ADNP-Related Syndrome
ADNP-related syndrome (Helsmoortel-Van der Aa syndrome; HVDAS) is an autosomal dominant multisystem neurodevelopmental disorder caused mainly by heterozygous, usually de novo, protein-truncating ADNP variants. The molecular consequence is allele dependent rather than uniformly haploinsufficient: most recurrent last-exon variants escape nonsense-mediated decay, but mutant protein has not been unambiguously demonstrated in patient material and the relative contributions of functional insufficiency, dominant interference, and toxic gain of function remain unresolved. A rare splice-acceptor deletion with no detectable truncated protein establishes that true haploinsufficiency can cause the syndrome. ADNP participates in chromatin regulatory complexes and binds microtubule end-binding proteins; disruption of these functions converges on altered neurodevelopmental transcription, neuronal differentiation, dendritic spines, and synaptic plasticity. Intellectual and developmental disability, marked speech and motor delay, autistic and other behavioral features, hypotonia, characteristic facial features, sleep and feeding problems, visual abnormalities, congenital anomalies, and premature primary-tooth eruption form a variable clinical spectrum. Mutation-position-dependent blood DNA-methylation episignatures support diagnosis and variant interpretation but are biomarkers rather than established causal mediators or severity predictors.
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Inheritance
1
Autosomal dominant inheritance
HP:0000006
ADNP-related syndrome is autosomal dominant and is usually caused by a de novo pathogenic variant, although transmission from an apparently unaffected parent has rarely been reported.
Show evidence (1 reference)
"ADNP-related HVDAS is an autosomal dominant disorder. Most probands whose parents have undergone molecular genetic testing have the disorder as the result of a de novo ADNP pathogenic variant. In two families reported to date, probands diagnosed with ADNP-related HVDAS inherited a pathogenic..."
GeneReviews establishes dominant inheritance, the predominance of de novo variants, and the rare occurrence of inherited pathogenic variants.
Mechanistic Hypotheses
2NMD-Escaping Truncation Branch
Evidence balance
1 support
Most pathogenic last-exon truncating variants escape nonsense-mediated decay and produce mutant transcript. Whether their downstream effect is functional insufficiency, dominant interference, toxic gain of function, or a mixture remains unresolved because mutant protein has not been unambiguously demonstrated in patient material.
Pathograph links
Show evidence (1 reference)
"as many mutations cluster in the fifth and last exon and escape from NMD has been demonstrated, the majority of patients might still produce protein. Thought it needs to be mentioned that mutated protein has never been unambiguously demonstrated in patients, an additional gain of toxic function..."
This review defines the unresolved mechanism of the common NMD-escaping truncation branch and explicitly separates mutant transcript from proof of mutant protein.
Allele-Specific ADNP Haploinsufficiency Branch
Evidence balance
1 support
True ADNP haploinsufficiency is experimentally confirmed for a non-coding splice-acceptor deletion that causes exon skipping and no detectable truncated protein. This branch is allele specific and is not generalized to the common last-exon truncating variants.
Pathograph links
Allele-Specific ADNP Haploinsufficiency
->
ADNP Chromatin-Complex Dysfunction
Intermediates: reduced full-length ADNP availability for HP1/BRG1 and ChAHP complexes
Allele-Specific ADNP Haploinsufficiency
->
ADNP-EB Microtubule Dynamics Dysfunction
Intermediates: reduced ADNP-end-binding protein interaction capacity
Show evidence (1 reference)
"An N-terminal truncated protein could not be detected in transfection experiments with a mutant expression vector in HEK293T cells, strongly suggesting this is a first confirmed diagnosis exclusively due to haploinsufficiency of the ADNP gene."
The splice allele provides direct experimental support for an allele-specific true-null branch without establishing that mechanism for all pathogenic ADNP variants.
Discussions and Knowledge Gaps
5For common NMD-escaping truncating alleles, does disease result from reduced effective ADNP function, dominant interference, toxic gain of function, or an allele-specific mixture, and how does that compare with confirmed true-null and emerging missense alleles?
Attached to
Mutant RNA is demonstrable for common last-exon alleles, but mutant protein has not been unambiguously demonstrated in patients. A splice allele proves true haploinsufficiency can cause disease, while p.C687R supplies limited gain-of-function-like experimental evidence. Therapy and model selection therefore require allele-stratified mechanism.
Proposed experiments
Isogenic ADNP allele-mechanism panel in human neural lineages
exp_adnp_isogenic_allele_mechanism_panel
Create isogenic human iPSC lines carrying representative NMD-escaping truncations, the confirmed splice-null allele, p.C687R, matched knockouts, corrected controls, and allele-specific mutant knockdown. Compare allele-specific RNA and proteomics, ADNP localization and chromatin occupancy, methylome/transcriptome states, microtubule dynamics, neuronal differentiation, dendritic spines, and synaptic physiology, with wild-type addback and mutant-selective suppression arms.
Decision criterion
Support a dominant or toxic mutant mechanism only if an NMD-escaping or missense allele produces effects exceeding matched dosage loss and those effects are preferentially rescued by mutant-selective suppression; support pure dosage loss when matched knockout and variant phenotypes align and wild-type addback rescues both.
Show evidence (2 references)
"mutations cluster in the fifth and last exon and escape from NMD has been demonstrated, the majority of patients might still produce protein. Thought it needs to be mentioned that mutated protein has never been unambiguously demonstrated in patients, an additional gain of toxic function of the..."
The review explicitly frames the unresolved mutant-protein question.
"Our results suggest that p.C687R may exert gain-of-function-like effects in experimental systems and underscore chromatin-mediated regulation of GABAergic lineage genes in HVDAS.
"
A single missense allele supplies an emerging alternative mechanism that requires replication.
Which findings from heterozygous null mice translate to people with common NMD-escaping truncating variants, and which reflect a rare true-null branch or model-specific sex and background effects?
Attached to
The frequently used Adnp+/- mouse deletes one allele and therefore models dosage loss, whereas most common human alleles escape NMD. Several mouse phenotypes are sex dependent, and the 2026 frameshift study tested only males.
Show evidence (1 reference)
"While it is tempting to draw parallels between the clinical presentation of patients and the abnormalities observed in the mouse model, it should be stressed that the model described is a full deletion and the mutational mechanism of the Helsmoortel–Van der Aa syndrome has not been fully established.
"
The review explicitly identifies the null-model versus human-allele mismatch.
What are the age-specific developmental trajectories, true frequency and domains of regression, adult outcomes, and nonprogressive versus progressive subgroups in ADNP-related syndrome?
The main cohort was young and cross-sectional. Apparent skill loss was reported in 12 children without a feature-specific denominator, so a globally progressive or neurodegenerative label is not justified.
Proposed experiments
Allele-stratified longitudinal ADNP natural-history cohort
exp_adnp_longitudinal_natural_history
Follow children and adults prospectively with standardized developmental, adaptive, speech, motor, behavioral, sleep, seizure, sensory, growth, and organ-system measures, recording acquisition and loss of individual skills and stratifying by allele position, NMD prediction, episignature group, age, and sex.
Decision criterion
Classify regression or progression only from repeated within-person decline exceeding measurement variability, with domain-specific denominators and age-specific incidence; otherwise retain a variable lifelong neurodevelopmental course.
Show evidence (2 references)
"Apparent loss of acquired abilities was reported in 12 children for skills such as speaking, counting, riding a bicycle, or being toilet trained.
"
Reported regression requires prospective confirmation and a defined denominator.
"The main limitation of our study is the relatively young age of our study cohort. Longterm follow-up studies are necessary to define the developmental path of individuals with a mutation in ADNP.
"
The cohort authors explicitly call for longitudinal follow-up.
How sensitive and specific are ADNP episignatures for diagnosis and variant interpretation, and can any reproducible methylation measure predict phenotype after controlling for allele position and ascertainment?
Two mutation-position-dependent signatures are reproducible, but their correlation with behavioral severity is limited. Diagnostic and VUS-classification performance should be kept separate from prognosis.
Show evidence (1 reference)
"We found limited phenotypic differences between the two HVDAS-affected groups and no evidence that individuals with more widespread methylation changes are more severely affected.
"
The replication cohort argues against using methylation extent as a severity proxy.
Can davunetide or ketamine improve clinically meaningful outcomes in ADNP-related syndrome, and do efficacy or safety differ across true-null, NMD-escaping, and missense allele mechanisms?
Attached to
Davunetide evidence is preclinical. Ketamine has only a small single-dose open-label study; peripheral blood transcriptional changes do not establish central target engagement, and increasing mutant ADNP could have allele-specific consequences.
Show evidence (3 references)
"Ketamine was generally well tolerated, and there were no serious adverse events.
"
The small open-label study informs short-term tolerability but cannot establish efficacy.
"The ketamine rationale is based on the finding that ketamine increased ADNP expression, however, the possibility of ketamine increasing mutated ADNP expression needs to be further investigated
"
The review identifies an allele-specific safety and mechanism question.
"We discovered that Adnp deficiency reduced dendritic spine density and altered synaptic gene expression, both of which were partly ameliorated by NAP treatment.
"
NAP rescue remains preclinical model evidence.
Pathophysiology
7Heterozygous ADNP Pathogenic Variation
The initiating lesion is a heterozygous pathogenic ADNP variant. Most established alleles are protein-truncating and usually de novo, but their molecular consequences differ by position and RNA processing. This root therefore represents pathogenic variation without presupposing uniform haploinsufficiency.
Downstream
Show evidence (1 reference)
"We found 46 unique mutations on the DNA level, of which 25 were nonsense and 21 frameshift (Supplemental Table S2). All but three mutations were located in the fifth and last exon of the ADNP gene and were predicted to escape nonsense-mediated decay."
The 78-person cohort establishes the predominance and position of truncating variants while showing why a uniform null model is unsafe.
NMD-Escaping Mutant ADNP Transcripts
Common last-exon truncating alleles are transcribed and escape nonsense-mediated decay. Mutant RNA is established, but the abundance, stability, localization, and action of any corresponding truncated protein in patient tissues remain unresolved.
Downstream
Show evidence (1 reference)
"demonstrating that the excessADNPmRNA in patients corresponds to the mRNA transcribed from the mutant allele."
Allele-aware expression in patient lymphoblastoid cells demonstrates production of mutant transcript.
Allele-Specific ADNP Haploinsufficiency
A splice-acceptor deletion that causes exon 4 skipping and no detectable truncated protein establishes a true dosage-loss mechanism for that allele. The node is deliberately allele specific.
Downstream
Show evidence (1 reference)
"An N-terminal truncated protein could not be detected in transfection experiments with a mutant expression vector in HEK293T cells, strongly suggesting this is a first confirmed diagnosis exclusively due to haploinsufficiency of the ADNP gene."
The functional assay directly supports true loss of ADNP dosage for this splice allele.
ADNP Chromatin-Complex Dysfunction
ADNP participates in HP1/BRG1-associated chromatin regulation and the CHD4-containing ChAHP complex. Pathogenic variation can alter ADNP abundance, localization, chromatin association, or binding specificity, but the exact perturbation is allele dependent. A 2026 male-mouse frameshift model showed reduced chromatin association, increased accessibility, and Wnt-pathway downregulation; these model findings are not treated as direct human proof.
Downstream
Show evidence (2 references)
"The protein is associated with the pericentromeric protein HP1, the SWI/SNF core complex protein BRG1, and other members of this chromatin remodeling complex and, in murine stem cells, with the chromodomain helicase CHD4 in a ChAHP complex."
The review synthesizes ADNP membership in multiple chromatin-regulatory complexes.
"Introduction of the 14-base pair deletion reduced cellular Adnp levels in the brain (p = 0.0008) and decreased its chromatin association (p = 0.001), parallelled by a genome-wide increase in chromatin accessibility."
A male-mouse frameshift model directly links an Adnp allele to altered chromatin association and accessibility.
ADNP-EB Microtubule Dynamics Dysfunction
ADNP and its NAP motif interact with end-binding proteins at growing microtubule plus ends. ADNP-mutant cell models show reduced microtubule content and phenocopy after pharmacologic microtubule disruption, supporting a microtubule branch while leaving allele-specific human intermediates incompletely resolved.
Downstream
Show evidence (2 references)
"ADNP and its derived peptides, NAP and SKIP, directly interact with end-binding proteins (EBs), which decorate plus-tips of the growing axonal cytoskeleton-microtubules (MTs)."
The review synthesizes the direct ADNP/NAP-to-EB microtubule interaction.
"reduced microtubule content was observed in the ADNP-mutated cell lines. In parallel, disrupting microtubules by zinc or nocodazole intoxication mimicked ADNP mutation phenotypes"
Engineered mutant neuronal cells support microtubule dysfunction as a convergent cellular phenotype.
Neurodevelopmental Transcription and Differentiation Dysregulation
Altered ADNP-dependent chromatin regulation perturbs transcriptional programs for nervous-system development and neuronal differentiation. Evidence spans an allele-specific human iPSC study and mouse multi-omics; Wnt dysregulation is currently model-qualified rather than an established universal human pathway.
Downstream
Show evidence (2 references)
"Our findings demonstrate a role for Adnp in chromatin regulation and Wnt signalling, coupled to aberrant expression of cytoskeletal components and synaptic dysfunction."
The engineered male-mouse model supports convergent transcriptional and Wnt dysregulation.
"This study is based on a single patient-derived line in combination with complementary experimental models. In the heterozygous endogenous context, distinguishing increased functional activity from dosage-related effects requires further investigation."
The p.C687R iPSC study informs an emerging allele-specific differentiation mechanism but explicitly limits generalization.
Dendritic Spine and Synaptic Plasticity Dysfunction
Adnp-deficient and frameshift mouse models show reduced dendritic spine density, altered synaptic gene expression, disrupted Camk2a/Dbn1 interactions, abnormal CaMKII phosphorylation, and excessive long-term potentiation. These findings support a synaptic branch but remain model-derived rather than direct measurements in affected human brain.
Downstream
Show evidence (3 references)
"We discovered that Adnp deficiency reduced dendritic spine density and altered synaptic gene expression, both of which were partly ameliorated by NAP treatment."
Adnp-haploinsufficient mice directly support spine and synaptic-expression abnormalities.
"The adult Adnp-HT hippocampus shows hyperphosphorylated CaMKIIα and its substrates, including SynGAP1, and excessive long-term potentiation that is normalized by CaMKIIα inhibition."
A mouse model links Adnp deficiency to CaMKII dysregulation and altered long-term potentiation.
"Adnp directly regulated mechanisms of synaptic plasticity through interaction with Camk2a and Dbn1. In heterozygous mice, these protein interactions were disrupted, resulting in aberrant Camk2a phosphorylation at synapses (p = 0.012)."
The 2026 male-mouse frameshift model independently supports disrupted synaptic interactions.
Pathograph
Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Phenotypes
23Cardiovascular 1
Cardiac Anomalies
FREQUENT
Abnormal heart morphology
HP:0001627
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
"endocrine and cardiac findings, hearing loss, seizures, and urinary tract anomalies"
GeneReviews lists cardiac findings among common features.
"Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities."
The 78-individual cohort study lists congenital heart defects among common comorbidities.
"Thirty-eight percent had one or more congenital cardiac defects."
The 38% estimate supports a frequent classification.
Digestive 2
Feeding Difficulties
HP:0011968
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"Other common findings include additional behavioral problems, sleep disturbance, structural brain abnormalities, feeding issues, gastrointestinal problems"
GeneReviews lists feeding issues among common findings.
Gastrointestinal Problems
Abnormality of the gastrointestinal tract
HP:0011024
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Gastrointestinal problems, annotated with Abnormality of the gastrointestinal tract (HP:0011024). HP:0011024 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities."
The cohort study lists gastrointestinal problems among common comorbidities.
Ear 1
Hearing Loss
OCCASIONAL
Hearing impairment
HP:0000365
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"endocrine and cardiac findings, hearing loss, seizures, and urinary tract anomalies"
GeneReviews lists hearing loss among common findings.
"Some individuals (11.7%) were diagnosed with mild hearing loss in childhood."
The 11.7% estimate supports an occasional classification.
Eye 2
Hypermetropia
FREQUENT
HP:0000540
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Hypermetropia (HP:0000540). HP:0000540 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"visual dysfunction (hypermetropia, strabismus, cortical visual impairment)"
GeneReviews lists hypermetropia among common visual findings.
"In 73.6% of the individuals, visual problems, especially hypermetropia (40.3%) and strabismus (49.2%), but also myopia and astigmatism, were present (Figure 3E)."
The feature-specific 40.3% estimate supports a frequent classification.
Strabismus
FREQUENT
HP:0000486
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"visual dysfunction (hypermetropia, strabismus, cortical visual impairment)"
GeneReviews lists strabismus among common visual findings.
"In 73.6% of the individuals, visual problems, especially hypermetropia (40.3%) and strabismus (49.2%), but also myopia and astigmatism, were present (Figure 3E)."
The feature-specific 49.2% estimate supports a frequent classification.
Genitourinary 1
Urinary Tract Anomalies
OCCASIONAL
Abnormality of the urinary system
HP:0000079
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Urinary tract anomalies, annotated with Abnormality of the urinary system (HP:0000079). HP:0000079 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"endocrine and cardiac findings, hearing loss, seizures, and urinary tract anomalies"
GeneReviews lists urinary tract anomalies among the features of the syndrome.
"Six individuals (12.5%) were born with renal anomalies (narrow ureters, bilateral vesicoureteral reflux that was surgically repaired) (Table 1)."
The congenital renal-anomaly estimate supports an occasional urinary-system phenotype.
Head and Neck 1
Characteristic Facial Features
Abnormal facial shape
HP:0001999
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Characteristic facial features, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"characteristic facial features (prominent forehead, high anterior hairline, wide and depressed nasal bridge, and short nose with full, upturned nasal tip)"
GeneReviews describes the recognizable facial gestalt of the syndrome.
Immune 1
Recurrent Infections
FREQUENT
HP:0002719
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"musculoskeletal anomalies, recurrent infections, endocrine issues including short stature and thyroid and/or growth hormone deficiencies"
GeneReviews lists recurrent infections among common comorbidities.
"Fifty-one percent of the individuals had recurrent infections."
The cohort supports recurrent infections in the frequent range.
Musculoskeletal 1
Hypotonia
FREQUENT
HP:0001252
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"is characterized by hypotonia, speech and motor delay, mild-to-severe intellectual disability, and characteristic facial features"
GeneReviews lists hypotonia as a characteristic feature.
"Seventy-eight percent of the children had hypotonia, while hypertonia was present in 3 children."
The observed 78% lies in the frequent range and applies to the assessed children.
Nervous System 8
Intellectual Disability
OBLIGATE
HP:0001249
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"is characterized by hypotonia, speech and motor delay, mild-to-severe intellectual disability, and characteristic facial features"
GeneReviews lists mild-to-severe intellectual disability as a defining characteristic.
"Fifty-two percent of the individuals in this cohort presented with severe ID at the age of assessment, 36% had a moderate disability, and 12% had a mild disability."
The severity categories sum to the full cohort, supporting intellectual disability as obligate in this clinically ascertained series.
