complication to warrant evaluation.
  - target: High myopia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Severe myopia is a recurrent ocular manifestation of the ASXL1-related
      syndrome; its intervening developmental mechanism is not established.
    evidence:
    - reference: PMID:25921057
      reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Bohring-Opitz syndrome is a rare genetic condition characterized by
        distinctive facial features, variable microcephaly, hypertrichosis,
        nevus flammeus, severe myopia, unusual posture (flexion at the elbows
        with ulnar deviation, and flexion of the wrists and metacarpophalangeal
        joints), severe intellectual disability, and feeding issues.
      explanation: The clinical-management series lists severe myopia among the characteristic BOS manifestations.
  - target: Intrauterine growth restriction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Prenatal growth restriction is a common early manifestation, although the
      specific downstream growth pathway is not known.
    evidence:
    - reference: PMID:25921057
      reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Bohring-Opitz syndrome has previously been associated with high infant
        mortality (11 out of 43 reported patients (26%), intrauterine growth
        retardation, feeding difficulties often requiring a feeding tube,
        failure to thrive, severe to profound developmental delays, recurrent
        infections, nonspecific brain abnormalities, variable microcephaly,
        distinctive facial features
      explanation: The clinical series directly supports intrauterine growth restriction as a BOS manifestation.
  - target: Failure to thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Growth failure follows the developmental and feeding phenotype of BOS.
    evidence:
    - reference: PMID:29446906
      reference_title: Bohring-Opitz Syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Feeding difficulties in early childhood, including cyclic vomiting, have
        a significant impact on overall health; feeding tends to improve with
        age.
      explanation: This supports the feeding-related growth failure that contributes to failure to thrive in BOS.
  - target: Feeding difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Disrupted development and hypotonia contribute to feeding intolerance and poor oral intake.
    evidence:
    - reference: PMID:25921057
      reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Bohring-Opitz syndrome is a rare genetic condition characterized by
        distinctive facial features, variable microcephaly, hypertrichosis,
        nevus flammeus, severe myopia, unusual posture (flexion at the elbows
        with ulnar deviation, and flexion of the wrists and metacarpophalangeal
        joints), severe intellectual disability, and feeding issues.
      explanation: This directly supports feeding difficulties as a core BOS phenotype.
  - target: Hypertrichosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      ASXL1-related developmental gene-expression disruption is associated with
      the characteristic BOS hypertrichosis phenotype.
    evidence:
    - reference: PMID:25921057
      reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Bohring-Opitz syndrome is a rare genetic condition characterized by
        distinctive facial features, variable microcephaly, hypertrichosis,
        nevus flammeus, severe myopia, unusual posture (flexion at the elbows
        with ulnar deviation, and flexion of the wrists and metacarpophalangeal
        joints), severe intellectual disability, and feeding issues.
      explanation: >-
        Clinical management evidence lists hypertrichosis among the
        characteristic BOS manifestations downstream of ASXL1-associated disease.
  - target: Characteristic BOS posture
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The typical flexed elbow, wrist, and metacarpophalangeal posture is part
      of the ASXL1-related developmental syndrome.
    evidence:
    - reference: PMID:25921057
      reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Bohring-Opitz syndrome is a rare genetic condition characterized by
        distinctive facial features, variable microcephaly, hypertrichosis,
        nevus flammeus, severe myopia, unusual posture (flexion at the elbows
        with ulnar deviation, and flexion of the wrists and metacarpophalangeal
        joints), severe intellectual disability, and feeding issues.
      explanation: >-
        The same clinical-management evidence supports unusual posture as a
        characteristic BOS manifestation.
  - target: Nephroblastoma (Wilms tumor)
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Constitutional ASXL1 truncation is associated with increased Wilms tumor
      surveillance concern in BOS, although the intervening tumor mechanism is
      not fully specified.
    evidence:
    - reference: PMID:25921057
      reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Including the patients discussed herein, there are 43 published patients
        with BOS of which two had Wilms tumor and one had bilateral
        nephroblastomatosis in infancy, making the incidence of a renal
        neoplastic process 7% among published patients, although this may be
        inflated due to biased ascertainment.
      explanation: >-
        The surveillance paper provides exact human clinical support for Wilms
        tumor/nephroblastomatosis as a downstream BOS manifestation.
  evidence:
  - reference: PMID:21706002
    reference_title: De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We sequenced the exomes of three individuals with Bohring-Opitz syndrome
      and in each identified heterozygous de novo nonsense mutations in ASXL1,
      which is required for maintenance of both activation and silencing of Hox
      genes.
    explanation: This is the core molecular evidence linking BOS to de novo ASXL1 loss-of-function and disrupted developmental gene regulation.
  - reference: PMID:37053013
    reference_title: Multiomics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and noncanonical Wnt signaling dysregulation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ASXL1 (additional sex combs-like 1) plays key roles in epigenetic
      regulation of early developmental gene expression.
    explanation: This supports the broader epigenetic mechanism of BOS in patient-derived cell models.
- name: ASXL1 truncation dysregulates Wnt signaling and tissue patterning
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Multiomics studies in patient-derived cells show canonical and noncanonical
    Wnt pathway perturbation, including broad activation of canonical Wnt
    signaling and increased VANGL2 expression. The cell-level signal is
    replicated across blood and fibroblast assays, but its causal translation
    to embryonic craniofacial and organ phenotypes remains provisional because
    the study examined differentiated postnatal cells.
  genes:
  - preferred_term: ASXL1
    modifier: ABNORMAL
    term:
      id: hgnc:18318
      label: ASXL1
  biological_processes:
  - preferred_term: Wnt signaling pathway
    modifier: ABNORMAL
    term:
      id: GO:0016055
      label: Wnt signaling pathway
  - preferred_term: canonical Wnt signaling pathway
    modifier: ABNORMAL
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
  - preferred_term: Wnt signaling pathway, planar cell polarity pathway
    modifier: ABNORMAL
    term:
      id: GO:0060071
      label: Wnt signaling pathway, planar cell polarity pathway
  downstream:
  - target: Trigonocephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Disturbed craniofacial patterning contributes to abnormal skull shape and metopic ridge prominence.
    evidence:
    - reference: PMID:29446906
      reference_title: Bohring-Opitz Syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The facial features may include microcephaly or trigonocephaly /
        prominent (but not fused) metopic ridge, hypotonic facies with full
        cheeks, synophrys, glabellar and eyelid nevus flammeus (simplex),
        prominent globes, widely set eyes, palate anomalies, and micrognathia.
      explanation: This supports trigonocephaly as a characteristic BOS craniofacial manifestation that fits downstream developmental patterning defects.
  - target: Micrognathia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Disturbed craniofacial development contributes to the characteristic small jaw phenotype.
    evidence:
    - reference: PMID:25921057
      reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The differential is broad for these patients with hypertrichosis and
        IUGR resembling Cornelia de Lange syndrome, coarse facial features
        resembling a storage disease or RASopathy, and micrognathia resembling
        Treacher Collins syndrome.
      explanation: This supports micrognathia as a major BOS facial feature and frames it within the syndrome's craniofacial patterning phenotype.
  - target: Nevus flammeus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disturbed tissue patterning in BOS is associated with the glabellar and
      eyelid nevus flammeus component of the craniofacial gestalt.
    evidence:
    - reference: PMID:29446906
      reference_title: Bohring-Opitz Syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The facial features may include microcephaly or trigonocephaly /
        prominent (but not fused) metopic ridge, hypotonic facies with full
        cheeks, synophrys, glabellar and eyelid nevus flammeus (simplex),
        prominent globes, widely set eyes, palate anomalies, and micrognathia.
      explanation: >-
        GeneReviews evidence lists nevus flammeus as part of the BOS
        craniofacial pattern.
  evidence:
  - reference: PMID:37053013
    reference_title: Multiomics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and noncanonical Wnt signaling dysregulation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The data showed a broad activation of canonical Wnt signaling at the
      transcriptional and protein levels and upregulation of VANGL2, which
      encodes a planar cell polarity pathway protein that acts through
      noncanonical Wnt signaling to direct tissue patterning and cell
      migration.
    explanation: This directly supports Wnt pathway dysregulation and altered tissue-patterning mechanisms in BOS patient-derived cells.
phenotypes:
- name: Severe intellectual disability
  category: Neurologic
  diagnostic: true
  description: >-
    Severe intellectual disability is a defining BOS neurodevelopmental
    manifestation.
  phenotype_term:
    preferred_term: Severe intellectual disability
    term:
      id: HP:0010864
      label: Severe intellectual disability
  evidence:
  - reference: PMID:21706002
    reference_title: De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bohring-Opitz syndrome is characterized by severe intellectual
      disability, distinctive facial features and multiple congenital
      malformations.
    explanation: This explicitly supports severe intellectual disability as a core BOS feature.
- name: Global developmental delay
  category: Neurologic
  diagnostic: true
  description: >-
