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Classifications

ISDS Skeletal Nosology

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Definitions

1

Clinical ACC/TTLD spectrum definition

AOS denotes the clinical spectrum centered on the combination of scalp aplasia cutis congenita and terminal transverse limb defects. Marked intrafamilial variability and clinically overlapping ACC/TTLD presentations mean that this is a spectrum definition, not a sensitivity- or specificity-validated algorithm.

OTHER Individuals with aplasia cutis congenita and/or terminal transverse limb defects

Show evidence (2 references)

PMID:19610107 SUPPORT Human Clinical

"The combination of aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD) is often referred to as the eponymous Adams-Oliver syndrome (AOS)."

The clinical-spectrum study directly supports the core ACC/TTLD disease boundary.

PMID:27077170 SUPPORT Other

"Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD)."

The archived GeneReviews chapter independently states the clinical core; it is tagged as a retired historical baseline rather than a current guideline.

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Inheritance

2

Autosomal dominant inheritance HP:0000006

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:29924900 SUPPORT Human Clinical

"Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance."

Defines the established autosomal-dominant AOS genes in the pre-VCP cohort.

Autosomal recessive inheritance HP:0000007

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:29924900 SUPPORT Human Clinical

"Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance."

Defines DOCK6- and EOGT-associated AOS as autosomal recessive.

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Subtypes

7

AOS1 (ARHGAP31, autosomal dominant) MONDO:0024506

ARHGAP31 hgnc:29216 Autosomal dominant inheritance

Autosomal dominant form caused by gain-of-function mutations in ARHGAP31, encoding a Rho GTPase-activating protein. The mutant protein shows constitutive GAP activity with demonstrated depletion of active Cdc42 and disruption of actin-cytoskeleton organization.

Show evidence (1 reference)

PMID:21565291 SUPPORT Human Clinical

"Candidate-gene- and exome-based sequencing led to the identification of independent premature truncating mutations in the terminal exon of the Rho GTPase-activating protein 31 gene, ARHGAP31, which encodes a Cdc42/Rac1 regulatory protein."

Original identification of ARHGAP31 as causative for autosomal dominant AOS.

AOS2 (DOCK6, autosomal recessive) MONDO:0013635

DOCK6 hgnc:19189 Autosomal recessive inheritance

Autosomal recessive form caused by loss-of-function mutations in DOCK6, a guanine nucleotide exchange factor for Cdc42 and Rac1. Loss of DOCK6 function impairs actin-cytoskeleton organization.

Show evidence (1 reference)

PMID:21820096 SUPPORT Human Clinical

"we combined autozygome analysis with exome sequencing to identify a homozygous truncating mutation in dedicator of cytokinesis 6 gene (DOCK6) which encodes an atypical guanidine exchange factor (GEF) known to activate two members of the Rho GTPase family: Cdc42 and Rac1."

Original identification of DOCK6 as causative for autosomal recessive AOS.

AOS3 (RBPJ, autosomal dominant) MONDO:0013895

RBPJ hgnc:5724 Autosomal dominant inheritance

Autosomal dominant form caused by dominant-negative mutations in RBPJ, the central transcriptional mediator of canonical Notch signaling. Mutant RBPJ retains cofactor binding but has impaired DNA binding, sequestering Notch pathway cofactors from target gene promoters.

Show evidence (1 reference)

PMID:22883147 SUPPORT Human Clinical

"we identified two unique mutations in recombination signal binding protein for immunoglobulin kappa J (RBPJ) in two independent families affected by Adams-Oliver syndrome (AOS)"

Original identification of RBPJ mutations in AOS families.

AOS4 (EOGT, autosomal recessive) MONDO:0014124

EOGT hgnc:28526 Autosomal recessive inheritance

Autosomal recessive form caused by loss-of-function mutations in EOGT, which encodes an EGF-domain-specific O-linked N-acetylglucosamine transferase that modifies Notch receptors.

Show evidence (1 reference)

PMID:23522784 SUPPORT Human Clinical

"exome sequencing in one family revealed one missense mutation in EOGT (C3orf64), and subsequent targeted sequencing of this gene revealed a homozygous missense mutation and a homozygous frameshift deletion mutation in the other two families."

Original identification of EOGT mutations in autosomal recessive AOS.

AOS5 (NOTCH1, autosomal dominant) MONDO:0014459

NOTCH1 hgnc:7881 Autosomal dominant inheritance

Autosomal dominant form caused by loss-of-function mutations in NOTCH1. NOTCH1 was the largest single contributor in a 194-proband/family AOS/ACC/TTLD cohort. Haploinsufficiency reduces canonical Notch signaling, and cardiac anomalies are enriched among reported NOTCH1 variant carriers.

Show evidence (1 reference)

PMID:25963545 SUPPORT Human Clinical

"This report establishes NOTCH1 mutation as the primary cause of AOS, accounting for 17% of cases in our cohort, and an important genetic factor in AOS with associated cardiovascular complications."

Establishes NOTCH1 haploinsufficiency and its cardiac association in the reported cohort.

AOS6 (DLL4, autosomal dominant) MONDO:0014703

DLL4 hgnc:2910 Autosomal dominant inheritance

Autosomal dominant form caused by loss-of-function mutations in DLL4, a Notch ligand critical for angiogenesis and vascular patterning.

Show evidence (1 reference)

PMID:26299364 SUPPORT Human Clinical

"nine heterozygous mutations in DLL4 were identified, including two nonsense and seven missense variants"

Original identification of DLL4 mutations as a cause of autosomal dominant AOS.

VCP-associated Adams-Oliver syndrome

VCP hgnc:12666

Newly reported AOS caused by hypermorphic VCP variants. The discovery series included six families with pulmonary hypertension and one without; it does not establish penetrance or the age of pulmonary-hypertension onset in each family. This entry does not assign a numbered AOS subtype or mode of inheritance because the available primary abstract does not establish either.

Show evidence (1 reference)

PMID:41979051 SUPPORT Human Clinical

"We report a new genetic etiology for AOS in 6 families with PH and 1 family without it."

Establishes VCP as an additional AOS genetic cause and bounds the observed pulmonary-hypertension association in the discovery series.

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Mechanistic Hypotheses

3

Notch-pathway vascular disruption model

aos_notch_vascular_disruption ALTERNATIVE AOS3 AOS4 AOS5 AOS6

Evidence balance 2 support

Reduced canonical Notch output in vascular endothelium can account for cardiovascular defects in AOS models. Extension of that model to the human scalp and limb defects remains a vascular-disruption hypothesis rather than a demonstrated human causal chain.

Pathograph links

Abnormal Vascular Development in Notch-Pathway Models -> Aplasia Cutis Congenita of the Scalp INDIRECT UNKNOWN INTERMEDIATES A vascular route to human scalp aplasia has been proposed but not demonstrated.

Abnormal Vascular Development in Notch-Pathway Models -> Terminal Transverse Limb Defects INDIRECT UNKNOWN INTERMEDIATES A vascular route to human terminal limb defects has been proposed but not demonstrated.

Abnormal Vascular Development in Notch-Pathway Models -> Congenital Heart Defects INDIRECT KNOWN INTERMEDIATES Endothelial Notch dysfunction causes cardiovascular defects in the sensitized RBPJ/Notch1 mouse model. Intermediates: endothelial Notch dysfunction during cardiovascular development

Show evidence (2 references)

PMID:41055965 SUPPORT Model Organism

"These data establish that reduced Notch1 signaling in the vasculature is a key driver of pathogenesis in this AOS mouse model."

Supports the endothelial mechanism within the sensitized RBPJ/Notch1 mouse model.

PMID:25132448 SUPPORT Human Clinical

"We propose that the limb and scalp defects might also be due to a vasculopathy in NOTCH1-related AOS."

Explicitly frames the human scalp/limb vascular route as a proposal.

Rho-GTPase cytoskeletal-development model

aos_rho_cytoskeletal_development CANONICAL AOS1 AOS2

Evidence balance 2 support

Opposite biochemical lesions in ARHGAP31 and DOCK6 perturb CDC42 and/or RAC1 signaling and disturb actin organization. The intervening developmental events connecting those cellular defects to human scalp and terminal-limb malformations remain incompletely mapped.

Pathograph links

Reduced CDC42 and/or RAC1 Signaling -> Actin Cytoskeleton Defects DIRECT Reduced CDC42 and/or RAC1 activity disrupts actin organization and cell behavior.

Reduced CDC42 and/or RAC1 Signaling -> RAC1-SRF Cranial Mesenchyme Defect INDIRECT UNKNOWN INTERMEDIATES Conditional Rac1 loss defines a cranial-mesenchyme route in mice, but not an AOS-allele-specific route.

Actin Cytoskeleton Defects -> Terminal Transverse Limb Defects INDIRECT UNKNOWN INTERMEDIATES The cellular defect is established, but its route to human terminal limb loss is unresolved.

Actin Cytoskeleton Defects -> Aplasia Cutis Congenita of the Scalp INDIRECT UNKNOWN INTERMEDIATES The cellular defect is established, but its route to human scalp aplasia is unresolved.

RAC1-SRF Cranial Mesenchyme Defect -> Calvarial Skull Defect INDIRECT UNKNOWN INTERMEDIATES The mouse knockout reproduces a severe AOS-like calvarial and dermal defect, but is not an AOS allele.

RAC1-SRF Cranial Mesenchyme Defect -> Aplasia Cutis Congenita of the Scalp INDIRECT UNKNOWN INTERMEDIATES Loss of overlying dermis in the model resembles severe scalp aplasia, but translation to human AOS remains uncertain.

Show evidence (2 references)

PMID:21565291 SUPPORT In Vitro

"Constitutively active ARHGAP31 mutations result in a loss of available active Cdc42 and consequently disrupt actin cytoskeletal structures."

Defines the proximal ARHGAP31-to-Rho-GTPase cytoskeletal mechanism.

PMID:21820096 SUPPORT In Vitro

"Consistent with the established role of Cdc42 and Rac1 in the organization of the actin cytoskeleton, we demonstrate a cellular phenotype typical of a defective actin cytoskeleton in patient cells."

Supports cytoskeletal dysfunction in DOCK6-deficient patient cells.

VCP developmental and pulmonary-vascular bridge

aos_vcp_developmental_bridge EMERGING VCP-Associated AOS

Evidence balance 1 support

AOS-associated VCP variants increase ATP hydrolysis and alter conformational coupling, but the developmental route to scalp and limb defects and the route to pulmonary veno-occlusive disease or other forms of pulmonary hypertension are not yet established.

Pathograph links

AOS-Associated VCP Variant Effects -> Aplasia Cutis Congenita of the Scalp INDIRECT UNKNOWN INTERMEDIATES VCP variants cause AOS, but the developmental route to scalp aplasia is unresolved.

AOS-Associated VCP Variant Effects -> Terminal Transverse Limb Defects INDIRECT UNKNOWN INTERMEDIATES VCP variants cause AOS, but the developmental route to terminal limb defects is unresolved.

AOS-Associated VCP Variant Effects -> Pulmonary Hypertension INDIRECT UNKNOWN INTERMEDIATES Pulmonary hypertension occurred in six discovery families and was absent in one; the organ-level mechanism is unresolved.

Show evidence (1 reference)

PMID:41979051 SUPPORT In Vitro

"We show that AOS-related VCP variants are hypermorphic with respect to ATP hydrolysis and cause N-terminal domain hyperflexibility with impairment of interdomain coupling."

Establishes the proximal VCP biochemical effect while leaving the developmental bridge unresolved.

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Discussions and Knowledge Gaps

3

What developmental mechanisms connect the separate Notch, CDC42/RAC1, and VCP biochemical branches to the shared scalp-aplasia and terminal-limb pattern, and do any branches truly converge in the relevant human tissues?

KNOWLEDGE GAP OPEN gap_aos_shared_developmental_route

Attached to

pathophysiology#Reduced Canonical Notch Signaling pathophysiology#Actin Cytoskeleton Defects pathophysiology#AOS-Associated VCP Variant Effects

Human genetics establishes all three branches, but the scalp/limb vascular route is proposed, the Rho branch has an incomplete developmental bridge, and the VCP organ-level bridge is newly unresolved. No evidence currently justifies connecting VCP to Notch or Rho signaling.

Show evidence (2 references)

PMID:25132448 SUPPORT Human Clinical

"We propose that the limb and scalp defects might also be due to a vasculopathy in NOTCH1-related AOS."

Shows that even the best-known human scalp/limb vascular route is framed as a proposal.

PMID:41979051 SUPPORT In Vitro

"We show that AOS-related VCP variants are hypermorphic with respect to ATP hydrolysis and cause N-terminal domain hyperflexibility with impairment of interdomain coupling."

Establishes the VCP proximal effect but not an organ-development mechanism.

Why does Eogt loss reproduce reduced Notch signaling and retinal vascular defects in mice without reproducing the predicted human AOS abnormalities?

HUMAN MODEL MISMATCH OPEN mismatch_eogt_null_mouse

Attached to

pathophysiology#EOGT-Dependent Notch O-GlcNAcylation Deficiency

The model supports the proximal DLL-selective Notch mechanism but not the human scalp/limb phenotype, limiting organism-level causal inference.

Show evidence (1 reference)

PMID:28395734 SUPPORT Model Organism

"Unexpectedly,Eogt-null mice do not exhibit abnormalities predicted from the symptoms of AOS patients."

The primary model report explicitly identifies the mismatch.

Can the in-vitro normalization of hyperactive AOS-associated VCP by CB-5083 be translated safely or effectively, and at what developmental window?

KNOWLEDGE GAP OPEN gap_vcp_inhibitor_translation

Attached to

pathophysiology#VCP Hypermorphic ATPase Activity

The only current evidence is biochemical inhibition in vitro. CB-5083 is not modeled as an AOS treatment, and there is no human safety, dosing, or efficacy evidence in this disease.

Show evidence (1 reference)

PMID:41979051 SUPPORT In Vitro

"Additionally, we find that CB-5083 inhibits the overactive ATP hydrolysis."

Supports only the proximal in-vitro assay result.

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Pathophysiology

16

NOTCH1 Haploinsufficiency

Heterozygous loss-of-function variants reduce NOTCH1 transcript abundance and receptor dosage in AOS5.

NOTCH1 hgnc:7881

Downstream

Reduced Canonical Notch Signaling Reduced NOTCH1 dosage lowers pathway output.

Show evidence (1 reference)

PMID:25963545 SUPPORT In Vitro

"NOTCH1 transcript levels were significantly reduced by comparison to an unaffected control individual, demonstrating approximately 50% expression in all samples tested"

Supports NOTCH1 haploinsufficiency in variant carriers.

DLL4 Loss of Function

Heterozygous loss-of-function variants in the canonical Notch ligand DLL4 cause AOS6 and reduce ligand capacity within the DLL4-NOTCH signaling axis.

DLL4 hgnc:2910

Downstream

Reduced Canonical Notch Signaling DLL4 loss reduces activation of the canonical receptor-effector cascade.

DLL4-Dependent Second Heart Field Defect DLL4 loss depletes the second-heart-field progenitor pool in the cardiac mouse model.

Show evidence (1 reference)

PMID:26299364 SUPPORT Human Clinical

"nine heterozygous mutations in DLL4 were identified, including two nonsense and seven missense variants"

Establishes the disease-associated DLL4 variant series.

RBPJ Dominant-Negative Cofactor Sequestration

AOS3-associated RBPJ missense variants compromise DNA binding while retaining cofactor binding, supporting dominant-negative sequestration of canonical Notch transcriptional cofactors.

RBPJ hgnc:5724

Downstream

Reduced Canonical Notch Signaling Cofactor sequestration reduces DNA-bound canonical Notch transcriptional activity.

Show evidence (1 reference)

PMID:41055965 SUPPORT In Vitro

"Here, we used quantitative binding assays to show that AOS-associated RBPJ missense variants compromise DNA binding but not cofactor binding."

Defines the proximal biochemical defect.

EOGT-Dependent Notch O-GlcNAcylation Deficiency

AOS4-associated EOGT variants impair O-GlcNAcylation of EGF-repeat proteins. EOGT-deficient cells show selectively reduced DLL1/DLL4 binding and impaired ligand-induced Notch signaling, whereas JAG1 binding is preserved.

EOGT hgnc:28526

Downstream

Reduced Canonical Notch Signaling EOGT deficiency weakens DLL-selective Notch receptor activation.

Show evidence (1 reference)

PMID:25488668 SUPPORT In Vitro

"As compared with wild-type EOGT, O-GlcNAcylation in the ER is nearly abolished in HEK293T cells exogenously expressing EOGT variants associated with AOS."

Demonstrates loss of enzymatic product for AOS-associated EOGT variants in vitro.

ARHGAP31 Gain of Function

Terminal-exon truncating ARHGAP31 variants produce stable proteins with increased GAP activity; depletion of active Cdc42 was demonstrated directly.

ARHGAP31 hgnc:29216

Downstream

Reduced CDC42 and/or RAC1 Signaling Excess GAP activity depletes active Cdc42; the cited assay does not establish simultaneous Rac1 depletion.

Show evidence (1 reference)

PMID:21565291 SUPPORT In Vitro

"Mutant transcripts are stable and increase ARHGAP31 activity in vitro through a gain-of-function mechanism."

Establishes the ARHGAP31 gain-of-function mechanism.

DOCK6 Loss of GEF Function

Biallelic loss-of-function variants disrupt DOCK6, a guanine-nucleotide exchange factor known to activate CDC42 and RAC1.

DOCK6 hgnc:19189

Downstream

Reduced CDC42 and/or RAC1 Signaling Loss of DOCK6 GEF function is expected to reduce activation of CDC42 and/or RAC1; the cited study did not directly measure the active GTPase pool.

Show evidence (1 reference)

PMID:21820096 SUPPORT In Vitro

"Consistent with the established role of Cdc42 and Rac1 in the organization of the actin cytoskeleton, we demonstrate a cellular phenotype typical of a defective actin cytoskeleton in patient cells."

Demonstrates the downstream cellular phenotype in patient cells.

AOS-Associated VCP Variant Effects

AOS-associated VCP variants have two reported parallel proximal effects: increased ATP hydrolysis and impaired conformational coupling. Which effect, if either, mediates the congenital and pulmonary-vascular manifestations is unknown, so the unresolved clinical bridge is attached to this neutral variant-effects node rather than to either biochemical effect.

VCP developmental and pulmonary-vascular bridge

VCP hgnc:12666

Downstream

VCP Hypermorphic ATPase Activity AOS-associated VCP variants increase ATP hydrolysis in vitro.

VCP Conformational Coupling Defect AOS-associated VCP variants cause N-terminal hyperflexibility and impaired interdomain coupling.

Aplasia Cutis Congenita of the Scalp VCP variants cause AOS, but the developmental route to scalp aplasia is unresolved.

Terminal Transverse Limb Defects VCP variants cause AOS, but the developmental route to terminal limb defects is unresolved.

Pulmonary Hypertension Pulmonary hypertension occurred in six discovery families and was absent in one; the organ-level mechanism is unresolved.

Show evidence (1 reference)

PMID:41979051 SUPPORT Human Clinical

"We report a new genetic etiology for AOS in 6 families with PH and 1 family without it."