Autistic Behavior
VERY_FREQUENT
HP:0000729
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"Features of autism spectrum disorder are common (stereotypic behavior, impaired social interaction)."
GeneReviews documents autism spectrum disorder features as common.
"Ninety-three percent of the individuals presented with autistic features (Figure 3B)."
The 78-person cohort supports a very-frequent frequency band for broad autistic features.
Speech Delay
VERY_FREQUENT
Delayed speech and language development
HP:0000750
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"is characterized by hypotonia, speech and motor delay, mild-to-severe intellectual disability, and characteristic facial features"
GeneReviews lists speech and motor delay as a defining characteristic.
"Another key feature was speech delay, which presented in 98.6% of individuals."
The cohort supports speech delay as very frequent.
Motor Delay
VERY_FREQUENT
HP:0001270
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Motor delay (HP:0001270), qualified as infantile onset. HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
"is characterized by hypotonia, speech and motor delay, mild-to-severe intellectual disability, and characteristic facial features"
GeneReviews lists motor delay as a defining characteristic of the syndrome.
"a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay"
The Van Dijck cohort describes severe speech and motor delay as part of the distinctive clinical combination.
"observed in 86.8% of the children, with an average age of 2 years 5.5 months"
Delayed independent walking supports a very-frequent motor-delay classification in assessed children.
Sleep Disturbance
FREQUENT
HP:0002360
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Sleep disturbance (HP:0002360). HP:0002360 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"Other common findings include additional behavioral problems, sleep disturbance, structural brain abnormalities, feeding issues, gastrointestinal problems"
GeneReviews lists sleep disturbance among common findings.
"Sleep problems were present in 65.2%."
The cohort supports sleep disturbance in the frequent range.
Seizures
OCCASIONAL
HP:0001250
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities."
The cohort study lists epilepsy among common comorbidities.
"Sixteen percent had seizures, including absence seizures, focal seizures with reduced awareness, epilepsy with continuous spike and waves during slow-wave sleep, or unclassified seizures."
The 16% estimate supports an occasional classification.
Global Developmental Delay
OBLIGATE
HP:0001263
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Global developmental delay (HP:0001263), qualified as infantile onset. HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"Developmental delay was present in all individuals, with motor delay being one of the key features."
The main cohort supports developmental delay as obligate, although individual developmental domains vary.
Behavioral Problems
FREQUENT
Atypical behavior
HP:0000708
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Behavioral problems, annotated with Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities."
The 78-individual cohort study lists behavioral problems among common comorbidities.
"Although parents report that 88% of the children were overall happy and friendly, behavioral problems were reported in 77.6% of them."
The caregiver-reported 77.6% estimate supports a frequent classification.
Growth 1
Short Stature
OCCASIONAL
HP:0004322
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"endocrine issues including short stature and thyroid and/or growth hormone deficiencies"
GeneReviews lists short stature among endocrine findings.
"Twenty-three percent of the individuals had short stature (height < −2 SD, range 2–23 years old) (Supplemental Table S3, Supplemental Figure S1E)."
The 23% estimate supports an occasional classification.
Other 4
Structural Brain Abnormalities
FREQUENT
Abnormal brain morphology
HP:0012443
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Abnormal brain morphology (HP:0012443). HP:0012443 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"Other common findings include additional behavioral problems, sleep disturbance, structural brain abnormalities, feeding issues, gastrointestinal problems"
GeneReviews lists structural brain abnormalities among common findings.
"In this cohort, magnetic resonance imaging of the brain was performed in 75.6% of the individuals. Fifty-six percent of them appeared to have cerebral abnormalities, including atypical white matter lesions, delayed myelination, cortical dysplasia or atrophy, perinatal hypoxic ischemic..."
The 56% frequency applies only to the imaged subgroup; perinatal hypoxic-ischemic injury is not treated as a primary ADNP mechanism.
Musculoskeletal Anomalies
FREQUENT
Abnormality of the musculoskeletal system
HP:0033127
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Abnormality of the musculoskeletal system (HP:0033127). HP:0033127 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"musculoskeletal anomalies, recurrent infections, endocrine issues including short stature and thyroid and/or growth hormone deficiencies"
GeneReviews lists musculoskeletal anomalies among common findings.
"Musculoskeletal problems were common (Figure 3F)."
The cohort's clinical synthesis places musculoskeletal abnormalities among frequent comorbidities.
Advanced Tooth Eruption
VERY_FREQUENT
Advanced eruption of teeth
HP:0006288
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Premature primary tooth eruption, annotated with Advanced eruption of teeth (HP:0006288). HP:0006288 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"we discovered premature tooth eruption as a potential early diagnostic biomarker for ADNP mutation. The parents of 44/54 ADNP-mutated children reported an almost full erupted dentition by 1 year of age, including molars"
Caregivers reported premature primary dentition in 44/54 (81.5%) children in this selected cohort, supporting a potential early diagnostic clue rather than a standalone biomarker.
Cerebral Visual Impairment
FREQUENT
HP:0100704
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Cortical visual impairment, annotated with Cerebral visual impairment (HP:0100704). HP:0100704 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"visual dysfunction (hypermetropia, strabismus, cortical visual impairment)"
GeneReviews lists cortical visual impairment among common visual findings.
"Forty-one percent of the individuals had a diagnosis of cerebral visual impairment."
The 41% estimate supports a frequent classification.
Genetic Associations
1
ADNP Pathogenic Variants
(Causative)
Show evidence (5 references)
"Here, we report ten patients with ASD and other shared clinical characteristics, including intellectual disability and facial dysmorphisms caused by a mutation in ADNP, a transcription factor involved in the SWI/SNF remodeling complex.
"
The founding series establishes ADNP as a causal disease gene.
"We found 46 unique mutations on the DNA level, of which 25 were nonsense and 21 frameshift (Supplemental Table S2). All but three mutations were located in the fifth and last exon of the ADNP gene and were predicted to escape nonsense-mediated decay.
"
The 78-person cohort establishes the predominant truncating, last-exon allele spectrum.
"Sixty-eight mutations in our cohort were confirmed de novo, eight mutations were of unknown inheritance, and two C-terminal mutations were inherited.
"
The cohort quantifies the predominance of de novo origin while preserving inherited exceptions.
+ 2 more references
Medical Actions
6
Symptom-Directed Supportive Care
Management is individualized and symptomatic, including developmental and educational supports, nutritional assistance, and standard care for gastrointestinal, ophthalmologic, musculoskeletal, infectious, endocrine, cardiac, hearing, seizure, and urinary manifestations.
Show evidence (2 references)
"Treatment is symptomatic and can include: speech, occupational, and physical therapy; specialized learning programs depending on individual needs; treatment of neuropsychiatric features; nutritional support as needed"
GeneReviews describes symptomatic, multidisciplinary supportive management as the standard of care.
"It underscores the multisystemic nature of the disorder and the need for multidisciplinary management."
A 2025 systematic review independently supports multidisciplinary management while documenting expanding phenotypic heterogeneity.
Speech Therapy
Speech therapy addresses the severe speech delay characteristic of the syndrome.
Show evidence (1 reference)
"Treatment is symptomatic and can include: speech, occupational, and physical therapy"
GeneReviews recommends speech therapy as part of symptomatic management.
Physical and Occupational Therapy
Physical and occupational therapy support motor development and hypotonia.
Show evidence (1 reference)
"Treatment is symptomatic and can include: speech, occupational, and physical therapy"
GeneReviews recommends physical and occupational therapy.
Genetic Counseling
Genetic counseling is recommended for families. ADNP-related syndrome is an autosomal dominant disorder, most often arising de novo. Once the ADNP variant is identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Show evidence (1 reference)
"Once the ADNP pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."
GeneReviews describes the autosomal dominant inheritance and the availability of prenatal and preimplantation genetic testing, supporting genetic counseling.
Davunetide (NAP, investigational)
Davunetide (NAP, CP201) is an ADNP-derived peptide candidate with preclinical target engagement. It partially rescues spine, behavioral, microtubule, and cellular abnormalities in Adnp-deficient mouse and engineered-cell models. Human efficacy for ADNP-related syndrome has not been established.
Show evidence (2 references)
"This malformation was corrected upon neuronal differentiation by the ADNP-derived fragment drug candidate NAP (davunetide)."
In ADNP-mutated neuronal cell models, davunetide (NAP) corrects cellular abnormalities, supporting it as an investigational mechanism-based candidate therapy.
"Adnp+/-mice further exhibited global developmental delays, vocalization impediments, gait and motor dysfunctions, and social and object memory impairments, all of which were partially reversed by daily NAP administration (systemic/nasal).
"
Daily NAP partially reversed multiple developmental and behavioral phenotypes in an Adnp-haploinsufficient mouse model; this remains preclinical evidence.
Low-Dose Ketamine (investigational)
A single-dose open-label study of 0.5 mg/kg intravenous ketamine in 10 children reported no serious adverse events and nominal short-term behavioral changes. The small uncontrolled design makes efficacy findings hypothesis-generating. A blood-transcriptomic study found a transient, monocyte-enriched peripheral response that does not establish central nervous-system target engagement; the effect of increasing mutant ADNP expression remains unresolved.
Show evidence (2 references)
"Ketamine was generally well tolerated, and there were no serious adverse events."
An open-label trial of low-dose IV ketamine in 10 children with ADNP syndrome found it generally well tolerated with no serious adverse events.
"We show that ketamine triggers immediate and profound gene expression alterations, with specific enrichment of monocyte-related expression patterns."
Longitudinal blood transcriptomics in ADNP-syndrome individuals shows a transient, monocyte-enriched gene-expression response to a single low-dose ketamine infusion.
Biochemical Markers
1
Mutation-Position-Dependent Blood DNA Methylation Episignatures
(PRESENT)
Context: Peripheral-blood DNA methylation biomarker for diagnostic support and variant interpretation; not an established causal mediator or severity predictor.
Pathograph Readouts
Readout Of
Heterozygous ADNP Pathogenic Variation
Present Absent
Diagnostic
Show evidence (1 reference)
"Whereas exome sequencing failed to detect the non-coding deletion, genome-wide CpG methylation analysis revealed an episignature suggestive of a Helsmoortel-Van der Aa syndrome diagnosis.
"
The biomarker readout helped prioritize ADNP in a molecularly resolved WES-negative case.
Show evidence (3 references)
"we conducted an independent study on 24 individuals with HVDAS and replicated the existence of the two mutation-dependent episignatures.
"
An independent 24-person cohort reproduced two mutation-position-dependent blood methylation signatures.
"We found limited phenotypic differences between the two HVDAS-affected groups and no evidence that individuals with more widespread methylation changes are more severely affected.
"
The replicated signatures should not be used as established severity or prognostic classifiers.
"Advances in ADNP methylation profiling further enhance diagnostic precision and variant interpretation in this evolving neurodevelopmental syndrome.
"
The 2025 systematic review supports the diagnostic and variant-interpretation role while the primary replication study constrains prognostic use.
Diagnosis
2
ADNP Molecular Genetic Confirmation
Molecular diagnosis is established by identifying a heterozygous pathogenic ADNP variant in a person with a compatible neurodevelopmental and multisystem phenotype.
molecular genetic testing
NCIT:C19770
NCI Thesaurus (NCIT)
Results: A heterozygous pathogenic ADNP variant establishes molecular confirmation in a compatible clinical context.
Show evidence (1 reference)
"The diagnosis of ADNP-related HVDAS is established by identification of a heterozygous ADNP pathogenic variant by molecular genetic testing.
"
GeneReviews defines the molecular diagnostic criterion.
Episignature-Assisted Evaluation After Negative Exome Sequencing
A compatible peripheral-blood DNA-methylation episignature and phenotype classifier can prioritize ADNP after unrevealing exome sequencing; whole-genome and transcriptome sequencing may then identify and confirm a non-coding splice variant. The episignature is complementary, not a standalone severity or prognostic test.
genome-wide DNA methylation analysis
Results: A compatible episignature can trigger genome-wide variant detection and RNA confirmation of an otherwise missed non-coding ADNP allele.
Show evidence (2 references)
"Whereas exome sequencing failed to detect the non-coding deletion, genome-wide CpG methylation analysis revealed an episignature suggestive of a Helsmoortel-Van der Aa syndrome diagnosis.
"
A molecularly resolved case demonstrates an episignature-assisted route after negative exome sequencing.
"with transcriptome sequencing showing this deletion leads to skipping of exon 4.
"
Genome and transcriptome sequencing supplied variant-level confirmation after the screening clue.
Imaging Findings
2
Abnormal Brain MRI
FREQUENT
Among individuals who underwent brain MRI, reported abnormalities included atypical white-matter lesions, delayed myelination, cortical dysplasia or atrophy, hydrocephalus, and hippocampal hypoplasia. Perinatal hypoxic-ischemic injury was also recorded in the cohort but is not modeled as a primary ADNP mechanism.
Abnormal brain morphology
HP:0012443
Human Phenotype Ontology (HP)
Show evidence (1 reference)
"In this cohort, magnetic resonance imaging of the brain was performed in 75.6% of the individuals. Fifty-six percent of them appeared to have cerebral abnormalities, including atypical white matter lesions, delayed myelination, cortical dysplasia or atrophy, perinatal hypoxic ischemic..."
The 56% estimate applies to the 75.6% imaged subgroup, not the entire cohort; the findings are heterogeneous and not individually assigned that frequency.
Developmental Brain-Structure Pattern on MRI
Detailed rereview of five MRIs identified recurrent underdevelopment or simplified gyration of the frontal lobes, thin or short corpus callosum, inferior vermis hypoplasia, abnormal opercularization, ventricular dilatation, and dilated perivascular spaces. The small selected reread set does not support feature-specific population frequencies.
Developmental brain-structure abnormalities
Show evidence (1 reference)
"Magnetic resonance images of 5 individuals were studied in detail. The following abnormalities were seen in multiple individuals: underdevelopment of the frontal lobes with simplified gyral pattern of the cortex and occasional hypoplasia of the bulbus olfactorius and chiasma opticum; a thin..."
This detailed imaging pattern derives from only five selected MRIs and is therefore presented without individual finding frequencies.
Progression
2Infancy and early-childhood neurodevelopment
Hypotonia and global developmental delay are recognized early, followed by marked speech and motor delay. The disorder is developmental and multisystemic; the available evidence does not establish a uniformly progressive or neurodegenerative human course.
Show evidence (1 reference)
"is characterized by hypotonia, speech and motor delay, mild-to-severe intellectual disability, and characteristic facial features
"
GeneReviews defines the early neurodevelopmental presentation without describing a universal progressive course.
Variable later developmental course
Apparent loss of previously acquired abilities has been reported in a subset. The denominator and trajectories are insufficient to classify ADNP-related syndrome as globally regressive; long-term longitudinal follow-up remains a major evidence gap.
Show evidence (2 references)
"Apparent loss of acquired abilities was reported in 12 children for skills such as speaking, counting, riding a bicycle, or being toilet trained.
"
The cohort documents reported skill loss in 12 children but does not supply a feature-specific assessed denominator or prove a progressive disease course.
"The main limitation of our study is the relatively young age of our study cohort. Longterm follow-up studies are necessary to define the developmental path of individuals with a mutation in ADNP.
"
The authors explicitly identify long-term natural history as unresolved.
Differential Diagnoses
5Conditions with similar clinical presentations that must be differentiated from ADNP-Related Syndrome:
Overlapping Features
This syndrome was evaluated before ADNP molecular diagnosis in the main cohort because it can share developmental delay and autism-related features. The cited evidence does not establish feature-by-feature discrimination.
Distinguishing Features
- Syndrome-specific molecular confirmation distinguishes this diagnosis from ADNP-related syndrome.
- Identification of a heterozygous pathogenic ADNP variant supports ADNP-related syndrome in a compatible clinical context.
Show evidence (1 reference)
"The clinical symptoms of Helsmoortel-Van der Aa syndrome show partial overlap with other genetic syndromes that include developmental delay and ASD, as evidenced by genetic testing of our cohort for disorders such as Angelman, Prader-Willi, Kleefstra, Smith-Magenis, or Rett syndromes prior to..."
The 78-person cohort directly documents this syndrome among diagnoses evaluated before ADNP molecular confirmation.
Overlapping Features
This syndrome was evaluated before ADNP molecular diagnosis in the main cohort because it can share developmental delay and autism-related features. The cited evidence does not establish feature-by-feature discrimination.
Distinguishing Features
- Syndrome-specific molecular confirmation distinguishes this diagnosis from ADNP-related syndrome.
- Identification of a heterozygous pathogenic ADNP variant supports ADNP-related syndrome in a compatible clinical context.
Show evidence (1 reference)
"The clinical symptoms of Helsmoortel-Van der Aa syndrome show partial overlap with other genetic syndromes that include developmental delay and ASD, as evidenced by genetic testing of our cohort for disorders such as Angelman, Prader-Willi, Kleefstra, Smith-Magenis, or Rett syndromes prior to..."
The 78-person cohort directly documents this syndrome among diagnoses evaluated before ADNP molecular confirmation.
Overlapping Features
This syndrome was evaluated before ADNP molecular diagnosis in the main cohort because it can share developmental delay and autism-related features. The cited evidence does not establish feature-by-feature discrimination.
Distinguishing Features
- Syndrome-specific molecular confirmation distinguishes this diagnosis from ADNP-related syndrome.
- Identification of a heterozygous pathogenic ADNP variant supports ADNP-related syndrome in a compatible clinical context.
Show evidence (1 reference)
"The clinical symptoms of Helsmoortel-Van der Aa syndrome show partial overlap with other genetic syndromes that include developmental delay and ASD, as evidenced by genetic testing of our cohort for disorders such as Angelman, Prader-Willi, Kleefstra, Smith-Magenis, or Rett syndromes prior to..."
The 78-person cohort directly documents this syndrome among diagnoses evaluated before ADNP molecular confirmation.
Overlapping Features
This syndrome was evaluated before ADNP molecular diagnosis in the main cohort because it can share developmental delay and autism-related features. The cited evidence does not establish feature-by-feature discrimination.
Distinguishing Features
- Syndrome-specific molecular confirmation distinguishes this diagnosis from ADNP-related syndrome.
- Identification of a heterozygous pathogenic ADNP variant supports ADNP-related syndrome in a compatible clinical context.
Show evidence (1 reference)
"The clinical symptoms of Helsmoortel-Van der Aa syndrome show partial overlap with other genetic syndromes that include developmental delay and ASD, as evidenced by genetic testing of our cohort for disorders such as Angelman, Prader-Willi, Kleefstra, Smith-Magenis, or Rett syndromes prior to..."
The 78-person cohort directly documents this syndrome among diagnoses evaluated before ADNP molecular confirmation.
Overlapping Features
This syndrome was evaluated before ADNP molecular diagnosis in the main cohort because it can share developmental delay and autism-related features. The cited evidence does not establish feature-by-feature discrimination.
Distinguishing Features
- Syndrome-specific molecular confirmation distinguishes this diagnosis from ADNP-related syndrome.
- Identification of a heterozygous pathogenic ADNP variant supports ADNP-related syndrome in a compatible clinical context.