    Global developmental delay is common in BOS and reflects pervasive
    neurodevelopmental impairment.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:25921057
    reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bohring-Opitz syndrome has previously been associated with high infant
      mortality (11 out of 43 reported patients (26%), intrauterine growth
      retardation, feeding difficulties often requiring a feeding tube,
      failure to thrive, severe to profound developmental delays, recurrent
      infections, nonspecific brain abnormalities, variable microcephaly,
      distinctive facial features
    explanation: This supports broad developmental delay as a common BOS manifestation.
- name: Seizures
  category: Neurologic
  description: >-
    Seizures are common in BOS and are generally responsive to standard
    antiseizure treatment.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:29446906
    reference_title: Bohring-Opitz Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Seizures are common and typically responsive to standard epileptic
      medications.
    explanation: GeneReviews directly supports the seizure phenotype and usual treatment response.
- name: Recurrent infections
  category: Immunologic
  description: >-
    Recurrent infections contribute substantially to early-life morbidity but
    often become less frequent with age.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:29446906
    reference_title: Bohring-Opitz Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Affected individuals may experience recurrent infections, which also tend
      to improve with age.
    explanation: GeneReviews directly supports recurrent infections and their age-related improvement.
- name: Obstructive sleep apnea
  category: Respiratory
  description: >-
    Obstructive sleep apnea is an important airway complication that may require
    polysomnography and escalating respiratory or craniofacial management.
  phenotype_term:
    preferred_term: Obstructive sleep apnea
    term:
      id: HP:0002870
      label: Obstructive sleep apnea
  evidence:
  - reference: PMID:29446906
    reference_title: Bohring-Opitz Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Due to the prevalence of obstructive sleep apnea, polysomnography should
      be considered.
    explanation: GeneReviews directly supports obstructive sleep apnea as a clinically important BOS complication.
- name: High myopia
  category: Ophthalmologic
  description: >-
    Severe or high myopia is a characteristic ocular manifestation and
    motivates regular vision follow-up.
  phenotype_term:
    preferred_term: High myopia
    term:
      id: HP:0011003
      label: High myopia
  evidence:
  - reference: PMID:25921057
    reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bohring-Opitz syndrome is a rare genetic condition characterized by
      distinctive facial features, variable microcephaly, hypertrichosis,
      nevus flammeus, severe myopia, unusual posture (flexion at the elbows
      with ulnar deviation, and flexion of the wrists and metacarpophalangeal
      joints), severe intellectual disability, and feeding issues.
    explanation: The clinical series explicitly lists severe myopia among the characteristic manifestations.
- name: Intrauterine growth restriction
  category: Growth
  diagnostic: true
  description: >-
    Prenatal growth restriction is a common early component of the BOS growth
    phenotype.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:25921057
    reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bohring-Opitz syndrome has previously been associated with high infant
      mortality (11 out of 43 reported patients (26%), intrauterine growth
      retardation, feeding difficulties often requiring a feeding tube,
      failure to thrive, severe to profound developmental delays, recurrent
      infections, nonspecific brain abnormalities, variable microcephaly,
      distinctive facial features
    explanation: The clinical series directly supports prenatal growth restriction as a BOS feature.
- name: Failure to thrive
  category: Growth
  diagnostic: true
  description: >-
    Poor postnatal weight gain and failure to thrive are common in BOS and are
    strongly influenced by feeding difficulty.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:29446906
    reference_title: Bohring-Opitz Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Feeding difficulties in early childhood, including cyclic vomiting, have
      a significant impact on overall health; feeding tends to improve with
      age.
    explanation: This supports the feeding-related mechanism that drives failure to thrive in BOS.
- name: Feeding difficulties
  category: Gastrointestinal
  diagnostic: true
  description: >-
    Feeding intolerance, often with cyclic vomiting or aspiration, is a major
    early-life BOS complication.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:29446906
    reference_title: Bohring-Opitz Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Feeding difficulties in early childhood, including cyclic vomiting, have
      a significant impact on overall health; feeding tends to improve with
      age.
    explanation: This directly supports feeding difficulties as a major BOS feature.
- name: Hypertrichosis
  category: Dermatologic
  diagnostic: true
  description: >-
    Hypertrichosis is a recurrent dysmorphic feature in BOS.
  phenotype_term:
    preferred_term: Hypertrichosis
    term:
      id: HP:0000998
      label: Hypertrichosis
  evidence:
  - reference: PMID:25921057
    reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bohring-Opitz syndrome is a rare genetic condition characterized by
      distinctive facial features, variable microcephaly, hypertrichosis,
      nevus flammeus, severe myopia, unusual posture (flexion at the elbows
      with ulnar deviation, and flexion of the wrists and metacarpophalangeal
      joints), severe intellectual disability, and feeding issues.
    explanation: This directly supports hypertrichosis as a BOS phenotype.
- name: Micrognathia
  category: Craniofacial
  diagnostic: true
  description: >-
    Micrognathia is part of the characteristic BOS craniofacial gestalt.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:29446906
    reference_title: Bohring-Opitz Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The facial features may include microcephaly or trigonocephaly /
      prominent (but not fused) metopic ridge, hypotonic facies with full
      cheeks, synophrys, glabellar and eyelid nevus flammeus (simplex),
      prominent globes, widely set eyes, palate anomalies, and micrognathia.
    explanation: This directly supports micrognathia as part of the BOS facial phenotype.
- name: Trigonocephaly
  category: Craniofacial
  diagnostic: true
  description: >-
    Trigonocephaly or a prominent metopic ridge is a recurring cranial shape
    abnormality in BOS.
  phenotype_term:
    preferred_term: Trigonocephaly
    term:
      id: HP:0000243
      label: Trigonocephaly
  evidence:
  - reference: PMID:29446906
    reference_title: Bohring-Opitz Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The facial features may include microcephaly or trigonocephaly /
      prominent (but not fused) metopic ridge, hypotonic facies with full
      cheeks, synophrys, glabellar and eyelid nevus flammeus (simplex),
      prominent globes, widely set eyes, palate anomalies, and micrognathia.
    explanation: This directly supports trigonocephaly as a BOS craniofacial feature.
- name: Nevus flammeus
  category: Dermatologic
  diagnostic: true
  description: >-
    Glabellar and eyelid nevus flammeus is part of the characteristic BOS
    facial gestalt.
  phenotype_term:
    preferred_term: Port-wine stain
    term:
      id: HP:0001052
      label: Nevus flammeus
  evidence:
  - reference: PMID:29446906
    reference_title: Bohring-Opitz Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The facial features may include microcephaly or trigonocephaly /
      prominent (but not fused) metopic ridge, hypotonic facies with full
      cheeks, synophrys, glabellar and eyelid nevus flammeus (simplex),
      prominent globes, widely set eyes, palate anomalies, and micrognathia.
    explanation: This directly supports nevus flammeus as a BOS craniofacial feature.
- name: Characteristic BOS posture
  category: Musculoskeletal
  diagnostic: true
  description: >-
    The typical flexed elbow, wrist, and metacarpophalangeal posture is a
    defining BOS clinical sign.
  phenotype_term:
    preferred_term: Characteristic BOS posture
    term:
      id: HP:0001376
      label: Limitation of joint mobility
  evidence:
  - reference: PMID:25921057
    reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bohring-Opitz syndrome is a rare genetic condition characterized by
      distinctive facial features, variable microcephaly, hypertrichosis,
      nevus flammeus, severe myopia, unusual posture (flexion at the elbows
      with ulnar deviation, and flexion of the wrists and metacarpophalangeal
      joints), severe intellectual disability, and feeding issues.
    explanation: This directly supports the characteristic BOS posture phenotype.
- name: Nephroblastoma (Wilms tumor)
  category: Oncologic
  diagnostic: false
  description: >-
    Individuals with BOS appear to have an elevated risk of Wilms tumor,
    motivating surveillance in childhood.
  phenotype_term:
    preferred_term: Nephroblastoma
    term:
      id: HP:0002667
      label: Nephroblastoma
  evidence:
  - reference: PMID:25921057
    reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Including the patients discussed herein, there are 43 published patients
      with BOS of which two had Wilms tumor and one had bilateral
      nephroblastomatosis in infancy, making the incidence of a renal
      neoplastic process 7% among published patients, although this may be
      inflated due to biased ascertainment.
    explanation: This provides human clinical evidence for elevated Wilms tumor risk in BOS.
differential_diagnoses:
- name: Cornelia de Lange syndrome
  description: >-
    Cornelia de Lange syndrome overlaps with BOS through growth restriction and
    hypertrichosis, but the shared presentation should be resolved by
    BOS-typical ASXL1 testing and the broader BOS facial/postural pattern.
  disease_term:
    preferred_term: Cornelia de Lange syndrome
    term:
      id: MONDO:0016033
      label: Cornelia de Lange syndrome
  distinguishing_features:
  - BOS typically shows ASXL1 truncating variants rather than cohesin-pathway defects.
  - BOS posture and the characteristic facial gestalt help separate BOS from CdLS.
  evidence:
  - reference: PMID:25921057
    reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The differential is broad for these patients with hypertrichosis and
      IUGR resembling Cornelia de Lange syndrome, coarse facial features
      resembling a storage disease or RASopathy, and micrognathia resembling
      Treacher Collins syndrome.
    explanation: This explicitly names Cornelia de Lange syndrome as a BOS mimic.
- name: Treacher Collins syndrome
  description: >-
    Treacher Collins syndrome is a craniofacial differential because BOS can
    present with micrognathia and facial dysmorphism, but BOS has more global