Establishes the VCP-associated disease branch while leaving its disease-mediating biochemical route unresolved.

VCP Hypermorphic ATPase Activity

AOS-associated VCP substitution variants increase ATP hydrolysis in vitro. This effect is modeled in parallel with the reported conformational-coupling defect; neither has been established as the disease-mediating route.

VCP hgnc:12666

ATP hydrolysis activity GO:0016887

Show evidence (1 reference)

PMID:41979051 SUPPORT In Vitro

"We show that AOS-related VCP variants are hypermorphic with respect to ATP hydrolysis and cause N-terminal domain hyperflexibility with impairment of interdomain coupling."

Defines ATPase hyperactivity as one parallel proximal VCP effect.

VCP Conformational Coupling Defect

AOS-related VCP variants cause N-terminal-domain hyperflexibility and impair coupling between VCP domains. This effect is modeled in parallel with ATPase hyperactivity; neither has been established as the disease-mediating route.

VCP hgnc:12666

Show evidence (1 reference)

PMID:41979051 SUPPORT In Vitro

"We show that AOS-related VCP variants are hypermorphic with respect to ATP hydrolysis and cause N-terminal domain hyperflexibility with impairment of interdomain coupling."

Defines the conformational defect as one parallel proximal VCP effect.

Pulmonary Veno-Occlusive Disease in AOS

Review of published AOS cases with pulmonary hypertension suggests that pulmonary veno-occlusive disease is the most common mechanism, but not a universal finding.

Downstream

Pulmonary Hypertension Pulmonary venous obstruction can produce pulmonary hypertension.

Show evidence (1 reference)

PMID:41979051 SUPPORT Human Clinical

"Review of published cases of AOS with PH suggests that pulmonary veno-occlusive disease is the most common mechanism."

Literature synthesis within the VCP discovery report supports the qualified claim.

Reduced Canonical Notch Signaling

NOTCH1 haploinsufficiency, DLL4 loss of function, dominant-negative RBPJ variants, and EOGT-dependent glycosylation defects reduce canonical Notch pathway output by distinct proximal mechanisms. Conditional mouse genetics establishes vascular endothelium as sufficient for lethality and cardiovascular defects in the sensitized RBPJ/Notch1 model; it does not by itself establish endothelial causality for human scalp or limb defects.

NOTCH1 hgnc:7881 DLL4 hgnc:2910 RBPJ hgnc:5724 EOGT hgnc:28526

Notch signaling pathway GO:0007219

Show evidence (3 references)

PMID:25963545 SUPPORT In Vitro

"NOTCH1 expression is down-regulated in AOS subjects harboring NOTCH1 mutation in vivo"

Demonstrates reduced NOTCH1 expression in variant carriers.

PMID:41055965 SUPPORT Model Organism

"expression of the Rbpj AOS allele in endothelial cells is both necessary and sufficient to cause lethality and cardiovascular defects"

Supports the endothelial mechanism for cardiovascular outcomes in the sensitized mouse model.

PMID:22883147 SUPPORT Human Clinical

"These identified mutations link RBPJ, the primary transcriptional regulator for the Notch pathway, with AOS, a human genetic disorder."

Human genetics links RBPJ to the canonical Notch branch of AOS.

Reduced CDC42 and/or RAC1 Signaling

ARHGAP31 gain of GAP activity directly depletes active Cdc42, while DOCK6 loss is expected from its known GEF function to reduce CDC42 and/or RAC1 activation. Their relationship to the Notch branch is not established.

Rho-GTPase cytoskeletal-development model

ARHGAP31 hgnc:29216 DOCK6 hgnc:19189

Rho protein signal transduction GO:0007266

Downstream

Actin Cytoskeleton Defects Reduced CDC42 and/or RAC1 activity disrupts actin organization and cell behavior.

RAC1-SRF Cranial Mesenchyme Defect Conditional Rac1 loss defines a cranial-mesenchyme route in mice, but not an AOS-allele-specific route.

Show evidence (2 references)

PMID:21565291 SUPPORT In Vitro

"Constitutively active ARHGAP31 mutations result in a loss of available active Cdc42 and consequently disrupt actin cytoskeletal structures."

Demonstrates the proximal ARHGAP31 gain-of-function mechanism.

PMID:21820096 SUPPORT In Vitro

"Consistent with the established role of Cdc42 and Rac1 in the organization of the actin cytoskeleton, we demonstrate a cellular phenotype typical of a defective actin cytoskeleton in patient cells."

Confirms a defective actin-cytoskeleton phenotype in DOCK6 patient cells.

Abnormal Vascular Development in Notch-Pathway Models

Reduced Notch signaling perturbs endothelial and vascular development. Cardiovascular outcomes are experimentally supported in the sensitized RBPJ/Notch1 mouse model; vascular disruption of the human scalp and limb remains a NOTCH1-related hypothesis. This node is not asserted as the common mechanism for every Notch-pathway subtype or for ARHGAP31-, DOCK6-, or VCP-associated AOS. Gene and subtype fields are intentionally omitted because the cardiovascular mouse evidence and human scalp/limb hypothesis have different, narrower scopes.

Notch-pathway vascular disruption model

blood vessel endothelial cell CL:0000071

vasculogenesis GO:0001570 angiogenesis GO:0001525

Downstream

Aplasia Cutis Congenita of the Scalp A vascular route to human scalp aplasia has been proposed but not demonstrated.

Terminal Transverse Limb Defects A vascular route to human terminal limb defects has been proposed but not demonstrated.

Congenital Heart Defects Endothelial Notch dysfunction causes cardiovascular defects in the sensitized RBPJ/Notch1 mouse model.

Show evidence (2 references)

PMID:25132448 SUPPORT Human Clinical

"We propose that the limb and scalp defects might also be due to a vasculopathy in NOTCH1-related AOS."

Proposes the vascular disruption hypothesis for limb and scalp defects in AOS.

PMID:41055965 SUPPORT Model Organism

"reduced Notch1 signaling in the vasculature is a key driver of pathogenesis in this AOS mouse model"

Direct evidence from conditional mouse genetics that vascular-specific Notch signaling defects drive AOS.

Actin Cytoskeleton Defects

Reduced CDC42 and/or RAC1 signaling disrupts actin organization in ARHGAP31- and DOCK6-associated AOS. The downstream human developmental steps producing scalp and limb defects are not fully known.

Rho-GTPase cytoskeletal-development model

ARHGAP31 hgnc:29216 DOCK6 hgnc:19189

actin cytoskeleton organization GO:0030036

Downstream

Terminal Transverse Limb Defects The cellular defect is established, but its route to human terminal limb loss is unresolved.

Aplasia Cutis Congenita of the Scalp The cellular defect is established, but its route to human scalp aplasia is unresolved.

Show evidence (2 references)

PMID:21565291 SUPPORT In Vitro

"Constitutively active ARHGAP31 mutations result in a loss of available active Cdc42 and consequently disrupt actin cytoskeletal structures."

Directly supports actin-cytoskeleton disruption downstream of ARHGAP31 gain of function.

PMID:21820096 SUPPORT In Vitro

"Consistent with the established role of Cdc42 and Rac1 in the organization of the actin cytoskeleton, we demonstrate a cellular phenotype typical of a defective actin cytoskeleton in patient cells."

Supports the same cellular endpoint in DOCK6-deficient patient cells.

RAC1-SRF Cranial Mesenchyme Defect

Conditional Rac1 loss in mouse cranial mesenchyme reduces proliferation and SRF-linked mechanoresponsive programs, causing absent apical calvarium and overlying dermis. This is a downstream pathway model, not an AOS-allele model, and its fidelity to human ARHGAP31- or DOCK6-associated disease is uncertain.

Rho-GTPase cytoskeletal-development model

RAC1 hgnc:9801

Downstream

Calvarial Skull Defect The mouse knockout reproduces a severe AOS-like calvarial and dermal defect, but is not an AOS allele.

Aplasia Cutis Congenita of the Scalp Loss of overlying dermis in the model resembles severe scalp aplasia, but translation to human AOS remains uncertain.

Show evidence (1 reference)

PMID:41126757 SUPPORT Model Organism

"Together, these data suggest a model where Rac1 and SRF maintain apical fibroblasts in a mechanoresponsive and proliferative state to complete cranial development."

Defines the model's proposed cellular mechanism.

DLL4-Dependent Second Heart Field Defect

In a mouse model, second-heart-field-specific Dll4 loss reduces progenitor proliferation, increases apoptosis, and depletes the progenitor pool, producing outflow-tract malalignment. This is an AOS6/DLL4 cardiac model, not a mechanism established for pooled AOS cardiac defects.

DLL4 hgnc:2910

Notch signaling pathway GO:0007219

secondary heart field UBERON:0009889

Downstream

Congenital Heart Defects Second-heart-field depletion produces outflow-tract malalignment in the Dll4 mouse model.

Show evidence (1 reference)

PMID:33899511 SUPPORT Model Organism

"Dll4-mediated Notch signaling is critically required for SHF proliferation such that Dll4 knockout results in a 33% reduction in proliferation and a fourfold increase in apoptosis in SHF cells, leading to a 56% decline in the size of the SHF progenitor pool."

Mouse model demonstrates the mechanism by which DLL4 haploinsufficiency causes cardiac defects in AOS.

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Pathograph

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Phenotypes

10

Cardiovascular 2

Congenital Heart Defects OCCASIONAL Abnormal heart morphology HP:0001627

Show evidence (2 references)

PMID:28160419 SUPPORT Human Clinical

"the most commonly associated anomalies included a wide variety of central nervous system (CNS) anomalies and congenital heart defects each seen in 23%."

Large literature review establishing 23% frequency of congenital heart defects in AOS.

PMID:25963545 SUPPORT Human Clinical

"cardiovascular anomalies were identified in 47% (8/17) of all affected variant carriers, thereby indicating that NOTCH1 variants may represent a distinct subtype of AOS associated with cardiac malformations."

NOTCH1-related AOS shows particularly high frequency of cardiac defects.

Hepatoportal Sclerosis with Portal Hypertension HP:0001409

Show evidence (1 reference)

PMID:28160419 SUPPORT Human Clinical

"A relatively large number of non-familial probands were reported to have hepatoportal sclerosis with portal hypertension and esophageal varices."

Literature review documenting hepatoportal sclerosis as a notable feature particularly in non-familial AOS cases.

Integument 1

Nail Dystrophy HP:0008404

Show evidence (1 reference)

PMID:40874655 SUPPORT Human Clinical

"The condition presents with a range of cutaneous features, most notably ACC, cutis marmorata telangiectatica congenita, and nail anomalies."

The clinical review identifies nail anomalies among the characteristic cutaneous findings.

Other 7

Aplasia Cutis Congenita of the Scalp Aplasia cutis congenita of scalp HP:0007385

Show evidence (1 reference)

PMID:28160419 SUPPORT Human Clinical

"The Adams-Oliver syndrome (AOS) is defined as aplasia cutis congenita (ACC) with transverse terminal limb defects (TTLD)."

ACC is a defining feature of AOS.

Terminal Transverse Limb Defects Transverse terminal limb defect HP:6000818

Show evidence (1 reference)

PMID:28160419 SUPPORT Human Clinical

"The Adams-Oliver syndrome (AOS) is defined as aplasia cutis congenita (ACC) with transverse terminal limb defects (TTLD)."

TTLD is a defining feature of AOS.

Calvarial Skull Defect HP:0001362

Show evidence (1 reference)

PMID:25963545 SUPPORT Human Clinical

"Patient 3-III:1 was born with a large area of scalp ACC with an underlying calvarial defect and shortened distal phalanges of the toes"

Clinical documentation of calvarial skull defects accompanying aplasia cutis in AOS patients.

Cutis Marmorata Telangiectatica Congenita OCCASIONAL HP:0025107

Show evidence (1 reference)

PMID:28160419 SUPPORT Human Clinical

"Cutis marmorata telangiectasia congenita (CMTC) was found in 19% of the study population and other vascular anomalies were seen in 14%."

Literature review establishing 19% frequency of CMTC in AOS.

Pulmonary Hypertension

Show evidence (3 references)

PMID:41979051 SUPPORT Human Clinical

"A minority of individuals with AOS develop potentially lethal pulmonary hypertension (PH) in infancy, a subgroup that has been refractory to genetic explanation."

Establishes the bounded overall clinical context without assigning a frequency band.

PMID:41979051 SUPPORT Human Clinical

"We report a new genetic etiology for AOS in 6 families with PH and 1 family without it."

Reports the discovery-series distribution without assigning penetrance or age of onset to the VCP-associated families.

PMID:41979051 SUPPORT Human Clinical

"Review of published cases of AOS with PH suggests that pulmonary veno-occlusive disease is the most common mechanism. Clinical risk factors for PH in AOS include CMTC, prominent dilated subcutaneous veins and intra-uterine growth restriction."

Supports the qualified mechanism and risk-marker statements.

Central Nervous System Anomalies OCCASIONAL Morphological central nervous system abnormality HP:0002011

Show evidence (2 references)

PMID:28160419 SUPPORT Human Clinical

"the most commonly associated anomalies included a wide variety of central nervous system (CNS) anomalies and congenital heart defects each seen in 23%. CNS anomalies included structural anomalies, microcephaly, vascular defects, and vascular sequelae. CNS migration defects were common."

Literature review establishing 23% frequency of CNS anomalies in AOS.

PMID:25824905 SUPPORT Human Clinical

"DOCK6 mutations were strongly associated with structural brain abnormalities, ocular anomalies, and intellectual disability"

Supports enrichment of neurologic involvement in DOCK6-associated AOS2.

Ocular Anomalies in DOCK6-Associated AOS Abnormality of the eye HP:0000478

Show evidence (1 reference)

PMID:25824905 SUPPORT Human Clinical

"DOCK6 mutations were strongly associated with structural brain abnormalities, ocular anomalies, and intellectual disability"

Defines the DOCK6-associated ocular and neurologic enrichment.

🧬

Genetic Associations

7

ARHGAP31 (AOS1) (CAUSAL)

Gene: ARHGAP31 hgnc:29216 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant inheritance

Show evidence (2 references)

PMID:21565291 SUPPORT In Vitro

"Mutant transcripts are stable and increase ARHGAP31 activity in vitro through a gain-of-function mechanism."

Demonstrates gain-of-function mechanism of ARHGAP31 mutations.

PMID:29924900 SUPPORT Human Clinical

"ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort."

Establishes a 3% ARHGAP31-attributable fraction in the mixed AOS/isolated-ACC/TTLD cohort.

DOCK6 (AOS2) (CAUSAL)

Gene: DOCK6 hgnc:19189 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive inheritance

Show evidence (3 references)

PMID:21820096 SUPPORT Human Clinical

"we combined autozygome analysis with exome sequencing to identify a homozygous truncating mutation in dedicator of cytokinesis 6 gene (DOCK6)"

Original identification of DOCK6 mutations in AOS.

PMID:29924900 SUPPORT Human Clinical

"DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort."

Establishes a 6% DOCK6-attributable fraction in the mixed AOS/isolated-ACC/TTLD cohort.

CGGV:assertion_ea64d74c-583d-4ed1-af91-6a7c6f80a1d3-2022-06-28T160000.000Z SUPPORT Other

ClinGen classifies the DOCK6-Adams-Oliver syndrome gene-disease relationship as definitive with autosomal recessive inheritance.

RBPJ (AOS3) (CAUSAL)

Gene: RBPJ hgnc:5724 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant inheritance

Show evidence (2 references)

PMID:22883147 SUPPORT In Vitro

"Functional assays confirmed impaired DNA binding of mutated RBPJ, placing it among other notch-pathway proteins altered in human genetic syndromes."

Demonstrates functional impact of RBPJ mutations on DNA binding.

PMID:41055965 SUPPORT In Vitro

"AOS-associated RBPJ missense variants compromise DNA binding but not cofactor binding. These findings suggest that AOS-associated RBPJ variants do not function as loss-of-function alleles but instead act as dominant-negative proteins that sequester cofactors from DNA."

Demonstrates dominant-negative mechanism of RBPJ mutations - they retain cofactor binding while losing DNA binding, titrating cofactors away from DNA.

EOGT (AOS4) (CAUSAL)

Gene: EOGT hgnc:28526 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive inheritance

Show evidence (2 references)

PMID:23522784 SUPPORT Human Clinical

"EOGT encodes EGF-domain-specific O-linked N-acetylglucosamine (O-GlcNAc) transferase, which is involved in the O-GlcNAcylation (attachment of O-GlcNAc to serine and threonine residues) of a subset of extracellular EGF-domain-containing proteins."

Identifies EOGT function and its connection to Notch signaling.

PMID:29924900 SUPPORT Human Clinical

"ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort."

Establishes a 3% EOGT-attributable fraction in the mixed AOS/isolated-ACC/TTLD cohort.

NOTCH1 (AOS5) (CAUSAL)

Gene: NOTCH1 hgnc:7881 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant inheritance

Show evidence (3 references)

PMID:25132448 SUPPORT Human Clinical

"we report five heterozygous NOTCH1 variants in unrelated individuals with Adams-Oliver syndrome (AOS), a rare disease with major features of aplasia cutis of the scalp and terminal transverse limb defects."

Original identification of NOTCH1 mutations in AOS.

PMID:25963545 SUPPORT In Vitro

"NOTCH1 transcript levels were significantly reduced by comparison to an unaffected control individual, demonstrating approximately 50% expression in all samples tested"

Demonstrates NOTCH1 haploinsufficiency as the molecular mechanism.

PMID:29924900 SUPPORT Human Clinical

"NOTCH1 is the major contributor, underlying 10% of AOS/ACC/TTLD cases"

Identifies NOTCH1 as the largest contributor, at 10%, within the mixed AOS/isolated-ACC/TTLD cohort.

DLL4 (AOS6) (CAUSAL)

Gene: DLL4 hgnc:2910 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant inheritance

Show evidence (3 references)

PMID:26299364 SUPPORT Human Clinical

"Our findings demonstrate that DLL4 mutations are an additional cause of autosomal-dominant AOS or isolated ACC and provide further evidence for a key role of NOTCH signaling in the etiology of this disorder."

Establishes DLL4 as a cause of autosomal dominant AOS.

PMID:29924900 SUPPORT Human Clinical

"DLL4 (6%), DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort."

Establishes a 6% DLL4-attributable fraction in the mixed AOS/isolated-ACC/TTLD cohort.

PMID:33899511 SUPPORT Model Organism

"Similar to the clinical syndrome, 32% of SHF-specific Dll4 heterozygotes demonstrate foreshortened and misaligned OFT, resulting in a double outlet right ventricle."

Mouse model providing molecular mechanism for cardiac defects in DLL4-related AOS.

VCP-Associated AOS (CAUSAL)

Gene: VCP hgnc:12666 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:41979051 SUPPORT Human Clinical

"We report a new genetic etiology for AOS in 6 families with PH and 1 family without it."

Establishes VCP as an additional AOS genetic cause and bounds the pulmonary-hypertension association.

PMID:41979051 SUPPORT In Vitro

"We show that AOS-related VCP variants are hypermorphic with respect to ATP hydrolysis and cause N-terminal domain hyperflexibility with impairment of interdomain coupling."

Defines the experimentally observed biochemical and structural effects.