Show evidence (1 reference)
"The clinical symptoms of Helsmoortel-Van der Aa syndrome show partial overlap with other genetic syndromes that include developmental delay and ASD, as evidenced by genetic testing of our cohort for disorders such as Angelman, Prader-Willi, Kleefstra, Smith-Magenis, or Rett syndromes prior to..."
The 78-person cohort directly documents this syndrome among diagnoses evaluated before ADNP molecular confirmation.
Clinical Trials
2
NCT04388774
PHASE_II
COMPLETED
Completed Phase 2A single-dose, open-label study of low-dose (0.5 mg/kg) intravenous ketamine in 10 children ages 6-12 with ADNP syndrome, evaluating safety, tolerability, behavioral outcomes, and candidate electrophysiologic and molecular biomarkers.
Show evidence (2 references)
"This is a Phase 2A, single dose, open-label study to evaluate the safety, tolerability, and efficacy of a low-dose, 40-minute infusion into the veins (intravenous infusion or "IV") of ketamine in children with ADNP syndrome (Activity-Dependent Neuroprotective Protein)."
ClinicalTrials.gov describes this completed Phase 2A open-label trial of low-dose IV ketamine in children with ADNP syndrome.
"This study utilized a single-dose (0.5 mg/kg), open-label design, with ketamine infused intravenously over 40 min. Ten children with ADNP syndrome ages 6 to 12 years were enrolled.
"
The peer-reviewed completed study confirms the design, dose, infusion, actual enrollment, and age range.
NCT03718936
NOT_APPLICABLE
RECRUITING
Seaver Autism Center assessment study characterizing ADNP-related neurodevelopmental disorders with genetic, medical, and neuropsychological measures.
Show evidence (1 reference)
"This study seeks to characterize ADNP-related neurodevelopmental disorders using a number of genetic, medical and neuropsychological measures."
ClinicalTrials.gov describes this observational study characterizing ADNP-related neurodevelopmental disorders.
Animal Models
4
Complete Adnp knockout Mouse (Mus musculus)
Knockout
Complete Adnp deletion causes embryonic lethality around E8.5-E9.0 with failed neural-tube closure. It establishes an essential developmental function but cannot model the postnatal human syndrome.
Species
Mouse (Mus musculus)
Genotype
Complete Adnp knockout
Genes
Show evidence (1 reference)
"Full knockouts, lacking the entire protein coding sequence of the Adnp gene, are embryonically lethal and die around E8.5–9.0 with failure of the neural tube closure, suggesting a role in brain development.
"
The complete-null mouse demonstrates an essential embryonic role and a severe model-human boundary.
Heterozygous Adnp null allele (Adnp+/-) Mouse (Mus musculus)
Heterozygous knockout
The heterozygous null model reduces Adnp RNA and protein by about 50% and shows cognitive, motor, vocalization, spine, and synaptic phenotypes. It models a true dosage-loss branch that may not represent common NMD-escaping human alleles.
Species
Mouse (Mus musculus)
Genotype
Heterozygous Adnp null allele (Adnp+/-)
Genes
Show evidence (3 references)
"These mice showed the expected 50% reduction in Adnp RNA and protein levels and exhibited cognitive deficits in the Morris water maze in adolescence and older age
"
The heterozygous null mouse directly models reduced dosage and cognitive phenotypes.
"We discovered that Adnp deficiency reduced dendritic spine density and altered synaptic gene expression, both of which were partly ameliorated by NAP treatment.
"
Primary mouse work supports synaptic pathology and partial preclinical NAP rescue.
"Adnp+/-mice further exhibited global developmental delays, vocalization impediments, gait and motor dysfunctions, and social and object memory impairments, all of which were partially reversed by daily NAP administration (systemic/nasal).
"
Primary mouse evidence supports the model's developmental, vocalization, gait, motor, social-memory, and object-memory phenotypes.
Heterozygous Adnp p.Tyr718* knock-in (human p.Tyr719* ortholog) Mouse (Mus musculus)
Knock-in
This recurrent-allele ortholog expresses mutant and wild-type RNA, but the predicted truncated protein was not visualized. Its phenotypes therefore do not by themselves resolve loss-of-function versus toxic-mutant action.
Species
Mouse (Mus musculus)
Genotype
Heterozygous Adnp p.Tyr718* knock-in (human p.Tyr719* ortholog)
Genes
Show evidence (3 references)
"A truncated protein product in the mutant animals was predicted but not visualized.
"
Failure to visualize the predicted protein preserves the central allele-mechanism uncertainty.
"Phenotypically, Tyr mice had delayed development and with sex-dependent gait defect and syntax abnormalities. Grooming duration and nociception threshold autistic traits were significantly affected in males. Anatomically, dendritic spine densities were reduced an morphologies altered.
"
The knock-in reproduces developmental, behavioral, motor, and spine phenotypes with sex dependence.
"Early-onset tauopathy in hippocampus and visual cortex was accentuated in males and was paralleled by impaired visual evoked potentials.
"
The allele-matched mouse review reports male-accentuated tau pathology together with impaired visual evoked potentials.
Heterozygous Adnp c.2463_2476del (p.Leu822Hisfs*6) frameshift Mouse (Mus musculus)
Knock-in
A 2026 CRISPR frameshift model was studied only in male mice. Multi-omic and behavioral results connect chromatin, Wnt, cytoskeletal, and synaptic abnormalities, but sex restriction and the engineered allele limit direct human generalization.
Species
Mouse (Mus musculus)
Genotype
Heterozygous Adnp c.2463_2476del (p.Leu822Hisfs*6) frameshift
Genes
Show evidence (1 reference)
"Our findings demonstrate a role for Adnp in chromatin regulation and Wnt signalling, coupled to aberrant expression of cytoskeletal components and synaptic dysfunction.
"
The male-mouse frameshift model supports convergence across the curated mechanism nodes.
Source YAML
click to showname: ADNP-Related Syndrome
creation_date: "2026-06-04T00:00:00Z"
synonyms:
- Helsmoortel-Van der Aa syndrome
- HVDAS
- ADNP syndrome
description: >-
ADNP-related syndrome (Helsmoortel-Van der Aa syndrome; HVDAS) is an
autosomal dominant multisystem neurodevelopmental disorder caused mainly by
heterozygous, usually de novo, protein-truncating ADNP variants. The molecular
consequence is allele dependent rather than uniformly haploinsufficient:
most recurrent last-exon variants escape nonsense-mediated decay, but mutant
protein has not been unambiguously demonstrated in patient material and the
relative contributions of functional insufficiency, dominant interference,
and toxic gain of function remain unresolved. A rare splice-acceptor deletion
with no detectable truncated protein establishes that true
haploinsufficiency can cause the syndrome. ADNP participates in chromatin
regulatory complexes and binds microtubule end-binding proteins; disruption
of these functions converges on altered neurodevelopmental transcription,
neuronal differentiation, dendritic spines, and synaptic plasticity.
Intellectual and developmental disability, marked speech and motor delay,
autistic and other behavioral features, hypotonia, characteristic facial
features, sleep and feeding problems, visual abnormalities, congenital
anomalies, and premature primary-tooth eruption form a variable clinical
spectrum. Mutation-position-dependent blood DNA-methylation episignatures
support diagnosis and variant interpretation but are biomarkers rather than
established causal mediators or severity predictors.
category: Mendelian
disease_term:
preferred_term: ADNP-related syndrome
term:
id: MONDO:0014379
label: ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
ADNP-related syndrome is autosomal dominant and is usually caused by a de
novo pathogenic variant, although transmission from an apparently
unaffected parent has rarely been reported.
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ADNP-related HVDAS is an autosomal dominant disorder. Most probands whose
parents have undergone molecular genetic testing have the disorder as the
result of a de novo ADNP pathogenic variant. In two families reported to
date, probands diagnosed with ADNP-related HVDAS inherited a pathogenic
variant from an unaffected parent.
explanation: >-
GeneReviews establishes dominant inheritance, the predominance of de novo
variants, and the rare occurrence of inherited pathogenic variants.
penetrance: UNKNOWN
expressivity: VARIABLE
parents:
- autosomal dominant syndromic intellectual disability
- autism spectrum disorder
references:
- reference: PMID:24531329
title: "A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP."
- reference: PMID:27054228
title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
tags:
- GeneReviews
- reference: PMID:28221363
title: "Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children."
- reference: PMID:29724491
title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
- reference: PMID:30106381
title: "Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome."
- reference: PMID:32758449
title: "Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype."
- reference: PMID:33453943
title: "Activity-dependent neuroprotective protein (ADNP)-end-binding protein (EB) interactions regulate microtubule dynamics toward protection against tauopathy."
- reference: PMID:36119806
title: "An open-label study evaluating the safety, behavioral, and electrophysiological outcomes of low-dose ketamine in children with ADNP syndrome."
- reference: PMID:36945042
title: "Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism."
- reference: PMID:37365244
title: "Adnp-mutant mice with cognitive inflexibility, CaMKIIα hyperactivity, and synaptic plasticity deficits."
- reference: PMID:37759476
title: "NAP (Davunetide): The Neuroprotective ADNP Drug Candidate Penetrates Cell Nuclei Explaining Pleiotropic Mechanisms."
- reference: PMID:38424297
title: "Loss-of-function of activity-dependent neuroprotective protein (ADNP) by a splice-acceptor site mutation causes Helsmoortel-Van der Aa syndrome."
- reference: PMID:39054328
title: "Transient peripheral blood transcriptomic response to ketamine treatment in children with ADNP syndrome."
- reference: PMID:41594725
title: "A Systematic Review Illustrates the Expanding Clinical and Molecular Landscape of Helsmoortel-Van der Aa Syndrome."
- reference: PMID:41943166
title: "ADNP missense variant p.C687R disrupts chromatin regulation and GABAergic differentiation in Helsmoortel-Van der Aa syndrome."
- reference: PMID:42208149
title: "An Adnp frameshift variant disrupts Wnt signalling inducing chromatocytoskeletal defects and autism-related behaviour in male mice."
- reference: clinicaltrials:NCT03718936
title: "The Seaver Autism Center for Research and Treatment - Assessment Core"
- reference: clinicaltrials:NCT04388774
title: "A Phase 2A Open-Label Study Evaluating the Safety and Efficacy of Low-Dose Ketamine in Children With ADNP Syndrome"
progression:
- phase: Infancy and early-childhood neurodevelopment
age_range: Infancy through early childhood
notes: >
Hypotonia and global developmental delay are recognized early, followed by marked speech and motor delay. The disorder is developmental and multisystemic; the available evidence does not establish a uniformly progressive or neurodegenerative human course.
evidence:
- reference: PMID:27054228
reference_title: ADNP-Related Helsmoortel-Van der Aa Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
is characterized by hypotonia, speech and motor delay, mild-to-severe intellectual disability, and characteristic facial features
explanation: >
GeneReviews defines the early neurodevelopmental presentation without describing a universal progressive course.
- phase: Variable later developmental course
age_range: Childhood through adulthood
notes: >
Apparent loss of previously acquired abilities has been reported in a subset. The denominator and trajectories are insufficient to classify ADNP-related syndrome as globally regressive; long-term longitudinal follow-up remains a major evidence gap.
evidence:
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Apparent loss of acquired abilities was reported in 12 children for skills such as speaking, counting, riding a bicycle, or being toilet trained.
explanation: >
The cohort documents reported skill loss in 12 children but does not supply a feature-specific assessed denominator or prove a progressive disease course.
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
The main limitation of our study is the relatively young age of our study cohort. Longterm follow-up studies are necessary to define the developmental path of individuals with a mutation in ADNP.
explanation: >
The authors explicitly identify long-term natural history as unresolved.
mechanistic_hypotheses:
- hypothesis_group_id: nmd_escape_truncation_branch
hypothesis_label: NMD-Escaping Truncation Branch
status: ALTERNATIVE
description: >-
Most pathogenic last-exon truncating variants escape nonsense-mediated
decay and produce mutant transcript. Whether their downstream effect is
functional insufficiency, dominant interference, toxic gain of function,
or a mixture remains unresolved because mutant protein has not been
unambiguously demonstrated in patient material.
evidence:
- reference: PMID:36945042
reference_title: "Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
as many mutations cluster in the fifth and last exon and escape from NMD
has been demonstrated, the majority of patients might still produce
protein. Thought it needs to be mentioned that mutated protein has never
been unambiguously demonstrated in patients, an additional gain of toxic
function of the mutant protein, if present, could also be envisaged
explanation: >-
This review defines the unresolved mechanism of the common NMD-escaping
truncation branch and explicitly separates mutant transcript from proof
of mutant protein.
- hypothesis_group_id: allele_specific_haploinsufficiency_branch
hypothesis_label: Allele-Specific ADNP Haploinsufficiency Branch
status: CANONICAL
description: >-
True ADNP haploinsufficiency is experimentally confirmed for a non-coding
splice-acceptor deletion that causes exon skipping and no detectable
truncated protein. This branch is allele specific and is not generalized
to the common last-exon truncating variants.
evidence:
- reference: PMID:38424297
reference_title: "Loss-of-function of activity-dependent neuroprotective protein (ADNP) by a splice-acceptor site mutation causes Helsmoortel-Van der Aa syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
An N-terminal truncated protein could not be detected in transfection
experiments with a mutant expression vector in HEK293T cells, strongly
suggesting this is a first confirmed diagnosis exclusively due to
haploinsufficiency of the ADNP gene.
explanation: >-
The splice allele provides direct experimental support for an
allele-specific true-null branch without establishing that mechanism for
all pathogenic ADNP variants.
pathophysiology:
- name: Heterozygous ADNP Pathogenic Variation
description: >-
The initiating lesion is a heterozygous pathogenic ADNP variant. Most
established alleles are protein-truncating and usually de novo, but their
molecular consequences differ by position and RNA processing. This root
therefore represents pathogenic variation without presupposing uniform
haploinsufficiency.
mechanism_confidence: ESTABLISHED
genes:
- preferred_term: ADNP
term:
id: hgnc:15766
label: ADNP
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We found 46 unique mutations on the DNA level, of which 25 were nonsense
and 21 frameshift (Supplemental Table S2). All but three mutations were
located in the fifth and last exon of the ADNP gene and were predicted to
escape nonsense-mediated decay.
explanation: >-
The 78-person cohort establishes the predominance and position of
truncating variants while showing why a uniform null model is unsafe.
downstream:
- target: NMD-Escaping Mutant ADNP Transcripts
causal_link_type: DIRECT
hypothesis_groups:
- nmd_escape_truncation_branch
evidence:
- reference: PMID:24531329
reference_title: "A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Indeed, the mutations were present in the cDNA generated from
lymphoblastoid cell lines of patients 1, 2, 6 and 8.
explanation: >-
Patient-derived lymphoblastoid-cell cDNA directly demonstrates mutant
transcript escape from NMD for the tested last-exon alleles.
- target: Allele-Specific ADNP Haploinsufficiency
causal_link_type: DIRECT
hypothesis_groups:
- allele_specific_haploinsufficiency_branch
evidence:
- reference: PMID:38424297
reference_title: "Loss-of-function of activity-dependent neuroprotective protein (ADNP) by a splice-acceptor site mutation causes Helsmoortel-Van der Aa syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
An N-terminal truncated protein could not be detected in transfection
experiments with a mutant expression vector in HEK293T cells, strongly
suggesting this is a first confirmed diagnosis exclusively due to
haploinsufficiency of the ADNP gene.
explanation: >-
The splice-acceptor allele produces an experimentally supported
true-null branch.
- target: Hypotonia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Seventy-eight percent of the children had hypotonia, while hypertonia was present in 3 children."
explanation: The cohort links pathogenic ADNP variation to hypotonia; the intervening mechanism is unresolved.
- target: Characteristic Facial Features
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "characteristic facial features (prominent forehead, high anterior hairline, wide and depressed nasal bridge, and short nose with full, upturned nasal tip)"
explanation: GeneReviews supports the recognizable facial phenotype, without establishing an intervening molecular path.
- target: Sleep Disturbance
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Sleep problems were present in 65.2%."
explanation: The clinical cohort supports sleep disturbance as a recurrent endpoint.
- target: Feeding Difficulties
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Eighty-three percent of the individuals had feeding or gastrointestinal problems, mainly gastroesophageal reflux, frequent vomiting, and constipation (Figure 3D)."
explanation: The combined feeding-or-gastrointestinal measure supports a feeding endpoint but not an independent 83% feeding-only frequency.
- target: Hypermetropia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In 73.6% of the individuals, visual problems, especially hypermetropia (40.3%) and strabismus (49.2%), but also myopia and astigmatism, were present (Figure 3E)."
explanation: The cohort directly reports hypermetropia among ADNP-associated visual endpoints.
- target: Strabismus
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In 73.6% of the individuals, visual problems, especially hypermetropia (40.3%) and strabismus (49.2%), but also myopia and astigmatism, were present (Figure 3E)."
explanation: The cohort directly reports strabismus among ADNP-associated visual endpoints.
- target: Recurrent Infections
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Fifty-one percent of the individuals had recurrent infections."
explanation: The cohort supports recurrent infections while leaving the molecular bridge unresolved.
- target: Musculoskeletal Anomalies
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Musculoskeletal problems were common (Figure 3F)."
explanation: The cohort supports a multisystem musculoskeletal endpoint without assigning it to an unproven neuronal mechanism.
- target: Short Stature
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Twenty-three percent of the individuals had short stature (height < −2 SD, range 2–23 years old) (Supplemental Table S3, Supplemental Figure S1E)."
explanation: The cohort directly associates pathogenic ADNP variation with short stature.
- target: Cardiac Anomalies
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Thirty-eight percent had one or more congenital cardiac defects."
explanation: The cohort supports congenital cardiac anomalies while the developmental bridge remains unknown.
- target: Seizures
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Sixteen percent had seizures, including absence seizures, focal seizures with reduced awareness, epilepsy with continuous spike and waves during slow-wave sleep, or unclassified seizures."
explanation: The cohort directly supports a seizure endpoint.
- target: Advanced Tooth Eruption
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:28221363
reference_title: "Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The parents of 44/54 ADNP-mutated children reported an almost full erupted dentition by 1 year of age, including molars and only 10 of the children had teeth within the normal developmental time range."
explanation: A caregiver-reported cohort supports premature primary dentition as an ADNP-associated endpoint.
- target: Gastrointestinal Problems
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Eighty-three percent of the individuals had feeding or gastrointestinal problems, mainly gastroesophageal reflux, frequent vomiting, and constipation (Figure 3D)."
explanation: The combined measure supports gastrointestinal involvement without assigning an independent 83% gastrointestinal-only frequency.
- target: Cerebral Visual Impairment
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Forty-one percent of the individuals had a diagnosis of cerebral visual impairment."
explanation: The cohort directly supports cerebral visual impairment.
- target: Urinary Tract Anomalies
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Six individuals (12.5%) were born with renal anomalies (narrow ureters, bilateral vesicoureteral reflux that was surgically repaired) (Table 1)."
explanation: The cohort supports congenital urinary-system involvement.
- target: Hearing Loss
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Some individuals (11.7%) were diagnosed with mild hearing loss in childhood."
explanation: The cohort directly supports childhood hearing loss.