    neurodevelopmental involvement and hypertrichosis.
  disease_term:
    preferred_term: Treacher Collins syndrome
    term:
      id: MONDO:0007944
      label: Treacher Collins syndrome 1
  distinguishing_features:
  - BOS usually has profound developmental delay and hypertrichosis, which are not defining features of Treacher Collins syndrome.
  - BOS facial pattern is broader than isolated mandibulofacial dysostosis.
  evidence:
  - reference: PMID:25921057
    reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The differential is broad for these patients with hypertrichosis and
      IUGR resembling Cornelia de Lange syndrome, coarse facial features
      resembling a storage disease or RASopathy, and micrognathia resembling
      Treacher Collins syndrome.
    explanation: This explicitly names Treacher Collins syndrome as a BOS mimic.
- name: RASopathy
  description: >-
    RASopathy is a useful broad differential for BOS because coarse facial
    features may resemble a RAS/MAPK syndrome, but BOS is driven by ASXL1
    truncation and has the BOS posture and neurodevelopmental profile.
  disease_term:
    preferred_term: RASopathy
    term:
      id: MONDO:0021060
      label: RASopathy
  distinguishing_features:
  - BOS has ASXL1-related chromatin dysregulation rather than RAS/MAPK pathway activation.
  - BOS usually has marked feeding issues, hypertrichosis, and a characteristic posture.
  evidence:
  - reference: PMID:25921057
    reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The differential is broad for these patients with hypertrichosis and
      IUGR resembling Cornelia de Lange syndrome, coarse facial features
      resembling a storage disease or RASopathy, and micrognathia resembling
      Treacher Collins syndrome.
    explanation: This explicitly names RASopathy as a BOS mimic.
- name: Lysosomal storage disease
  description: >-
    Lysosomal storage disease can resemble BOS when coarse facial features are
    prominent, but BOS lacks the enzyme-deficiency and biochemical storage
    signature of a true lysosomal disorder.
  disease_term:
    preferred_term: lysosomal storage disease
    term:
      id: MONDO:0002561
      label: lysosomal storage disease
  distinguishing_features:
  - BOS is molecularly confirmed by ASXL1 testing rather than by lysosomal enzyme analysis.
  - BOS typically shows early developmental delay and hypertrichosis rather than a storage biochemistry profile.
  evidence:
  - reference: PMID:25921057
    reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The differential is broad for these patients with hypertrichosis and
      IUGR resembling Cornelia de Lange syndrome, coarse facial features
      resembling a storage disease or RASopathy, and micrognathia resembling
      Treacher Collins syndrome.
    explanation: This explicitly names storage disease as a BOS mimic.
genetic:
- name: ASXL1
  gene_term:
    preferred_term: ASXL1
    term:
      id: hgnc:18318
      label: ASXL1
  association: Heterozygous protein-truncating pathogenic variants
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  notes: >-
    Most molecularly confirmed cases result from de novo constitutional
    truncating variants. Because ASXL1 is also recurrently mutated somatically
    in myeloid neoplasia, the diagnostic assertion is specifically
    constitutional rather than a blood-only somatic finding.
  evidence:
  - reference: CGGV:assertion_31e0ce4d-aeb7-4983-9ec2-85178d7f40f0-2021-07-30T160000.000Z
    reference_title: "ASXL1 / Bohring-Opitz syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ASXL1 | HGNC:18318 | Bohring-Opitz syndrome | MONDO:0011510 | AD | Definitive"
    explanation: ClinGen classifies the ASXL1-Bohring-Opitz syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
  - reference: PMID:21706002
    reference_title: De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We sequenced the exomes of three individuals with Bohring-Opitz syndrome
      and in each identified heterozygous de novo nonsense mutations in ASXL1,
      which is required for maintenance of both activation and silencing of Hox
      genes.
    explanation: >-
      The discovery series directly supports heterozygous de novo truncating
      ASXL1 variants as causal.
  - reference: PMID:37053013
    reference_title: Multiomics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and noncanonical Wnt signaling dysregulation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These BOS-causing ASXL1 variants are also high-prevalence somatic driver
      mutations in acute myeloid leukemia.
    explanation: >-
      The overlap with somatic myeloid driver variants supports explicitly
      requiring a constitutional diagnostic interpretation.
diagnosis:
- name: ASXL1 molecular genetic testing
  description: >-
    Molecular testing for a constitutional heterozygous pathogenic ASXL1
    variant confirms the diagnosis in a proband with suggestive clinical
    features.
  presence: Identification of a constitutional heterozygous pathogenic ASXL1 variant establishes the diagnosis.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: ASXL1
        term:
          id: hgnc:18318
          label: ASXL1
  evidence:
  - reference: PMID:29446906
    reference_title: Bohring-Opitz Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      DIAGNOSIS/TESTING: The diagnosis of Bohring-Opitz syndrome (BOS) is
      established in a proband with suggestive clinical features and/or the
      identification of a constitutional heterozygous pathogenic variant in
      ASXL1 by molecular genetic testing.
    explanation: This directly supports ASXL1 molecular testing as the confirmatory diagnostic approach.
datasets:
- accession: geo:GSE230696
  title: Multiomics of Bohring-Opitz syndrome truncating ASXL1 mutations
  description: >-
    Human primary-cell multi-omics dataset from Bohring-Opitz syndrome patients
    and controls, including peripheral blood and skin fibroblast assays used to
    study epigenomic dysregulation and Wnt signaling.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MULTI_OMICS_PERTURBATION
  sample_types:
  - preferred_term: peripheral blood
    term:
      id: UBERON:0000178
      label: blood
    tissue_term:
      preferred_term: blood
      term:
        id: UBERON:0000178
        label: blood
  - preferred_term: skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
    cell_type_term:
      preferred_term: skin fibroblast
      term:
        id: CL:0002620
        label: skin fibroblast
  sample_count: 67
  conditions:
  - Bohring-Opitz syndrome
  - control
  publication: PMID:37053013
  notes: >-
    The reported total comprises 18 individuals with BOS and 49 controls;
    assay-specific sample sizes differ, and only four affected individuals
    contributed both blood and fibroblast specimens.
  evidence:
  - reference: PMID:37053013
    reference_title: Multiomics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and noncanonical Wnt signaling dysregulation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We used primary cells from individuals with BOS (n = 18) and controls
      (n = 49) to dissect gene regulatory changes caused by ASXL1 mutations
      using comprehensive multiomics assays for chromatin accessibility
      (ATAC-seq), DNA methylation, histone methylation binding, and
      transcriptome in peripheral blood and skin fibroblasts.
    explanation: >-
      This directly supports the cohort size, specimen types, and multi-omics
      content represented by GSE230696.
  findings:
  - statement: Patient-derived primary cells from BOS and controls reveal cross-tissue epigenomic disruption and Wnt signaling dysregulation.
    evidence:
    - reference: PMID:37053013
      reference_title: Multiomics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and noncanonical Wnt signaling dysregulation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We used primary cells from individuals with BOS (n = 18) and controls
        (n = 49) to dissect gene regulatory changes caused by ASXL1 mutations
        using comprehensive multiomics assays for chromatin accessibility
        (ATAC-seq), DNA methylation, histone methylation binding, and
        transcriptome in peripheral blood and skin fibroblasts.
      explanation: This supports the dataset as a human primary-cell BOS resource for mechanistic epigenomic analysis.
    - reference: PMID:37053013
      reference_title: Multiomics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and noncanonical Wnt signaling dysregulation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Our data show that regardless of cell type, ASXL1 mutations drive
        strong cross-tissue effects that disrupt multiple layers of the
        epigenome.
      explanation: This supports the dataset as a primary-cell BOS resource for multi-omics epigenomic analysis.
clinical_trials:
- name: NCT03303716
  status: RECRUITING
  description: >-
    Recruiting observational natural-history registry for ASXL-related
    disorders, including Bohring-Opitz syndrome, focused on longitudinal
    natural history, management, and treatment experience. This is not an
    interventional therapy trial; registry status was checked on 2026-07-24.
  evidence:
  - reference: clinicaltrials:NCT03303716
    reference_title: Natural History Study for the ASXL-Related Disorders and Chromatinopathies
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A registry focused on the natural history, management and treatment of
      patients with Bohring-Opitz Syndrome (ASXL1), Shashi-Pena Syndrome
      (ASXL2) and Bainbridge-Ropers Syndrome (ASXL3).
    explanation: >-
      The ClinicalTrials.gov summary directly supports inclusion of BOS in this
      ASXL natural-history registry.
- name: NCT01793168
  status: RECRUITING
  description: >-
    Recruiting international rare-disease patient registry that lists
    Bohring-Opitz syndrome among many eligible conditions. It is a broad
    observational registry rather than a BOS-specific treatment study; registry
    status was checked on 2026-07-24.
  evidence:
  - reference: clinicaltrials:NCT01793168
    reference_title: Coordination of Rare Diseases at Sanford
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It provides researchers with a centralized, international patient registry
      for all rare diseases.
    explanation: >-
      The ClinicalTrials.gov summary supports the registry's broad observational
      scope.
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT01793168
    reference_title: "https://clinicaltrials.gov/api/v2/studies/NCT01793168"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bohring-Opitz Syndrome"
    explanation: >-
      The current structured registry record specifically lists Bohring-Opitz
      syndrome as an eligible condition.
treatments:
- name: Enteral feeding support
  action_category: THERAPEUTIC
  description: >-
    Gastrostomy or gastrojejunal tube feeding is commonly used when oral intake
    is inadequate because of severe feeding difficulty and cyclic emesis.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:25921057
    reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All eight patients struggled with adequate caloric intake by mouth, and