💊

Medical Actions

4

Individualized Conservative Care for Scalp Aplasia

Category: Therapeutic Action: supportive care Ontology label: Supportive Care NCIT:C15747

Conservative management is one option for scalp aplasia, but published AOS evidence does not establish a universal dressing protocol or size threshold. Selection must balance hemorrhage, infection, neurologic, and procedural risks for the individual defect.

Show evidence (2 references)

PMID:22670005 SUPPORT Human Clinical

"Various papers have been published related to ACC, yet there is no consensus on the therapeutic approach. The management decision hinges upon balancing the risks of complications including spontaneous sagittal sinus haemorrhage and the risk of surgical intervention."

Supports individualized choice while documenting the low-level evidence and absence of consensus.

PMID:27077170 SUPPORT Other

"Goals of non-operative therapy are to prevent infection and promote healing."

The archived GeneReviews chapter supplies the historical goals of conservative scalp-ACC care; its retired status precludes treating details as a current universal protocol.

Surgical Closure or Reconstruction of Scalp Aplasia

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

Surgical closure or later reconstruction is an alternative for selected scalp defects. Evidence is limited to case-based experience, and the same absence of consensus requires individualized risk assessment rather than a universal threshold.

Show evidence (2 references)

PMID:22670005 SUPPORT Human Clinical

"Both treatment modalities proved successful in these cases."

Two siblings were managed with different conservative/surgical strategies; this does not establish comparative efficacy.

PMID:27077170 SUPPORT Other

"Large and/or deep lesions with calvarial involvement require acute care and may eventually also require reconstruction by a neurosurgeon."

The archived GeneReviews chapter supports historical specialist reconstruction practice while remaining explicitly retired and potentially outdated.

Coordinated Multidisciplinary Assessment

Category: Monitoring Action: clinical assessment Ontology label: Clinical Evaluation NCIT:C124351

Coordinate phenotype- and genotype-directed assessment across dermatology, clinical genetics, cardiology, vascular/pulmonary medicine, neurology, ophthalmology, developmental services, and relevant surgical specialties. Published evidence supports an adjusted multidisciplinary approach but not universal fixed surveillance intervals.

Show evidence (3 references)

PMID:31654484 SUPPORT Human Clinical

"It appears that degrees of genotype-phenotype correlations exist for patients with identified pathogenic mutations, underlining the need to undertake a systematic but adjusted multidisciplinary assessment."

Supports systematic but individualized assessment rather than a uniform schedule.

PMID:40874655 SUPPORT Human Clinical

"Given that skin findings are often the earliest and most recognizable signs of AOS, dermatologists play an important role in early diagnosis, enabling prompt genetic evaluation and coordinated multidisciplinary care."

Supports coordinated care and early genetics involvement.

PMID:27077170 SUPPORT Other

"Cardiovascular. Echocardiography annually until age three years for signs of pulmonary hypertension. Neurologic. Annual pediatric care, including neurologic examination and ongoing assessment of psychomotor development. Ocular. Annual assessment by pediatric ophthalmologist until age three years..."

The archived chapter documents a historical surveillance schedule, but because it was retired as outdated this entry retains individualized current assessment rather than adopting those intervals as a universal recommendation.

Genetic Counseling

Category: Counseling / Informational Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Genetic counseling for families with AOS to discuss inheritance patterns, recurrence implications, and molecular testing. For established dominant forms, each child of an affected heterozygous individual has a 50% chance of inheriting the variant; for established recessive forms, each sibling of an affected individual has a 25% chance of being affected when both parents are carriers. Counseling should not assign VCP inheritance from the currently available abstract.

Show evidence (3 references)

PMID:29924900 SUPPORT Human Clinical

"Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance."

The heterogeneous inheritance architecture is directly relevant to family counseling.

PMID:27077170 SUPPORT Other

"Each child of an individual with autosomal dominant AOS has a 50% chance of inheriting the pathogenic variant."

The archived GeneReviews chapter provides the recurrence-risk figure for established dominant AOS; it does not apply this risk to the newly reported VCP-associated form.

PMID:27077170 SUPPORT Other

"At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."

The archived GeneReviews chapter provides the sibling recurrence risks for established DOCK6- and EOGT-related recessive AOS.

🔬

Diagnosis

2

Clinical Assessment of the ACC/TTLD Spectrum

Clinical assessment establishes whether the congenital presentation lies within the AOS spectrum centered on scalp aplasia cutis and terminal transverse limb defects, while documenting cardiac, vascular, neurologic, ocular, and skull involvement. An archived, retired GeneReviews chapter described diagnosis from both core findings, one core finding plus an affected first-degree relative, or one core finding plus molecular confirmation. Because that chapter is historical and reports no validation metrics, these routes are not presented as a sensitivity- or specificity-validated current algorithm.

clinical assessment NCIT:C124351

Results: A compatible congenital ACC/TTLD pattern supports a clinical AOS diagnosis and guides subtype testing.

Show evidence (2 references)

PMID:19610107 SUPPORT Human Clinical

"The combination of aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD) is often referred to as the eponymous Adams-Oliver syndrome (AOS)."

Supports the core clinical disease boundary.

PMID:27077170 SUPPORT Other

"The diagnosis of AOS can be established in a proband with one of the following: Clinical findings of ACC of the scalp and TTLD. ACC or TTLD and a first-degree relative with findings consistent with AOS."

The archived GeneReviews chapter supplies the historical diagnostic routes while its retired status and absence of validation metrics are retained explicitly.

Molecular Genetic Testing

Sequence analysis of established AOS genes can identify an etiologic subtype. A 2018 mixed AOS/isolated-ACC/TTLD cohort received a molecular diagnosis in 30% of cases before VCP was discovered; that cohort-specific yield must not be treated as disease prevalence or as a current sensitivity estimate.

molecular genetic testing NCIT:C19770

Results: A pathogenic variant in an established AOS gene supports molecular subtype assignment; a negative result does not erase the clinical ACC/TTLD phenotype.

Show evidence (3 references)

PMID:29924900 SUPPORT Human Clinical

"Molecular diagnostic screening of 194 AOS/ACC/TTLD probands/families was conducted using next-generation and/or capillary sequencing analyses. In total, we identified 63 (likely) pathogenic mutations, comprising 56 distinct and 22 novel mutations, providing a molecular diagnosis in 30% of patients."

Provides the bounded historical molecular-yield estimate.

PMID:41979051 SUPPORT Human Clinical

"We report a new genetic etiology for AOS in 6 families with PH and 1 family without it."

Supports inclusion of VCP among current AOS testing considerations without assigning inheritance.

PMID:27077170 SUPPORT Other

"ACC or TTLD and either a pathogenic variant in an autosomal dominant AOS-related gene (ARHGAP31, DLL4, NOTCH1, or RBPJ) or two pathogenic variants in an autosomal recessive AOS-related gene (DOCK6 or EOGT)."

The archived GeneReviews chapter supports molecular confirmation for the six established historical gene subtypes; VCP is added separately from the 2026 primary report.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Adams-Oliver Syndrome:

Aplasia cutis-enamel dysplasia syndrome Not Yet Curated MONDO:0968978

Overlapping Features The FOSL2-related disorder overlaps AOS through localized scalp aplasia cutis with or without skull defects. Its reported combination of enamel hypoplasia, neurodevelopmental delay or autism, congenital cataracts, and prenatal growth restriction distinguishes it from the classic AOS ACC/terminal-limb pattern.

Distinguishing Features

Enamel hypoplasia with neurodevelopmental delay or autism favors the FOSL2-related disorder.
Congenital cataracts and prenatal growth restriction were recurrent in the reported FOSL2 series.
A pathogenic last-exon truncating FOSL2 variant supports this differential; FOSL2 is not modeled as an AOS gene.

Show evidence (1 reference)

PMID:36197437 SUPPORT Human Clinical

"We identified 11 individuals from 10 families with mostly de novo truncating FOSL2 variants sharing a strikingly similar phenotype characterized by prenatal growth retardation, localized cutis scalp aplasia with or without skull defects, neurodevelopmental delay with autism spectrum disorder,..."

Directly supports both the scalp overlap and the distinguishing phenotype constellation.

🔬

Clinical Trials

1

NCT01630421

Observational study of families and isolated cases with aplasia cutis congenita to identify causal genes or regulatory elements and study cellular mechanisms. It is relevant to AOS because scalp ACC is a core feature, but it is not an AOS-specific interventional or treatment trial.

Show evidence (1 reference)

clinicaltrials:NCT01630421 SUPPORT Human Clinical

"The goal of this research study is to identify genes and regulatory elements on chromosomes that cause ACC. The investigators also study tissue samples from patients to learn about the processes that lead to this disorder."

Establishes the observational genetics and mechanism scope without implying AOS-specific treatment efficacy.

🐁

Animal Models

4

AOS-associated Rbpj missense allele with Notch1 heterozygosity and endothelial conditional expression Mouse (Mus musculus) Genetically engineered mouse model

The AOS-associated Rbpj allele produces dominant phenotypes on a Notch1 heterozygous background. Endothelial expression is necessary and sufficient for lethality and cardiovascular defects in this model. The sensitized background and cardiovascular endpoint limit extrapolation to the complete human scalp/limb phenotype.

Species

Mouse (Mus musculus)

Genotype

AOS-associated Rbpj missense allele with Notch1 heterozygosity and endothelial conditional expression

Background

Notch1-sensitized genetic background

Genes

RBPJ hgnc:5724 NOTCH1 hgnc:7881

Show evidence (1 reference)

PMID:41055965 SUPPORT Model Organism

"Consistent with this idea, mice carrying an AOS-associated Rbpj allele develop dominant phenotypes that include increased lethality and cardiovascular defects in a Notch1 heterozygous background, whereas Notch1 and Rbpj compound heterozygous null alleles are well tolerated."

Defines the sensitized genotype and its phenotype.

Second-heart-field-specific Dll4 heterozygosity or knockout Mouse (Mus musculus) Conditional genetically engineered mouse model

Models the DLL4/AOS6 cardiac branch by perturbing Dll4 in the second heart field. It is not a model of the pooled 23% cardiac frequency across all AOS.

Species

Mouse (Mus musculus)

Genotype

Second-heart-field-specific Dll4 heterozygosity or knockout

Genes

DLL4 hgnc:2910

Show evidence (1 reference)

PMID:33899511 SUPPORT Model Organism

"Similar to the clinical syndrome, 32% of SHF-specific Dll4 heterozygotes demonstrate foreshortened and misaligned OFT, resulting in a double outlet right ventricle."

Supports the cardiac phenotype in the DLL4 model.

Pdgfra-Cre conditional Rac1 deletion in cranial mesenchyme Mouse (Mus musculus) Conditional pathway-level mouse model

A pathway-level cranial-development model downstream of the ARHGAP31/DOCK6 branch. It is not an AOS-variant model and therefore supports a possible mechanism rather than direct disease fidelity.

Species

Mouse (Mus musculus)

Genotype

Pdgfra-Cre conditional Rac1 deletion in cranial mesenchyme

Genes

RAC1 hgnc:9801

Show evidence (1 reference)

PMID:41126757 SUPPORT Model Organism

"Rac1-KO mice died perinatally and lacked the apical calvarium and overlying dermis, resembling defects seen in severe AOS."

Supports phenotypic resemblance and the explicit pathway-level limitation.

Global or endothelial Eogt deletion Mouse (Mus musculus) Genetically engineered pathway model

Eogt loss impairs retinal angiogenesis and endothelial Notch output, but the null mouse does not reproduce the abnormalities predicted from human AOS. It is therefore a proximal pathway model with a material human-model mismatch.

Species

Mouse (Mus musculus)

Genotype

Global or endothelial Eogt deletion

Genes

EOGT hgnc:28526

Show evidence (2 references)

PMID:28395734 SUPPORT Model Organism

"Global or endothelial cell-specific deletion of Eogt resulted in defective retinal angiogenesis, with a mild phenotype similar to that caused by reduced Notch signaling in retina."

Supports the proximal vascular phenotype.

PMID:28395734 SUPPORT Model Organism

"Unexpectedly,Eogt-null mice do not exhibit abnormalities predicted from the symptoms of AOS patients."

Directly documents the mismatch with the human syndrome.