- name: NMD-Escaping Mutant ADNP Transcripts
description: >-
Common last-exon truncating alleles are transcribed and escape
nonsense-mediated decay. Mutant RNA is established, but the abundance,
stability, localization, and action of any corresponding truncated protein
in patient tissues remain unresolved.
mechanism_confidence: ESTABLISHED
evidence:
- reference: PMID:24531329
reference_title: "A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
demonstrating that the excessADNPmRNA in patients corresponds to the mRNA
transcribed from the mutant allele.
explanation: >-
Allele-aware expression in patient lymphoblastoid cells demonstrates
production of mutant transcript.
downstream:
- target: ADNP Chromatin-Complex Dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
hypothesis_groups:
- nmd_escape_truncation_branch
evidence:
- reference: PMID:36945042
reference_title: "Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
mutant mRNA has been detected in patient-derived sample materials and
mouse models
explanation: >-
Mutant RNA is established, but absence of patient-protein evidence makes
its route to chromatin dysfunction provisional.
- target: ADNP-EB Microtubule Dynamics Dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
hypothesis_groups:
- nmd_escape_truncation_branch
evidence:
- reference: PMID:37759476
reference_title: "NAP (Davunetide): The Neuroprotective ADNP Drug Candidate Penetrates Cell Nuclei Explaining Pleiotropic Mechanisms."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "reduced microtubule content was observed in the ADNP-mutated cell lines. In parallel, disrupting microtubules by zinc or nocodazole intoxication mimicked ADNP mutation phenotypes"
explanation: >-
Engineered ADNP-mutant neuronal cell lines constrain a microtubule route,
but do not establish the intervening mutant-protein mechanism in humans.
- name: Allele-Specific ADNP Haploinsufficiency
description: >-
A splice-acceptor deletion that causes exon 4 skipping and no detectable
truncated protein establishes a true dosage-loss mechanism for that allele.
The node is deliberately allele specific.
mechanism_confidence: ESTABLISHED
evidence:
- reference: PMID:38424297
reference_title: "Loss-of-function of activity-dependent neuroprotective protein (ADNP) by a splice-acceptor site mutation causes Helsmoortel-Van der Aa syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
An N-terminal truncated protein could not be detected in transfection
experiments with a mutant expression vector in HEK293T cells, strongly
suggesting this is a first confirmed diagnosis exclusively due to
haploinsufficiency of the ADNP gene.
explanation: >-
The functional assay directly supports true loss of ADNP dosage for this
splice allele.
downstream:
- target: ADNP Chromatin-Complex Dysfunction
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- reduced full-length ADNP availability for HP1/BRG1 and ChAHP complexes
hypothesis_groups:
- allele_specific_haploinsufficiency_branch
evidence:
- reference: PMID:36945042
reference_title: "Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism."
supports: SUPPORT
evidence_source: OTHER
snippet: "The protein is associated with the pericentromeric protein HP1, the SWI/SNF core complex protein BRG1, and other members of this chromatin remodeling complex and, in murine stem cells, with the chromodomain helicase CHD4 in a ChAHP complex."
explanation: >-
Reduced full-length ADNP availability is expected to impair established
ADNP-containing chromatin complexes.
- target: ADNP-EB Microtubule Dynamics Dysfunction
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- reduced ADNP-end-binding protein interaction capacity
hypothesis_groups:
- allele_specific_haploinsufficiency_branch
evidence:
- reference: PMID:33453943
reference_title: "Activity-dependent neuroprotective protein (ADNP)-end-binding protein (EB) interactions regulate microtubule dynamics toward protection against tauopathy."
supports: SUPPORT
evidence_source: OTHER
snippet: "ADNP and its derived peptides, NAP and SKIP, directly interact with end-binding proteins (EBs), which decorate plus-tips of the growing axonal cytoskeleton-microtubules (MTs)."
explanation: >-
Loss of full-length ADNP reduces capacity for the established ADNP-EB
interaction that regulates microtubule plus ends.
- name: ADNP Chromatin-Complex Dysfunction
description: >-
ADNP participates in HP1/BRG1-associated chromatin regulation and the
CHD4-containing ChAHP complex. Pathogenic variation can alter ADNP abundance,
localization, chromatin association, or binding specificity, but the exact
perturbation is allele dependent. A 2026 male-mouse frameshift model showed
reduced chromatin association, increased accessibility, and Wnt-pathway
downregulation; these model findings are not treated as direct human proof.
mechanism_confidence: PROVISIONAL
cell_types:
- preferred_term: Neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: Chromatin remodeling
term:
id: GO:0006338
label: chromatin remodeling
modifier: ABNORMAL
- preferred_term: Regulation of transcription by RNA polymerase II
term:
id: GO:0006357
label: regulation of transcription by RNA polymerase II
modifier: ABNORMAL
evidence:
- reference: PMID:36945042
reference_title: "Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism."
supports: SUPPORT
evidence_source: OTHER
snippet: "The protein is associated with the pericentromeric protein HP1, the SWI/SNF core complex protein BRG1, and other members of this chromatin remodeling complex and, in murine stem cells, with the chromodomain helicase CHD4 in a ChAHP complex."
explanation: The review synthesizes ADNP membership in multiple chromatin-regulatory complexes.
- reference: PMID:42208149
reference_title: "An Adnp frameshift variant disrupts Wnt signalling inducing chromatocytoskeletal defects and autism-related behaviour in male mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Introduction of the 14-base pair deletion reduced cellular Adnp levels in the brain (p = 0.0008) and decreased its chromatin association (p = 0.001), parallelled by a genome-wide increase in chromatin accessibility."
explanation: >-
A male-mouse frameshift model directly links an Adnp allele to altered
chromatin association and accessibility.
downstream:
- target: Neurodevelopmental Transcription and Differentiation Dysregulation
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:42208149
reference_title: "An Adnp frameshift variant disrupts Wnt signalling inducing chromatocytoskeletal defects and autism-related behaviour in male mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Transcriptome sequencing of the frontal cortex, an essential region involved in executive functions, cognition, and motor control, revealed predominant downregulation of the Wnt signalling pathway (p = 0.03)."
explanation: >-
The model connects altered chromatin state to a dysregulated
neurodevelopmental transcriptional program.
- reference: PMID:41943166
reference_title: "ADNP missense variant p.C687R disrupts chromatin regulation and GABAergic differentiation in Helsmoortel-Van der Aa syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In patient-derived iPSCs, a distinct set of neurodevelopmental genes, including key regulators of GABAergic differentiation, showed increased bivalent histone marks (H3K4me3/H3K27me3)."
explanation: >-
One p.C687R patient-derived line supports allele-specific coupling of
chromatin marks to differentiation programs but is not broadly
generalizable.
- name: ADNP-EB Microtubule Dynamics Dysfunction
description: >-
ADNP and its NAP motif interact with end-binding proteins at growing
microtubule plus ends. ADNP-mutant cell models show reduced microtubule
content and phenocopy after pharmacologic microtubule disruption, supporting
a microtubule branch while leaving allele-specific human intermediates
incompletely resolved.
mechanism_confidence: PROVISIONAL
cell_types:
- preferred_term: Neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: Microtubule cytoskeleton organization
term:
id: GO:0000226
label: microtubule cytoskeleton organization
modifier: ABNORMAL
evidence:
- reference: PMID:33453943
reference_title: "Activity-dependent neuroprotective protein (ADNP)-end-binding protein (EB) interactions regulate microtubule dynamics toward protection against tauopathy."
supports: SUPPORT
evidence_source: OTHER
snippet: "ADNP and its derived peptides, NAP and SKIP, directly interact with end-binding proteins (EBs), which decorate plus-tips of the growing axonal cytoskeleton-microtubules (MTs)."
explanation: The review synthesizes the direct ADNP/NAP-to-EB microtubule interaction.
- reference: PMID:37759476
reference_title: "NAP (Davunetide): The Neuroprotective ADNP Drug Candidate Penetrates Cell Nuclei Explaining Pleiotropic Mechanisms."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "reduced microtubule content was observed in the ADNP-mutated cell lines. In parallel, disrupting microtubules by zinc or nocodazole intoxication mimicked ADNP mutation phenotypes"
explanation: Engineered mutant neuronal cells support microtubule dysfunction as a convergent cellular phenotype.
downstream:
- target: Dendritic Spine and Synaptic Plasticity Dysfunction
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- altered EB1/EB3 microtubule plus-end tracking
- reduced microtubule content and dendritic spine formation
evidence:
- reference: PMID:30106381
reference_title: "Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "ADNP includes a SIP motif embedded in the ADNP-derived snippet drug candidate NAP (NAPVSIPQ, also known as CP201), which binds to microtubule end-binding protein 3, essential for dendritic spine formation."
explanation: >-
Mouse-model work connects the NAP/EB3 microtubule interaction to
dendritic spine formation.
- reference: PMID:42208149
reference_title: "An Adnp frameshift variant disrupts Wnt signalling inducing chromatocytoskeletal defects and autism-related behaviour in male mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Cytoskeletal abnormalities were further coupled to synaptic plasticity deficits, dysregulation of transcription factors implicated in lineage specification, and alterations in neuronal cell numbers."
explanation: A male-mouse frameshift model independently couples cytoskeletal and synaptic defects.
- name: Neurodevelopmental Transcription and Differentiation Dysregulation
description: >-
Altered ADNP-dependent chromatin regulation perturbs transcriptional programs
for nervous-system development and neuronal differentiation. Evidence spans
an allele-specific human iPSC study and mouse multi-omics; Wnt dysregulation
is currently model-qualified rather than an established universal human
pathway.
mechanism_confidence: PROVISIONAL
cell_types:
- preferred_term: Neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: Nervous system development
term:
id: GO:0007399
label: nervous system development
modifier: ABNORMAL
- preferred_term: Neuron differentiation
term:
id: GO:0030182
label: neuron differentiation
modifier: ABNORMAL
- preferred_term: Wnt signaling pathway (male-mouse model)
term:
id: GO:0016055
label: Wnt signaling pathway
modifier: ABNORMAL
evidence:
- reference: PMID:42208149
reference_title: "An Adnp frameshift variant disrupts Wnt signalling inducing chromatocytoskeletal defects and autism-related behaviour in male mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Our findings demonstrate a role for Adnp in chromatin regulation and Wnt signalling, coupled to aberrant expression of cytoskeletal components and synaptic dysfunction."
explanation: The engineered male-mouse model supports convergent transcriptional and Wnt dysregulation.
- reference: PMID:41943166
reference_title: "ADNP missense variant p.C687R disrupts chromatin regulation and GABAergic differentiation in Helsmoortel-Van der Aa syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "This study is based on a single patient-derived line in combination with complementary experimental models. In the heterozygous endogenous context, distinguishing increased functional activity from dosage-related effects requires further investigation."
explanation: >-
The p.C687R iPSC study informs an emerging allele-specific differentiation
mechanism but explicitly limits generalization.
downstream:
- target: Intellectual Disability
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Fifty-two percent of the individuals in this cohort presented with severe ID at the age of assessment, 36% had a moderate disability, and 12% had a mild disability."
explanation: All assessed cohort members had intellectual disability, but the molecular bridge remains inferential.
- target: Autistic Behavior
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Ninety-three percent of the individuals presented with autistic features (Figure 3B)."
explanation: The cohort strongly links ADNP variation to autistic features without resolving all intermediates.
- target: Speech Delay
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Another key feature was speech delay, which presented in 98.6% of individuals."
explanation: Speech delay is a near-universal neurodevelopmental endpoint.
- target: Motor Delay
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "observed in 86.8% of the children, with an average age of 2 years 5.5 months"
explanation: Delayed walking supports a very frequent motor-development endpoint.
- target: Structural Brain Abnormalities
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In this cohort, magnetic resonance imaging of the brain was performed in 75.6% of the individuals. Fifty-six percent of them appeared to have cerebral abnormalities"
explanation: Abnormal MRI findings occurred in 56% of the imaged subgroup, not 56% of the full cohort.
- target: Global Developmental Delay
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Developmental delay was present in all individuals, with motor delay being one of the key features."
explanation: Developmental delay was obligate in the 78-person cohort.
- name: Dendritic Spine and Synaptic Plasticity Dysfunction
description: >-
Adnp-deficient and frameshift mouse models show reduced dendritic spine
density, altered synaptic gene expression, disrupted Camk2a/Dbn1
interactions, abnormal CaMKII phosphorylation, and excessive long-term
potentiation. These findings support a synaptic branch but remain
model-derived rather than direct measurements in affected human brain.
mechanism_confidence: PROVISIONAL
cell_types:
- preferred_term: Neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: Regulation of synaptic plasticity
term:
id: GO:0048167
label: regulation of synaptic plasticity
modifier: ABNORMAL
- preferred_term: Dendritic spine development
term:
id: GO:0060996
label: dendritic spine development
modifier: DECREASED
evidence:
- reference: PMID:30106381
reference_title: "Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We discovered that Adnp deficiency reduced dendritic spine density and altered synaptic gene expression, both of which were partly ameliorated by NAP treatment."
explanation: Adnp-haploinsufficient mice directly support spine and synaptic-expression abnormalities.
- reference: PMID:37365244
reference_title: "Adnp-mutant mice with cognitive inflexibility, CaMKIIα hyperactivity, and synaptic plasticity deficits."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The adult Adnp-HT hippocampus shows hyperphosphorylated CaMKIIα and its substrates, including SynGAP1, and excessive long-term potentiation that is normalized by CaMKIIα inhibition."
explanation: A mouse model links Adnp deficiency to CaMKII dysregulation and altered long-term potentiation.
- reference: PMID:42208149
reference_title: "An Adnp frameshift variant disrupts Wnt signalling inducing chromatocytoskeletal defects and autism-related behaviour in male mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Adnp directly regulated mechanisms of synaptic plasticity through interaction with Camk2a and Dbn1. In heterozygous mice, these protein interactions were disrupted, resulting in aberrant Camk2a phosphorylation at synapses (p = 0.012)."
explanation: The 2026 male-mouse frameshift model independently supports disrupted synaptic interactions.
downstream:
- target: Intellectual Disability
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:30106381
reference_title: "Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Adnp+/-mice further exhibited global developmental delays, vocalization impediments, gait and motor dysfunctions, and social and object memory impairments, all of which were partially reversed by daily NAP administration (systemic/nasal)."
explanation: Mouse cognitive phenotypes support, but do not prove, the synaptic route to human intellectual disability.
- target: Autistic Behavior
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:42208149
reference_title: "An Adnp frameshift variant disrupts Wnt signalling inducing chromatocytoskeletal defects and autism-related behaviour in male mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Behavioural testing confirmed cognitive impairment in the Morris water maze (p < 0.05), increased anxiety-like behaviour in the elevated plus maze (p = 0.0035), repetitive behaviour in the marble burying assay (p = 0.045), and impaired social interactions (p < 0.05)."
explanation: Male-mouse behavior supports a synaptic contribution but cannot establish the human causal bridge alone.
- target: Behavioral Problems
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Although parents report that 88% of the children were overall happy and friendly, behavioral problems were reported in 77.6% of them."
explanation: Human cohort evidence supports behavioral problems as a frequent endpoint while intermediates remain uncertain.
phenotypes:
- category: Neurologic
name: Intellectual Disability
description: >
Mild-to-severe intellectual disability affected all individuals in the main 78-person cohort, with severity ranging from mild to severe.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
frequency: OBLIGATE
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "is characterized by hypotonia, speech and motor delay, mild-to-severe intellectual disability, and characteristic facial features"
explanation: >
GeneReviews lists mild-to-severe intellectual disability as a defining characteristic.
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Fifty-two percent of the individuals in this cohort presented with severe ID at the age of assessment, 36% had a moderate disability, and 12% had a mild disability.
explanation: The severity categories sum to the full cohort, supporting intellectual disability as obligate in this clinically ascertained series.
- category: Psychiatric
name: Autistic Behavior
description: >
Autistic features were reported in 93% of the main cohort; a formal ASD diagnosis was recorded in a smaller subset.
phenotype_term:
preferred_term: Autistic behavior
term:
id: HP:0000729
label: Autistic behavior
frequency: VERY_FREQUENT
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Features of autism spectrum disorder are common (stereotypic behavior, impaired social interaction)."
explanation: >
GeneReviews documents autism spectrum disorder features as common.
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Ninety-three percent of the individuals presented with autistic features (Figure 3B).
explanation: The 78-person cohort supports a very-frequent frequency band for broad autistic features.
- category: Neurologic
name: Hypotonia
description: >
Hypotonia was reported in 78% of children in the main cohort.
phenotype_term:
preferred_term: Hypotonia
term:
id: HP:0001252
label: Hypotonia
frequency: FREQUENT
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "is characterized by hypotonia, speech and motor delay, mild-to-severe intellectual disability, and characteristic facial features"
explanation: >
GeneReviews lists hypotonia as a characteristic feature.
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Seventy-eight percent of the children had hypotonia, while hypertonia was present in 3 children.
explanation: The observed 78% lies in the frequent range and applies to the assessed children.
- category: Neurodevelopmental
name: Speech Delay
description: >
Severe delay in speech and language development is a near-universal feature and is distinct from the separately curated motor-delay phenotype.
phenotype_term:
preferred_term: Delayed speech and language development
term:
id: HP:0000750
label: Delayed speech and language development
frequency: VERY_FREQUENT
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "is characterized by hypotonia, speech and motor delay, mild-to-severe intellectual disability, and characteristic facial features"
explanation: >
GeneReviews lists speech and motor delay as a defining characteristic.
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Another key feature was speech delay, which presented in 98.6% of individuals.
explanation: The cohort supports speech delay as very frequent.
- category: Neurodevelopmental
name: Motor Delay
description: >
Motor developmental delay is a near-universal defining feature; 86.8% of assessed children walked independently after 18 months.
phenotype_term:
preferred_term: Motor delay
term:
id: HP:0001270
label: Motor delay
onset:
onset_category: INFANTILE
frequency: VERY_FREQUENT
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "is characterized by hypotonia, speech and motor delay, mild-to-severe intellectual disability, and characteristic facial features"
explanation: >
GeneReviews lists motor delay as a defining characteristic of the syndrome.
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay"
explanation: >
The Van Dijck cohort describes severe speech and motor delay as part of the
distinctive clinical combination.
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: observed in 86.8% of the children, with an average age of 2 years 5.5 months
explanation: Delayed independent walking supports a very-frequent motor-delay classification in assessed children.
- category: Craniofacial
name: Characteristic Facial Features
description: >
Characteristic facial features include a prominent forehead, high anterior hairline,
wide and depressed nasal bridge, and a short nose with full, upturned nasal tip.
phenotype_term:
preferred_term: Characteristic facial features
term:
id: HP:0001999
label: Abnormal facial shape
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "characteristic facial features (prominent forehead, high anterior hairline, wide and depressed nasal bridge, and short nose with full, upturned nasal tip)"
explanation: >
GeneReviews describes the recognizable facial gestalt of the syndrome.