      Patients 2 and 5 had significant episodes of cyclic emesis.
    explanation: This supports feeding support as a central management need in BOS.
  - reference: PMID:25921057
    reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients 2–6 required gastrostomy tubes due to aspiration and/or an
      inability to take adequate calories orally.
    explanation: This directly supports gastrostomy-based enteral feeding support in BOS.
- name: Cyclic vomiting prevention and early abortive treatment
  action_category: THERAPEUTIC
  description: >-
    Identify and avoid individual emesis triggers, consider daily preventive
    medication, and use an early abortive antiemetic plan. Controlling severe
    vomiting can reduce dehydration, aspiration, hospitalization, and infectious
    exposure.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:29446906
    reference_title: Bohring-Opitz Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cyclic vomiting may be managed by identification and avoidance of
      triggers, daily maintenance medication, and early abortive treatment;
      G-tubes or GJ-tubes may decrease aspiration and improve nutrition.
    explanation: >-
      GeneReviews directly supports trigger avoidance, maintenance therapy, and
      early abortive management of cyclic vomiting.
- name: Sleep-apnea and aspiration-related airway management
  action_category: THERAPEUTIC
  description: >-
    Consider polysomnography and craniofacial or respiratory evaluation.
    Management can include noninvasive positive airway pressure, craniofacial
    surgery, or tracheostomy when severe obstructive apnea or aspiration-related
    lung disease is not adequately controlled.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Obstructive sleep apnea
    term:
      id: HP:0002870
      label: Obstructive sleep apnea
  evidence:
  - reference: PMID:29446906
    reference_title: Bohring-Opitz Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Due to the prevalence of obstructive sleep apnea, polysomnography should
      be considered. Referral to a craniofacial team should be considered for
      those with palatal abnormalities, micrognathia, or obstructive sleep
      apnea. Tracheostomy may be considered for those with recurrent aspiration
      who develop secondary lung disease, or in those with severe sleep apnea
      that is not adequately treated with noninvasive pressure support (e.g.,
      CPAP, BiPAP) or surgical intervention (e.g., mandibular distraction).
    explanation: >-
      GeneReviews supplies the sleep evaluation and escalation options for
      severe apnea or aspiration-related respiratory disease.
- name: Standard antiseizure management
  action_category: THERAPEUTIC
  description: >-
    Treat seizures with standard syndrome-appropriate antiseizure medication
    and neurologic follow-up; no BOS-specific antiseizure regimen has been
    established.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:29446906
    reference_title: Bohring-Opitz Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Standard management is indicated for seizures, congenital heart defects,
      intellectual disability, myopia, urinary tract infections, urinary
      retention, and kidney stones.
    explanation: GeneReviews recommends standard management rather than a BOS-specific seizure regimen.
- name: Wilms tumor renal-ultrasound surveillance
  action_category: SCREENING
  description: >-
    Perform renal ultrasound every three months from birth through age eight
    years. The recommendation is precautionary: it is based on isolated reports
    and a small case series rather than a population-level risk estimate.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:29446906
    reference_title: Bohring-Opitz Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Surveillance: Renal ultrasound every three months from birth to age eight
      to screen for the development of Wilms tumor
    explanation: >-
      GeneReviews directly states the surveillance interval and age range.
  - reference: PMID:25921057
    reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Including the patients discussed herein, there are 43 published patients
      with BOS of which two had Wilms tumor and one had bilateral
      nephroblastomatosis in infancy, making the incidence of a renal
      neoplastic process 7% among published patients, although this may be
      inflated due to biased ascertainment.
    explanation: >-
      The source supports surveillance concern while explicitly warning that
      the observed proportion may be inflated by ascertainment bias.
- name: Growth, feeding, development, and vision follow-up
  action_category: MONITORING
  description: >-
    Provide frequent growth and developmental monitoring, specialist follow-up
    for feeding intolerance, and regular ophthalmologic care to optimize vision.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:29446906
    reference_title: Bohring-Opitz Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      frequent monitoring of growth and development; close monitoring of
      feeding intolerance with a gastroenterology specialist; regular follow up
      for vision optimization.
    explanation: GeneReviews directly states these longitudinal monitoring needs.
discussions:
- discussion_id: bos_truncation_molecular_consequence
  prompt: >-
    Do late ASXL1 truncating variants cause BOS mainly through loss of
    full-length repressive function, a dominant-negative effect, gain of
    function by a truncated protein, or a combination of these mechanisms?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#ASXL1 truncation disrupts epigenetic regulation of developmental gene expression
  rationale: >-
    The causal gene-disease relationship and the cross-tissue epigenomic
    disturbance are strong, but the variants should not be reduced to simple
    gene under-expression. The pathophysiology graph therefore records abnormal
    ASXL1 function and leaves the precise molecular consequence open.
  evidence:
  - reference: PMID:37053013
    reference_title: Multiomics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and noncanonical Wnt signaling dysregulation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our data show that regardless of cell type, ASXL1 mutations drive strong
      cross-tissue effects that disrupt multiple layers of the epigenome.
    explanation: >-
      Patient-derived cells establish a broad epigenomic consequence without
      resolving one exclusive dosage or protein-effect mechanism.
- discussion_id: bos_wnt_developmental_translation
  prompt: >-
    Does Wnt and VANGL2 dysregulation measured in postnatal blood and skin
    fibroblasts directly cause BOS craniofacial and organ-patterning phenotypes
    during embryogenesis?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#ASXL1 truncation dysregulates Wnt signaling and tissue patterning
  rationale: >-
    Cross-tissue multi-omics and protein data support Wnt-pathway dysregulation,
    but the disease-defining malformations arise in embryonic cell populations
    that were not assayed. The graph therefore marks the Wnt node provisional
    and its phenotype links as indirect with unknown intermediates.
  evidence:
  - reference: PMID:37053013
    reference_title: Multiomics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and noncanonical Wnt signaling dysregulation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We used primary cells from individuals with BOS (n = 18) and controls
      (n = 49) to dissect gene regulatory changes caused by ASXL1 mutations
      using comprehensive multiomics assays for chromatin accessibility
      (ATAC-seq), DNA methylation, histone methylation binding, and
      transcriptome in peripheral blood and skin fibroblasts.
    explanation: >-
      The assayed patient-derived specimens are blood and skin fibroblasts, not
      the embryonic progenitors in which the malformations originate.
- discussion_id: bos_wilms_tumor_risk_precision
  prompt: >-
    What is the age-specific absolute risk of Wilms tumor in molecularly
    confirmed BOS, and does it justify the same surveillance intensity for all
    affected children?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Nephroblastoma (Wilms tumor)
  - treatments#Wilms tumor renal-ultrasound surveillance
  rationale: >-
    Current surveillance is clinically actionable, but the published numerator
    comes from a tiny, selected literature cohort. A prospective molecularly
    confirmed registry with person-time denominators is needed to estimate
    absolute and age-specific risk.
  evidence:
  - reference: PMID:25921057
    reference_title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Including the patients discussed herein, there are 43 published patients
      with BOS of which two had Wilms tumor and one had bilateral
      nephroblastomatosis in infancy, making the incidence of a renal
      neoplastic process 7% among published patients, although this may be
      inflated due to biased ascertainment.
    explanation: >-
      The original surveillance series explicitly identifies its small
      denominator and potential ascertainment inflation.
  - reference: PMID:29446906
    reference_title: Bohring-Opitz Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Isolated case reports suggest that individuals with BOS are at greater
      risk for Wilms tumor than the general population, but large-scale
      epidemiologic studies have not been conducted.
    explanation: GeneReviews confirms that population-scale risk data are absent.
review_notes: >-
  2026 re-review retained the strong ASXL1-centered core, changed the gene
  modifier from DECREASED to ABNORMAL to avoid encoding an unresolved
  truncation mechanism as simple haploinsufficiency, added explicit causal-link
  directness and mechanism confidence, natural history, high clinical burden,
  surveillance and supportive management, and two recruiting observational
  registries found in a ClinicalTrials.gov query checked on 2026-07-24. The
  disease-specific ASXL natural-history registry is distinguished from the
  broad CoRDS registry, and neither is represented as a therapeutic trial. The
  Wilms tumor recommendation is retained with its ascertainment-bias caveat.
  The disease-to-phenotype audit still reports 90 externally asserted granular
  phenotype gaps (30 carrying a PMID pointer); those rows were not bulk-imported
  because the local source cache does not provide exact support for most
  individual feature-frequency claims. Five clinically central features with
  direct cached support were added instead.
  The bundled Asta research report mixed unrelated disorders and was used only
  for source discovery; curated assertions were checked against the direct
  reference caches.
references:
- reference: PMID:29446906
  title: "Bohring-Opitz Syndrome."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:21706002
  title: De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome.
  findings: []
- reference: PMID:25921057
  title: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
  findings: []
- reference: PMID:37053013
  title: Multiomics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and noncanonical Wnt signaling dysregulation.
  findings: []
📚