{ }

Source YAML

click to show

name: Adams-Oliver Syndrome
creation_date: '2026-04-22T00:00:00Z'
category: Genetic
synonyms:
- AOS
- Aplasia cutis congenita with terminal transverse limb defects
description: >
  Adams-Oliver syndrome (AOS) is a genetically heterogeneous congenital
  developmental disorder defined clinically by scalp aplasia cutis congenita
  and terminal transverse limb defects, with variable cardiac, vascular,
  neurologic, ocular, and skull involvement. Established causes include
  autosomal-dominant ARHGAP31, RBPJ, NOTCH1, and DLL4 variants and
  autosomal-recessive DOCK6 and EOGT variants. Hypermorphic VCP variants are a
  newly reported additional cause; the ascertainment-enriched discovery series
  included six families with pulmonary hypertension and one without. The known molecular mechanisms form at
  least three branches: impaired canonical Notch signaling, CDC42 and/or RAC1
  dysregulation with cytoskeletal dysfunction, and altered VCP
  ATPase/conformational coupling. How these branches produce the shared scalp
  and limb pattern is not fully resolved.
disease_term:
  preferred_term: Adams-Oliver syndrome
  term:
    id: MONDO:0007034
    label: Adams-Oliver syndrome
parents:
- Ectodermal dysplasia
- Congenital limb malformation
- Congenital heart disease
references:
- reference: PMID:27077170
  title: "Adams-Oliver Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
  tags:
  - GeneReviews
  findings:
  - statement: The archived GeneReviews chapter defines the core ACC/TTLD clinical spectrum and historical diagnostic routes.
  - statement: It provides historical scalp-ACC management and surveillance recommendations; the chapter is retired and may be outdated.
  - statement: It gives 50% offspring risk for established dominant AOS and 25% affected-sibling risk when both parents carry an established recessive AOS cause.
- reference: PMID:19610107
  title: The spectra of clinical phenotypes in aplasia cutis congenita and terminal transverse limb defects.
  findings:
  - statement: Defines the ACC/TTLD clinical spectrum and documents marked intrafamilial phenotypic variability.
- reference: PMID:29924900
  title: Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.
  findings:
  - statement: Reports molecular screening of 194 AOS/ACC/TTLD probands or families and cohort-specific contributions of six established genes.
- reference: PMID:28160419
  title: "Adams-Oliver syndrome review of the literature: Refining the diagnostic phenotype."
  findings:
  - statement: Provides pooled literature frequencies for major associated cardiac, neurologic, and vascular findings.
- reference: PMID:41055965
  title: Defective Notch1 signaling in endothelial cells drives pathogenesis in a mouse model of Adams-Oliver syndrome.
  findings:
  - statement: Establishes a dominant-negative mechanism for AOS-associated RBPJ variants and an endothelial requirement in a sensitized mouse model.
- reference: PMID:41979051
  title: Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
  findings:
  - statement: Identifies hypermorphic VCP variants as an AOS cause in seven families and defines their ATPase and conformational effects.
- reference: PMID:40874655
  title: "Cutaneous Features of Adams-Oliver Syndrome: Diagnosis, Differentiation, and Management."
  findings:
  - statement: Reviews recognition, genetic evaluation, and coordinated multidisciplinary care.
classifications:
  isds_skeletal_category:
  - classification_value: limb_hypoplasia_reduction_defects
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019 revision
      (Mortier et al., PMID:31633310), Table 1 group 39 "Limb hypoplasia-reduction
      defects group"; listed as "Adams-Oliver syndrome".
definitions:
- name: Clinical ACC/TTLD spectrum definition
  definition_type: OTHER
  scope: Individuals with aplasia cutis congenita and/or terminal transverse limb defects
  description: >-
    AOS denotes the clinical spectrum centered on the combination of scalp
    aplasia cutis congenita and terminal transverse limb defects. Marked
    intrafamilial variability and clinically overlapping ACC/TTLD presentations
    mean that this is a spectrum definition, not a sensitivity- or
    specificity-validated algorithm.
  evidence:
  - reference: PMID:19610107
    reference_title: The spectra of clinical phenotypes in aplasia cutis congenita and terminal transverse limb defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The combination of aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD) is often referred to as the eponymous Adams-Oliver syndrome (AOS).
    explanation: The clinical-spectrum study directly supports the core ACC/TTLD disease boundary.
  - reference: PMID:27077170
    reference_title: "Adams-Oliver Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD).
    explanation: The archived GeneReviews chapter independently states the clinical core; it is tagged as a retired historical baseline rather than a current guideline.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:29924900
    reference_title: Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance.
    explanation: Defines the established autosomal-dominant AOS genes in the pre-VCP cohort.
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:29924900
    reference_title: Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance.
    explanation: Defines DOCK6- and EOGT-associated AOS as autosomal recessive.
has_subtypes:
- name: AOS1
  display_name: AOS1 (ARHGAP31, autosomal dominant)
  subtype_term:
    preferred_term: Adams-Oliver syndrome 1
    term:
      id: MONDO:0024506
      label: Adams-Oliver syndrome 1
  genes:
  - preferred_term: ARHGAP31
    term:
      id: hgnc:29216
      label: ARHGAP31
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >
    Autosomal dominant form caused by gain-of-function mutations in ARHGAP31,
    encoding a Rho GTPase-activating protein. The mutant protein shows
    constitutive GAP activity with demonstrated depletion of active Cdc42 and
    disruption of actin-cytoskeleton organization.
  evidence:
  - reference: PMID:21565291
    reference_title: "Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Candidate-gene- and exome-based sequencing led to the identification of independent premature truncating mutations in the terminal exon of the Rho GTPase-activating protein 31 gene, ARHGAP31, which encodes a Cdc42/Rac1 regulatory protein."
    explanation: Original identification of ARHGAP31 as causative for autosomal dominant AOS.
- name: AOS2
  display_name: AOS2 (DOCK6, autosomal recessive)
  subtype_term:
    preferred_term: Adams-Oliver syndrome 2
    term:
      id: MONDO:0013635
      label: Adams-Oliver syndrome 2
  genes:
  - preferred_term: DOCK6
    term:
      id: hgnc:19189
      label: DOCK6
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >
    Autosomal recessive form caused by loss-of-function mutations in DOCK6,
    a guanine nucleotide exchange factor for Cdc42 and Rac1. Loss of DOCK6
    function impairs actin-cytoskeleton organization.
  evidence:
  - reference: PMID:21820096
    reference_title: "Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we combined autozygome analysis with exome sequencing to identify a homozygous truncating mutation in dedicator of cytokinesis 6 gene (DOCK6) which encodes an atypical guanidine exchange factor (GEF) known to activate two members of the Rho GTPase family: Cdc42 and Rac1."
    explanation: Original identification of DOCK6 as causative for autosomal recessive AOS.
- name: AOS3
  display_name: AOS3 (RBPJ, autosomal dominant)
  subtype_term:
    preferred_term: Adams-Oliver syndrome 3
    term:
      id: MONDO:0013895
      label: Adams-Oliver syndrome 3
  genes:
  - preferred_term: RBPJ
    term:
      id: hgnc:5724
      label: RBPJ
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >
    Autosomal dominant form caused by dominant-negative mutations in RBPJ,
    the central transcriptional mediator of canonical Notch signaling.
    Mutant RBPJ retains cofactor binding but has impaired DNA binding,
    sequestering Notch pathway cofactors from target gene promoters.
  evidence:
  - reference: PMID:22883147
    reference_title: "RBPJ mutations identified in two families affected by Adams-Oliver syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified two unique mutations in recombination signal binding protein for immunoglobulin kappa J (RBPJ) in two independent families affected by Adams-Oliver syndrome (AOS)"
    explanation: Original identification of RBPJ mutations in AOS families.
- name: AOS4
  display_name: AOS4 (EOGT, autosomal recessive)
  subtype_term:
    preferred_term: Adams-Oliver syndrome 4
    term:
      id: MONDO:0014124
      label: Adams-Oliver syndrome 4
  genes:
  - preferred_term: EOGT
    term:
      id: hgnc:28526
      label: EOGT
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >
    Autosomal recessive form caused by loss-of-function mutations in EOGT,
    which encodes an EGF-domain-specific O-linked N-acetylglucosamine
    transferase that modifies Notch receptors.
  evidence:
  - reference: PMID:23522784
    reference_title: "Mutations in EOGT confirm the genetic heterogeneity of autosomal-recessive Adams-Oliver syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "exome sequencing in one family revealed one missense mutation in EOGT (C3orf64), and subsequent targeted sequencing of this gene revealed a homozygous missense mutation and a homozygous frameshift deletion mutation in the other two families."
    explanation: Original identification of EOGT mutations in autosomal recessive AOS.
- name: AOS5
  display_name: AOS5 (NOTCH1, autosomal dominant)
  subtype_term:
    preferred_term: Adams-Oliver syndrome 5
    term:
      id: MONDO:0014459
      label: Adams-Oliver syndrome 5
  genes:
  - preferred_term: NOTCH1
    term:
      id: hgnc:7881
      label: NOTCH1
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >
    Autosomal dominant form caused by loss-of-function mutations in NOTCH1.
    NOTCH1 was the largest single contributor in a 194-proband/family
    AOS/ACC/TTLD cohort. Haploinsufficiency reduces canonical Notch signaling,
    and cardiac anomalies are enriched among reported NOTCH1 variant carriers.
  evidence:
  - reference: PMID:25963545
    reference_title: "Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams-Oliver Syndrome With Variable Cardiac Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report establishes NOTCH1 mutation as the primary cause of AOS, accounting for 17% of cases in our cohort, and an important genetic factor in AOS with associated cardiovascular complications."
    explanation: Establishes NOTCH1 haploinsufficiency and its cardiac association in the reported cohort.
- name: AOS6
  display_name: AOS6 (DLL4, autosomal dominant)
  subtype_term:
    preferred_term: Adams-Oliver syndrome 6
    term:
      id: MONDO:0014703
      label: Adams-Oliver syndrome 6
  genes:
  - preferred_term: DLL4
    term:
      id: hgnc:2910
      label: DLL4
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >
    Autosomal dominant form caused by loss-of-function mutations in DLL4,
    a Notch ligand critical for angiogenesis and vascular patterning.
  evidence:
  - reference: PMID:26299364
    reference_title: "Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "nine heterozygous mutations in DLL4 were identified, including two nonsense and seven missense variants"
    explanation: Original identification of DLL4 mutations as a cause of autosomal dominant AOS.
- name: VCP-Associated AOS
  display_name: VCP-associated Adams-Oliver syndrome
  genes:
  - preferred_term: VCP
    term:
      id: hgnc:12666
      label: VCP
  description: >-
    Newly reported AOS caused by hypermorphic VCP variants. The discovery series
    included six families with pulmonary hypertension and one without; it does
    not establish penetrance or the age of pulmonary-hypertension onset in each
    family. This entry does not assign a numbered AOS subtype or mode of
    inheritance because the available primary abstract does not establish either.
  evidence:
  - reference: PMID:41979051
    reference_title: Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a new genetic etiology for AOS in 6 families with PH and 1 family without it.
    explanation: Establishes VCP as an additional AOS genetic cause and bounds the observed pulmonary-hypertension association in the discovery series.
mechanistic_hypotheses:
- hypothesis_group_id: aos_notch_vascular_disruption
  hypothesis_label: Notch-pathway vascular disruption model
  status: ALTERNATIVE
  applies_to_subtypes:
  - AOS3
  - AOS4
  - AOS5
  - AOS6
  description: >-
    Reduced canonical Notch output in vascular endothelium can account for
    cardiovascular defects in AOS models. Extension of that model to the human
    scalp and limb defects remains a vascular-disruption hypothesis rather than
    a demonstrated human causal chain.
  evidence:
  - reference: PMID:41055965
    reference_title: Defective Notch1 signaling in endothelial cells drives pathogenesis in a mouse model of Adams-Oliver syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These data establish that reduced Notch1 signaling in the vasculature is a key driver of pathogenesis in this AOS mouse model.
    explanation: Supports the endothelial mechanism within the sensitized RBPJ/Notch1 mouse model.
  - reference: PMID:25132448
    reference_title: Mutations in NOTCH1 cause Adams-Oliver syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We propose that the limb and scalp defects might also be due to a vasculopathy in NOTCH1-related AOS.
    explanation: Explicitly frames the human scalp/limb vascular route as a proposal.
- hypothesis_group_id: aos_rho_cytoskeletal_development
  hypothesis_label: Rho-GTPase cytoskeletal-development model
  status: CANONICAL
  applies_to_subtypes:
  - AOS1
  - AOS2
  description: >-
    Opposite biochemical lesions in ARHGAP31 and DOCK6 perturb CDC42 and/or
    RAC1 signaling and disturb actin organization. The intervening
    developmental events connecting those cellular defects to human scalp and
    terminal-limb malformations remain incompletely mapped.
  evidence:
  - reference: PMID:21565291
    reference_title: "Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Constitutively active ARHGAP31 mutations result in a loss of available active Cdc42 and consequently disrupt actin cytoskeletal structures.
    explanation: Defines the proximal ARHGAP31-to-Rho-GTPase cytoskeletal mechanism.
  - reference: PMID:21820096
    reference_title: "Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Consistent with the established role of Cdc42 and Rac1 in the organization of the actin cytoskeleton, we demonstrate a cellular phenotype typical of a defective actin cytoskeleton in patient cells.
    explanation: Supports cytoskeletal dysfunction in DOCK6-deficient patient cells.
- hypothesis_group_id: aos_vcp_developmental_bridge
  hypothesis_label: VCP developmental and pulmonary-vascular bridge
  status: EMERGING
  applies_to_subtypes:
  - VCP-Associated AOS
  description: >-
    AOS-associated VCP variants increase ATP hydrolysis and alter conformational
    coupling, but the developmental route to scalp and limb defects and the
    route to pulmonary veno-occlusive disease or other forms of pulmonary
    hypertension are not yet established.
  evidence:
  - reference: PMID:41979051
    reference_title: Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that AOS-related VCP variants are hypermorphic with respect to ATP hydrolysis and cause N-terminal domain hyperflexibility with impairment of interdomain coupling.
    explanation: Establishes the proximal VCP biochemical effect while leaving the developmental bridge unresolved.
pathophysiology:
- name: NOTCH1 Haploinsufficiency
  description: >-
    Heterozygous loss-of-function variants reduce NOTCH1 transcript abundance
    and receptor dosage in AOS5.
  genes:
  - preferred_term: NOTCH1
    term:
      id: hgnc:7881
      label: NOTCH1
  subtypes:
  - AOS5
  downstream:
  - target: Reduced Canonical Notch Signaling
    causal_link_type: DIRECT
    description: Reduced NOTCH1 dosage lowers pathway output.
    evidence:
    - reference: PMID:25963545
      reference_title: Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams-Oliver Syndrome With Variable Cardiac Anomalies.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        NOTCH1 transcript levels were significantly reduced by comparison to an unaffected control individual, demonstrating approximately 50% expression in all samples tested
      explanation: Patient RNA demonstrates reduced NOTCH1 dosage.
  evidence:
  - reference: PMID:25963545
    reference_title: Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams-Oliver Syndrome With Variable Cardiac Anomalies.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      NOTCH1 transcript levels were significantly reduced by comparison to an unaffected control individual, demonstrating approximately 50% expression in all samples tested
    explanation: Supports NOTCH1 haploinsufficiency in variant carriers.
- name: DLL4 Loss of Function
  description: >-
    Heterozygous loss-of-function variants in the canonical Notch ligand DLL4
    cause AOS6 and reduce ligand capacity within the DLL4-NOTCH signaling axis.
  genes:
  - preferred_term: DLL4
    term:
      id: hgnc:2910
      label: DLL4
  subtypes:
  - AOS6
  downstream:
  - target: Reduced Canonical Notch Signaling
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced DLL4-mediated Notch receptor activation
    description: DLL4 loss reduces activation of the canonical receptor-effector cascade.
    evidence:
    - reference: PMID:26299364
      reference_title: Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our findings demonstrate that DLL4 mutations are an additional cause of autosomal-dominant AOS or isolated ACC and provide further evidence for a key role of NOTCH signaling in the etiology of this disorder.
      explanation: Human genetics supports DLL4 loss within the Notch-pathway AOS branch.
  - target: DLL4-Dependent Second Heart Field Defect
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced DLL4-mediated Notch signaling in second-heart-field progenitors
    description: DLL4 loss depletes the second-heart-field progenitor pool in the cardiac mouse model.
    evidence:
    - reference: PMID:33899511
      reference_title: Murine Model of Cardiac Defects Observed in Adams-Oliver Syndrome Driven by Delta-Like Ligand-4 Haploinsufficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Dll4-mediated Notch signaling is critically required for SHF proliferation such that Dll4 knockout results in a 33% reduction in proliferation and a fourfold increase in apoptosis in SHF cells, leading to a 56% decline in the size of the SHF progenitor pool.
      explanation: Defines the DLL4-dependent second-heart-field mechanism in mice.
  evidence:
  - reference: PMID:26299364
    reference_title: Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      nine heterozygous mutations in DLL4 were identified, including two nonsense and seven missense variants
    explanation: Establishes the disease-associated DLL4 variant series.
- name: RBPJ Dominant-Negative Cofactor Sequestration
  description: >-
    AOS3-associated RBPJ missense variants compromise DNA binding while
    retaining cofactor binding, supporting dominant-negative sequestration of
    canonical Notch transcriptional cofactors.
  genes:
  - preferred_term: RBPJ
    term:
      id: hgnc:5724
      label: RBPJ
  subtypes:
  - AOS3
  downstream:
  - target: Reduced Canonical Notch Signaling
    causal_link_type: DIRECT
    description: Cofactor sequestration reduces DNA-bound canonical Notch transcriptional activity.
    evidence:
    - reference: PMID:41055965
      reference_title: Defective Notch1 signaling in endothelial cells drives pathogenesis in a mouse model of Adams-Oliver syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        These findings suggest that AOS-associated RBPJ variants do not function as loss-of-function alleles but instead act as dominant-negative proteins that sequester cofactors from DNA.
      explanation: Quantitative binding assays support the dominant-negative route.
  evidence:
  - reference: PMID:41055965
    reference_title: Defective Notch1 signaling in endothelial cells drives pathogenesis in a mouse model of Adams-Oliver syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we used quantitative binding assays to show that AOS-associated RBPJ missense variants compromise DNA binding but not cofactor binding.
    explanation: Defines the proximal biochemical defect.
- name: EOGT-Dependent Notch O-GlcNAcylation Deficiency
  description: >-
    AOS4-associated EOGT variants impair O-GlcNAcylation of EGF-repeat proteins.
    EOGT-deficient cells show selectively reduced DLL1/DLL4 binding and impaired
    ligand-induced Notch signaling, whereas JAG1 binding is preserved.
  genes:
  - preferred_term: EOGT
    term:
      id: hgnc:28526
      label: EOGT
  subtypes:
  - AOS4
  downstream:
  - target: Reduced Canonical Notch Signaling
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced O-GlcNAcylation of NOTCH EGF repeats
    - impaired DLL1/DLL4 binding and ligand-induced activation
    description: EOGT deficiency weakens DLL-selective Notch receptor activation.
    evidence:
    - reference: PMID:28395734
      reference_title: O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In EOGT-deficient cells, the binding of DLL1 and DLL4, but not JAG1, canonical Notch ligands was reduced, and ligand-induced Notch signaling was impaired.
      explanation: Directly supports the ligand-selective signaling defect.
  evidence:
  - reference: PMID:25488668
    reference_title: Impaired O-linked N-acetylglucosaminylation in the endoplasmic reticulum by mutated epidermal growth factor (EGF) domain-specific O-linked N-acetylglucosamine transferase found in Adams-Oliver syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      As compared with wild-type EOGT, O-GlcNAcylation in the ER is nearly abolished in HEK293T cells exogenously expressing EOGT variants associated with AOS.
    explanation: Demonstrates loss of enzymatic product for AOS-associated EOGT variants in vitro.
- name: ARHGAP31 Gain of Function
  description: >-
    Terminal-exon truncating ARHGAP31 variants produce stable proteins with
    increased GAP activity; depletion of active Cdc42 was demonstrated directly.
  genes:
  - preferred_term: ARHGAP31
    term:
      id: hgnc:29216
      label: ARHGAP31
  subtypes:
  - AOS1
  downstream:
  - target: Reduced CDC42 and/or RAC1 Signaling
    causal_link_type: DIRECT
    description: Excess GAP activity depletes active Cdc42; the cited assay does not establish simultaneous Rac1 depletion.
    evidence:
    - reference: PMID:21565291
      reference_title: "Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Constitutively active ARHGAP31 mutations result in a loss of available active Cdc42 and consequently disrupt actin cytoskeletal structures.
      explanation: Demonstrates the proximal gain-of-function effect on active Rho GTPase.
  evidence:
  - reference: PMID:21565291
    reference_title: "Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mutant transcripts are stable and increase ARHGAP31 activity in vitro through a gain-of-function mechanism.
    explanation: Establishes the ARHGAP31 gain-of-function mechanism.
- name: DOCK6 Loss of GEF Function
  description: >-
    Biallelic loss-of-function variants disrupt DOCK6, a guanine-nucleotide
    exchange factor known to activate CDC42 and RAC1.
  genes:
  - preferred_term: DOCK6
    term:
      id: hgnc:19189
      label: DOCK6
  subtypes:
  - AOS2
  downstream:
  - target: Reduced CDC42 and/or RAC1 Signaling
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - loss of DOCK6 GEF activity toward CDC42 and RAC1
    description: Loss of DOCK6 GEF function is expected to reduce activation of CDC42 and/or RAC1; the cited study did not directly measure the active GTPase pool.
    evidence:
    - reference: PMID:21820096
      reference_title: "Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        we combined autozygome analysis with exome sequencing to identify a homozygous truncating mutation in dedicator of cytokinesis 6 gene (DOCK6) which encodes an atypical guanidine exchange factor (GEF) known to activate two members of the Rho GTPase family: Cdc42 and Rac1.
      explanation: Links biallelic DOCK6 disruption to its CDC42/RAC1 GEF function.
  evidence:
  - reference: PMID:21820096
    reference_title: "Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Consistent with the established role of Cdc42 and Rac1 in the organization of the actin cytoskeleton, we demonstrate a cellular phenotype typical of a defective actin cytoskeleton in patient cells.
    explanation: Demonstrates the downstream cellular phenotype in patient cells.
- name: AOS-Associated VCP Variant Effects
  description: >-
    AOS-associated VCP variants have two reported parallel proximal effects:
    increased ATP hydrolysis and impaired conformational coupling. Which effect,
    if either, mediates the congenital and pulmonary-vascular manifestations is
    unknown, so the unresolved clinical bridge is attached to this neutral
    variant-effects node rather than to either biochemical effect.
  genes:
  - preferred_term: VCP
    term:
      id: hgnc:12666
      label: VCP
  subtypes:
  - VCP-Associated AOS
  downstream:
  - target: VCP Hypermorphic ATPase Activity
    causal_link_type: DIRECT
    description: AOS-associated VCP variants increase ATP hydrolysis in vitro.
    evidence:
    - reference: PMID:41979051
      reference_title: Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We show that AOS-related VCP variants are hypermorphic with respect to ATP hydrolysis and cause N-terminal domain hyperflexibility with impairment of interdomain coupling.
      explanation: Directly supports ATPase hyperactivity as one parallel proximal variant effect.
  - target: VCP Conformational Coupling Defect
    causal_link_type: DIRECT
    description: AOS-associated VCP variants cause N-terminal hyperflexibility and impaired interdomain coupling.
    evidence:
    - reference: PMID:41979051
      reference_title: Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We show that AOS-related VCP variants are hypermorphic with respect to ATP hydrolysis and cause N-terminal domain hyperflexibility with impairment of interdomain coupling.
      explanation: Directly supports the conformational defect as a parallel proximal variant effect.
  - target: Aplasia Cutis Congenita of the Scalp
    hypothesis_groups:
    - aos_vcp_developmental_bridge
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: VCP variants cause AOS, but the developmental route to scalp aplasia is unresolved.
    evidence:
    - reference: PMID:41979051
      reference_title: Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report a new genetic etiology for AOS in 6 families with PH and 1 family without it.
      explanation: Human genetic evidence connects VCP variants to AOS without defining the intervening developmental mechanism.
  - target: Terminal Transverse Limb Defects
    hypothesis_groups:
    - aos_vcp_developmental_bridge
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: VCP variants cause AOS, but the developmental route to terminal limb defects is unresolved.
    evidence:
    - reference: PMID:41979051
      reference_title: Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report a new genetic etiology for AOS in 6 families with PH and 1 family without it.
      explanation: Human genetic evidence establishes the syndrome association but not the intermediate mechanism.
  - target: Pulmonary Hypertension
    hypothesis_groups:
    - aos_vcp_developmental_bridge
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Pulmonary hypertension occurred in six discovery families and was absent in one; the organ-level mechanism is unresolved.
    evidence:
    - reference: PMID:41979051
      reference_title: Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report a new genetic etiology for AOS in 6 families with PH and 1 family without it.
      explanation: Bounds the observed association without assigning penetrance or an intervening mechanism.
  evidence:
  - reference: PMID:41979051
    reference_title: Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a new genetic etiology for AOS in 6 families with PH and 1 family without it.
    explanation: Establishes the VCP-associated disease branch while leaving its disease-mediating biochemical route unresolved.
- name: VCP Hypermorphic ATPase Activity
  description: >-
    AOS-associated VCP substitution variants increase ATP hydrolysis in vitro.
    This effect is modeled in parallel with the reported conformational-coupling
    defect; neither has been established as the disease-mediating route.
  genes:
  - preferred_term: VCP
    term:
      id: hgnc:12666
      label: VCP
  subtypes:
  - VCP-Associated AOS
  molecular_functions:
  - preferred_term: ATP hydrolysis activity
    term:
      id: GO:0016887
      label: ATP hydrolysis activity
  evidence:
  - reference: PMID:41979051
    reference_title: Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that AOS-related VCP variants are hypermorphic with respect to ATP hydrolysis and cause N-terminal domain hyperflexibility with impairment of interdomain coupling.
    explanation: Defines ATPase hyperactivity as one parallel proximal VCP effect.
- name: VCP Conformational Coupling Defect
  description: >-
    AOS-related VCP variants cause N-terminal-domain hyperflexibility and impair
    coupling between VCP domains. This effect is modeled in parallel with ATPase
    hyperactivity; neither has been established as the disease-mediating route.
  genes:
  - preferred_term: VCP
    term:
      id: hgnc:12666
      label: VCP
  subtypes:
  - VCP-Associated AOS
  evidence:
  - reference: PMID:41979051
    reference_title: Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that AOS-related VCP variants are hypermorphic with respect to ATP hydrolysis and cause N-terminal domain hyperflexibility with impairment of interdomain coupling.
    explanation: Defines the conformational defect as one parallel proximal VCP effect.
- name: Pulmonary Veno-Occlusive Disease in AOS
  description: >-
    Review of published AOS cases with pulmonary hypertension suggests that
    pulmonary veno-occlusive disease is the most common mechanism, but not a
    universal finding.
  downstream:
  - target: Pulmonary Hypertension
    causal_link_type: DIRECT
    description: Pulmonary venous obstruction can produce pulmonary hypertension.
    evidence:
    - reference: PMID:41979051