- category: Behavioral
name: Sleep Disturbance
description: >
Sleep problems were reported in 65.2% of the main cohort.
phenotype_term:
preferred_term: Sleep disturbance
term:
id: HP:0002360
label: Sleep disturbance
frequency: FREQUENT
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Other common findings include additional behavioral problems, sleep disturbance, structural brain abnormalities, feeding issues, gastrointestinal problems"
explanation: >
GeneReviews lists sleep disturbance among common findings.
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Sleep problems were present in 65.2%.
explanation: The cohort supports sleep disturbance in the frequent range.
- category: Neurologic
name: Structural Brain Abnormalities
description: >
Brain MRI was obtained in 75.6% of the main cohort; 56% of that imaged subgroup had cerebral abnormalities. This is a conditional imaging denominator, not 56% of the full cohort.
phenotype_term:
preferred_term: Abnormal brain morphology
term:
id: HP:0012443
label: Abnormal brain morphology
frequency: FREQUENT
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Other common findings include additional behavioral problems, sleep disturbance, structural brain abnormalities, feeding issues, gastrointestinal problems"
explanation: >
GeneReviews lists structural brain abnormalities among common findings.
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In this cohort, magnetic resonance imaging of the brain was performed in 75.6% of the individuals. Fifty-six percent of them appeared to have cerebral abnormalities, including atypical white matter lesions, delayed myelination, cortical dysplasia or atrophy, perinatal hypoxic ischemic encephalopathy, hydrocephalus, and hippocampal hypoplasticity (Figure 3C).
explanation: The 56% frequency applies only to the imaged subgroup; perinatal hypoxic-ischemic injury is not treated as a primary ADNP mechanism.
- category: Gastrointestinal
name: Feeding Difficulties
description: >
Feeding issues are common, particularly in infancy.
phenotype_term:
preferred_term: Feeding difficulties
term:
id: HP:0011968
label: Feeding difficulties
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Other common findings include additional behavioral problems, sleep disturbance, structural brain abnormalities, feeding issues, gastrointestinal problems"
explanation: >
GeneReviews lists feeding issues among common findings.
- category: Ophthalmologic
name: Hypermetropia
description: >
Hypermetropia was reported in 40.3% of the main cohort.
phenotype_term:
preferred_term: Hypermetropia
term:
id: HP:0000540
label: Hypermetropia
frequency: FREQUENT
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "visual dysfunction (hypermetropia, strabismus, cortical visual impairment)"
explanation: >
GeneReviews lists hypermetropia among common visual findings.
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In 73.6% of the individuals, visual problems, especially hypermetropia (40.3%) and strabismus (49.2%), but also myopia and astigmatism, were present (Figure 3E).
explanation: The feature-specific 40.3% estimate supports a frequent classification.
- category: Ophthalmologic
name: Strabismus
description: >
Strabismus was reported in 49.2% of the main cohort.
phenotype_term:
preferred_term: Strabismus
term:
id: HP:0000486
label: Strabismus
frequency: FREQUENT
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "visual dysfunction (hypermetropia, strabismus, cortical visual impairment)"
explanation: >
GeneReviews lists strabismus among common visual findings.
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In 73.6% of the individuals, visual problems, especially hypermetropia (40.3%) and strabismus (49.2%), but also myopia and astigmatism, were present (Figure 3E).
explanation: The feature-specific 49.2% estimate supports a frequent classification.
- category: Immunologic
name: Recurrent Infections
description: >
Recurrent infections were reported in 51% of the main cohort.
phenotype_term:
preferred_term: Recurrent infections
term:
id: HP:0002719
label: Recurrent infections
frequency: FREQUENT
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "musculoskeletal anomalies, recurrent infections, endocrine issues including short stature and thyroid and/or growth hormone deficiencies"
explanation: >
GeneReviews lists recurrent infections among common comorbidities.
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Fifty-one percent of the individuals had recurrent infections.
explanation: The cohort supports recurrent infections in the frequent range.
- category: Musculoskeletal
name: Musculoskeletal Anomalies
description: >
Musculoskeletal abnormalities were frequent in the main clinical cohort and included joint hypermobility, scoliosis, and hip problems.
phenotype_term:
preferred_term: Abnormality of the musculoskeletal system
term:
id: HP:0033127
label: Abnormality of the musculoskeletal system
frequency: FREQUENT
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "musculoskeletal anomalies, recurrent infections, endocrine issues including short stature and thyroid and/or growth hormone deficiencies"
explanation: >
GeneReviews lists musculoskeletal anomalies among common findings.
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Musculoskeletal problems were common (Figure 3F).
explanation: The cohort's clinical synthesis places musculoskeletal abnormalities among frequent comorbidities.
- category: Endocrine
name: Short Stature
description: >
Short stature was reported in 23% of the main cohort.
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
frequency: OCCASIONAL
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "endocrine issues including short stature and thyroid and/or growth hormone deficiencies"
explanation: >
GeneReviews lists short stature among endocrine findings.
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Twenty-three percent of the individuals had short stature (height < −2 SD, range 2–23 years old) (Supplemental Table S3, Supplemental Figure S1E).
explanation: The 23% estimate supports an occasional classification.
- category: Cardiovascular
name: Cardiac Anomalies
description: >
One or more congenital cardiac defects were reported in 38% of the main cohort.
phenotype_term:
preferred_term: Abnormal heart morphology
term:
id: HP:0001627
label: Abnormal heart morphology
frequency: FREQUENT
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "endocrine and cardiac findings, hearing loss, seizures, and urinary tract anomalies"
explanation: >
GeneReviews lists cardiac findings among common features.
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities."
explanation: >
The 78-individual cohort study lists congenital heart defects among common comorbidities.
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Thirty-eight percent had one or more congenital cardiac defects.
explanation: The 38% estimate supports a frequent classification.
- category: Neurologic
name: Seizures
description: >
Seizures were reported in 16% of the main cohort.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
frequency: OCCASIONAL
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities."
explanation: >
The cohort study lists epilepsy among common comorbidities.
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Sixteen percent had seizures, including absence seizures, focal seizures with reduced awareness, epilepsy with continuous spike and waves during slow-wave sleep, or unclassified seizures.
explanation: The 16% estimate supports an occasional classification.
- category: Dental
name: Advanced Tooth Eruption
description: >
Early eruption of the primary (deciduous) teeth is a recognizable, distinctive feature
of the syndrome reported in the defining clinical cohort.
phenotype_term:
preferred_term: Premature primary tooth eruption
term:
id: HP:0006288
label: Advanced eruption of teeth
frequency: VERY_FREQUENT
evidence:
- reference: PMID:28221363
reference_title: "Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we discovered premature tooth eruption as a potential early diagnostic biomarker for ADNP mutation. The parents of 44/54 ADNP-mutated children reported an almost full erupted dentition by 1 year of age, including molars"
explanation: >
Caregivers reported premature primary dentition in 44/54 (81.5%) children in this selected cohort, supporting a potential early diagnostic clue rather than a standalone biomarker.
- category: Neurodevelopmental
name: Global Developmental Delay
description: >
Developmental delay was present in all individuals in the main cohort; global delay with speech and motor dysfunction is a core presentation.
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
onset:
onset_category: INFANTILE
frequency: OBLIGATE
evidence:
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Developmental delay was present in all individuals, with motor delay being one of the key features.
explanation: The main cohort supports developmental delay as obligate, although individual developmental domains vary.
- category: Behavioral
name: Behavioral Problems
description: >
Behavioral problems were caregiver-reported in 77.6% of children in the main cohort.
phenotype_term:
preferred_term: Behavioral problems
term:
id: HP:0000708
label: Atypical behavior
frequency: FREQUENT
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities."
explanation: >
The 78-individual cohort study lists behavioral problems among common comorbidities.
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Although parents report that 88% of the children were overall happy and friendly, behavioral problems were reported in 77.6% of them.
explanation: The caregiver-reported 77.6% estimate supports a frequent classification.
- category: Gastrointestinal
name: Gastrointestinal Problems
description: >
Gastrointestinal problems are a common comorbidity in ADNP syndrome.
phenotype_term:
preferred_term: Gastrointestinal problems
term:
id: HP:0011024
label: Abnormality of the gastrointestinal tract
evidence:
- reference: PMID:29724491
reference_title: "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities."
explanation: >
The cohort study lists gastrointestinal problems among common comorbidities.
- category: Ophthalmologic
name: Cerebral Visual Impairment
description: >
Cerebral visual impairment was diagnosed in 41% of the main cohort.
phenotype_term:
preferred_term: Cortical visual impairment
term:
id: HP:0100704
label: Cerebral visual impairment
frequency: FREQUENT
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "visual dysfunction (hypermetropia, strabismus, cortical visual impairment)"
explanation: >
GeneReviews lists cortical visual impairment among common visual findings.
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Forty-one percent of the individuals had a diagnosis of cerebral visual impairment.
explanation: The 41% estimate supports a frequent classification.
- category: Genitourinary
name: Urinary Tract Anomalies
description: >
Congenital renal anomalies were reported in 12.5% of the main cohort; the broader urogenital category has a higher reported frequency.
phenotype_term:
preferred_term: Urinary tract anomalies
term:
id: HP:0000079
label: Abnormality of the urinary system
frequency: OCCASIONAL
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "endocrine and cardiac findings, hearing loss, seizures, and urinary tract anomalies"
explanation: >
GeneReviews lists urinary tract anomalies among the features of the syndrome.
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Six individuals (12.5%) were born with renal anomalies (narrow ureters, bilateral vesicoureteral reflux that was surgically repaired) (Table 1).
explanation: The congenital renal-anomaly estimate supports an occasional urinary-system phenotype.
- category: Otolaryngologic
name: Hearing Loss
description: >
Mild hearing loss in childhood was reported in 11.7% of the main cohort.
phenotype_term:
preferred_term: Hearing impairment
term:
id: HP:0000365
label: Hearing impairment
frequency: OCCASIONAL
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "endocrine and cardiac findings, hearing loss, seizures, and urinary tract anomalies"
explanation: >
GeneReviews lists hearing loss among common findings.
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Some individuals (11.7%) were diagnosed with mild hearing loss in childhood.
explanation: The 11.7% estimate supports an occasional classification.
imaging_findings:
- name: Abnormal Brain MRI
modality: MRI
imaging_finding_term:
preferred_term: Abnormal brain morphology
term:
id: HP:0012443
label: Abnormal brain morphology
description: >
Among individuals who underwent brain MRI, reported abnormalities included atypical white-matter lesions, delayed myelination, cortical dysplasia or atrophy, hydrocephalus, and hippocampal hypoplasia. Perinatal hypoxic-ischemic injury was also recorded in the cohort but is not modeled as a primary ADNP mechanism.
diagnostic: false
frequency: FREQUENT
evidence:
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
In this cohort, magnetic resonance imaging of the brain was performed in 75.6% of the individuals. Fifty-six percent of them appeared to have cerebral abnormalities, including atypical white matter lesions, delayed myelination, cortical dysplasia or atrophy, perinatal hypoxic ischemic encephalopathy, hydrocephalus, and hippocampal hypoplasticity (Figure 3C).
explanation: >
The 56% estimate applies to the 75.6% imaged subgroup, not the entire cohort; the findings are heterogeneous and not individually assigned that frequency.
- name: Developmental Brain-Structure Pattern on MRI
modality: MRI
imaging_finding_term:
preferred_term: Developmental brain-structure abnormalities
description: >
Detailed rereview of five MRIs identified recurrent underdevelopment or simplified gyration of the frontal lobes, thin or short corpus callosum, inferior vermis hypoplasia, abnormal opercularization, ventricular dilatation, and dilated perivascular spaces. The small selected reread set does not support feature-specific population frequencies.
diagnostic: false
evidence:
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Magnetic resonance images of 5 individuals were studied in detail. The following abnormalities were seen in multiple individuals: underdevelopment of the frontal lobes with simplified gyral pattern of the cortex and occasional hypoplasia of the bulbus olfactorius and chiasma opticum; a thin and/or short, underdeveloped corpus callosum and inferior vermis hypoplasia; abnormal, often asymmetric opercularization of the Sylvian fissure with sometimes abnormal overlying cortex; dilatation of the lateral ventricles, mostly in the frontal areas; and dilated perivascular spaces of Virchow-Robin in the cerebral white matter (Figure 6).
explanation: >
This detailed imaging pattern derives from only five selected MRIs and is therefore presented without individual finding frequencies.
diagnosis:
- name: ADNP Molecular Genetic Confirmation
description: >
Molecular diagnosis is established by identifying a heterozygous pathogenic ADNP variant in a person with a compatible neurodevelopmental and multisystem phenotype.
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: NCIT:C19770
label: Molecular Analysis
qualifiers:
- predicate:
preferred_term: has participant
term:
id: RO:0000057
label: has participant
value:
preferred_term: ADNP
term:
id: hgnc:15766
label: ADNP
results: A heterozygous pathogenic ADNP variant establishes molecular confirmation in a compatible clinical context.
evidence:
- reference: PMID:27054228
reference_title: ADNP-Related Helsmoortel-Van der Aa Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
The diagnosis of ADNP-related HVDAS is established by identification of a heterozygous ADNP pathogenic variant by molecular genetic testing.
explanation: >
GeneReviews defines the molecular diagnostic criterion.
- name: Episignature-Assisted Evaluation After Negative Exome Sequencing
description: >
A compatible peripheral-blood DNA-methylation episignature and phenotype classifier can prioritize ADNP after unrevealing exome sequencing; whole-genome and transcriptome sequencing may then identify and confirm a non-coding splice variant. The episignature is complementary, not a standalone severity or prognostic test.
diagnosis_term:
preferred_term: genome-wide DNA methylation analysis
results: A compatible episignature can trigger genome-wide variant detection and RNA confirmation of an otherwise missed non-coding ADNP allele.
evidence:
- reference: PMID:38424297
reference_title: Loss-of-function of activity-dependent neuroprotective protein (ADNP) by a splice-acceptor site mutation causes Helsmoortel-Van der Aa syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Whereas exome sequencing failed to detect the non-coding deletion, genome-wide CpG methylation analysis revealed an episignature suggestive of a Helsmoortel-Van der Aa syndrome diagnosis.
explanation: >
A molecularly resolved case demonstrates an episignature-assisted route after negative exome sequencing.
- reference: PMID:38424297
reference_title: Loss-of-function of activity-dependent neuroprotective protein (ADNP) by a splice-acceptor site mutation causes Helsmoortel-Van der Aa syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
with transcriptome sequencing showing this deletion leads to skipping of exon 4.
explanation: >
Genome and transcriptome sequencing supplied variant-level confirmation after the screening clue.
differential_diagnoses:
- name: Angelman syndrome
disease_term:
preferred_term: Angelman syndrome
term:
id: MONDO:0007113
label: Angelman syndrome
description: >
This syndrome was evaluated before ADNP molecular diagnosis in the main cohort because it can share developmental delay and autism-related features. The cited evidence does not establish feature-by-feature discrimination.
distinguishing_features:
- Syndrome-specific molecular confirmation distinguishes this diagnosis from ADNP-related syndrome.
- Identification of a heterozygous pathogenic ADNP variant supports ADNP-related syndrome in a compatible clinical context.
evidence:
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
The clinical symptoms of Helsmoortel-Van der Aa syndrome show partial overlap with other genetic syndromes that include developmental delay and ASD, as evidenced by genetic testing of our cohort for disorders such as Angelman, Prader-Willi, Kleefstra, Smith-Magenis, or Rett syndromes prior to the diagnosis of an ADNP mutation.
explanation: >
The 78-person cohort directly documents this syndrome among diagnoses evaluated before ADNP molecular confirmation.
- name: Prader-Willi syndrome
disease_term:
preferred_term: Prader-Willi syndrome
term:
id: MONDO:0008300
label: Prader-Willi syndrome
description: >
This syndrome was evaluated before ADNP molecular diagnosis in the main cohort because it can share developmental delay and autism-related features. The cited evidence does not establish feature-by-feature discrimination.
distinguishing_features:
- Syndrome-specific molecular confirmation distinguishes this diagnosis from ADNP-related syndrome.
- Identification of a heterozygous pathogenic ADNP variant supports ADNP-related syndrome in a compatible clinical context.
evidence:
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
The clinical symptoms of Helsmoortel-Van der Aa syndrome show partial overlap with other genetic syndromes that include developmental delay and ASD, as evidenced by genetic testing of our cohort for disorders such as Angelman, Prader-Willi, Kleefstra, Smith-Magenis, or Rett syndromes prior to the diagnosis of an ADNP mutation.
explanation: >
The 78-person cohort directly documents this syndrome among diagnoses evaluated before ADNP molecular confirmation.
- name: Kleefstra syndrome
disease_term:
preferred_term: Kleefstra syndrome
term:
id: MONDO:0012455
label: Kleefstra syndrome
description: >
This syndrome was evaluated before ADNP molecular diagnosis in the main cohort because it can share developmental delay and autism-related features. The cited evidence does not establish feature-by-feature discrimination.
distinguishing_features:
- Syndrome-specific molecular confirmation distinguishes this diagnosis from ADNP-related syndrome.
- Identification of a heterozygous pathogenic ADNP variant supports ADNP-related syndrome in a compatible clinical context.
evidence:
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
The clinical symptoms of Helsmoortel-Van der Aa syndrome show partial overlap with other genetic syndromes that include developmental delay and ASD, as evidenced by genetic testing of our cohort for disorders such as Angelman, Prader-Willi, Kleefstra, Smith-Magenis, or Rett syndromes prior to the diagnosis of an ADNP mutation.
explanation: >
The 78-person cohort directly documents this syndrome among diagnoses evaluated before ADNP molecular confirmation.
- name: Smith-Magenis syndrome
disease_term:
preferred_term: Smith-Magenis syndrome
term:
id: MONDO:0008434
label: Smith-Magenis syndrome
description: >
This syndrome was evaluated before ADNP molecular diagnosis in the main cohort because it can share developmental delay and autism-related features. The cited evidence does not establish feature-by-feature discrimination.
distinguishing_features:
- Syndrome-specific molecular confirmation distinguishes this diagnosis from ADNP-related syndrome.
- Identification of a heterozygous pathogenic ADNP variant supports ADNP-related syndrome in a compatible clinical context.
evidence:
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
The clinical symptoms of Helsmoortel-Van der Aa syndrome show partial overlap with other genetic syndromes that include developmental delay and ASD, as evidenced by genetic testing of our cohort for disorders such as Angelman, Prader-Willi, Kleefstra, Smith-Magenis, or Rett syndromes prior to the diagnosis of an ADNP mutation.
explanation: >
The 78-person cohort directly documents this syndrome among diagnoses evaluated before ADNP molecular confirmation.
- name: Rett syndrome
disease_term:
preferred_term: Rett syndrome
term:
id: MONDO:0010726
label: Rett syndrome
description: >
This syndrome was evaluated before ADNP molecular diagnosis in the main cohort because it can share developmental delay and autism-related features. The cited evidence does not establish feature-by-feature discrimination.
distinguishing_features:
- Syndrome-specific molecular confirmation distinguishes this diagnosis from ADNP-related syndrome.