References & Deep Research

References

4
PMID:29446906
Bohring-Opitz Syndrome.
No top-level findings curated for this source.
PMID:21706002
De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome.
No top-level findings curated for this source.
PMID:25921057
Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
No top-level findings curated for this source.
PMID:37053013
Multiomics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and noncanonical Wnt signaling dysregulation.
No top-level findings curated for this source.

Deep Research

1
Asta ▸
Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Bohring-Opitz syndrome. Core disease mechanisms, molecular and cellular pa...
Asta Scientific Corpus Retrieval 20 citations 2026-04-16T14:41:35.966811

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Bohring-Opitz syndrome. Core disease mechanisms, molecular and cellular pa...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] New therapeutic targets in rare genetic skeletal diseases

  • Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
  • Year: 2015
  • Venue: Expert Opinion on Orphan Drugs
  • URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
  • DOI: 10.1517/21678707.2015.1083853
  • PMID: 26635999
  • PMCID: 4643203
  • Citations: 37
  • Influential citations: 1
  • Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
  • Evidence snippets:
  • Snippet 1 (score: 0.396) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[2] Exploring the molecular mechanisms of subarachnoid hemorrhage and potential therapeutic targets: insights from bioinformatics and drug prediction

  • Authors: Yi Liu, Yang Zhang, Huan Wei, Li Wang, Lishang Liao
  • Year: 2025
  • Venue: Scientific Reports
  • URL: https://www.semanticscholar.org/paper/19a91d9c8cabec6a5a186729d545077e252ecb67
  • DOI: 10.1038/s41598-025-97642-8
  • PMID: 40229542
  • PMCID: 11997208
  • Summary: The findings not only elucidate the molecular mechanisms underlying SAH but also provide robust bioinformatics and experimental evidence supporting IRN as a promising therapeutic candidate, offering novel insights for future intervention strategies in SAH.
  • Evidence snippets:
  • Snippet 1 (score: 0.375) > involved in SAH pathology. As a result, our understanding of the cellular composition and microenvironment in SAH remains incomplete 8 . > Advances in bioinformatics provide powerful tools to analyze large-scale gene expression data and understand complex biological processes. By integrating transcriptomic data with immune cell infiltration analysis, we can gain a deeper understanding of the molecular mechanisms underlying SAH and identify potential key genes as therapeutic targets 9,10 . Previous studies have indicated that inflammation, oxidative stress, and cell death play crucial roles in the development of SAH, processes that are often closely associated with changes in specific cell types and immune responses 11 . > The goal of this study is to explore the molecular mechanisms of SAH, with a focus on immune cell infiltration and its role in disease progression. We aim to identify key genes and signaling pathways associated with SAH and investigate potential therapeutic strategies. Specifically, we will examine Isorhynchophylline (IRN) as a potential treatment for SAH and analyze its effects on relevant targets and signaling pathways. Through a comprehensive understanding of the pathological features of SAH, this study aims to provide valuable insights into future clinical interventions and treatment strategies.

[3] Cardiomyocytes Derived from Induced Pluripotent Stem Cells as a Disease Model for Propionic Acidemia

  • Authors: Esmeralda Alonso-Barroso, B. Pérez, L. Desviat, E. Richard
  • Year: 2021
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/da649a0f04477c53b448c5ac5f873f8762235290
  • DOI: 10.3390/ijms22031161
  • PMID: 33503868
  • PMCID: 7865492
  • Citations: 16
  • Influential citations: 1
  • Summary: The novel results show that PA iPSC-cardiomyocytes represent a promising model for investigating the pathological mechanisms underlying PA cardiomyopathies, also serving as an ex vivo platform for therapeutic evaluation.
  • Evidence snippets:
  • Snippet 1 (score: 0.373) > The study of the mechanisms involved in disease physiopathology has been mainly performed using the hypomorphic PA mouse model that mimics the biochemical and clinical phenotype [5]. Using this model, bioenergetic failure, oxidative damage and deregulation of miRNAs induced by accumulating propionyl-CoA have been described as potential mechanisms contributing to PA physiopathology [6][7][8]. The limitations of animal models for the study of cardiac energy metabolism [9] and of the commonly available cellular human models such as fibroblasts, underline the importance of generating new relevant cell models to provide deeper insight into the underlying mechanisms of disease. The use of in vitro models with human cellular context is highly recommended and, in this sense, induced pluripotent stem cells (iPSCs) have certain advantages since they provide the genetic background of the patient and represent an unlimited source of biological material for the study of pathophysiology and treatment effectiveness [10]. We have previously generated an iPSC line from a PA patient with defects in the PCCA gene that showed full pluripotency, differentiation capacity and genetic stability [11]. > In the present study, we aimed to establish a platform that served as a disease model to study the cellular and molecular alterations operating in cardiac tissue affected by PA disease. We described the characterization of cardiomyocytes derived from the PCCA iPSC line (PCCA iPSC-CMs) and the analysis of specific pathways potentially involved in cardiac PA physiopathology.

[4] The role of Extracellular Genomic Materials (EGMs) in psychiatric disorders

  • Authors: A. Kurtulmuş, Cemal Çağıl Koçana, S. Toprak, Selçuk Sözer
  • Year: 2023
  • Venue: Translational Psychiatry
  • URL: https://www.semanticscholar.org/paper/7997a9b821a1676ad0f2dc5e4a06ba6582806127
  • DOI: 10.1038/s41398-023-02549-5
  • PMID: 37464177
  • PMCID: 10354097
  • Citations: 4
  • Summary: Many aspects of EGMs have been elegantly reviewed, including their potential in diagnosis as biomarkers, application in treatment modalities, and functional effects in the pathophysiology of psychiatric disorders.
  • Evidence snippets:
  • Snippet 1 (score: 0.367) > Investigation of EGMs according to disease stages (such as acute exacerbation-remission or different stages of bipolar), disease subgroups, and phenotypic characteristics of patients holds the potential to uncover the related biological mechanisms and target more specific relevant pathways for treatment. Studies exploring the changes in expression levels of free EGMs, such as cimiRNAs and lncRNAs, as well as variations in metabolite and protein cargoes of EVs throughout different stages of the disease and in association with clinical phenotypes, would provide valuable insight into underlying mechanisms and pathways. Moreover, considering the overlapping symptomatology observed in different psychiatric diseases and the common genetic, neuroanatomical, and neurobiological findings, cross-disorders studies can also provide important information about at what points these diseases overlap and differ from each other, both biological and epigenetic wise. Furthermore, prospective studies with high-risk clinical individuals and prodromal patients may shed light on the biological processes associated with disease progression and transformation. Additionally, EGM studies have the potential to contribute valuable information on the neurobiological and epigenetic mechanisms underlying some environmental risk factors, such as stress, trauma and drug abuse, that contribute to the development of the diseases. > Another potential application of EGMs is to investigate the mechanisms of action of various treatment methods, such as lithium and electroconvulsive therapy (ECT), which are highly effective and widely used in treatment but still lack a complete understanding of underlying mechanisms. In this regard, EVs studies are very promising in particular. Analyzing changes in cargo contents following these treatments could help bridge the gap between neurobiology and clinical outcomes. For example, it has been hypothesized that ECT may act by inducing CNS cells to secrete EVs containing harmful and neurotoxic proteins/metabolites [124]. > The research on CNS including post-mortem or preclinical studies which allow in situ analysis of the organ system has certain limitations, such as ethical concerns and criticism regarding to the extent to which these studies accurately reflect real diseases in vivo. However, the concept of analyzing the peripheral markers that are expected to reflect disease status in the CNS remains a subject of debate. Nevertheless, the potential of EGMs may overcome such obstacles.