      reference_title: Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Review of published cases of AOS with PH suggests that pulmonary veno-occlusive disease is the most common mechanism.
      explanation: Supports PVOD as the leading reported mechanism among AOS cases with pulmonary hypertension, not as universal.
  evidence:
  - reference: PMID:41979051
    reference_title: Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Review of published cases of AOS with PH suggests that pulmonary veno-occlusive disease is the most common mechanism.
    explanation: Literature synthesis within the VCP discovery report supports the qualified claim.
- name: Reduced Canonical Notch Signaling
  description: >-
    NOTCH1 haploinsufficiency, DLL4 loss of function, dominant-negative RBPJ
    variants, and EOGT-dependent glycosylation defects reduce canonical Notch
    pathway output by distinct proximal mechanisms. Conditional mouse genetics
    establishes vascular endothelium as sufficient for lethality and
    cardiovascular defects in the sensitized RBPJ/Notch1 model; it does not by
    itself establish endothelial causality for human scalp or limb defects.
  genes:
  - preferred_term: NOTCH1
    term:
      id: hgnc:7881
      label: NOTCH1
  - preferred_term: DLL4
    term:
      id: hgnc:2910
      label: DLL4
  - preferred_term: RBPJ
    term:
      id: hgnc:5724
      label: RBPJ
  - preferred_term: EOGT
    term:
      id: hgnc:28526
      label: EOGT
  subtypes:
  - AOS3
  - AOS4
  - AOS5
  - AOS6
  biological_processes:
  - preferred_term: Notch signaling pathway
    term:
      id: GO:0007219
      label: Notch signaling pathway
  evidence:
  - reference: PMID:25963545
    reference_title: "Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams-Oliver Syndrome With Variable Cardiac Anomalies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "NOTCH1 expression is down-regulated in AOS subjects harboring NOTCH1 mutation in vivo"
    explanation: Demonstrates reduced NOTCH1 expression in variant carriers.
  - reference: PMID:41055965
    reference_title: "Defective Notch1 signaling in endothelial cells drives pathogenesis in a mouse model of Adams-Oliver syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "expression of the Rbpj AOS allele in endothelial cells is both necessary and sufficient to cause lethality and cardiovascular defects"
    explanation: Supports the endothelial mechanism for cardiovascular outcomes in the sensitized mouse model.
  - reference: PMID:22883147
    reference_title: "RBPJ mutations identified in two families affected by Adams-Oliver syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These identified mutations link RBPJ, the primary transcriptional regulator for the Notch pathway, with AOS, a human genetic disorder."
    explanation: Human genetics links RBPJ to the canonical Notch branch of AOS.
- name: Reduced CDC42 and/or RAC1 Signaling
  description: >-
    ARHGAP31 gain of GAP activity directly depletes active Cdc42, while DOCK6
    loss is expected from its known GEF function to reduce CDC42 and/or RAC1
    activation. Their relationship to the Notch branch is not established.
  genes:
  - preferred_term: ARHGAP31
    term:
      id: hgnc:29216
      label: ARHGAP31
  - preferred_term: DOCK6
    term:
      id: hgnc:19189
      label: DOCK6
  subtypes:
  - AOS1
  - AOS2
  biological_processes:
  - preferred_term: Rho protein signal transduction
    term:
      id: GO:0007266
      label: Rho protein signal transduction
  downstream:
  - target: Actin Cytoskeleton Defects
    hypothesis_groups:
    - aos_rho_cytoskeletal_development
    causal_link_type: DIRECT
    description: Reduced CDC42 and/or RAC1 activity disrupts actin organization and cell behavior.
    evidence:
    - reference: PMID:21565291
      reference_title: "Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Constitutively active ARHGAP31 mutations result in a loss of available active Cdc42 and consequently disrupt actin cytoskeletal structures.
      explanation: Directly links reduced active Cdc42 to cytoskeletal disruption.
    - reference: PMID:21820096
      reference_title: "Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Consistent with the established role of Cdc42 and Rac1 in the organization of the actin cytoskeleton, we demonstrate a cellular phenotype typical of a defective actin cytoskeleton in patient cells.
      explanation: Patient-cell evidence supports the DOCK6-to-cytoskeleton edge.
  - target: RAC1-SRF Cranial Mesenchyme Defect
    hypothesis_groups:
    - aos_rho_cytoskeletal_development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Conditional Rac1 loss defines a cranial-mesenchyme route in mice, but not an AOS-allele-specific route.
    evidence:
    - reference: PMID:41126757
      reference_title: Mouse scalp development requires Rac1 and SRF for the maintenance of mechanoresponsive mesenchyme.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Together, these data suggest a model where Rac1 and SRF maintain apical fibroblasts in a mechanoresponsive and proliferative state to complete cranial development.
      explanation: Supports the pathway-level cranial mechanism while retaining the model limitation.
  evidence:
  - reference: PMID:21565291
    reference_title: "Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Constitutively active ARHGAP31 mutations result in a loss of available active Cdc42 and consequently disrupt actin cytoskeletal structures."
    explanation: Demonstrates the proximal ARHGAP31 gain-of-function mechanism.
  - reference: PMID:21820096
    reference_title: "Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Consistent with the established role of Cdc42 and Rac1 in the organization of the actin cytoskeleton, we demonstrate a cellular phenotype typical of a defective actin cytoskeleton in patient cells."
    explanation: Confirms a defective actin-cytoskeleton phenotype in DOCK6 patient cells.
- name: Abnormal Vascular Development in Notch-Pathway Models
  description: >-
    Reduced Notch signaling perturbs endothelial and vascular development.
    Cardiovascular outcomes are experimentally supported in the sensitized
    RBPJ/Notch1 mouse model; vascular disruption of the human scalp and limb
    remains a NOTCH1-related hypothesis. This node is not asserted as the common
    mechanism for every Notch-pathway subtype or for ARHGAP31-, DOCK6-, or
    VCP-associated AOS. Gene and subtype fields are intentionally omitted
    because the cardiovascular mouse evidence and human scalp/limb hypothesis
    have different, narrower scopes.
  cell_types:
  - preferred_term: blood vessel endothelial cell
    term:
      id: CL:0000071
      label: blood vessel endothelial cell
  biological_processes:
  - preferred_term: vasculogenesis
    term:
      id: GO:0001570
      label: vasculogenesis
  - preferred_term: angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
  evidence:
  - reference: PMID:25132448
    reference_title: "Mutations in NOTCH1 cause Adams-Oliver syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We propose that the limb and scalp defects might also be due to a vasculopathy in NOTCH1-related AOS."
    explanation: Proposes the vascular disruption hypothesis for limb and scalp defects in AOS.
  - reference: PMID:41055965
    reference_title: "Defective Notch1 signaling in endothelial cells drives pathogenesis in a mouse model of Adams-Oliver syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "reduced Notch1 signaling in the vasculature is a key driver of pathogenesis in this AOS mouse model"
    explanation: Direct evidence from conditional mouse genetics that vascular-specific Notch signaling defects drive AOS.
  downstream:
  - target: Aplasia Cutis Congenita of the Scalp
    hypothesis_groups:
    - aos_notch_vascular_disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: A vascular route to human scalp aplasia has been proposed but not demonstrated.
    evidence:
    - reference: PMID:25132448
      reference_title: Mutations in NOTCH1 cause Adams-Oliver syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We propose that the limb and scalp defects might also be due to a vasculopathy in NOTCH1-related AOS.
      explanation: The source explicitly presents this edge as a hypothesis.
  - target: Terminal Transverse Limb Defects
    hypothesis_groups:
    - aos_notch_vascular_disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: A vascular route to human terminal limb defects has been proposed but not demonstrated.
    evidence:
    - reference: PMID:25132448
      reference_title: Mutations in NOTCH1 cause Adams-Oliver syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We propose that the limb and scalp defects might also be due to a vasculopathy in NOTCH1-related AOS.
      explanation: The source explicitly presents this edge as a hypothesis.
  - target: Congenital Heart Defects
    hypothesis_groups:
    - aos_notch_vascular_disruption
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - endothelial Notch dysfunction during cardiovascular development
    description: Endothelial Notch dysfunction causes cardiovascular defects in the sensitized RBPJ/Notch1 mouse model.
    evidence:
    - reference: PMID:41055965
      reference_title: Defective Notch1 signaling in endothelial cells drives pathogenesis in a mouse model of Adams-Oliver syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Importantly, our studies show that expression of the Rbpj AOS allele in endothelial cells is both necessary and sufficient to cause lethality and cardiovascular defects.
      explanation: Supports the model-organism cardiovascular edge without extending it to all human AOS subtypes.
- name: Actin Cytoskeleton Defects
  description: >-
    Reduced CDC42 and/or RAC1 signaling disrupts actin organization in
    ARHGAP31- and DOCK6-associated AOS. The downstream human developmental steps
    producing scalp and limb defects are not fully known.
  genes:
  - preferred_term: ARHGAP31
    term:
      id: hgnc:29216
      label: ARHGAP31
  - preferred_term: DOCK6
    term:
      id: hgnc:19189
      label: DOCK6
  subtypes:
  - AOS1
  - AOS2
  biological_processes:
  - preferred_term: actin cytoskeleton organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
  evidence:
  - reference: PMID:21565291
    reference_title: "Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Constitutively active ARHGAP31 mutations result in a loss of available active Cdc42 and consequently disrupt actin cytoskeletal structures.
    explanation: Directly supports actin-cytoskeleton disruption downstream of ARHGAP31 gain of function.
  - reference: PMID:21820096
    reference_title: "Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Consistent with the established role of Cdc42 and Rac1 in the organization of the actin cytoskeleton, we demonstrate a cellular phenotype typical of a defective actin cytoskeleton in patient cells.
    explanation: Supports the same cellular endpoint in DOCK6-deficient patient cells.
  downstream:
  - target: Terminal Transverse Limb Defects
    hypothesis_groups:
    - aos_rho_cytoskeletal_development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The cellular defect is established, but its route to human terminal limb loss is unresolved.
    evidence:
    - reference: PMID:21565291
      reference_title: "Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Candidate-gene- and exome-based sequencing led to the identification of independent premature truncating mutations in the terminal exon of the Rho GTPase-activating protein 31 gene, ARHGAP31, which encodes a Cdc42/Rac1 regulatory protein.
      explanation: Human genetics links the proximal pathway lesion to the AOS limb phenotype without defining intermediates.
  - target: Aplasia Cutis Congenita of the Scalp
    hypothesis_groups:
    - aos_rho_cytoskeletal_development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The cellular defect is established, but its route to human scalp aplasia is unresolved.
    evidence:
    - reference: PMID:21565291
      reference_title: "Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Candidate-gene- and exome-based sequencing led to the identification of independent premature truncating mutations in the terminal exon of the Rho GTPase-activating protein 31 gene, ARHGAP31, which encodes a Cdc42/Rac1 regulatory protein.
      explanation: Human genetics links ARHGAP31 to syndromic cutis aplasia while leaving the developmental bridge unresolved.
- name: RAC1-SRF Cranial Mesenchyme Defect
  description: >-
    Conditional Rac1 loss in mouse cranial mesenchyme reduces proliferation and
    SRF-linked mechanoresponsive programs, causing absent apical calvarium and
    overlying dermis. This is a downstream pathway model, not an AOS-allele
    model, and its fidelity to human ARHGAP31- or DOCK6-associated disease is
    uncertain.
  genes:
  - preferred_term: RAC1
    term:
      id: hgnc:9801
      label: RAC1
  downstream:
  - target: Calvarial Skull Defect
    hypothesis_groups:
    - aos_rho_cytoskeletal_development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The mouse knockout reproduces a severe AOS-like calvarial and dermal defect, but is not an AOS allele.
    evidence:
    - reference: PMID:41126757
      reference_title: Mouse scalp development requires Rac1 and SRF for the maintenance of mechanoresponsive mesenchyme.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Rac1-KO mice died perinatally and lacked the apical calvarium and overlying dermis, resembling defects seen in severe AOS.
      explanation: Supports phenotypic resemblance while preserving the model-to-human limitation.
  - target: Aplasia Cutis Congenita of the Scalp
    hypothesis_groups:
    - aos_rho_cytoskeletal_development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Loss of overlying dermis in the model resembles severe scalp aplasia, but translation to human AOS remains uncertain.
    evidence:
    - reference: PMID:41126757
      reference_title: Mouse scalp development requires Rac1 and SRF for the maintenance of mechanoresponsive mesenchyme.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Rac1-KO mice died perinatally and lacked the apical calvarium and overlying dermis, resembling defects seen in severe AOS.
      explanation: Supports a pathway-level cranial model rather than a direct human causal edge.
  evidence:
  - reference: PMID:41126757
    reference_title: Mouse scalp development requires Rac1 and SRF for the maintenance of mechanoresponsive mesenchyme.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Together, these data suggest a model where Rac1 and SRF maintain apical fibroblasts in a mechanoresponsive and proliferative state to complete cranial development.
    explanation: Defines the model's proposed cellular mechanism.
- name: DLL4-Dependent Second Heart Field Defect
  description: >-
    In a mouse model, second-heart-field-specific Dll4 loss reduces progenitor
    proliferation, increases apoptosis, and depletes the progenitor pool,
    producing outflow-tract malalignment. This is an AOS6/DLL4 cardiac model,
    not a mechanism established for pooled AOS cardiac defects.
  genes:
  - preferred_term: DLL4
    term:
      id: hgnc:2910
      label: DLL4
  subtypes:
  - AOS6
  locations:
  - preferred_term: secondary heart field
    term:
      id: UBERON:0009889
      label: secondary heart field
  biological_processes:
  - preferred_term: Notch signaling pathway
    term:
      id: GO:0007219
      label: Notch signaling pathway
  evidence:
  - reference: PMID:33899511
    reference_title: "Murine Model of Cardiac Defects Observed in Adams-Oliver Syndrome Driven by Delta-Like Ligand-4 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Dll4-mediated Notch signaling is critically required for SHF proliferation such that Dll4 knockout results in a 33% reduction in proliferation and a fourfold increase in apoptosis in SHF cells, leading to a 56% decline in the size of the SHF progenitor pool."
    explanation: Mouse model demonstrates the mechanism by which DLL4 haploinsufficiency causes cardiac defects in AOS.
  downstream:
  - target: Congenital Heart Defects
    causal_link_type: DIRECT
    description: Second-heart-field depletion produces outflow-tract malalignment in the Dll4 mouse model.
    evidence:
    - reference: PMID:33899511
      reference_title: Murine Model of Cardiac Defects Observed in Adams-Oliver Syndrome Driven by Delta-Like Ligand-4 Haploinsufficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Similar to the clinical syndrome, 32% of SHF-specific Dll4 heterozygotes demonstrate foreshortened and misaligned OFT, resulting in a double outlet right ventricle.
      explanation: Directly supports the cardiac edge within the DLL4 mouse model.
phenotypes:
- category: Dermatological
  name: Aplasia Cutis Congenita of the Scalp
  diagnostic: true
  description: >
    Congenital absence of skin, typically at the vertex of the scalp.
    Ranges from small, well-circumscribed defects to large areas of absent
    skin with exposed skull or dura. This is a hallmark feature of AOS.
  phenotype_term:
    preferred_term: Aplasia cutis congenita of scalp
    term:
      id: HP:0007385
      label: Aplasia cutis congenita of scalp
  evidence:
  - reference: PMID:28160419
    reference_title: "Adams-Oliver syndrome review of the literature: Refining the diagnostic phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Adams-Oliver syndrome (AOS) is defined as aplasia cutis congenita (ACC) with transverse terminal limb defects (TTLD)."
    explanation: ACC is a defining feature of AOS.
- category: Musculoskeletal
  name: Terminal Transverse Limb Defects
  diagnostic: true
  description: >
    Congenital terminal transverse limb defects ranging from nail
    dystrophy and short distal phalanges to oligodactyly or complete
    absence of digits, hands, or feet. Lower limbs are more frequently
    affected than upper limbs.
  phenotype_term:
    preferred_term: Terminal transverse limb defect
    term:
      id: HP:6000818
      label: Transverse terminal limb defect
  evidence:
  - reference: PMID:28160419
    reference_title: "Adams-Oliver syndrome review of the literature: Refining the diagnostic phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Adams-Oliver syndrome (AOS) is defined as aplasia cutis congenita (ACC) with transverse terminal limb defects (TTLD)."
    explanation: TTLD is a defining feature of AOS.
- category: Dermatological
  name: Nail Dystrophy
  description: >-
    Nail abnormalities can be part of the distal-limb spectrum, including mild
    presentations in which terminal phalangeal and nail changes predominate.
  phenotype_term:
    preferred_term: Nail dystrophy
    term:
      id: HP:0008404
      label: Nail dystrophy
  evidence:
  - reference: PMID:40874655
    reference_title: "Cutaneous Features of Adams-Oliver Syndrome: Diagnosis, Differentiation, and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The condition presents with a range of cutaneous features, most notably ACC, cutis marmorata telangiectatica congenita, and nail anomalies.
    explanation: The clinical review identifies nail anomalies among the characteristic cutaneous findings.
- category: Musculoskeletal
  name: Calvarial Skull Defect
  description: >
    Calvarial defects may accompany scalp aplasia cutis and range from thinning
    to complete absence of calvarium.
  phenotype_term:
    preferred_term: Calvarial skull defect
    term:
      id: HP:0001362
      label: Calvarial skull defect
  evidence:
  - reference: PMID:25963545
    reference_title: "Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams-Oliver Syndrome With Variable Cardiac Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient 3-III:1 was born with a large area of scalp ACC with an underlying calvarial defect and shortened distal phalanges of the toes"
    explanation: Clinical documentation of calvarial skull defects accompanying aplasia cutis in AOS patients.
- category: Cardiovascular
  name: Congenital Heart Defects
  frequency: OCCASIONAL
  description: >
    Various structural heart defects reported in AOS, most commonly
    ventricular septal defects, tetralogy of Fallot, and coarctation
    of the aorta. A pooled literature review reported 23%; a separate
    NOTCH1-positive series reported cardiovascular anomalies in 47% of variant
    carriers, with incomplete assessment in some carriers.
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:28160419
    reference_title: "Adams-Oliver syndrome review of the literature: Refining the diagnostic phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the most commonly associated anomalies included a wide variety of central nervous system (CNS) anomalies and congenital heart defects each seen in 23%."
    explanation: Large literature review establishing 23% frequency of congenital heart defects in AOS.
  - reference: PMID:25963545
    reference_title: "Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams-Oliver Syndrome With Variable Cardiac Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiovascular anomalies were identified in 47% (8/17) of all affected variant carriers, thereby indicating that NOTCH1 variants may represent a distinct subtype of AOS associated with cardiac malformations."
    explanation: NOTCH1-related AOS shows particularly high frequency of cardiac defects.
- category: Cardiovascular
  name: Cutis Marmorata Telangiectatica Congenita
  frequency: OCCASIONAL
  description: >
    A vascular skin anomaly characterized by a persistent reticular
    mottling pattern with telangiectasias. A pooled literature review reported
    CMTC in 19% of its study population.
  phenotype_term:
    preferred_term: Cutis marmorata telangiectatica congenita
    term:
      id: HP:0025107
      label: Cutis marmorata telangiectatica congenita
  evidence:
  - reference: PMID:28160419
    reference_title: "Adams-Oliver syndrome review of the literature: Refining the diagnostic phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cutis marmorata telangiectasia congenita (CMTC) was found in 19% of the study population and other vascular anomalies were seen in 14%."
    explanation: Literature review establishing 19% frequency of CMTC in AOS.
- category: Cardiovascular
  name: Pulmonary Hypertension
  description: >-
    Pulmonary hypertension can be potentially lethal and present in infancy in
    a minority of AOS. The ascertainment-enriched VCP discovery series included
    six families with pulmonary hypertension and one without; that ratio does
    not establish penetrance or the age of onset in each family. Review of AOS
    cases with pulmonary hypertension suggests pulmonary veno-occlusive disease
    as the most common mechanism; CMTC, prominent dilated subcutaneous veins,
    and intrauterine growth restriction were reported risk markers.
  evidence:
  - reference: PMID:41979051
    reference_title: Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A minority of individuals with AOS develop potentially lethal pulmonary hypertension (PH) in infancy, a subgroup that has been refractory to genetic explanation.
    explanation: Establishes the bounded overall clinical context without assigning a frequency band.
  - reference: PMID:41979051
    reference_title: Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a new genetic etiology for AOS in 6 families with PH and 1 family without it.
    explanation: Reports the discovery-series distribution without assigning penetrance or age of onset to the VCP-associated families.
  - reference: PMID:41979051
    reference_title: Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Review of published cases of AOS with PH suggests that pulmonary veno-occlusive disease is the most common mechanism. Clinical risk factors for PH in AOS include CMTC, prominent dilated subcutaneous veins and intra-uterine growth restriction.
    explanation: Supports the qualified mechanism and risk-marker statements.
- category: Hepatic
  name: Hepatoportal Sclerosis with Portal Hypertension
  description: >
    Non-cirrhotic portal hypertension due to hepatoportal sclerosis,
    with potential for esophageal varices. Observed particularly in
    non-familial AOS cases.
  phenotype_term:
    preferred_term: Portal hypertension
    term:
      id: HP:0001409
      label: Portal hypertension
  evidence:
  - reference: PMID:28160419
    reference_title: "Adams-Oliver syndrome review of the literature: Refining the diagnostic phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A relatively large number of non-familial probands were reported to have hepatoportal sclerosis with portal hypertension and esophageal varices."
    explanation: Literature review documenting hepatoportal sclerosis as a notable feature particularly in non-familial AOS cases.
- category: Neurological
  name: Central Nervous System Anomalies
  frequency: OCCASIONAL
  description: >
    A wide variety of CNS anomalies including structural defects,
    microcephaly, vascular malformations, and migration defects.
    Reported in approximately 23% of AOS cases.
  phenotype_term:
    preferred_term: CNS structural anomaly
    term:
      id: HP:0002011
      label: Morphological central nervous system abnormality
  evidence:
  - reference: PMID:28160419
    reference_title: "Adams-Oliver syndrome review of the literature: Refining the diagnostic phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the most commonly associated anomalies included a wide variety of central nervous system (CNS) anomalies and congenital heart defects each seen in 23%. CNS anomalies included structural anomalies, microcephaly, vascular defects, and vascular sequelae. CNS migration defects were common."
    explanation: Literature review establishing 23% frequency of CNS anomalies in AOS.
  - reference: PMID:25824905
    reference_title: DOCK6 mutations are responsible for a distinct autosomal-recessive variant of Adams-Oliver syndrome associated with brain and eye anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DOCK6 mutations were strongly associated with structural brain abnormalities, ocular anomalies, and intellectual disability
    explanation: Supports enrichment of neurologic involvement in DOCK6-associated AOS2.
- category: Ophthalmological
  name: Ocular Anomalies in DOCK6-Associated AOS
  subtype: AOS2
  description: >-
    Ocular anomalies are enriched in reported individuals with DOCK6-associated
    autosomal-recessive AOS, alongside structural brain abnormalities and
    intellectual disability; a pooled subtype-specific frequency was not
    established.
  phenotype_term:
    preferred_term: Abnormality of the eye
    term:
      id: HP:0000478
      label: Abnormality of the eye
  evidence:
  - reference: PMID:25824905
    reference_title: DOCK6 mutations are responsible for a distinct autosomal-recessive variant of Adams-Oliver syndrome associated with brain and eye anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DOCK6 mutations were strongly associated with structural brain abnormalities, ocular anomalies, and intellectual disability
    explanation: Defines the DOCK6-associated ocular and neurologic enrichment.
genetic:
- name: ARHGAP31 (AOS1)
  gene_term:
    preferred_term: ARHGAP31
    term:
      id: hgnc:29216
      label: ARHGAP31
  association: CAUSAL
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AOS1
  case_fractions:
  - population: AOS/ACC/TTLD probands or families in the 2018 European molecular-screening cohort
    case_fraction_percent: 3
    cohort_size: 194
    notes: Mixed AOS/isolated-ACC/TTLD cohort; gene-attributable fraction, not population prevalence; predates VCP discovery.
    evidence:
    - reference: PMID:29924900
      reference_title: Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort.
      explanation: Supports the cohort-specific ARHGAP31 case fraction.
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:29924900
      reference_title: Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance.
      explanation: Explicitly classifies ARHGAP31-associated AOS as autosomal dominant.
  features: >
    Gain-of-function mutations produce C-terminally truncated proteins with
    constitutive GAP activity and demonstrated depletion of active Cdc42,
    disrupting actin-cytoskeleton organization. ARHGAP31 explained 3% of the mixed 194-case
    AOS/isolated-ACC/TTLD cohort reported in 2018.
  evidence:
  - reference: PMID:21565291
    reference_title: "Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mutant transcripts are stable and increase ARHGAP31 activity in vitro through a gain-of-function mechanism."
    explanation: Demonstrates gain-of-function mechanism of ARHGAP31 mutations.
  - reference: PMID:29924900
    reference_title: "Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort."
    explanation: Establishes a 3% ARHGAP31-attributable fraction in the mixed AOS/isolated-ACC/TTLD cohort.
- name: DOCK6 (AOS2)
  gene_term:
    preferred_term: DOCK6
    term:
      id: hgnc:19189
      label: DOCK6
  association: CAUSAL
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AOS2
  case_fractions:
  - population: AOS/ACC/TTLD probands or families in the 2018 European molecular-screening cohort
    case_fraction_percent: 6
    cohort_size: 194
    notes: Mixed AOS/isolated-ACC/TTLD cohort; gene-attributable fraction, not population prevalence; predates VCP discovery.
    evidence:
    - reference: PMID:29924900
      reference_title: Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort.
      explanation: Supports the cohort-specific DOCK6 case fraction.
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:21820096
      reference_title: "Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we combined autozygome analysis with exome sequencing to identify a homozygous truncating mutation in dedicator of cytokinesis 6 gene (DOCK6)"
      explanation: Homozygous loss-of-function DOCK6 mutations identify autosomal recessive inheritance for AOS2.
  features: >
    Loss-of-function mutations in DOCK6 affect a GEF for Cdc42 and Rac1 and
    impair actin-cytoskeleton organization.
    Structural brain, ocular, and intellectual involvement is enriched in
    reported DOCK6-associated disease. DOCK6 explained 6% of the mixed 2018
    AOS/isolated-ACC/TTLD cohort.
  evidence:
  - reference: PMID:21820096
    reference_title: "Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we combined autozygome analysis with exome sequencing to identify a homozygous truncating mutation in dedicator of cytokinesis 6 gene (DOCK6)"
    explanation: Original identification of DOCK6 mutations in AOS.
  - reference: PMID:29924900
    reference_title: "Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort."
    explanation: Establishes a 6% DOCK6-attributable fraction in the mixed AOS/isolated-ACC/TTLD cohort.