- Identification of a heterozygous pathogenic ADNP variant supports ADNP-related syndrome in a compatible clinical context.
evidence:
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
The clinical symptoms of Helsmoortel-Van der Aa syndrome show partial overlap with other genetic syndromes that include developmental delay and ASD, as evidenced by genetic testing of our cohort for disorders such as Angelman, Prader-Willi, Kleefstra, Smith-Magenis, or Rett syndromes prior to the diagnosis of an ADNP mutation.
explanation: >
The 78-person cohort directly documents this syndrome among diagnoses evaluated before ADNP molecular confirmation.
animal_models:
- species: Mouse (Mus musculus)
genotype: Complete Adnp knockout
category: Knockout
genes:
- preferred_term: Adnp
term:
id: hgnc:15766
label: ADNP
associated_phenotypes:
- Embryonic lethality
- Failure of neural-tube closure
description: >
Complete Adnp deletion causes embryonic lethality around E8.5-E9.0 with failed neural-tube closure. It establishes an essential developmental function but cannot model the postnatal human syndrome.
evidence:
- reference: PMID:36945042
reference_title: Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >
Full knockouts, lacking the entire protein coding sequence of the Adnp gene, are embryonically lethal and die around E8.5–9.0 with failure of the neural tube closure, suggesting a role in brain development.
explanation: >
The complete-null mouse demonstrates an essential embryonic role and a severe model-human boundary.
- species: Mouse (Mus musculus)
genotype: Heterozygous Adnp null allele (Adnp+/-)
category: Heterozygous knockout
genes:
- preferred_term: Adnp
term:
id: hgnc:15766
label: ADNP
associated_phenotypes:
- Reduced dendritic spine density
- Altered synaptic gene expression
- Cognitive and social-memory impairment
- Gait and motor dysfunction
description: >
The heterozygous null model reduces Adnp RNA and protein by about 50% and shows cognitive, motor, vocalization, spine, and synaptic phenotypes. It models a true dosage-loss branch that may not represent common NMD-escaping human alleles.
evidence:
- reference: PMID:36945042
reference_title: Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >
These mice showed the expected 50% reduction in Adnp RNA and protein levels and exhibited cognitive deficits in the Morris water maze in adolescence and older age
explanation: >
The heterozygous null mouse directly models reduced dosage and cognitive phenotypes.
- reference: PMID:30106381
reference_title: Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >
We discovered that Adnp deficiency reduced dendritic spine density and altered synaptic gene expression, both of which were partly ameliorated by NAP treatment.
explanation: >
Primary mouse work supports synaptic pathology and partial preclinical NAP rescue.
- reference: PMID:30106381
reference_title: Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >
Adnp+/-mice further exhibited global developmental delays, vocalization impediments, gait and motor dysfunctions, and social and object memory impairments, all of which were partially reversed by daily NAP administration (systemic/nasal).
explanation: >
Primary mouse evidence supports the model's developmental, vocalization, gait, motor, social-memory, and object-memory phenotypes.
- species: Mouse (Mus musculus)
genotype: Heterozygous Adnp p.Tyr718* knock-in (human p.Tyr719* ortholog)
category: Knock-in
genes:
- preferred_term: Adnp
term:
id: hgnc:15766
label: ADNP
associated_phenotypes:
- Delayed development
- Sex-dependent gait and behavior
- Altered dendritic spines
- Tau pathology and visual-evoked-potential abnormalities
description: >
This recurrent-allele ortholog expresses mutant and wild-type RNA, but the predicted truncated protein was not visualized. Its phenotypes therefore do not by themselves resolve loss-of-function versus toxic-mutant action.
evidence:
- reference: PMID:36945042
reference_title: Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >
A truncated protein product in the mutant animals was predicted but not visualized.
explanation: >
Failure to visualize the predicted protein preserves the central allele-mechanism uncertainty.
- reference: PMID:36945042
reference_title: Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >
Phenotypically, Tyr mice had delayed development and with sex-dependent gait defect and syntax abnormalities. Grooming duration and nociception threshold autistic traits were significantly affected in males. Anatomically, dendritic spine densities were reduced an morphologies altered.
explanation: >
The knock-in reproduces developmental, behavioral, motor, and spine phenotypes with sex dependence.
- reference: PMID:36945042
reference_title: Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >
Early-onset tauopathy in hippocampus and visual cortex was accentuated in males and was paralleled by impaired visual evoked potentials.
explanation: >
The allele-matched mouse review reports male-accentuated tau pathology together with impaired visual evoked potentials.
- species: Mouse (Mus musculus)
genotype: Heterozygous Adnp c.2463_2476del (p.Leu822Hisfs*6) frameshift
category: Knock-in
genes:
- preferred_term: Adnp
term:
id: hgnc:15766
label: ADNP
associated_phenotypes:
- Increased chromatin accessibility
- Wnt-pathway downregulation
- Cytoskeletal and synaptic dysfunction
- Cognitive and autism-related behavior
description: >
A 2026 CRISPR frameshift model was studied only in male mice. Multi-omic and behavioral results connect chromatin, Wnt, cytoskeletal, and synaptic abnormalities, but sex restriction and the engineered allele limit direct human generalization.
evidence:
- reference: PMID:42208149
reference_title: An Adnp frameshift variant disrupts Wnt signalling inducing chromatocytoskeletal defects and autism-related behaviour in male mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >
Our findings demonstrate a role for Adnp in chromatin regulation and Wnt signalling, coupled to aberrant expression of cytoskeletal components and synaptic dysfunction.
explanation: >
The male-mouse frameshift model supports convergence across the curated mechanism nodes.
biochemical:
- name: Mutation-Position-Dependent Blood DNA Methylation Episignatures
presence: PRESENT
context: Peripheral-blood DNA methylation biomarker for diagnostic support and variant interpretation; not an established causal mediator or severity predictor.
cell_types:
- preferred_term: Leukocyte (peripheral blood)
term:
id: CL:0000738
label: leukocyte
readouts:
- target: Heterozygous ADNP Pathogenic Variation
relationship: READOUT_OF
direction: PRESENT_ABSENT
endpoint_context: DIAGNOSTIC
evidence:
- reference: PMID:38424297
reference_title: Loss-of-function of activity-dependent neuroprotective protein (ADNP) by a splice-acceptor site mutation causes Helsmoortel-Van der Aa syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Whereas exome sequencing failed to detect the non-coding deletion, genome-wide CpG methylation analysis revealed an episignature suggestive of a Helsmoortel-Van der Aa syndrome diagnosis.
explanation: >
The biomarker readout helped prioritize ADNP in a molecularly resolved WES-negative case.
evidence:
- reference: PMID:32758449
reference_title: Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
we conducted an independent study on 24 individuals with HVDAS and replicated the existence of the two mutation-dependent episignatures.
explanation: >
An independent 24-person cohort reproduced two mutation-position-dependent blood methylation signatures.
- reference: PMID:32758449
reference_title: Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
We found limited phenotypic differences between the two HVDAS-affected groups and no evidence that individuals with more widespread methylation changes are more severely affected.
explanation: >
The replicated signatures should not be used as established severity or prognostic classifiers.
- reference: PMID:41594725
reference_title: A Systematic Review Illustrates the Expanding Clinical and Molecular Landscape of Helsmoortel-Van der Aa Syndrome.
supports: SUPPORT
evidence_source: OTHER
snippet: >
Advances in ADNP methylation profiling further enhance diagnostic precision and variant interpretation in this evolving neurodevelopmental syndrome.
explanation: >
The 2025 systematic review supports the diagnostic and variant-interpretation role while the primary replication study constrains prognostic use.
notes: >
Two opposing mutation-position-dependent signatures have been replicated. Their clinical role is complementary diagnosis and variant interpretation; limited phenotype correlation argues against placing the episignature in the causal pathophysiology chain.
genetic:
- name: ADNP Pathogenic Variants
gene_term:
preferred_term: ADNP
term:
id: hgnc:15766
label: ADNP
association: Causative
presence: Positive
relationship_type: CAUSATIVE
variant_origin: GERMLINE
notes: >
Heterozygous pathogenic ADNP variants are usually de novo and predominantly protein truncating. Most variants in the main cohort lie in the last exon and are predicted to escape NMD, so they should not be labeled uniformly haploinsufficient. Rare true-null alleles establish an allele-specific haploinsufficiency branch. Emerging missense alleles require variant-specific functional evidence and should not be generalized from a single experimental system. The recurrent p.Tyr719* allele was associated with later walking and higher pain threshold in the main cohort, but a blanket claim of globally greater severity is not retained.
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:27054228
reference_title: ADNP-Related Helsmoortel-Van der Aa Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
ADNP-related HVDAS is an autosomal dominant disorder. Most probands whose parents have undergone molecular genetic testing have the disorder as the result of a de novo ADNP pathogenic variant. In two families reported to date, probands diagnosed with ADNP-related HVDAS inherited a pathogenic variant from an unaffected parent.
explanation: >
GeneReviews supports dominant inheritance, predominantly de novo origin, and rare inherited cases.
description: >
ADNP-related syndrome is autosomal dominant. Most molecularly tested cases are de novo, with rare inheritance from an apparently unaffected parent.
evidence:
- reference: PMID:24531329
reference_title: A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Here, we report ten patients with ASD and other shared clinical characteristics, including intellectual disability and facial dysmorphisms caused by a mutation in ADNP, a transcription factor involved in the SWI/SNF remodeling complex.
explanation: >
The founding series establishes ADNP as a causal disease gene.
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
We found 46 unique mutations on the DNA level, of which 25 were nonsense and 21 frameshift (Supplemental Table S2). All but three mutations were located in the fifth and last exon of the ADNP gene and were predicted to escape nonsense-mediated decay.
explanation: >
The 78-person cohort establishes the predominant truncating, last-exon allele spectrum.
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Sixty-eight mutations in our cohort were confirmed de novo, eight mutations were of unknown inheritance, and two C-terminal mutations were inherited.
explanation: >
The cohort quantifies the predominance of de novo origin while preserving inherited exceptions.
- reference: PMID:38424297
reference_title: Loss-of-function of activity-dependent neuroprotective protein (ADNP) by a splice-acceptor site mutation causes Helsmoortel-Van der Aa syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >
An N-terminal truncated protein could not be detected in transfection experiments with a mutant expression vector in HEK293T cells, strongly suggesting this is a first confirmed diagnosis exclusively due to haploinsufficiency of the ADNP gene.
explanation: >
One splice allele establishes a true-null mechanism without generalizing it to all ADNP variants.
- reference: PMID:41943166
reference_title: ADNP missense variant p.C687R disrupts chromatin regulation and GABAergic differentiation in Helsmoortel-Van der Aa syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >
This study is based on a single patient-derived line in combination with complementary experimental models. In the heterozygous endogenous context, distinguishing increased functional activity from dosage-related effects requires further investigation.
explanation: >
The p.C687R study supplies emerging variant-specific evidence while explicitly limiting broader missense interpretation.
treatments:
- name: Symptom-Directed Supportive Care
description: >
Management is individualized and symptomatic, including developmental and educational supports, nutritional assistance, and standard care for gastrointestinal, ophthalmologic, musculoskeletal, infectious, endocrine, cardiac, hearing, seizure, and urinary manifestations.
action_category: THERAPEUTIC
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Treatment is symptomatic and can include: speech, occupational, and physical therapy; specialized learning programs depending on individual needs; treatment of neuropsychiatric features; nutritional support as needed"
explanation: >
GeneReviews describes symptomatic, multidisciplinary supportive management as the
standard of care.
- reference: PMID:41594725
reference_title: "A Systematic Review Illustrates the Expanding Clinical and Molecular Landscape of Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
It underscores the multisystemic nature of the disorder and the need for
multidisciplinary management.
explanation: >-
A 2025 systematic review independently supports multidisciplinary
management while documenting expanding phenotypic heterogeneity.
therapeutic_modality: OTHER
target_phenotypes:
- preferred_term: Feeding Difficulties
term:
id: HP:0011968
label: Feeding difficulties
- name: Speech Therapy
description: >
Speech therapy addresses the severe speech delay characteristic of the syndrome.
action_category: THERAPEUTIC
treatment_term:
preferred_term: speech therapy
term:
id: NCIT:C159273
label: Speech Language Therapy
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Treatment is symptomatic and can include: speech, occupational, and physical therapy"
explanation: >
GeneReviews recommends speech therapy as part of symptomatic management.
therapeutic_modality: BEHAVIORAL
target_phenotypes:
- preferred_term: Speech Delay
term:
id: HP:0000750
label: Delayed speech and language development
- name: Physical and Occupational Therapy
description: >
Physical and occupational therapy support motor development and hypotonia.
action_category: THERAPEUTIC
treatment_term:
preferred_term: physical therapy
term:
id: NCIT:C15302
label: Physical Therapy
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Treatment is symptomatic and can include: speech, occupational, and physical therapy"
explanation: >
GeneReviews recommends physical and occupational therapy.
therapeutic_modality: BEHAVIORAL
target_phenotypes:
- preferred_term: Hypotonia
term:
id: HP:0001252
label: Hypotonia
- preferred_term: Motor Delay
term:
id: HP:0001270
label: Motor delay
- name: Genetic Counseling
description: >
Genetic counseling is recommended for families. ADNP-related syndrome is an
autosomal dominant disorder, most often arising de novo. Once the ADNP variant
is identified in an affected family member, prenatal and preimplantation genetic
testing are possible.
action_category: COUNSELING_INFORMATIONAL
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:27054228
reference_title: "ADNP-Related Helsmoortel-Van der Aa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Once the ADNP pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."
explanation: >
GeneReviews describes the autosomal dominant inheritance and the availability of
prenatal and preimplantation genetic testing, supporting genetic counseling.
- name: Davunetide (NAP, investigational)
description: >
Davunetide (NAP, CP201) is an ADNP-derived peptide candidate with preclinical target engagement. It partially rescues spine, behavioral, microtubule, and cellular abnormalities in Adnp-deficient mouse and engineered-cell models. Human efficacy for ADNP-related syndrome has not been established.
action_category: THERAPEUTIC
therapeutic_modality: PEPTIDE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: davunetide
term:
id: CHEBI:177706
label: davunetide
evidence:
- reference: PMID:37759476
reference_title: "NAP (Davunetide): The Neuroprotective ADNP Drug Candidate Penetrates Cell Nuclei Explaining Pleiotropic Mechanisms."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "This malformation was corrected upon neuronal differentiation by the ADNP-derived fragment drug candidate NAP (davunetide)."
explanation: >
In ADNP-mutated neuronal cell models, davunetide (NAP) corrects cellular abnormalities,
supporting it as an investigational mechanism-based candidate therapy.
- reference: PMID:30106381
reference_title: Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >
Adnp+/-mice further exhibited global developmental delays, vocalization impediments, gait and motor dysfunctions, and social and object memory impairments, all of which were partially reversed by daily NAP administration (systemic/nasal).
explanation: >
Daily NAP partially reversed multiple developmental and behavioral phenotypes in an Adnp-haploinsufficient mouse model; this remains preclinical evidence.
target_mechanisms:
- target: ADNP-EB Microtubule Dynamics Dysfunction
treatment_effect: MODULATES
evidence:
- reference: PMID:37759476
reference_title: 'NAP (Davunetide): The Neuroprotective ADNP Drug Candidate Penetrates Cell Nuclei Explaining Pleiotropic Mechanisms.'
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >
Through a microtubule-linked mechanism, NAP rapidly localized to the cytoplasmic and nuclear compartments, ameliorating mutated ADNP-related deficiencies.
explanation: >
The engineered-cell study supports modulation of a microtubule-linked ADNP phenotype; it does not directly demonstrate restoration of measured microtubule content or dynamics.
- target: Dendritic Spine and Synaptic Plasticity Dysfunction
treatment_effect: RESTORES
evidence:
- reference: PMID:30106381
reference_title: Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >
We discovered that Adnp deficiency reduced dendritic spine density and altered synaptic gene expression, both of which were partly ameliorated by NAP treatment.
explanation: >
Mouse evidence supports partial restoration of spine and synaptic abnormalities.
- name: Low-Dose Ketamine (investigational)
description: >
A single-dose open-label study of 0.5 mg/kg intravenous ketamine in 10 children reported no serious adverse events and nominal short-term behavioral changes. The small uncontrolled design makes efficacy findings hypothesis-generating. A blood-transcriptomic study found a transient, monocyte-enriched peripheral response that does not establish central nervous-system target engagement; the effect of increasing mutant ADNP expression remains unresolved.
action_category: THERAPEUTIC
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: ketamine
term:
id: CHEBI:6121
label: ketamine
evidence:
- reference: PMID:36119806
reference_title: "An open-label study evaluating the safety, behavioral, and electrophysiological outcomes of low-dose ketamine in children with ADNP syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Ketamine was generally well tolerated, and there were no serious adverse events."
explanation: >
An open-label trial of low-dose IV ketamine in 10 children with ADNP syndrome found
it generally well tolerated with no serious adverse events.
- reference: PMID:39054328
reference_title: "Transient peripheral blood transcriptomic response to ketamine treatment in children with ADNP syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We show that ketamine triggers immediate and profound gene expression alterations, with specific enrichment of monocyte-related expression patterns."
explanation: >
Longitudinal blood transcriptomics in ADNP-syndrome individuals shows a transient,
monocyte-enriched gene-expression response to a single low-dose ketamine infusion.
target_phenotypes:
- preferred_term: Autistic Behavior
term:
id: HP:0000729
label: Autistic behavior
- preferred_term: Behavioral Problems
term:
id: HP:0000708
label: Atypical behavior
discussions:
- discussion_id: gap_adnp_allele_specific_molecular_mechanism
prompt: >
For common NMD-escaping truncating alleles, does disease result from reduced effective ADNP function, dominant interference, toxic gain of function, or an allele-specific mixture, and how does that compare with confirmed true-null and emerging missense alleles?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#NMD-Escaping Mutant ADNP Transcripts
- pathophysiology#Allele-Specific ADNP Haploinsufficiency
- pathophysiology#ADNP Chromatin-Complex Dysfunction
rationale: >
Mutant RNA is demonstrable for common last-exon alleles, but mutant protein has not been unambiguously demonstrated in patients. A splice allele proves true haploinsufficiency can cause disease, while p.C687R supplies limited gain-of-function-like experimental evidence. Therapy and model selection therefore require allele-stratified mechanism.
evidence:
- reference: PMID:36945042
reference_title: Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism.
supports: SUPPORT
evidence_source: OTHER
snippet: >
mutations cluster in the fifth and last exon and escape from NMD has been demonstrated, the majority of patients might still produce protein. Thought it needs to be mentioned that mutated protein has never been unambiguously demonstrated in patients, an additional gain of toxic function of the mutant protein, if present, could also be envisaged
explanation: >
The review explicitly frames the unresolved mutant-protein question.