[5] Recent Evidences of Epigenetic Alterations in Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review

  • Authors: R. Ragusa, Pasquale Bufano, A. Tognetti, M. Laurino, Chiara Caselli
  • Year: 2025
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/2660cdbbe1f205c631fe890e5c6a3c8d9b81ce5f
  • DOI: 10.3390/ijms26062571
  • PMID: 40141213
  • PMCID: 11942187
  • Citations: 4
  • Summary: A systematic review of the latest knowledge on epigenetic modifications that characterize COPD, summarizing epigenetic factors that could serve as potential novel biomarkers and therapeutic targets for the treatment of COPD patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.367) > The papers included were clustered according to epigenetic mechanisms involved in COPD (molecular and cellular processes, as biomarker or therapeutic target). Tables 4-9 describe the extracted information, including the following: Study = name of first author et al., year; Country (Region) = where the study took place; Number of participants = sample size; Type of sample = biological sample employed; Gene affected = gene or group of genes whose expression can be "regulated" by epigenetic mechanisms; Epigenetic alteration = type of epigenetic alteration observed in the presence of disease; Activity in COPD = involvement of epigenetic elements in different molecular and cellular mechanisms associated with COPD; and Role of epigenetic mechanisms = epigenetic modifications that can be used to explain the pathophysiology of COPD or as biomarkers and therapeutic targets.

[6] Molecular genetic basis of epidermolysis bullosa

  • Authors: Y. Kotalevskaya, V. Stepanov
  • Year: 2023
  • Venue: Vavilov Journal of Genetics and Breeding
  • URL: https://www.semanticscholar.org/paper/720cbefbd0435504a6ed670ccf4f491dfbd3f143
  • DOI: 10.18699/VJGB-23-04
  • PMID: 36923479
  • PMCID: 10009482
  • Citations: 8
  • Influential citations: 2
  • Summary: The study of clinical, genetic and ultrastructural changes in EB has significantly expanded the understanding of the natural history of the disease and supplemented the data on genotype-phenotype correlations, promotes the search and study of epigenetic and non-genetic disease modifier factors, and also allows developing approaches to radical treatment of the Disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.366) > Epidermolysis bullosa (EB) is an inherited disorder of skin fragility, caused by mutations in a large number of genes associated with skin integrity and dermal-epidermal adhesion. Skin fragility is manifested by a decrease in resistance to external mechanical influences, the clinical signs of which are the formation of blisters, erosions and wounds on the skin and mucous membranes. EB is a multisystemic disease and characterized by a wide phenotypic spectrum with extracutaneous complications in severe types, besides the skin and mucous membranes, with high mortality. More than 30 clinical subtypes have been identified, which are grouped into four main types: simplex EB, junctional EB, dystrophic EB and Kindler syndrome. To date, pathogenic variants in 16 different genes are associated with EB and encode proteins that are part of the skin anchoring structures or are signaling proteins. Genetic mutations cause dysfunction of cellular structures, differentiation, proliferation and apoptosis of cells, leading to mechanical instability of the skin. The formation of reduced proteins or decrease in their level leads mainly to functional disorders, forming mild or intermediate severe phenotypes. Absent protein expression is a result of null genetic variants and leads to structural abnormalities, causing a severe clinical phenotype. For most of the genes involved in the pathogenesis of EB, certain relationships have been established between the type and position of genetic variant and the severity of the clinical manifestations of the disease. Establishing an accurate diagnosis depends on the correlation of clinical, genealogical and immunohistological data in combination with molecular genetic testing. In general, the study of clinical, genetic and ultrastructural changes in EB has significantly expanded the understanding of the natural history of the disease and supplemented the data on genotype-phenotype correlations, promotes the search and study of epigenetic and non-genetic disease modifier factors, and also allows developing approaches to radical treatment of the disease. New advances of sequencing technologies have made it possible to describe new phenotypes and study their genetic and molecular mechanisms. This article describes the pathogenetic aspects and genes that cause main and rare syndromic subtypes of EB.

[7] Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy

  • Authors: Yaomeng Huang, Tongxin Li, Shichao Gao, Shuyu Li, Xiaoran Zhu et al.
  • Year: 2023
  • Venue: Frontiers in Pharmacology
  • URL: https://www.semanticscholar.org/paper/be229f6f2059faab4c97ec0a04bd055adab9dfe1
  • DOI: 10.3389/fphar.2023.1290253
  • PMID: 38026943
  • PMCID: 10662320
  • Citations: 3
  • Summary: Natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through bioinformatics analysis and led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression.
  • Evidence snippets:
  • Snippet 1 (score: 0.365) > Multiple pathways and molecules are involved in this process; however, the detailed underlying mechanisms remain unclear. In recent years, with the development of high-throughput sequencing and gene chip technologies, the use of bioinformatics technology to explore the occurrence, development, and prognosis of diseases has become a hot topic for scholars worldwide (Hwang et al., 2018;Nayor et al., 2019;Rinschen et al., 2019;Sturm et al., 2019;Montaner et al., 2020). > The present study aimed to use bioinformatics technology to screen for DCM-related genes and investigate their mechanisms, with the purpose of revealing the pathogenesis of DCM and seeking treatment methods. The GSE3586 dataset, containing expression profiles related to DCM, was selected from the Gene Expression Omnibus (GEO) database. This study aimed to predict the core genes that may play crucial roles in disease progression at the molecular level through the enrichment of relevant molecular pathways associated with DCM. Furthermore, the phenotype of the core genes was validated to further support the results of the bioinformatics analysis through basic and clinical experiments. Additionally, the role of glucocorticoids in DCM treatment is discussed in this article with the purpose of providing a theoretical and experimental basis for exploring the pathogenesis of DCM and elucidating therapeutic methods. This study also provides a theoretical reference for the interpretation, early diagnosis, and treatment of DCM.

[8] Modeling psychiatric disorders: from genomic findings to cellular phenotypes

  • Authors: Anna Falk, Vivi M. Heine, A. Harwood, Patrick F. Sullivan, M. Peitz et al.
  • Year: 2016
  • Venue: Molecular Psychiatry
  • URL: https://www.semanticscholar.org/paper/235b41240d78140de7ab06a3ad8a7d0b1bdff1a5
  • DOI: 10.1038/mp.2016.89
  • PMID: 27240529
  • PMCID: 4995546
  • Citations: 77
  • Influential citations: 2
  • Summary: The challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes are critically reviewed.
  • Evidence snippets:
  • Snippet 1 (score: 0.363) > The key challenge for iPSC-based disease modeling is to identify one or more relevant cellular phenotypes that accurately represent the disease pathophysiology. Increasing numbers of reports have demonstrated that for many diseases specific pathophysiology can be captured in human iPSC-based disease models. These range from cardiovascular disease, 44,45 cancer, 46,47 ocular disease, 48,49 diabetes mellitus 50,51 and neurological disorders of the brain. 52,53 Can the same approach be applied to complex psychiatric disorders? > The problem is that almost all psychiatric disorders are characterized by clinical signs and symptoms, but lack independent verification from objective biomarkers. Thus, how might these clinical phenotypes manifest themselves in terms of cell behavior? The identity of robust cellular 'readouts', which typify any psychiatric disorder, is a crucial unsolved problem and an area of intense study 54 (Table 2). When satisfactorily answered, this will herald a new degree of biological objectivity and quantification for the study of psychiatric disorders. > The aim is to find a single or small number of cell phenotypes or parameters that strongly associate with psychiatric disorders, and establish a cellular profile characteristic of cells derived from the general patient population. Although a consensus set of cellular phenotypes for psychiatric disorder is yet to be established, we can define some of their desired characteristics. First, cellular phenotypes have to relate to the biological pathways identified by genetics. Second, although there are many risk genes in disparate biological pathways, at some level, phenotypes should converge onto a much smaller grouping. Third, phenotypes need to be quantifiable. Finally, to be useful for drug development cellular phenotypes should be reversed by pharmacological treatment, although not necessarily by drugs in current use. > Although human iPSC-based approaches underrepresent the complexity of the human central nervous system, cellular phenotypes are likely to lie more proximal to molecular disease mechanisms than phenotypes seen at the level of a tissue or organism, 55 and thus may bypass compensatory homeostatic (2) Gene expression profiles of SCZ human iPSC neurons identified altered expression of many components of the cyclic AMP and WNT signaling pathways. > (3

[9] Future research trends in understanding the mechanisms underlying allergic diseases for improved patient care