  - reference: CGGV:assertion_ea64d74c-583d-4ed1-af91-6a7c6f80a1d3-2022-06-28T160000.000Z
    reference_title: "DOCK6 / Adams-Oliver syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "DOCK6 | HGNC:19189 | Adams-Oliver syndrome | MONDO:0007034 | AR | Definitive"
    explanation: ClinGen classifies the DOCK6-Adams-Oliver syndrome gene-disease relationship as definitive with autosomal recessive inheritance.
- name: RBPJ (AOS3)
  gene_term:
    preferred_term: RBPJ
    term:
      id: hgnc:5724
      label: RBPJ
  association: CAUSAL
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AOS3
  case_fractions:
  - population: AOS/ACC/TTLD probands or families in the 2018 European molecular-screening cohort
    case_fraction_percent: 2
    cohort_size: 194
    notes: Mixed AOS/isolated-ACC/TTLD cohort; gene-attributable fraction, not population prevalence; predates VCP discovery.
    evidence:
    - reference: PMID:29924900
      reference_title: Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort.
      explanation: Supports the cohort-specific RBPJ case fraction.
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:29924900
      reference_title: Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance.
      explanation: Explicitly classifies RBPJ-associated AOS as autosomal dominant.
  features: >
    Dominant-negative mutations in RBPJ compromise DNA binding but retain
    cofactor binding, sequestering Notch pathway cofactors from target
    gene promoters. RBPJ explained 2% of the mixed 2018
    AOS/isolated-ACC/TTLD cohort.
  evidence:
  - reference: PMID:22883147
    reference_title: "RBPJ mutations identified in two families affected by Adams-Oliver syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional assays confirmed impaired DNA binding of mutated RBPJ, placing it among other notch-pathway proteins altered in human genetic syndromes."
    explanation: Demonstrates functional impact of RBPJ mutations on DNA binding.
  - reference: PMID:41055965
    reference_title: "Defective Notch1 signaling in endothelial cells drives pathogenesis in a mouse model of Adams-Oliver syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "AOS-associated RBPJ missense variants compromise DNA binding but not cofactor binding. These findings suggest that AOS-associated RBPJ variants do not function as loss-of-function alleles but instead act as dominant-negative proteins that sequester cofactors from DNA."
    explanation: Demonstrates dominant-negative mechanism of RBPJ mutations - they retain cofactor binding while losing DNA binding, titrating cofactors away from DNA.
- name: EOGT (AOS4)
  gene_term:
    preferred_term: EOGT
    term:
      id: hgnc:28526
      label: EOGT
  association: CAUSAL
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AOS4
  case_fractions:
  - population: AOS/ACC/TTLD probands or families in the 2018 European molecular-screening cohort
    case_fraction_percent: 3
    cohort_size: 194
    notes: Mixed AOS/isolated-ACC/TTLD cohort; gene-attributable fraction, not population prevalence; predates VCP discovery.
    evidence:
    - reference: PMID:29924900
      reference_title: Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort.
      explanation: Supports the cohort-specific EOGT case fraction.
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:29924900
      reference_title: Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance.
      explanation: Explicitly classifies EOGT-associated AOS as autosomal recessive.
  features: >
    Loss-of-function mutations in EOGT impair O-GlcNAcylation of Notch
    receptor EGF repeats and DLL-selective Notch activation. EOGT explained 3%
    of the mixed 2018 AOS/isolated-ACC/TTLD cohort.
  evidence:
  - reference: PMID:23522784
    reference_title: "Mutations in EOGT confirm the genetic heterogeneity of autosomal-recessive Adams-Oliver syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EOGT encodes EGF-domain-specific O-linked N-acetylglucosamine (O-GlcNAc) transferase, which is involved in the O-GlcNAcylation (attachment of O-GlcNAc to serine and threonine residues) of a subset of extracellular EGF-domain-containing proteins."
    explanation: Identifies EOGT function and its connection to Notch signaling.
  - reference: PMID:29924900
    reference_title: "Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort."
    explanation: Establishes a 3% EOGT-attributable fraction in the mixed AOS/isolated-ACC/TTLD cohort.
- name: NOTCH1 (AOS5)
  gene_term:
    preferred_term: NOTCH1
    term:
      id: hgnc:7881
      label: NOTCH1
  association: CAUSAL
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AOS5
  case_fractions:
  - population: AOS/ACC/TTLD probands or families in the 2018 European molecular-screening cohort
    case_fraction_percent: 10
    cohort_size: 194
    notes: Mixed AOS/isolated-ACC/TTLD cohort; gene-attributable fraction, not population prevalence; predates VCP discovery.
    evidence:
    - reference: PMID:29924900
      reference_title: Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        NOTCH1 is the major contributor, underlying 10% of AOS/ACC/TTLD cases, with DLL4 (6%), DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort.
      explanation: Supports the cohort-specific NOTCH1 case fraction.
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:29924900
      reference_title: Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance.
      explanation: Explicitly classifies NOTCH1-associated AOS as autosomal dominant.
  features: >
    Loss-of-function variants cause NOTCH1 haploinsufficiency. NOTCH1 explained
    10% of the mixed 2018 AOS/isolated-ACC/TTLD cohort. Cardiovascular anomalies
    were reported in 47% of affected variant carriers in a separate series,
    although some carriers lacked echocardiographic assessment.
  evidence:
  - reference: PMID:25132448
    reference_title: "Mutations in NOTCH1 cause Adams-Oliver syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report five heterozygous NOTCH1 variants in unrelated individuals with Adams-Oliver syndrome (AOS), a rare disease with major features of aplasia cutis of the scalp and terminal transverse limb defects."
    explanation: Original identification of NOTCH1 mutations in AOS.
  - reference: PMID:25963545
    reference_title: "Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams-Oliver Syndrome With Variable Cardiac Anomalies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "NOTCH1 transcript levels were significantly reduced by comparison to an unaffected control individual, demonstrating approximately 50% expression in all samples tested"
    explanation: Demonstrates NOTCH1 haploinsufficiency as the molecular mechanism.
  - reference: PMID:29924900
    reference_title: "Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NOTCH1 is the major contributor, underlying 10% of AOS/ACC/TTLD cases"
    explanation: Identifies NOTCH1 as the largest contributor, at 10%, within the mixed AOS/isolated-ACC/TTLD cohort.
- name: DLL4 (AOS6)
  gene_term:
    preferred_term: DLL4
    term:
      id: hgnc:2910
      label: DLL4
  association: CAUSAL
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AOS6
  case_fractions:
  - population: AOS/ACC/TTLD probands or families in the 2018 European molecular-screening cohort
    case_fraction_percent: 6
    cohort_size: 194
    notes: Mixed AOS/isolated-ACC/TTLD cohort; gene-attributable fraction, not population prevalence; predates VCP discovery.
    evidence:
    - reference: PMID:29924900
      reference_title: Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        DLL4 (6%), DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort.
      explanation: Supports the cohort-specific DLL4 case fraction.
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:26299364
      reference_title: "Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our findings demonstrate that DLL4 mutations are an additional cause of autosomal-dominant AOS or isolated ACC and provide further evidence for a key role of NOTCH signaling in the etiology of this disorder."
      explanation: Heterozygous DLL4 loss-of-function variants establish autosomal dominant inheritance for AOS6.
  features: >
    Loss-of-function mutations in DLL4, a key Notch ligand for
    angiogenesis and vascular patterning. DLL4 explained 6% of the mixed 2018
    AOS/isolated-ACC/TTLD cohort. A second-heart-field mouse model supports a
    DLL4-specific cardiac outflow-tract mechanism.
  evidence:
  - reference: PMID:26299364
    reference_title: "Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings demonstrate that DLL4 mutations are an additional cause of autosomal-dominant AOS or isolated ACC and provide further evidence for a key role of NOTCH signaling in the etiology of this disorder."
    explanation: Establishes DLL4 as a cause of autosomal dominant AOS.
  - reference: PMID:29924900
    reference_title: "Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DLL4 (6%), DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort."
    explanation: Establishes a 6% DLL4-attributable fraction in the mixed AOS/isolated-ACC/TTLD cohort.
  - reference: PMID:33899511
    reference_title: "Murine Model of Cardiac Defects Observed in Adams-Oliver Syndrome Driven by Delta-Like Ligand-4 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Similar to the clinical syndrome, 32% of SHF-specific Dll4 heterozygotes demonstrate foreshortened and misaligned OFT, resulting in a double outlet right ventricle."
    explanation: Mouse model providing molecular mechanism for cardiac defects in DLL4-related AOS.
- name: VCP-Associated AOS
  gene_term:
    preferred_term: VCP
    term:
      id: hgnc:12666
      label: VCP
  association: CAUSAL
  relationship_type: CAUSATIVE
  subtype: VCP-Associated AOS
  features: >-
    Reported AOS-associated VCP substitution variants are hypermorphic for ATP
    hydrolysis and cause N-terminal-domain hyperflexibility with impaired
    interdomain coupling. The discovery series included six families with
    pulmonary hypertension and one without, but does not establish penetrance
    or age of onset in each family. The available primary abstract does not
    establish inheritance, variant origin, or a numbered subtype.
  evidence:
  - reference: PMID:41979051
    reference_title: Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a new genetic etiology for AOS in 6 families with PH and 1 family without it.
    explanation: Establishes VCP as an additional AOS genetic cause and bounds the pulmonary-hypertension association.
  - reference: PMID:41979051
    reference_title: Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that AOS-related VCP variants are hypermorphic with respect to ATP hydrolysis and cause N-terminal domain hyperflexibility with impairment of interdomain coupling.
    explanation: Defines the experimentally observed biochemical and structural effects.
treatments:
- name: Individualized Conservative Care for Scalp Aplasia
  action_category: THERAPEUTIC
  description: >-
    Conservative management is one option for scalp aplasia, but published AOS
    evidence does not establish a universal dressing protocol or size threshold.
    Selection must balance hemorrhage, infection, neurologic, and procedural
    risks for the individual defect.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:22670005
    reference_title: Two different management modalities in a two sibling case report of Adams Oliver syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Various papers have been published related to ACC, yet there is no consensus on the therapeutic approach. The management decision hinges upon balancing the risks of complications including spontaneous sagittal sinus haemorrhage and the risk of surgical intervention.
    explanation: Supports individualized choice while documenting the low-level evidence and absence of consensus.
  - reference: PMID:27077170
    reference_title: "Adams-Oliver Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Goals of non-operative therapy are to prevent infection and promote healing.
    explanation: The archived GeneReviews chapter supplies the historical goals of conservative scalp-ACC care; its retired status precludes treating details as a current universal protocol.
- name: Surgical Closure or Reconstruction of Scalp Aplasia
  therapeutic_modality: SURGERY
  action_category: THERAPEUTIC
  description: >-
    Surgical closure or later reconstruction is an alternative for selected
    scalp defects. Evidence is limited to case-based experience, and the same
    absence of consensus requires individualized risk assessment rather than a
    universal threshold.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:22670005
    reference_title: Two different management modalities in a two sibling case report of Adams Oliver syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both treatment modalities proved successful in these cases.
    explanation: Two siblings were managed with different conservative/surgical strategies; this does not establish comparative efficacy.
  - reference: PMID:27077170
    reference_title: "Adams-Oliver Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Large and/or deep lesions with calvarial involvement require acute care and may eventually also require reconstruction by a neurosurgeon.
    explanation: The archived GeneReviews chapter supports historical specialist reconstruction practice while remaining explicitly retired and potentially outdated.
- name: Coordinated Multidisciplinary Assessment
  action_category: MONITORING
  description: >-
    Coordinate phenotype- and genotype-directed assessment across dermatology,
    clinical genetics, cardiology, vascular/pulmonary medicine, neurology,
    ophthalmology, developmental services, and relevant surgical specialties.
    Published evidence supports an adjusted multidisciplinary approach but not
    universal fixed surveillance intervals.
  treatment_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:31654484
    reference_title: Expanding the phenotype in Adams-Oliver syndrome correlating with the genotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It appears that degrees of genotype-phenotype correlations exist for patients with identified pathogenic mutations, underlining the need to undertake a systematic but adjusted multidisciplinary assessment.
    explanation: Supports systematic but individualized assessment rather than a uniform schedule.
  - reference: PMID:40874655
    reference_title: "Cutaneous Features of Adams-Oliver Syndrome: Diagnosis, Differentiation, and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Given that skin findings are often the earliest and most recognizable signs of AOS, dermatologists play an important role in early diagnosis, enabling prompt genetic evaluation and coordinated multidisciplinary care.
    explanation: Supports coordinated care and early genetics involvement.
  - reference: PMID:27077170
    reference_title: "Adams-Oliver Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cardiovascular. Echocardiography annually until age three years for signs of pulmonary hypertension. Neurologic. Annual pediatric care, including neurologic examination and ongoing assessment of psychomotor development. Ocular. Annual assessment by pediatric ophthalmologist until age three years for evidence of abnormal retinal vascular development.
    explanation: The archived chapter documents a historical surveillance schedule, but because it was retired as outdated this entry retains individualized current assessment rather than adopting those intervals as a universal recommendation.
- name: Genetic Counseling
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    Genetic counseling for families with AOS to discuss inheritance patterns,
    recurrence implications, and molecular testing. For established dominant
    forms, each child of an affected heterozygous individual has a 50% chance of
    inheriting the variant; for established recessive forms, each sibling of an
    affected individual has a 25% chance of being affected when both parents are
    carriers. Counseling should not assign VCP inheritance from the currently
    available abstract.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:29924900
    reference_title: Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance.
    explanation: The heterogeneous inheritance architecture is directly relevant to family counseling.
  - reference: PMID:27077170
    reference_title: "Adams-Oliver Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Each child of an individual with autosomal dominant AOS has a 50% chance of inheriting the pathogenic variant.
    explanation: The archived GeneReviews chapter provides the recurrence-risk figure for established dominant AOS; it does not apply this risk to the newly reported VCP-associated form.
  - reference: PMID:27077170
    reference_title: "Adams-Oliver Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
    explanation: The archived GeneReviews chapter provides the sibling recurrence risks for established DOCK6- and EOGT-related recessive AOS.
diagnosis:
- name: Clinical Assessment of the ACC/TTLD Spectrum
  description: >-
    Clinical assessment establishes whether the congenital presentation lies
    within the AOS spectrum centered on scalp aplasia cutis and terminal
    transverse limb defects, while documenting cardiac, vascular, neurologic,
    ocular, and skull involvement. An archived, retired GeneReviews chapter
    described diagnosis from both core findings, one core finding plus an
    affected first-degree relative, or one core finding plus molecular
    confirmation. Because that chapter is historical and reports no validation
    metrics, these routes are not presented as a sensitivity- or
    specificity-validated current algorithm.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: A compatible congenital ACC/TTLD pattern supports a clinical AOS diagnosis and guides subtype testing.
  evidence:
  - reference: PMID:19610107
    reference_title: The spectra of clinical phenotypes in aplasia cutis congenita and terminal transverse limb defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The combination of aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD) is often referred to as the eponymous Adams-Oliver syndrome (AOS).
    explanation: Supports the core clinical disease boundary.
  - reference: PMID:27077170
    reference_title: "Adams-Oliver Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of AOS can be established in a proband with one of the following: Clinical findings of ACC of the scalp and TTLD. ACC or TTLD and a first-degree relative with findings consistent with AOS.
    explanation: The archived GeneReviews chapter supplies the historical diagnostic routes while its retired status and absence of validation metrics are retained explicitly.
- name: Molecular Genetic Testing
  description: >-
    Sequence analysis of established AOS genes can identify an etiologic
    subtype. A 2018 mixed AOS/isolated-ACC/TTLD cohort received a
    molecular diagnosis in 30% of cases before VCP was discovered; that
    cohort-specific yield must not be treated as disease prevalence or as a
    current sensitivity estimate.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: A pathogenic variant in an established AOS gene supports molecular subtype assignment; a negative result does not erase the clinical ACC/TTLD phenotype.
  evidence:
  - reference: PMID:29924900
    reference_title: Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Molecular diagnostic screening of 194 AOS/ACC/TTLD probands/families was conducted using next-generation and/or capillary sequencing analyses. In total, we identified 63 (likely) pathogenic mutations, comprising 56 distinct and 22 novel mutations, providing a molecular diagnosis in 30% of patients.
    explanation: Provides the bounded historical molecular-yield estimate.
  - reference: PMID:41979051
    reference_title: Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a new genetic etiology for AOS in 6 families with PH and 1 family without it.
    explanation: Supports inclusion of VCP among current AOS testing considerations without assigning inheritance.
  - reference: PMID:27077170
    reference_title: "Adams-Oliver Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ACC or TTLD and either a pathogenic variant in an autosomal dominant AOS-related gene (ARHGAP31, DLL4, NOTCH1, or RBPJ) or two pathogenic variants in an autosomal recessive AOS-related gene (DOCK6 or EOGT).
    explanation: The archived GeneReviews chapter supports molecular confirmation for the six established historical gene subtypes; VCP is added separately from the 2026 primary report.
differential_diagnoses:
- name: Aplasia cutis-enamel dysplasia syndrome
  description: >-
    The FOSL2-related disorder overlaps AOS through localized scalp aplasia cutis
    with or without skull defects. Its reported combination of enamel
    hypoplasia, neurodevelopmental delay or autism, congenital cataracts, and
    prenatal growth restriction distinguishes it from the classic AOS
    ACC/terminal-limb pattern.
  distinguishing_features:
  - Enamel hypoplasia with neurodevelopmental delay or autism favors the FOSL2-related disorder.
  - Congenital cataracts and prenatal growth restriction were recurrent in the reported FOSL2 series.
  - A pathogenic last-exon truncating FOSL2 variant supports this differential; FOSL2 is not modeled as an AOS gene.
  disease_term:
    preferred_term: aplasia cutis-enamel dysplasia syndrome
    term:
      id: MONDO:0968978
      label: aplasia cutis-enamel dysplasia syndrome
  evidence:
  - reference: PMID:36197437
    reference_title: FOSL2 truncating variants in the last exon cause a neurodevelopmental disorder with scalp and enamel defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 11 individuals from 10 families with mostly de novo truncating FOSL2 variants sharing a strikingly similar phenotype characterized by prenatal growth retardation, localized cutis scalp aplasia with or without skull defects, neurodevelopmental delay with autism spectrum disorder, enamel hypoplasia, and congenital cataracts.
    explanation: Directly supports both the scalp overlap and the distinguishing phenotype constellation.
animal_models:
- species: Mouse (Mus musculus)
  genotype: AOS-associated Rbpj missense allele with Notch1 heterozygosity and endothelial conditional expression
  background: Notch1-sensitized genetic background
  genes:
  - preferred_term: RBPJ
    term:
      id: hgnc:5724
      label: RBPJ
  - preferred_term: NOTCH1
    term:
      id: hgnc:7881
      label: NOTCH1
  category: Genetically engineered mouse model
  associated_phenotypes:
  - Increased lethality
  - Cardiovascular defects
  description: >-
    The AOS-associated Rbpj allele produces dominant phenotypes on a Notch1
    heterozygous background. Endothelial expression is necessary and sufficient
    for lethality and cardiovascular defects in this model. The sensitized
    background and cardiovascular endpoint limit extrapolation to the complete
    human scalp/limb phenotype.
  evidence:
  - reference: PMID:41055965
    reference_title: Defective Notch1 signaling in endothelial cells drives pathogenesis in a mouse model of Adams-Oliver syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Consistent with this idea, mice carrying an AOS-associated Rbpj allele develop dominant phenotypes that include increased lethality and cardiovascular defects in a Notch1 heterozygous background, whereas Notch1 and Rbpj compound heterozygous null alleles are well tolerated.
    explanation: Defines the sensitized genotype and its phenotype.
- species: Mouse (Mus musculus)
  genotype: Second-heart-field-specific Dll4 heterozygosity or knockout
  genes:
  - preferred_term: DLL4
    term:
      id: hgnc:2910
      label: DLL4
  category: Conditional genetically engineered mouse model
  associated_phenotypes:
  - Reduced second-heart-field progenitor pool
  - Outflow-tract malalignment
  - Double-outlet right ventricle
  description: >-
    Models the DLL4/AOS6 cardiac branch by perturbing Dll4 in the second heart
    field. It is not a model of the pooled 23% cardiac frequency across all AOS.
  evidence:
  - reference: PMID:33899511
    reference_title: Murine Model of Cardiac Defects Observed in Adams-Oliver Syndrome Driven by Delta-Like Ligand-4 Haploinsufficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Similar to the clinical syndrome, 32% of SHF-specific Dll4 heterozygotes demonstrate foreshortened and misaligned OFT, resulting in a double outlet right ventricle.
    explanation: Supports the cardiac phenotype in the DLL4 model.
- species: Mouse (Mus musculus)
  genotype: Pdgfra-Cre conditional Rac1 deletion in cranial mesenchyme
  genes:
  - preferred_term: RAC1
    term:
      id: hgnc:9801
      label: RAC1
  category: Conditional pathway-level mouse model
  associated_phenotypes:
  - Absent apical calvarium
  - Absent overlying dermis
  - Perinatal lethality
  description: >-
    A pathway-level cranial-development model downstream of the ARHGAP31/DOCK6
    branch. It is not an AOS-variant model and therefore supports a possible
    mechanism rather than direct disease fidelity.
  evidence:
  - reference: PMID:41126757
    reference_title: Mouse scalp development requires Rac1 and SRF for the maintenance of mechanoresponsive mesenchyme.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Rac1-KO mice died perinatally and lacked the apical calvarium and overlying dermis, resembling defects seen in severe AOS.
    explanation: Supports phenotypic resemblance and the explicit pathway-level limitation.
- species: Mouse (Mus musculus)
  genotype: Global or endothelial Eogt deletion
  genes:
  - preferred_term: EOGT
    term:
      id: hgnc:28526
      label: EOGT
  category: Genetically engineered pathway model
  associated_phenotypes:
  - Defective retinal angiogenesis
  description: >-
    Eogt loss impairs retinal angiogenesis and endothelial Notch output, but the
    null mouse does not reproduce the abnormalities predicted from human AOS.
    It is therefore a proximal pathway model with a material human-model
    mismatch.
  evidence:
  - reference: PMID:28395734
    reference_title: O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Global or endothelial cell-specific deletion of Eogt resulted in defective retinal angiogenesis, with a mild phenotype similar to that caused by reduced Notch signaling in retina.
    explanation: Supports the proximal vascular phenotype.
  - reference: PMID:28395734
    reference_title: O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Unexpectedly,Eogt-null mice do not exhibit abnormalities predicted from the symptoms of AOS patients.
    explanation: Directly documents the mismatch with the human syndrome.
clinical_trials:
- name: NCT01630421
  description: >-
    Observational study of families and isolated cases with aplasia cutis
    congenita to identify causal genes or regulatory elements and study cellular
    mechanisms. It is relevant to AOS because scalp ACC is a core feature, but
    it is not an AOS-specific interventional or treatment trial.
  evidence:
  - reference: clinicaltrials:NCT01630421
    reference_title: Identification of Mutations That Lead to Aplasia Cutis Congenita in Families and Isolated Cases and Studies of Cellular and Molecular Mechanisms
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The goal of this research study is to identify genes and regulatory elements on chromosomes that cause ACC. The investigators also study tissue samples from patients to learn about the processes that lead to this disorder.
    explanation: Establishes the observational genetics and mechanism scope without implying AOS-specific treatment efficacy.
discussions:
- discussion_id: gap_aos_shared_developmental_route
  prompt: >-
    What developmental mechanisms connect the separate Notch, CDC42/RAC1, and
    VCP biochemical branches to the shared scalp-aplasia and terminal-limb
    pattern, and do any branches truly converge in the relevant human tissues?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced Canonical Notch Signaling
  - pathophysiology#Actin Cytoskeleton Defects
  - pathophysiology#AOS-Associated VCP Variant Effects
  rationale: >-
    Human genetics establishes all three branches, but the scalp/limb vascular
    route is proposed, the Rho branch has an incomplete developmental bridge,
    and the VCP organ-level bridge is newly unresolved. No evidence currently
    justifies connecting VCP to Notch or Rho signaling.
  evidence:
  - reference: PMID:25132448
    reference_title: Mutations in NOTCH1 cause Adams-Oliver syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We propose that the limb and scalp defects might also be due to a vasculopathy in NOTCH1-related AOS.
    explanation: Shows that even the best-known human scalp/limb vascular route is framed as a proposal.
  - reference: PMID:41979051
    reference_title: Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that AOS-related VCP variants are hypermorphic with respect to ATP hydrolysis and cause N-terminal domain hyperflexibility with impairment of interdomain coupling.
    explanation: Establishes the VCP proximal effect but not an organ-development mechanism.
- discussion_id: mismatch_eogt_null_mouse
  prompt: >-
    Why does Eogt loss reproduce reduced Notch signaling and retinal vascular
    defects in mice without reproducing the predicted human AOS abnormalities?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#EOGT-Dependent Notch O-GlcNAcylation Deficiency
  rationale: >-
    The model supports the proximal DLL-selective Notch mechanism but not the
    human scalp/limb phenotype, limiting organism-level causal inference.
  evidence:
  - reference: PMID:28395734
    reference_title: O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Unexpectedly,Eogt-null mice do not exhibit abnormalities predicted from the symptoms of AOS patients.
    explanation: The primary model report explicitly identifies the mismatch.
- discussion_id: gap_vcp_inhibitor_translation
  prompt: >-
    Can the in-vitro normalization of hyperactive AOS-associated VCP by CB-5083
    be translated safely or effectively, and at what developmental window?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#VCP Hypermorphic ATPase Activity
  rationale: >-
    The only current evidence is biochemical inhibition in vitro. CB-5083 is
    not modeled as an AOS treatment, and there is no human safety, dosing, or
    efficacy evidence in this disease.
  evidence:
  - reference: PMID:41979051
    reference_title: Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Additionally, we find that CB-5083 inhibits the overactive ATP hydrolysis.
    explanation: Supports only the proximal in-vitro assay result.