- reference: PMID:41943166
reference_title: ADNP missense variant p.C687R disrupts chromatin regulation and GABAergic differentiation in Helsmoortel-Van der Aa syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >
Our results suggest that p.C687R may exert gain-of-function-like effects in experimental systems and underscore chromatin-mediated regulation of GABAergic lineage genes in HVDAS.
explanation: >
A single missense allele supplies an emerging alternative mechanism that requires replication.
proposed_experiments:
- experiment_id: exp_adnp_isogenic_allele_mechanism_panel
name: Isogenic ADNP allele-mechanism panel in human neural lineages
description: >
Create isogenic human iPSC lines carrying representative NMD-escaping truncations, the confirmed splice-null allele, p.C687R, matched knockouts, corrected controls, and allele-specific mutant knockdown. Compare allele-specific RNA and proteomics, ADNP localization and chromatin occupancy, methylome/transcriptome states, microtubule dynamics, neuronal differentiation, dendritic spines, and synaptic physiology, with wild-type addback and mutant-selective suppression arms.
decision_criterion: >
Support a dominant or toxic mutant mechanism only if an NMD-escaping or missense allele produces effects exceeding matched dosage loss and those effects are preferentially rescued by mutant-selective suppression; support pure dosage loss when matched knockout and variant phenotypes align and wild-type addback rescues both.
would_support:
- pathophysiology#NMD-Escaping Mutant ADNP Transcripts
- pathophysiology#Allele-Specific ADNP Haploinsufficiency
- discussion_id: mismatch_adnp_null_mouse_common_human_alleles
prompt: >
Which findings from heterozygous null mice translate to people with common NMD-escaping truncating variants, and which reflect a rare true-null branch or model-specific sex and background effects?
kind: HUMAN_MODEL_MISMATCH
status: OPEN
attaches_to:
- pathophysiology#NMD-Escaping Mutant ADNP Transcripts
- pathophysiology#Allele-Specific ADNP Haploinsufficiency
- pathophysiology#Dendritic Spine and Synaptic Plasticity Dysfunction
rationale: >
The frequently used Adnp+/- mouse deletes one allele and therefore models dosage loss, whereas most common human alleles escape NMD. Several mouse phenotypes are sex dependent, and the 2026 frameshift study tested only males.
evidence:
- reference: PMID:36945042
reference_title: Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism.
supports: SUPPORT
evidence_source: OTHER
snippet: >
While it is tempting to draw parallels between the clinical presentation of patients and the abnormalities observed in the mouse model, it should be stressed that the model described is a full deletion and the mutational mechanism of the Helsmoortel–Van der Aa syndrome has not been fully established.
explanation: >
The review explicitly identifies the null-model versus human-allele mismatch.
- discussion_id: gap_adnp_longitudinal_natural_history_and_regression
prompt: >
What are the age-specific developmental trajectories, true frequency and domains of regression, adult outcomes, and nonprogressive versus progressive subgroups in ADNP-related syndrome?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- phenotypes#Global Developmental Delay
- phenotypes#Speech Delay
- phenotypes#Motor Delay
rationale: >
The main cohort was young and cross-sectional. Apparent skill loss was reported in 12 children without a feature-specific denominator, so a globally progressive or neurodegenerative label is not justified.
evidence:
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Apparent loss of acquired abilities was reported in 12 children for skills such as speaking, counting, riding a bicycle, or being toilet trained.
explanation: >
Reported regression requires prospective confirmation and a defined denominator.
- reference: PMID:29724491
reference_title: Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
The main limitation of our study is the relatively young age of our study cohort. Longterm follow-up studies are necessary to define the developmental path of individuals with a mutation in ADNP.
explanation: >
The cohort authors explicitly call for longitudinal follow-up.
proposed_experiments:
- experiment_id: exp_adnp_longitudinal_natural_history
name: Allele-stratified longitudinal ADNP natural-history cohort
description: >
Follow children and adults prospectively with standardized developmental, adaptive, speech, motor, behavioral, sleep, seizure, sensory, growth, and organ-system measures, recording acquisition and loss of individual skills and stratifying by allele position, NMD prediction, episignature group, age, and sex.
decision_criterion: >
Classify regression or progression only from repeated within-person decline exceeding measurement variability, with domain-specific denominators and age-specific incidence; otherwise retain a variable lifelong neurodevelopmental course.
- discussion_id: interpretation_adnp_episignature_scope
prompt: >
How sensitive and specific are ADNP episignatures for diagnosis and variant interpretation, and can any reproducible methylation measure predict phenotype after controlling for allele position and ascertainment?
kind: INTERPRETATION
status: OPEN
attaches_to:
- biochemical#Mutation-Position-Dependent Blood DNA Methylation Episignatures
rationale: >
Two mutation-position-dependent signatures are reproducible, but their correlation with behavioral severity is limited. Diagnostic and VUS-classification performance should be kept separate from prognosis.
evidence:
- reference: PMID:32758449
reference_title: Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
We found limited phenotypic differences between the two HVDAS-affected groups and no evidence that individuals with more widespread methylation changes are more severely affected.
explanation: >
The replication cohort argues against using methylation extent as a severity proxy.
- discussion_id: gap_adnp_controlled_treatment_evidence
prompt: >
Can davunetide or ketamine improve clinically meaningful outcomes in ADNP-related syndrome, and do efficacy or safety differ across true-null, NMD-escaping, and missense allele mechanisms?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- treatments#Davunetide (NAP, investigational)
- treatments#Low-Dose Ketamine (investigational)
rationale: >
Davunetide evidence is preclinical. Ketamine has only a small single-dose open-label study; peripheral blood transcriptional changes do not establish central target engagement, and increasing mutant ADNP could have allele-specific consequences.
evidence:
- reference: PMID:36119806
reference_title: An open-label study evaluating the safety, behavioral, and electrophysiological outcomes of low-dose ketamine in children with ADNP syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Ketamine was generally well tolerated, and there were no serious adverse events.
explanation: >
The small open-label study informs short-term tolerability but cannot establish efficacy.
- reference: PMID:36945042
reference_title: Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism.
supports: SUPPORT
evidence_source: OTHER
snippet: >
The ketamine rationale is based on the finding that ketamine increased ADNP expression, however, the possibility of ketamine increasing mutated ADNP expression needs to be further investigated
explanation: >
The review identifies an allele-specific safety and mechanism question.
- reference: PMID:30106381
reference_title: Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >
We discovered that Adnp deficiency reduced dendritic spine density and altered synaptic gene expression, both of which were partly ameliorated by NAP treatment.
explanation: >
NAP rescue remains preclinical model evidence.
clinical_trials:
- name: NCT04388774
phase: PHASE_II
status: COMPLETED
description: >
Completed Phase 2A single-dose, open-label study of low-dose (0.5 mg/kg) intravenous ketamine in 10 children ages 6-12 with ADNP syndrome, evaluating safety, tolerability, behavioral outcomes, and candidate electrophysiologic and molecular biomarkers.
target_phenotypes:
- preferred_term: Autistic behavior
term:
id: HP:0000729
label: Autistic behavior
- preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: clinicaltrials:NCT04388774
reference_title: "A Phase 2A Open-Label Study Evaluating the Safety and Efficacy of Low-Dose Ketamine in Children With ADNP Syndrome"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This is a Phase 2A, single dose, open-label study to evaluate the safety, tolerability, and efficacy of a low-dose, 40-minute infusion into the veins (intravenous infusion or \"IV\") of ketamine in children with ADNP syndrome (Activity-Dependent Neuroprotective Protein)."
explanation: >
ClinicalTrials.gov describes this completed Phase 2A open-label trial of low-dose IV
ketamine in children with ADNP syndrome.
- reference: PMID:36119806
reference_title: An open-label study evaluating the safety, behavioral, and electrophysiological outcomes of low-dose ketamine in children with ADNP syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
This study utilized a single-dose (0.5 mg/kg), open-label design, with ketamine infused intravenously over 40 min. Ten children with ADNP syndrome ages 6 to 12 years were enrolled.
explanation: >
The peer-reviewed completed study confirms the design, dose, infusion, actual enrollment, and age range.
- name: NCT03718936
phase: NOT_APPLICABLE
status: RECRUITING
description: >
Seaver Autism Center assessment study characterizing ADNP-related neurodevelopmental disorders with genetic, medical, and neuropsychological measures.
target_phenotypes:
- preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
- preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
evidence:
- reference: clinicaltrials:NCT03718936
reference_title: "The Seaver Autism Center for Research and Treatment - Assessment Core"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This study seeks to characterize ADNP-related neurodevelopmental disorders using a number of genetic, medical and neuropsychological measures."
explanation: >-
ClinicalTrials.gov describes this observational study characterizing ADNP-related
neurodevelopmental disorders.
References & Deep Research
References
18A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP.
No top-level findings curated for this source.
ADNP-Related Helsmoortel-Van der Aa Syndrome.
No top-level findings curated for this source.
Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children.
No top-level findings curated for this source.
Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
No top-level findings curated for this source.
Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome.
No top-level findings curated for this source.
Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype.
No top-level findings curated for this source.
Activity-dependent neuroprotective protein (ADNP)-end-binding protein (EB) interactions regulate microtubule dynamics toward protection against tauopathy.
No top-level findings curated for this source.
An open-label study evaluating the safety, behavioral, and electrophysiological outcomes of low-dose ketamine in children with ADNP syndrome.
No top-level findings curated for this source.
Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism.
No top-level findings curated for this source.
Adnp-mutant mice with cognitive inflexibility, CaMKIIα hyperactivity, and synaptic plasticity deficits.
No top-level findings curated for this source.
NAP (Davunetide): The Neuroprotective ADNP Drug Candidate Penetrates Cell Nuclei Explaining Pleiotropic Mechanisms.
No top-level findings curated for this source.
Loss-of-function of activity-dependent neuroprotective protein (ADNP) by a splice-acceptor site mutation causes Helsmoortel-Van der Aa syndrome.
No top-level findings curated for this source.
Transient peripheral blood transcriptomic response to ketamine treatment in children with ADNP syndrome.
No top-level findings curated for this source.
A Systematic Review Illustrates the Expanding Clinical and Molecular Landscape of Helsmoortel-Van der Aa Syndrome.
No top-level findings curated for this source.
ADNP missense variant p.C687R disrupts chromatin regulation and GABAergic differentiation in Helsmoortel-Van der Aa syndrome.
No top-level findings curated for this source.
An Adnp frameshift variant disrupts Wnt signalling inducing chromatocytoskeletal defects and autism-related behaviour in male mice.
No top-level findings curated for this source.
The Seaver Autism Center for Research and Treatment - Assessment Core
No top-level findings curated for this source.
A Phase 2A Open-Label Study Evaluating the Safety and Efficacy of Low-Dose Ketamine in Children With ADNP Syndrome
No top-level findings curated for this source.
Deep Research
1
Falcon
▸
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Disease Characteristics Research Template
Target Disease
- Disease Name: ADNP-Related Syndrome
- MONDO ID: (if available)
- Category: Mendelian
Research Objectives
Please provide a comprehensive research report on ADNP-Related Syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.
For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.
1. Disease Information
Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed
- What is the disease? Provide a concise overview.
- What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
- What are the common synonyms and alternative names?
- Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?
2. Etiology
- Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
- Risk Factors:
Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
- Genetic risk factors (causal variants, susceptibility loci, modifier genes)
- Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
- Protective Factors:
Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
- Genetic protective factors (protective variants, modifier alleles)
- Environmental protective factors (diet, lifestyle, exposures that reduce risk)
- Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?
Search first: CTD, PubMed, PheGenI, GxE databases
3. Phenotypes
Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC
For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities
For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype
4. Genetic/Molecular Information
- Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)
Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
- Pathogenic Variants:
- Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
- Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
- Variant type/class (missense, frameshift, nonsense, splice-site, structural)
- Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
- Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
- Functional consequences (loss of function, gain of function, dominant negative)
- Modifier Genes: Genes that modify disease severity or expression
- Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease
Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
- Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)
Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser
5. Environmental Information
- Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)
Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
- Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)
Search first: CDC databases, WHO, PubMed, NHANES
- Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)
Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON
6. Mechanism / Pathophysiology
- Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)
Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
- Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)
Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
- Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)
Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
- Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)
Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
- Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)
Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
- Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)
Search first: PubMed, Gene Ontology, Reactome
- Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)
Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
- Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease
Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
- Molecular Profiling (if available):
- Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
- Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
- Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
- Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
- Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
- Advanced Technologies (if applicable):
- Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
- Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
- Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
- Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS
For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types
7. Anatomical Structures Affected
- Organ Level:
- Primary organs directly affected
- Secondary organ involvement (complications, secondary effects)
- Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)
Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
- Tissue and Cell Level:
- Specific tissue types affected (epithelial, connective, muscle, nervous)
- Specific cell populations targeted (with Cell Ontology terms)
Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
- Subcellular Level:
- Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)
Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
- Localization:
- Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
- Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases
8. Temporal Development
- Onset:
- Typical age of onset (congenital, pediatric, adult, geriatric)
- Onset pattern (acute, subacute, chronic, insidious)
Search first: OMIM, Orphanet, HPO, PubMed
- Progression:
- Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
- Progression rate (rapid, slow, variable)
- Disease course pattern (episodic, relapsing-remitting, progressive, stable)
- Disease duration (self-limited, chronic lifelong)
Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
- Patterns:
- Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
- Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines
9. Inheritance and Population
- Epidemiology:
- Prevalence (cases per 100,000 at given time)
- Incidence (new cases per 100,000 per year)
Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
- For Genetic Etiology:
- Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
- Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
- Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
- Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
- Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
- Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
- Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
- Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
- Population Demographics:
- Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
- Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
- Geographic distribution of specific variants
- Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
- Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet
10. Diagnostics
- Clinical Tests:
- Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
- Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
- Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
- Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
- Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
- Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
- Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
- Genetic Testing:
Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
- Overview of recommended genetic testing approach
- Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
- Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
- Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
- Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
- Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
- Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
- FISH > Search first: ClinVar, cytogenetics databases, PubMed
- Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
- Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
- Omics-Based Diagnostics (if applicable):
- RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
- Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
- Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
- Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
- Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
- Clinical Criteria:
- Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
- Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
- Screening:
- Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR
11. Outcome/Prognosis
- Survival and Mortality:
- Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
- Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
- Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
- Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
- Morbidity and Function:
- Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
- Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
- Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
- Disease Course:
- Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
- Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
- Prediction:
- Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
- Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases
12. Treatment
- Pharmacotherapy:
- Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
- Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
- Advanced Therapeutics:
- Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
- Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
- RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
- Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
- Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
- Surgical and Interventional:
- Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
- Supportive and Rehabilitative:
- Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
- Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
- Experimental:
- Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
- Treatment Outcomes:
- Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
- Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
- Treatment Strategy:
- Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
- Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
- Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases
For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.
13. Prevention
- Prevention Levels:
- Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
- Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
- Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
- Immunization: Vaccine strategies (if applicable)
Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
- Screening and Early Detection:
- Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
- Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
- Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
- Behavioral Interventions: Lifestyle modifications to reduce risk
Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
- Counseling: Genetic counseling (risk assessment, family planning guidance)
Search first: NSGC resources, ACMG guidelines, GeneReviews
- Public Health:
- Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
- Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
- Prophylaxis: Preventive medications or procedures
Search first: Clinical guidelines, FDA approvals, PubMed
14. Other Species / Natural Disease
- Taxonomy: Species affected (with NCBI Taxon identifiers)
Search first: NCBI Taxonomy
- Breed: Specific breeds affected (with VBO identifiers if applicable)
Search first: VBO (Vertebrate Breed Ontology)
- Gene: Orthologous genes in other species (with NCBI Gene IDs)
Search first: NCBI Gene
- Natural Disease:
- Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
- Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
- Comparative Biology:
- Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
- Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
- Transmission (if applicable):
- Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
- Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed
15. Model Organisms
- Model Types:
- Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
- Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
- Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
- Genetic Models:
- Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
- Model Characteristics:
- Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
- Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
- Applications:
- Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
- Resources:
- Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC
Citation Requirements
- Cite primary literature (PMID preferred) for all mechanistic and clinical claims
- Prioritize recent reviews and landmark papers
- Include direct quotes from abstracts where possible to support key statements
- Distinguish evidence source types: human clinical, model organism, in vitro, computational
Output Format
Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease
This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details
Comprehensive Disease Characteristics Report: ADNP-Related Syndrome (Helsmoortel–Van der Aa syndrome)
Target disease
Disease name: ADNP-related syndrome (ADNP syndrome; Helsmoortel–Van der Aa syndrome, HVDAS) (grice2024transientperipheralblood pages 1-2, ge2024clinicalimpactand pages 1-2)
1. Disease information
1.1 Concise overview (current understanding)
ADNP-related syndrome is a rare, monogenic neurodevelopmental disorder caused by pathogenic variants in ADNP (activity dependent neuroprotector homeobox). It is characterized by global developmental delay/intellectual disability and frequent autism/autistic features, with multisystem medical comorbidity (e.g., hypotonia, feeding/GI issues, congenital heart disease, visual problems, sleep disturbance). (grice2024transientperipheralblood pages 1-2, d’incal2023chromatinremodeleractivitydependent pages 6-8)
Definition quote (abstract-level): “Activity-dependent neuroprotective protein (ADNP) syndrome is a rare neurodevelopmental disorder resulting in intellectual disability, developmental delay and autism spectrum disorder (ASD) and is due to mutations in the ADNP gene.” (Translational Psychiatry, published Jul 2024) (grice2024transientperipheralblood pages 1-2)
1.2 Key identifiers
- OMIM (disease): 615873 (Helsmoortel–Van der Aa syndrome) (ge2024clinicalimpactand pages 1-2, d’incal2023chromatinremodeleractivitydependent pages 6-8)
- MONDO: MONDO:0014379 “ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder” (OpenTargets evidence) (OpenTargets Search: ADNP-related syndrome,Helsmoortel-Van der Aa syndrome)
- Gene locus: 20q13.13 (ADNP) (ge2024clinicalimpactand pages 1-2)
Not found in the retrieved sources: Orphanet ORPHA code, ICD-10/ICD-11 mapping, and MeSH disease term were not present in the tool-retrieved full text/corpus used here; these should be confirmed directly in Orphanet/ICD/MeSH authoritative databases for knowledge-base completeness.
1.3 Synonyms / alternative names
- ADNP syndrome (ge2024clinicalimpactand pages 1-2)
- Helsmoortel–Van der Aa syndrome (HVDAS) (grice2024transientperipheralblood pages 1-2, d’incal2023chromatinremodeleractivitydependent pages 6-8)
- ADNP-related disorder (terminology used in some contexts) (grice2024transientperipheralblood pages 1-2)
1.4 Evidence provenance
Most clinical knowledge is derived from aggregated disease-level resources: cohort studies, genotype-first sequencing cohorts, and systematic reviews (e.g., n=78 cohort in 2019; review synthesis in 2023). (d’incal2023chromatinremodeleractivitydependent pages 6-8, dijck2019clinicalpresentationof pages 13-18)
2. Etiology
2.1 Disease causal factors
Primary cause: pathogenic heterozygous ADNP variants, typically de novo, most often predicted loss-of-function (nonsense/frameshift). (d’incal2023chromatinremodeleractivitydependent pages 6-8, helsmoortel2014aswisnfrelated pages 2-4, dijck2019clinicalpresentationof pages 13-18)
Variant mechanism nuance: Many recurrent truncating variants occur in the last exon and are predicted to escape nonsense-mediated decay, with mutant transcripts detectable; consequently, some disease biology may involve truncated protein effects rather than pure haploinsufficiency. (helsmoortel2014aswisnfrelated pages 2-4, d’incal2023chromatinremodeleractivitydependent pages 6-8)
2.2 Risk factors
- Genetic: A de novo pathogenic ADNP variant is the principal “risk factor”/cause; familial recurrence is expected to be low but not zero due to possible parental germline mosaicism (not quantified in the retrieved evidence). (helsmoortel2014aswisnfrelated pages 2-4)
- Environmental: No disease-specific environmental risk factors were identified in the retrieved evidence; the syndrome is primarily genetic.