  • Authors: H. Breiteneder, Z. Diamant, T. Eiwegger, W. Fokkens, C. Traidl‐Hoffmann et al.
  • Year: 2019
  • Venue: Allergy
  • URL: https://www.semanticscholar.org/paper/e19b0755c4f4903f68377333676edebf9bd73c89
  • DOI: 10.1111/all.13851
  • PMID: 31056763
  • PMCID: 6973012
  • Citations: 90
  • Influential citations: 3
  • Summary: Recent developments in research and patient care and future trends in the discipline are reviewed and topics on food allergy, biologics, small molecules, and novel therapeutic concepts in allergen‐specific immunotherapy for airway disease are highlighted.
  • Evidence snippets:
  • Snippet 1 (score: 0.362) > The past decades have witnessed extensive progress in unraveling cellular and molecular mechanisms of immune regulation in asthma, allergic diseases, organ transplantation, autoimmune diseases, tumor biology, and chronic infections. 1,2 Consequently, a better understanding of the functions, the reciprocal regulation, and the counterbalance of subsets of immune and inflammatory cells but also structural cells-for example, epithelial and vascular cells, airway smooth muscle cells, neuroendocrine system-that interact via various intercellular messengers will indicate avenues for immune interventions and novel treatment modalities of allergic diseases and immunological disorders. It is generally expected that drug development in the next decades will show a significant shift from chemicals to biologicals. > After more than 20 years without any breakthrough drug becoming available for patients, several disciplines including allergology are now experiencing extraordinary times with the recent licensing of several major biological drugs and novel allergen-specific immunotherapy (AIT) vaccines. Several biological modifiers of the immune response targeting intracellular messengers or their receptors have been developed to date. [3][4][5][6][7][8] In addition, a number of promising small molecule drugs and vaccines are in the development pipeline. [9][10][11] This new era is now calling for the development of biomarkers and phenoand endotyping of diseases for customized patient care, which is termed stratified medicine, precision medicine, or personalized medicine. 4 Distinguishing phenotypes of a complex disease covers the observable clinically relevant properties of the disease but does not show a direct relationship to disease etiology and pathophysiology. In a complex condition, such as asthma, different pathogenetic mechanisms can induce similar clinical manifestations; however, they may require different treatment approaches. 12,13 These pathophysiological mechanisms underlying disease subgroups are addressed by the term "endotype." [12][13][14] Classification of complex diseases based on the concept of endotypes provides advantages for epidemiological, genetic, and drug-related studies. Accurate endotyping by using reliable biomarkers reflects the natural history of the disease and aims to predict the response to (targeted) treatments. 15 Recent studies have focused on better understanding

[10] Precision Therapeutics in Lennox–Gastaut Syndrome: Targeting Molecular Pathophysiology in a Developmental and Epileptic Encephalopathy

  • Authors: Debopam Samanta
  • Year: 2025
  • Venue: Children
  • URL: https://www.semanticscholar.org/paper/455479c1bfbea7b90b73c109228f67c813d13888
  • DOI: 10.3390/children12040481
  • PMID: 40310132
  • PMCID: 12025602
  • Citations: 19
  • Influential citations: 1
  • Summary: A narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies, receptor and ligand dysfunction, receptor and ligand dysfunction, cell signaling abnormalities, cell signaling abnormalities, synaptopathies, and the repurposing of existing medications with mechanism-specific effects.
  • Evidence snippets:
  • Snippet 1 (score: 0.362) > A key advantage of disease-modifying therapies is their potential to target pathogenic mechanisms early in the disease course, potentially preventing the progression of some infantile epileptic encephalopathies to LGS. > This narrative review explores precision therapeutic strategies based on specific monogenic causes and disease mechanisms relevant to LGS. A comprehensive literature search (PubMed, MEDLINE, ClinicalTrials.gov, conference abstracts from the American Academy of Neurology and American Epilepsy Society, and gray literature) was conducted through 19 February 2025 to identify established ASMs, repurposed and novel drugs, as well as various gene therapy approaches with potential relevance to LGS. Given that over 900 monogenic causes of DEEs have been identified-implicating diverse cellular components such as ion channels, receptors, synaptic proteins, signaling pathways, metabolic processes, and epigenetic regulators-this review discusses current and emerging precision therapeutics based on shared molecular mechanisms and the pathophysiology of select genes associated with LGS [17] (Table 1).

[11] Role of Transcriptomics in Precision Oncology

  • Authors: Ruby Srivastava
  • Year: 2024
  • Venue: Reports of Radiotherapy and Oncology
  • URL: https://www.semanticscholar.org/paper/0bd862558bbb7286336111d9dfd232b5f905d3d9
  • DOI: 10.5812/rro-142195
  • Citations: 4
  • Summary: : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding o...
  • Evidence snippets:
  • Snippet 1 (score: 0.359) > : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding of cancer and opened a precise perspective for tumor diagnostics and therapy. The use of these approaches has strengthened our understanding of disease pathophysiology and classifications at the molecular level, including specific interference with drug mechanisms of action. Still, it has limited added value in the clinical setting. The omics data on precision medicine include the application of data from genes, transcripts, and proteins for diagnosis, monitoring of diseases, risk factor determination, counseling, and development of novel therapeutics. Bioinformatics applications have expanded statistics-based analysis toward deriving molecular pathways and process models for characterizing phenotypes and drug action mechanisms. In this review, we will discuss transcriptomics and interference analysis that allows the identification of predictive biomarkers at the molecular level to test drug response and analyze the molecular process interface of disease progression-relevant pathophysiology and mechanism of action to propose predictive biomarkers.

[12] Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

  • Authors: T. Nakajima, S. Tamura, M. Kurabayashi, Y. Kaneko
  • Year: 2021
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/3d299f57f344d42eff9d3565d1581dae7fb87a54
  • DOI: 10.3390/ijms22083930
  • PMID: 33920294
  • PMCID: 8069124
  • Citations: 6
  • Influential citations: 1
  • Summary: Since the epileptic phenotype appears to manifest prior to cardiac events in this mutation carrier, identifying KCND3 mutations in patients with epilepsy and providing optimal therapy will help prevent sudden unexpected death in epilepsy.
  • Evidence snippets:
  • Snippet 1 (score: 0.359) > Recent advances in molecular genetics have identified many causal genes for inherited arrhythmia syndromes (IASs) such as long QT syndrome (LQTS) [1], short QT syndrome (SQTS) [2], Brugada syndrome (BrS) [3,4] and early repolarization (ER) syndrome (ERS) [3,5]. Most causal genes for IASs encode cardiac ion channels or their related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterologous expression systems and experimental animal models, have revealed the pathophysiology of IASs and enabled the establishment of causal gene-specific precision medicine [6][7][8]. Furthermore, analyses of patient-specific and/or genome-edited induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have provided further insights into the pathophysiology of IASs and novel promising therapeutic strategies for IASs, although there are still some limitations of using iPSC-CMs, such as immature structure and function and mixed population of atrial, ventricular, and nodal cells, as a standard technology [9]. > The altered function of causal genes that encode cardiac ion channels is caused by multiple mechanisms, including trafficking defects, producing non-functional channels, altered channel gating properties, and a combination thereof. These altered functions of mutant channels underly the clinical phenotypes of IASs [10][11][12]. Particularly, unique electrophysiological properties of mutant channels have been shown to be associated with the atypical clinical phenotypes of IASs [10,13]. Furthermore, the elucidation of the mechanisms underlying the atypical clinical phenotypes of IASs has raised the possibility of mutation-specific precision medicine. > We herein review the current knowledge of genotype-phenotype relationships, underlying molecular and cellular mechanisms, and established pharmacological therapies of IASs, including LQTS, SQTS, and J wave syndrome (BrS and ERS).

[13] Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin

  • Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
  • Year: 2026
  • Venue: Nucleus
  • URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
  • DOI: 10.1080/19491034.2025.2611484
  • PMID: 41489464
  • PMCID: 12773485
  • Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
  • Evidence snippets:
  • Snippet 1 (score: 0.359) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

[14] Aberrant NLRP3 Inflammasome Activation Ignites the Fire of Inflammation in Neuromuscular Diseases

  • Authors: Christine Péladeau, J. Sandhu
  • Year: 2021
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/763a36db080236fca8cde89b2afcdf056f3584d0
  • DOI: 10.3390/ijms22116068
  • PMID: 34199845
  • PMCID: 8200055
  • Citations: 18
  • Influential citations: 1
  • Summary: Whether therapeutic targeting of the NLRP3 inflammasome components is a viable approach to alleviating the detrimental phenotype of neuromuscular diseases and improving clinical outcomes is examined.
  • Evidence snippets:
  • Snippet 1 (score: 0.356) > Despite a large number of mechanisms that have been identified in muscle degeneration and nerve cell loss, none have proven to be the primary cause of the disease. There is much need for a deeper understanding of the biology of the pathogeneses and the molecular mechanisms that are activated early in the diseases in order to identify "druggable" targets and disease-modifying treatments for these devastating diseases. > Human iPSC technologies are emerging as useful platforms for disease modeling to study pathogenic mechanisms and discover novel therapeutics for neuromuscular diseases [211,237]. Indeed, patient-derived iPSCs are being used to create a "patient-in-adish" disease model to derive relevant cell types for testing potential therapeutics, paving the way towards personalized medicine. This approach allows drug screening in a dish prior to administration to patients and "bench-to-bedside" translation of potential therapies. Additionally, iPSCs may also be used to stratify patients with various phenotypes and guide future clinical trials for bringing improved therapies to patients. Since multiple cell types are involved in disease pathogenesis, future research efforts need to be focused on deciphering "disease-specific signatures" at single-cell resolution, and not only in neuronal cells but also in non-neuronal cells. The application of modern technologies, including single-cell RNA sequencing and spatial transcriptomics, to neuromuscular diseases, will allow to ascertain cellular vulnerability and cell-specific mechanisms during various stages of disease progression. > The vital roles of the NLRP3 inflammasome in neuromuscular diseases such as DMD, LGMD and ALS, reveal that targeting this pathway is indeed a promising therapeutic strategy. Dysregulation of the NLRP3 inflammasome in muscle tissues by muscle damage, membrane instability, extracellular ATP and Ca 2+ ions or signals from infiltrating immune cells, clearly impacts the progression of neuromuscular and neurodegenerative disorders. Thus, modulation of these pathways involved with activation and assembly of NLRP3 inflammasome could be truly beneficial.