📚

References & Deep Research

References

7

PMID:27077170

Adams-Oliver Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.

3 findings

The archived GeneReviews chapter defines the core ACC/TTLD clinical spectrum and historical diagnostic routes.

It provides historical scalp-ACC management and surveillance recommendations; the chapter is retired and may be outdated.

It gives 50% offspring risk for established dominant AOS and 25% affected-sibling risk when both parents carry an established recessive AOS cause.

PMID:19610107

The spectra of clinical phenotypes in aplasia cutis congenita and terminal transverse limb defects.

1 finding

Defines the ACC/TTLD clinical spectrum and documents marked intrafamilial phenotypic variability.

PMID:29924900

Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.

1 finding

Reports molecular screening of 194 AOS/ACC/TTLD probands or families and cohort-specific contributions of six established genes.

PMID:28160419

Adams-Oliver syndrome review of the literature: Refining the diagnostic phenotype.

1 finding

Provides pooled literature frequencies for major associated cardiac, neurologic, and vascular findings.

PMID:41055965

Defective Notch1 signaling in endothelial cells drives pathogenesis in a mouse model of Adams-Oliver syndrome.

1 finding

Establishes a dominant-negative mechanism for AOS-associated RBPJ variants and an endothelial requirement in a sensitized mouse model.

PMID:41979051

Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.

1 finding

Identifies hypermorphic VCP variants as an AOS cause in seven families and defines their ATPase and conformational effects.

PMID:40874655

Cutaneous Features of Adams-Oliver Syndrome: Diagnosis, Differentiation, and Management.

1 finding

Reviews recognition, genetic evaluation, and coordinated multidisciplinary care.

Deep Research

1

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Adams-Oliver Syndrome. Core disease mechanisms, molecular and cellular pat...

Asta Scientific Corpus Retrieval 20 citations 2026-04-22T22:29:15.733952

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Adams-Oliver Syndrome. Core disease mechanisms, molecular and cellular pat...

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

Papers retrieved: 20
Snippets retrieved: 20

Relevant Papers

[1] 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: 0.375) > 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.

[2] The evolving burden of asthma and contemporary advances in management: Implications for clinical practice in Southern Africa

Authors: A. Kiboneka
Year: 2020
Venue: Unknown venue
URL: https://www.semanticscholar.org/paper/0ba536bc7dbea898dcaabe247c92c7897c7e059c
DOI: 10.30574/wjarr.2020.8.3.0315
Citations: 1
Summary: The development of novel asthma phenotyping & endo typing plus better classification of patients using machine learning and big data have markedly improved asthma treatment outcomes in both children and Adults, and several research groups have developed cluster analyses of phenotypes in severe asthma.
Evidence snippets:
Snippet 1 (score: 0.365) > Research Program (SARP) I and II cohorts to study mechanisms differentiating severe from non-severe asthma. SARP investigators characterized severe asthma as a heterogeneous syndrome with diverse molecular, biochemical, and cellular inflammatory features and structure-function abnormalities. > Adults and children with severe asthma were further categorized by unbiased statistical methods into clusters based on distinguishing clinical features. These studies have not been done in Sub-Sahara Africa. Research performed over the past one to two decades has sought to better understand the heterogeneous clinical nature of asthma. Whereas older attempts at phenotyping asthma emphasized the duality of allergic vs. non-allergic asthma, more recent non-biased analyses have attempted to cluster patients by a multitude of possible features, including age of onset, atopy, severity of airways obstruction, and requirement for medication. Examples of these phenotypes include early-onset mild allergic asthma, later-onset asthma associated with obesity, and severe non-atopic asthma with frequent exacerbations. The elucidation of asthma phenotypes has been further refined by including information regarding pathophysiologic mechanisms present in different groups. These groups, called endo-types, include examples such as aspirin-exacerbated respiratory disease and allergic bronchopulmonary mycosis. > A phenotype covers the clinically relevant properties of the disease, but does not show the direct relationship to disease etiology and pathophysiology. Different patho-genetic mechanisms might cause similar asthma symptoms and might be operant in a certain phenotype. These putative mechanisms are addressed by the term 'endotype'. > Classification of asthma based on endo-types provides advantages for epidemiological, genetic, and drug-related studies. A successful definition of endo-types should link key pathogenic mechanisms with the asthma phenotype. Thus, the identification of corresponding molecular biomarkers for individual pathogenic-mechanism underlying phenotypes or subgroups within a phenotype is important. > The term asthma encompasses a disease spectrum with mild to very severe disease phenotypes whose traditional common characteristic is reversible airflow limitation. Unlike milder disease, severe asthma is poorly controlled by the current standard of care.

[3] 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: 0.363) > 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).

[4] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
Year: 2025
Venue: Journal of Veterinary Internal Medicine
URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
DOI: 10.1111/jvim.70139
PMID: 40492724
PMCID: 12150350
Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
Evidence snippets:
Snippet 1 (score: 0.352) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[5] 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.

[6] 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: 0.350) > 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

[7] 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: 38
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: 0.350) > 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.

[8] Can network biology unravel the aetiology of congenital hyperinsulinism?

Authors: A. Stevens, K. Cosgrove, R. Padidela, M. Skae, P. Clayton et al.
Year: 2013
Venue: Orphanet Journal of Rare Diseases
URL: https://www.semanticscholar.org/paper/474ed97fdbb2a604459faa0b626a8b7d20ed6bf4
DOI: 10.1186/1750-1172-8-21
PMID: 23394473
PMCID: 3599136
Citations: 9
Influential citations: 1
Summary: A rational argument for the use of computational biology as a valuable resource for identifying new candidate genes which may cause disease and for understanding the complex mechanisms which define the pathophysiology of this rare disease is presented.
Evidence snippets:
Snippet 1 (score: 0.348) > Congenital Hyperinsulinism (CHI) is a rare disease, but is the most common cause of recurrent hypoglycaemia in infancy [1]. The treatment of CHI can be difficult and involves drugs which may not be successful and often are poorly tolerated. As a potentially life-threatening condition, CHI is associated with lifelong sequelae -including critical brain damage (epilepsy, cerebral palsy and neurological impairment) in up to 40% of cases. To date, nine candidate genes associate with CHI, but for the majority of patientsestimated to be approximately 65%, both the aetiology of the CHI and the mechanisms of disease are unknown. > Our current approach to the classification and treatment of CHI is based largely upon observational correlations between the pathological analysis of candidate gene defects and clinical symptoms of hypoglycaemia [1][2][3]. In this respect, there are similarities between CHI and many other diseases in which numerous mutations in different genes give rise to clinical phenotypes that are essentially indistinguishable from one another. However, under normal physiological conditions, cells function correctly because there is a high degree of interdependency between individual biochemical components (DNA, RNA, proteins and metabolites) and their complex interactions (DNA-protein interactions, protein-protein interactions, metabolic and biochemical pathways, etc.), and tissues function in a co-ordinated manner because there is interplay between different cell types. Diseases rarely result from an abnormality in a single gene, but are in fact the manifestation of disturbances in the multiple networks that integrate cellular processes, and those that link cells with tissues, and tissues with organ systems. As a result, current approaches to molecular diagnosis, however valuable, have shortcomings. These include a lack of sensitivity in identifying preclinical disease, a poor ability to predict prognosis, and ambiguity in defining and resolving a condition where several clinical phenotypes can be observed. All of these inadequacies are evident in CHI, with our current understanding of the causes of disease failing to distinguish transient from persistent disease at the point of presentation and to determine accurately the severity of disease.

[9] 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: 0.347) > 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).

[10] Conceptualizing Epigenetics and the Environmental Landscape of Autism Spectrum Disorders

Authors: G. Torres, Mervat Mourad, Saba Iqbal, Emmanuel Moses-Fynn, Ashani Pandita et al.
Year: 2023
Venue: Genes
URL: https://www.semanticscholar.org/paper/bf76f0682a8a1986ce889cee1fef818480abc83b
DOI: 10.3390/genes14091734
PMID: 37761876
PMCID: 10531442
Citations: 11
Summary: The present work reviews recent evolutionary, molecular, and epigenetic mechanisms potentially linked to the etiology of autism, and presents a clinical vignette to describe clusters of maladaptive behaviors frequently diagnosed in autistic patients.
Evidence snippets:
Snippet 1 (score: 0.346) > Currently, there are hundreds of gene variants associated with the onset of ASD. Thus, the clinical presentation of the disease is highly variable, as one or more behavioral symptoms may be related to other comorbid conditions (e.g., anxiety disorder, seizure disorder) besides autism. In addition, antagonistic pleiotropy and dosage-sensitive genes further fragment the phenotypic characteristics of ASD. Regardless, here, we present a prototypical autism clinical vignette with five behavioral specifiers: cognitive disability; deficits in social-emotional reciprocity; repetitive or stereotyped motor behavior; improper coordinated language communication; and gastrointestinal distress. Underneath this clinical vignette, we microdissected and correlated a particular phenotype of the disease to functionally and anatomically related regions of the brain and bilateral body plan. The structural organization imposed here will not only identify a wide network of cells, but also specific clusters of genes targeting a particular symptom within behaviorally relevant regions. It is expected that such structural organization will help lay a solid foundation in psychiatry and point to more focused approaches to a deeper understanding of ASD and its individualized treatment (Table 2). Autism Spectrum Disorders can be managed with appropriate pharmacotherapy. Selective dopamine (DA) and serotonin (5HT) based drugs are the mainstay of pharmacological treatment [43,44]. Additional neurotransmitter systems (e.g., norepinephrine (NE) and histamine) are also drug targets. It is not known whether the listed drugs regulate epigenetic mechanisms to counteract autistic symptoms. What is broadly known is that atypical, typical and psychoactive drugs act on DA and 5HT signaling pathways within regions of the human brain (e.g., cortex and basal ganglia) that are behaviorally relevant to the pathophysiology of ASD. Attention Deficit Hyperactivity Disorder (ADHD) and Fragile X Syndrome are debilitating neuropsychiatric conditions commonly diagnosed in pediatric populations. Fragile X Syndrome is a monogenic inherited disease leading to cognitive disability and ASD.

[11] 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.

[12] 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: 0.345) > 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.

[13] 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: 0.343) > : 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.

[14] Novel Approaches to Studying SLC13A5 Disease

Authors: Adriana S. Beltran
Year: 2024
Venue: Metabolites
URL: https://www.semanticscholar.org/paper/8469c534cd81d96f84b61e2d963dead12088feb7
DOI: 10.3390/metabo14020084
PMID: 38392976
PMCID: 10890222
Citations: 2
Summary: Current technologies for generating patient-specific induced pluripotent stem cells (iPSCs) and their inherent advantages and limitations are discussed, followed by a summary of the methods for differentiating iPSCs into neurons, hepatocytes, and organoids.
Evidence snippets:
Snippet 1 (score: 0.343) > The precise pathophysiology underlying how SLC13A5 loss-of-function results in epilepsy refractory to treatment is a subject of open and ongoing research. Several hypotheses suggest SLC13A5 alters metabolic pathways, leading to neuronal dysfunction. Conversely, therapeutic inhibition of NaCT in the liver is a target to improve metabolic diseases, including non-alcoholic fatty liver disease, obesity, and insulin resistance. Thus, functionally accurate modeling and characterization of the mechanisms involved in citrate transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes. They can also be used to define the spectrum of the disease and how different mutations might lead to various disease severities, screen for potential therapeutic compounds that can restore the transporter function or ameliorate the symptoms, and enable personalized medicine approaches that can tailor treatments to individual patients based on their genetic background and disease severity. > transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes.

[15] Common immunopathogenesis of central nervous system diseases: the protein-homeostasis-system hypothesis

Authors: Kyung-Yil Lee
Year: 2022
Venue: Cell & Bioscience
URL: https://www.semanticscholar.org/paper/2984270ae67451b93007040848d9694d19714c9f
DOI: 10.1186/s13578-022-00920-5
PMID: 36384812
PMCID: 9668226
Citations: 9
Influential citations: 1
Summary: This article proposes a common immunopathogenesis of CNS diseases, including prion diseases, Alzheimer’s disease, and genetic diseases, through the PHS hypothesis, which proposes that the immune systems in the host control those substances according to the size and biochemical properties of the substances.
Evidence snippets:
Snippet 1 (score: 0.342) > There are hundreds of genetic diseases of the CNS. The defective proteins in genetic disorders include structural proteins for neurotransmitter receptors and other receptors or ion channels on CNS cells, and proteins involved in enzymatic process, metabolism (transport), or signal transduction pathways in various communication systems [98]. Because a discussion of each genetic disease is beyond the scope of this review, only crucial points about the pathogenesis of genetic diseases are discussed. Singlegene defect diseases of the CNS can be caused by a defective product from a gene, i.e., a protein deficiency or a malfunctioning protein. In general, autosomal dominant genetic diseases are caused by structural protein defects, and autosomal recessive diseases are caused by defects in enzymatic proteins. However, certain genetic diseases that involve an enzymatic or multifunctional protein defect can induce structural cell injury during the natural course of the illness. > Patients with genetic diseases, including HD, familial JCD, GSS, and the genetic forms of AD and PD, show different clinical manifestations from other affected people in their family, including the time of onset of neurological symptoms, speed of progression of the disease, and prognosis, suggesting that phenotypes can vary even when the genotypes are identical. Likewise, similar phenotypes of CNS symptoms can be found in different genetic diseases. In genetic animal models, the phenotypes of single gene knockout can vary by strain in mice, and the clinical manifestations of a gene defect can differ between mice and humans, and mice null for some genes have also no observable phenotypic abnormalities compared with controls [99]. These findings suggest that default of a protein might be at least partly controlled by individual's control systems and that there might exist a similar immune/repair system against cell injury in genetic diseases. > The pathophysiology of most genetic diseases in the CNS is complex because any affected gene is associated with numerous proteins and their corresponding activations of genes and epigenetic changes that occur during disease processes. Thus, the use of a genetic marker for diagnosing or predicting a prognosis remains impractical in clinical settings [100].

[16] Systems pharmacology-based integration of human and mouse data for drug repurposing to treat thoracic aneurysms.

Authors: J. Hansen, J. Galatioto, Cristina I. Caescu, P. Arnaud, R. C. Calizo et al.
Year: 2019
Venue: JCI insight
URL: https://www.semanticscholar.org/paper/261628418de4c8b21daeb694301dc1b8759b622d
DOI: 10.1172/jci.insight.127652
PMID: 31167969
Citations: 20
Summary: System pharmacology approaches that compare patient- and mouse-derived transcriptomic data for subcellular pathway-based drug repurposing represent an effective strategy to identify potential new treatments of human diseases.
Evidence snippets:
Snippet 1 (score: 0.342) > TAA with ensuing dissection and rupture of the vessel wall is the clinical hallmark of Marfan syndrome (MFS), a relatively common connective tissue disease associated with mutations in the gene that codes for the multifunctional ECM glycoprotein fibrillin-1 (4,5). Fibrillin-1 assemblies (microfibrils and elastic fibers) impart specific physical properties to tissues, distribute mechanical forces within and across them, communicate to multiple types of vessel wall cells through integrin receptors, and modulate local bioavailability of ECM-bound latent TGF-β complexes (5). In spite of significant research effort, the molecular pathogenesis of arterial disease in MFS remains unresolved, therefore hindering advances in drug therapy. Earlier studies of MFS mice with nondissecting TAA (Fbn1 C1039G/+ mice) have correlated aneurysm onset and progression with increased TGF-β signaling in the media stimulated by improper angiotensin II (AngII) type I receptor (AT1r) activity (6,7). More recent findings indicate a more complex disease mechanism involving the gradual stratification of stress-stimulated interactions among different cell types and multiple regulatory pathways, of which the AT1r and TGF-β signaling pathways are a critical subset (8)(9)(10)(11)(12)(13)(14). > An overview of regulatory pathways and networks associated with a given pathology can often be obtained by examining changes in gene expression during disease progression. Systems pharmacology approaches that consider drug targets as nodes within cellular regulatory networks can use differentially expressed genes (DEGs) to predict dysregulated SCPs that underlie cell-level mechanisms (1,3). Further, computational analyses of the pharmacologically induced perturbations of gene expression listed in the Connectivity Map (CMap) database can predict drugs to be repurposed to normalize dysregulated SCPs (15).

[17] Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

Authors: M. M. Wong, L. Watson, Esther B. E. Becker
Year: 2017
Venue: Journal of neurology & neuromedicine
URL: https://www.semanticscholar.org/paper/0d962652305116e383ab260b9e82d3a5ffe1722f
DOI: 10.29245/2572.942X/2017/7.1134
PMID: 28825058
PMCID: 5558869
Citations: 9
Summary: This review focuses on recent breakthroughs in generating human iPSC-derived Purkinje cells and highlights the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.
Evidence snippets:
Snippet 1 (score: 0.341) > dominant polyglutamine spinocerebellar ataxias (SCAs) are the most studied forms of ataxias. Despite significant clinical and genetic heterogeneity, emerging evidence points to the existence of common pathogenic mechanisms that may be shared by several genetically distinct forms of cerebellar ataxias (reviewed in5-8). However, it is still unclear how the proposed pathological pathways ultimately result in cerebellar dysfunction and degeneration, predominantly affecting Purkinje cells. > Understanding disease mechanisms is key to treating neurodegenerative disorders. The heterogeneous nature of the cerebellar ataxias combined with the unavailability of human brain tissue and the lack of reliable disease models have, however, hampered our understanding of the molecular disease mechanisms underlying cerebellar ataxias and thus, the development of effective therapies. Although mouse models of several cerebellar ataxias, including FRDA and SCAs, have provided valuable insights into the pathophysiology of these disorders (reviewed in9), many questions remain about the observed species differences in disease phenotypes and the effectiveness of potential drugs in clinical trials. > To help translate research from animal models into novel treatments for ataxia patients, it is essential to validate findings in the relevant affected human cell types, particularly in cerebellar Purkinje cells. The current obstacles might be overcome by exploiting recently developed human induced pluripotent stem cell (iPSC) technology and neuronal differentiation protocols.

[18] Copy number variants (CNVs): a powerful tool for iPSC-based modelling of ASD

Authors: D. Drakulić, S. Djurovic, Y. A. Syed, Sebastiano Trattaro, N. Caporale et al.
Year: 2020
Venue: Molecular Autism
URL: https://www.semanticscholar.org/paper/c6cac51304043d34c93254007adca11883e387cd
DOI: 10.1186/s13229-020-00343-4
PMID: 32487215
PMCID: 7268297
Citations: 23
Influential citations: 1
Summary: Here, it is examined how iPSCs derived from ASD patients with an associated CNV inform the understanding of the genetic and biological mechanisms underlying the aetiology of ASD.
Evidence snippets:
Snippet 1 (score: 0.341) > external factors. These complications hinder identification of the basic pathophysiological mechanisms that lead to ASD and hence hamper development of effective therapies. > Molecular and cellular analysis of human patients is generally prospective with data mostly derived from post-mortem tissue. As mentioned above, such studies are subject to the confounds of secondary effects and record the outcomes of underlying disease mechanism rather than directly probe the causative mechanisms. Animal models can be highly informative for the study of a basic mechanism; however, it is difficult to directly translate between observed patient phenotype and animal models. A particular weakness is the ability to capture the phenotypic variation across the patient population. > Human stem cell models offer an opportunity to directly study the molecular and cellular mechanisms of diseases. Key to this approach is the generation of human-induced pluripotent stem cells (iPSCs) derived from patient cells. These are generated by reprogramming of somatic cells into pluripotent stem cells from which many cell types can be differentiated, including neurons and glial cells. Importantly, they can be easily obtained in the clinic from fibroblasts (skin biopsies), keratinocytes (hair roots) [3], T lymphocytes (peripheral blood) [4,5] and exfoliated renal epithelial cells from urine samples [6,7]. Importantly, patient iPSCs enable the in vitro study of different cells types in isolation or co-culture in order to investigate cell function. Uniquely they can track the development profile of patient cell differentiation. More recently the capacity of iPSCs to form 3D organoids has opened up the possibility to investigate the interaction of multiple cell types in a more brain-like microenvironment. Methods for increasing reproducibility of brain organoid differentiation are improving substantially [8,9] and being exploited to mechanistically dissect the effect of genetic lesions causing ASD and ID [10][11][12], as well as the role of specific genes and molecular modules key to human-specific neuronal differentiation trajectories and pathophysiology [13]. > The major question is how to identify the relevant cellular phenotypes that converge on the common pathophysiological mechanisms underlying patient aeti

[19] 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: 0.341) > 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.

[20] Heat Shock Proteins in Oxidative Stress and Ischemia/Reperfusion Injury and Benefits from Physical Exercises: A Review to the Current Knowledge

Authors: Jakub Szyller, I. Bil-Lula
Year: 2021
Venue: Oxidative Medicine and Cellular Longevity
URL: https://www.semanticscholar.org/paper/4ec4bee9f1b89cdf5a3c513d847990f3cfc18bb8
DOI: 10.1155/2021/6678457
PMID: 33603951
PMCID: 7868165
Citations: 113
Influential citations: 2
Summary: The latest research focuses on determining the role of H SPs in OS, their antioxidant activity, and the possibility of using HSPs in the treatment of I/R consequences, where reactive oxygen species play a major role.
Evidence snippets:
Snippet 1 (score: 0.340) > Heat shock proteins play a cytoprotective role under pathological conditions such as cardiovascular diseases. The knowledge about cellular and molecular mechanisms underlying ROS-mediated modulation of HSP expression can help to better understand the pathophysiology of OS, which is associated with the development of many diseases (cardiovascular, neurodegenerative, etc.). I/R injury is considered a major contributor to tissue damage in multiple clinical situations such as myocardial infarction, stroke, and organ transplantation. Oxidative damage is a key factor in the initiation of I/R. HSP expression is highly sensitive to I/R injury. > Understanding the exact mechanisms of HSP and the structure of the protein interaction network can help to better understand the pathophysiology and treatment of many diseases, as well as to develop new drugs. There is a need to understand the relationship between cell pathways-signaling, metabolism, etc. The relationships between HSP and OS discussed in this work seem to be very complicated and not yet fully understood. Data showed that modulation of HSP expression in reperfusion injuries may result in better treatment of myocardial infarction. This can also help to prepare organs for the transplantation.

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[14] Novel Approaches to Studying SLC13A5 Disease

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[17] Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

[18] Copy number variants (CNVs): a powerful tool for iPSC-based modelling of ASD

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

[20] Heat Shock Proteins in Oxidative Stress and Ischemia/Reperfusion Injury and Benefits from Physical Exercises: A Review to the Current Knowledge

Notes