[15] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

  • Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
  • Year: 2012
  • Venue: Croatian Medical Journal
  • URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
  • DOI: 10.3325/cmj.2012.53.529
  • PMID: 23275318
  • PMCID: 3541579
  • Citations: 28
  • Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
  • Evidence snippets:
  • Snippet 1 (score: 0.354) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[16] Mucopolysaccharidosis Type I and α-Mannosidosis—Phenotypically Comparable but Genetically Different: Diagnostic and Therapeutic Considerations

  • Authors: Marika Venezia, Martina Vinci, P. Colomba, C. Zizzo, Giovanni Duro et al.
  • Year: 2025
  • Venue: Biomedicines
  • URL: https://www.semanticscholar.org/paper/86e1374e2f6804658c4f40460f685cb1f3c02ba1
  • DOI: 10.3390/biomedicines13051199
  • PMID: 40427026
  • PMCID: 12108828
  • Citations: 1
  • Summary: Genotype–phenotype correlations, diagnostic difficulties, and the applicability of artificial intelligence for the assistance of differential diagnosis are reviewed, with the goal of facilitating the earlier and more accurate diagnosis of these rare lysosomal storage diseases.
  • Evidence snippets:
  • Snippet 1 (score: 0.353) > These mechanisms are particularly relevant in explaining the clinical heterogeneity of monogenic disorders, such as lysosomal storage diseases (LSDs), which exhibit marked phenotypic variability and often weak genotype-phenotype correlations. The review by Hassan is a notable example, exploring the main epigenetic mechanisms and their role in phenotypic variability and therapeutic prospects, with a focus on three representative LSDs-Gaucher disease, Fabry disease, and Niemann-Pick type C-to encourage interest in epigenetics as a key to interpreting the biological complexity of these rare disorders [32]. > The identification of specific miRNA signatures in different individuals presenting with clinical signs and symptoms of MPS or alpha-mannosidosis could contribute to future research aimed at understanding the underlying molecular mechanisms. Circulating extracellular miRNAs, found in the bloodstream within exosomes or in complexes with proteins and lipoproteins, could serve as unique signatures associated with diagnosis. According to Nasrin Khan et al., the capillary electrophoresis-mass spectrometry (CE-MS) method enables a multiplex and direct analysis of miRNAs from biological samples [33]. In particular, with regard to the response to enzyme replacement therapy (ERT), it has been observed that microRNAs (miRNAs) can regulate post-treatment. In the context of therapeutic interventions, the prevailing recommendation is to identify the epigenetic mechanisms that influence both diseases. This identification process is intended to facilitate the development of specific treatments that have the potential to enhance the efficacy of ERT [26]. Studies on epigenetics would be of paramount importance with regard to disease progression and therapy, as it is believed to have influences not only on disease progression but also on response to treatment.

[17] Therapies for Mitochondrial Disease: Past, Present, and Future

  • Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R Thorburn, S. Rahman et al.
  • Year: 2025
  • Venue: Journal of Inherited Metabolic Disease
  • URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
  • DOI: 10.1002/jimd.70065
  • PMID: 40714961
  • PMCID: 12301291
  • Citations: 3
  • Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.352) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

[18] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

  • Authors: P. Mesdom, R. Colle, É. Lebigot, S. Trabado, Eric Deflesselle et al.
  • Year: 2020
  • Venue: Current Neuropharmacology
  • URL: https://www.semanticscholar.org/paper/79368e365458486de96794333613c12a6063bf54
  • DOI: 10.2174/1570159X17666191021141057
  • PMID: 31631822
  • PMCID: 7327943
  • Citations: 12
  • Summary: This review highlights the great and still underused potential of HDF, which stands out as a very promising tool in the understanding of MDD and AD mechanisms of action.
  • Evidence snippets:
  • Snippet 1 (score: 0.351) > Background: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. Objective The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. Methods The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. Results HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. Conclusion The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action

[19] Cellular reprogramming and inherited peripheral neuropathies: perspectives and challenges

  • Authors: M. Saporta
  • Year: 2015
  • Venue: Neural Regeneration Research
  • URL: https://www.semanticscholar.org/paper/8c3dabb1b4abf93506e2026564b8a329c0ec37c6
  • DOI: 10.4103/1673-5374.158345
  • PMID: 26199602
  • PMCID: 4498347
  • Citations: 4
  • Summary: iPSC-based models of neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and inherited peripheral neuropathies, have successfully reproduced pathophysiological findings from previous animal and cellular models and have also identified new disease mechanisms with potential therapeutical implications.
  • Evidence snippets:
  • Snippet 1 (score: 0.349) > Inherited peripheral neuropathies (or Charcot-Marie-Tooth disease, CMT) are a phenotypically and genetically heterogeneous group of disorders, which are currently untreatable. They are the most common inherited neuromuscular disorder, affecting around 1 in every 2,500 people (over 120,000 people in the US). Based on clinical neurophysiological and histopathological features, inherited neuropathies can be divided into two major forms: demyelinating (type 1) and axonal (type 2) CMT (Saporta, 2014). From a biological standpoint, these two major forms of CMT are associated with mutations in different sets of genes, affecting Schwann cell development and myelination (type 1) or peripheral axon physiology (type 2), although some overlap does exist (Figure 1). To date, over 70 genes have been associated with a CMT phenotype, making CMT an attractive natural model to study peripheral nervous system biology. Despite significant advances made in our knowledge of disease mechanisms in CMT, findings from animal models have so far translated poorly in clinical trials, underscoring the need for innovative methods to investigate the pathophysiology of these human disorders. Induced pluripotent stem cells (iPSCs) offer an unlimited source of patient specific, disease-relevant cell lines that can be used as a platform for identification of disease mechanisms, discovery of molecular targets and development of phenotypic screens for drug discovery (Saporta et al., 2011). iPSC-based models of neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and inherited peripheral neuropathies, have successfully reproduced pathophysiological findings from previous animal and cellular models and have also identified new disease mechanisms with potential therapeutical implications.

[20] An overview on cardiac involvement in Inborn Errors of Metabolism: from clinical clues to nutritional management strategies

  • Authors: C. Montanari, V. Tagi, Martina Tosi, Eliana Stucchi, Eleonora Pisano et al.
  • Year: 2025
  • Venue: Frontiers in Cardiovascular Medicine
  • URL: https://www.semanticscholar.org/paper/53edcd65284033a78e81633fbeb8012f21599561
  • DOI: 10.3389/fcvm.2025.1648010
  • PMID: 41425985
  • PMCID: 12711851
  • Summary: This review examines nutritional strategies for managing patients affected by IEMs with cardiac involvement, providing clinicians with research-backed guidance to support cardiological care, since specific nutritional strategies have shown promise in reversing or improving cardiac function in specific IEMs.
  • Evidence snippets:
  • Snippet 1 (score: 0.345) > Approximately 10% to 30% of the known causes of cardiomyopathy in childhood are attributable to IEMs (10, 130,131). In IEMs, cardiac manifestations can be indicative symptoms discovered during regular multisystem screening. While in disorders like MPS, heart manifestations may dominate the clinical presentation, in others, such as PD, they represent the sole clinical manifestation. Four fundamental mechanisms underlie the pathophysiology of cardiac involvement. First, cardiac symptoms can be linked to a reduction in energy production resulting from genetic mutations in proteins involved in energy homeostasis, molecular transport, or cellular organelles. Second, the intracellular accumulation of intermediates or storage substrates within cardiac myocytes can lead to structural and functional damage of the cardiac tissue. Third, the accumulation of intermediate metabolites may exert toxic effects on cardiac and surrounding tissues, for example, by triggering apoptosis in cardiac myocytes. Fourth, altered cellular functions such as signal transduction, depolarization, and cell adhesion, caused by the absence or alteration of glyconjugates, can compromise tissue integrity and cardiac function. It is important to note that pathogenetic mechanisms, summarized in Figure 3, may often overlap, particularly in later stages of the illness progression (33). In this review, we offered a comprehensive description of the cardiovascular diseases primarily associated with various types of IEMs, to guide cardiologists in the differential diagnosis (Figure 4). Moreover, the diagnosis of an underlying metabolic disorder should rely on the recognition of associated signs and symptoms characteristic of each specific disease. > IEMs have a wide phenotypic spectrum and may be characterized by a late onset or mild organ involvement, remaining misdiagnosed. Following the diagnosis of heart complications, the cardiologist should first conduct a detailed investigation of the patient's and family's medical history, including an assessment of consanguinity and/or the presence of rare inherited disorders. The patient's history should include age of onset of each clinically relevant symptom, the presence of associated pathological conditions and/or symptoms (hypoglycemia, myalgia, neurological issues or liver problems) and the result of neonatal screening.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.