2.3 Protective factors
No validated protective genetic or environmental factors for ADNP-related syndrome were identified in the retrieved evidence corpus. (d’incal2023chromatinremodeleractivitydependent pages 6-8)
2.4 Gene–environment interactions
No ADNP-specific gene–environment interaction evidence was identified in the retrieved sources.
3. Phenotypes
3.1 High-frequency phenotypes (with frequencies)
A 2023 review synthesized phenotype frequencies (Table 1), reporting: intellectual disability 100%, speech delay 99%, motor delay 96%, autism/autistic features 93%, feeding/GI problems 83%, behavioral problems 78%, visual problems 74%, sleep problems 65%, hand/foot abnormalities 62%, brain abnormalities/seizures 62%, musculoskeletal issues 55%, frequent infections 51%. (d’incal2023chromatinremodeleractivitydependent pages 6-8, d’incal2023chromatinremodeleractivitydependent media ebbb8a81)
A 2019 cohort (n=78) provided additional quantified phenotypes, including visual problems (73.6%; e.g., strabismus 49.2%, hypermetropia 40.3%, cortical visual impairment 41%), recurrent infections (51%), oral movement problems (45.6%), and male cryptorchidism (34%). (dijck2019clinicalpresentationof pages 13-18)
A 2024 Chinese pediatric cohort (n=15) illustrates multisystem frequencies in an ascertained clinic cohort, including strabismus (6/15), atrial septal defect (5/15), oral movement problems (8/15), vomiting (6/15), and various urogenital/musculoskeletal findings. (ge2024clinicalimpactand pages 4-5)
3.2 Age of onset and course features
ADNP-related syndrome is a developmental disorder with onset in infancy/early childhood, typically recognized through early developmental delay, hypotonia, feeding difficulties, and later neurobehavioral features including ASD. (helsmoortel2014aswisnfrelated pages 2-4, grice2024transientperipheralblood pages 1-2)
Natural history signals include reported genotype–phenotype correlations and age-dependent functional outcomes (e.g., walking age predicting cognitive outcome noted in review summaries); robust longitudinal, population-based natural history remains limited. (d’incal2023chromatinremodeleractivitydependent pages 6-8)
3.3 Quality-of-life (QoL) impact
Direct standardized QoL instruments (e.g., EQ-5D/SF-36) were not identified in the retrieved evidence set; however, phenotypes such as severe speech delay, motor delay, feeding/oral-motor difficulties, sleep disturbance, and ASD features imply substantial impact on activities of daily living and caregiver burden. (d’incal2023chromatinremodeleractivitydependent pages 6-8, kolevzon2022anopenlabelstudy pages 1-2)
3.4 Suggested HPO terms (examples; not exhaustive)
- Intellectual disability HP:0001249
- Global developmental delay HP:0001263
- Autism HP:0000717
- Speech delay HP:0000750 / Absent speech HP:0001344
- Hypotonia HP:0001252
- Feeding difficulties HP:0011968 / Oral motor dysfunction HP:0010299
- Strabismus HP:0000486; Hypermetropia HP:0000540; Cortical visual impairment HP:0100704
- Congenital heart defect HP:0001627; Atrial septal defect HP:0001631
- Sleep disturbance HP:0002360
- Recurrent infections HP:0002719
- Cryptorchidism HP:0000028
- Scoliosis HP:0002650; Joint laxity HP:0001382
- Seizures HP:0001250
4. Genetic / molecular information
4.1 Causal gene
- ADNP (activity dependent neuroprotector homeobox; ENSG00000101126 per OpenTargets context) (OpenTargets Search: ADNP-related syndrome,Helsmoortel-Van der Aa syndrome)
4.2 Pathogenic variant spectrum (human)
- Predominantly heterozygous de novo truncating variants (frameshift/nonsense) (helsmoortel2014aswisnfrelated pages 2-4, d’incal2023chromatinremodeleractivitydependent pages 6-8)
- Clustering in the C-terminal portion of the final exon (exon 5 in canonical transcript) with predicted NMD escape and detectable mutant transcripts (helsmoortel2014aswisnfrelated pages 2-4)
- Recurrent/hotspot variants reported across cohorts include p.Tyr719, p.Arg730, and p.Asn832Lysfs81 / p.Leu831Ilefs82** (d’incal2023chromatinremodeleractivitydependent pages 6-8, dijck2019clinicalpresentationof pages 13-18)
- Missense variants also occur but are less frequent in available cohorts (e.g., 2/15 in one 2024 cohort). (ge2024clinicalimpactand pages 1-2)
ASD contribution statistic: The original discovery study reported 10 ADNP mutations among 5,776 screened patients and estimated “mutated in at least 0.17% of ASD cases.” (Nature Genetics, published Feb 2014) (helsmoortel2014aswisnfrelated pages 1-2)
4.3 Functional consequences
Current evidence supports predicted loss-of-function as the dominant pathogenic class, but NMD-escape truncations with mutation-position-dependent epigenetic signatures support more complex downstream consequences (possibly hypomorphic or gain-of-function contributions in some settings). (d’incal2023chromatinremodeleractivitydependent pages 6-8, breen2020episignaturesstratifyingadnp pages 4-6)
4.4 Modifier genes
No validated modifier genes were identified in the retrieved evidence corpus.
4.5 Epigenetic information (disease-associated episignatures)
Blood DNA methylation studies identify two ADNP episignatures stratified by variant position (“class I” vs “class II”), with distinct directionality and magnitude of methylation changes. (breen2020episignaturesstratifyinghelsmoortelvan pages 2-4, breen2020episignaturesstratifyinghelsmoortelvan pages 4-5)
5. Environmental information
The retrieved evidence emphasizes genetic causation; no disease-specific environmental, lifestyle, or infectious contributors were identified. (grice2024transientperipheralblood pages 1-2)
6. Mechanism / pathophysiology
6.1 Key concepts (integrated mechanistic model)
ADNP is a multifunctional protein linking chromatin remodeling/transcription, RNA/R-loop regulation, and cytoskeletal (microtubule) regulation. (d’incal2023chromatinremodeleractivitydependent pages 1-2, d’incal2023chromatinremodeleractivitydependent pages 19-20)
A coherent causal chain supported by multiple sources is: 1) Pathogenic ADNP variants disrupt ADNP protein level/function (often truncating variants escaping NMD) (helsmoortel2014aswisnfrelated pages 2-4, d’incal2023chromatinremodeleractivitydependent pages 6-8) 2) Chromatin remodeling dysregulation via SWI/SNF-BAF interactions (e.g., BRG1) and ChAHP/HP1/CHD4 complexes alters developmental gene regulation and cell fate programs (d’incal2023chromatinremodeleractivitydependent pages 1-2, d’incal2023chromatinremodeleractivitydependent pages 11-13) 3) Neuronal development and connectivity impairments, including neuritogenesis changes and synaptic/cytoskeletal dysregulation (EB1/EB3 dynamics; dendritic spine formation) (d’incal2023chromatinremodeleractivitydependent pages 4-6, hacohenkleiman2018activitydependentneuroprotectiveprotein pages 1-2) 4) Neurodevelopmental phenotype: global developmental delay, intellectual disability, ASD features, plus multisystem comorbidities. (d’incal2023chromatinremodeleractivitydependent pages 6-8, dijck2019clinicalpresentationof pages 13-18)
6.2 Molecular pathways and processes (with ontology suggestions)
Chromatin remodeling / nuclear regulation - ADNP associates with HP1 and BRG1/SWI-SNF and in murine stem cells with CHD4 in the ChAHP complex. (d’incal2023chromatinremodeleractivitydependent pages 1-2, d’incal2023chromatinremodeleractivitydependent pages 11-13) - Loss of ADNP disrupts ChAHP and exposes masked CTCF motifs, altering chromatin architecture and differentiation trajectories. (d’incal2023chromatinremodeleractivitydependent pages 11-13) - Suggested GO terms: - GO:0006338 chromatin remodeling - GO:0006355 regulation of transcription, DNA-templated - GO:0043044 ATP-dependent chromatin remodeling - GO:0140678 regulation of chromatin organization
Wnt/β-catenin signaling ADNP N-terminus binds β-catenin, stabilizing it and protecting it from degradation, linking ADNP to Wnt/β-catenin neurodevelopmental signaling. (d’incal2023chromatinremodeleractivitydependent pages 4-6) - Suggested GO:0016055 Wnt signaling pathway
Microtubules and synapse biology - ADNP contains an SxIP/SIP motif (embedded in NAP) enabling binding to EB1/EB3, which regulate microtubule dynamics relevant to axonal/dendritic development and spine formation; ADNP mutations reduce EB3 growth-track speed/length in model systems. (d’incal2023chromatinremodeleractivitydependent pages 11-13, hacohenkleiman2018activitydependentneuroprotectiveprotein pages 1-2) - Suggested GO terms: - GO:0007018 microtubule-based movement - GO:0008017 microtubule binding - GO:0048167 regulation of synaptic plasticity - GO:0043191 axon development - GO:0061564 axon guidance
Autophagy ADNP and ADNP-related pathways interact with autophagy regulators (e.g., LC3B, BECN1), with evidence of altered autophagy markers in Adnp haploinsufficient models and in a postmortem case. (d’incal2023chromatinremodeleractivitydependent pages 13-14) - Suggested GO:0006914 autophagy
6.3 Immune system involvement / transcriptomics (2024 development)
A 2024 ketamine-response transcriptomic study (10 individuals) showed acute, transient blood transcriptome changes enriched for monocyte-related signatures with “upregulation of immune and inflammatory-related processes and down-regulation of RNA processing mechanisms and metabolism,” returning to baseline by 24h–1 week. (Translational Psychiatry, published Jul 2024) (grice2024transientperipheralblood pages 1-2)
6.4 Cell types and anatomical structures (ontology suggestions)
- Suggested CL (cell types):
- CL:0000540 neuron
- CL:0000129 microglial cell (immune signatures are peripheral/monocytic; CNS cell specificity not established)
- CL:0000576 monocyte (supported by ketamine transcriptome enrichment) (grice2024transientperipheralblood pages 1-2)
- Suggested UBERON (anatomy):
- UBERON:0000955 brain
- UBERON:0001954 hippocampus (expression and mouse synaptic phenotypes) (d’incal2023chromatinremodeleractivitydependent pages 6-8, cho2023adnpmutantmicewith pages 9-10)
- UBERON:0002107 liver/UBERON:0000948 heart and UBERON:0002106 intestine may be relevant to comorbidities but mechanistic specificity is limited in current evidence.
7. Anatomical structures affected
Primary involvement is neurodevelopmental (brain/central nervous system) with frequent involvement of vision/ocular system, heart (congenital defects), gastrointestinal/oral-motor function, musculoskeletal system, and immune susceptibility (recurrent infections). (d’incal2023chromatinremodeleractivitydependent pages 6-8, dijck2019clinicalpresentationof pages 13-18)
8. Temporal development
- Onset: congenital/infantile; typically recognized in early childhood with developmental delay, hypotonia, feeding issues, and emerging ASD features. (helsmoortel2014aswisnfrelated pages 2-4, grice2024transientperipheralblood pages 1-2)
- Progression/course: lifelong neurodevelopmental disability with variable trajectory; evidence includes age-dependent differences in mouse synaptic phenotypes and limited human genotype–phenotype correlations, but comprehensive staging frameworks are not established. (cho2023adnpmutantmicewith pages 9-10, dijck2019clinicalpresentationof pages 13-18)
9. Inheritance and population
9.1 Inheritance pattern
Predominantly autosomal dominant, de novo pathogenic variants (heterozygous truncating variants; de novo in tested families in initial report). (helsmoortel2014aswisnfrelated pages 2-4, helsmoortel2014aswisnfrelated pages 1-2)
9.2 Epidemiology (available quantitative statements)
- The initial Nature Genetics discovery screened 5,776 patients and reported 10 ADNP mutations, estimating ADNP is mutated in ≥0.17% of ASD cases (this is an ASD-cohort contribution estimate, not population prevalence of ADNP syndrome). (helsmoortel2014aswisnfrelated pages 1-2)
Population prevalence/incidence: not identified in the retrieved sources; Orphanet/registry-based estimates should be added if available from authoritative epidemiology resources.
10. Diagnostics
10.1 Clinical recognition
A distinctive combination of neurodevelopmental delay (ID, severe speech and motor delay) with characteristic facial features and multiple medical comorbidities supports clinical suspicion. (dijck2019clinicalpresentationof pages 1-5, dijck2019clinicalpresentationof pages 13-18)
10.2 Genetic testing
- Common discovery/diagnostic routes include trio-based whole-exome sequencing and targeted sequencing panels in ASD/ID cohorts. (dijck2019clinicalpresentationof pages 1-5, helsmoortel2014aswisnfrelated pages 2-4)
- For knowledge-base encoding, the core action is detection of a pathogenic/likely pathogenic ADNP variant consistent with ACMG/AMP interpretation (ACMG classifications noted in cohort tables, but full ClinVar-level aggregation not present in retrieved text). (ge2024clinicalimpactand pages 4-5)
10.3 Epigenomic (episignature) diagnostics (important development)
ADNP syndrome has robust, mutation-location-dependent blood DNA methylation episignatures replicated across studies, supporting diagnostic utility particularly for variant interpretation: - Independent replication used Illumina EPIC 850K arrays on 24 affected individuals and replicated two episignatures. (breen2020episignaturesstratifyinghelsmoortelvan pages 1-2) - Class I vs II show large differences in differentially methylated CpGs (6,448 vs 2,582), with 888 shared CpGs often in inverse directions. (breen2020episignaturesstratifyinghelsmoortelvan pages 2-4, breen2020episignaturesstratifyinghelsmoortelvan pages 4-5)
Cautionary expert interpretation: Despite reproducible episignatures, the study reports “limited phenotypic differences… and no evidence that individuals with more widespread methylation changes are more severely affected,” and “no profound alterations in the blood transcriptome,” arguing against using methylation alone for behavioral severity stratification. (breen2020episignaturesstratifyinghelsmoortelvan pages 1-2)
10.4 Differential diagnosis
Not systematically enumerated in the retrieved evidence; in practice, differential diagnoses include other syndromic ASD/ID and chromatin-remodeling disorders (e.g., SWI/SNF-related syndromes), but authoritative differential lists should be drawn from GeneReviews/OMIM/Orphanet clinical summaries.
11. Outcome / prognosis
Prognosis is incompletely characterized in the retrieved evidence; a 2024 cohort paper explicitly notes that “little is known with certainty about the prognosis.” (Molecular Autism, published Jan 2024) (ge2024clinicalimpactand pages 1-2)
No survival or mortality statistics were identified in the retrieved sources.
12. Treatment
12.1 Supportive and rehabilitative care (current real-world implementation)
No formal guideline was retrieved, but the phenotype profile supports multidisciplinary management typical for neurodevelopmental syndromes (developmental therapies; management of feeding/oral-motor issues; vision and cardiac evaluation; sleep and seizure management as indicated). Evidence here is indirect via phenotype burden rather than explicit guideline statements. (d’incal2023chromatinremodeleractivitydependent pages 6-8, dijck2019clinicalpresentationof pages 13-18)
Suggested MAXO terms (examples): - MAXO:0000016 physical therapy - MAXO:0000176 occupational therapy - MAXO:0000120 speech therapy - MAXO:0000490 behavioral therapy - MAXO:0000136 special education intervention
12.2 Ketamine (recent clinical development; 2022–2024)
Clinical trial (open-label): A single-dose, open-label trial administered racemic ketamine 0.5 mg/kg IV over 40 minutes to 10 children with molecularly confirmed ADNP syndrome (ages 5–12), with continuous monitoring and follow-up through week 4. (Human Genetics and Genomics Advances; published Oct 2022) (kolevzon2022anopenlabelstudy pages 3-5)
Safety and outcomes: No serious adverse events were reported; common adverse events included elation/silliness (50%), aggression (40%), fatigue (40%), and nausea/vomiting/restlessness (20% each). Multiple caregiver-rated behavioral scales improved nominally at 1 week (e.g., ABC irritability 20.5→10.9, p=0.015; social withdrawal 9.9→4.2, p=0.007). (kolevzon2022anopenlabelstudy pages 1-2, kolevzon2022anopenlabelstudy pages 5-6, kolevzon2022anopenlabelstudy pages 3-5)
Trial registry record: NCT04388774 (COMPLETED; results posted 2023-07-07) describes extensive secondary outcomes and planned molecular profiling (RNA/DNA sequencing; methylation profiles). (NCT04388774 chunk 1)
Molecular follow-up (2024): In a longitudinal blood transcriptomic study of the same dosing paradigm (10 individuals), ketamine triggered “immediate and profound gene expression alterations” enriched for monocytes, with immune/inflammatory upregulation and RNA-processing/metabolism downregulation, returning to baseline by 24h–1 week. (Translational Psychiatry; published Jul 2024) (grice2024transientperipheralblood pages 1-2)
Suggested MAXO term: MAXO:0000736 ketamine administration (term label may vary; map to “ketamine therapy”/“intravenous drug administration” depending on MAXO granularity).
12.3 NAP / davunetide / CP201 (translational and preclinical)
Mechanism: NAP (NAPVSIPQ; davunetide; CP201) contains a SIP motif that binds microtubule end–binding proteins EB1/EB3, supporting dendritic spine formation and microtubule-linked synaptic function. (hacohenkleiman2018activitydependentneuroprotectiveprotein pages 1-2)
Preclinical efficacy: In Adnp+/– models, ADNP deficiency reduces dendritic spine density and alters synaptic gene expression; NAP partly rescues synaptic deficits and partially reverses developmental and behavioral phenotypes (vocalization, gait/motor, social and memory impairments), with daily administration described as systemic or nasal/intranasal in mice. (hacohenkleiman2018activitydependentneuroprotectiveprotein pages 1-2)
Biomarker concepts: Gut microbiota shifts in Adnp+/– mice show genotype and sex effects and can be rapidly corrected by NAP, proposed as treatment-dependent biomarkers. (kapitansky2020microbiotachangesassociated pages 1-2)
Development status notes: Case-series literature states CP201/davunetide has prior human clinical exposure with a “clean toxicology profile… more than 500 patients,” and notes orphan drug designation and pre-IND interactions for ADNP syndrome development; these statements are not from randomized ADNP syndrome efficacy trials. (levine2019developmentalphenotypeof pages 8-9)
Suggested MAXO terms: - MAXO:0000010 peptide therapy - MAXO:0000647 intranasal drug administration (for intranasal NAP paradigms)
13. Prevention
No primary prevention exists for de novo monogenic occurrence; prevention is largely genetic counseling and reproductive options.
Suggested MAXO terms: MAXO:0000079 genetic counseling; MAXO:0000127 prenatal genetic testing; MAXO:0000128 preimplantation genetic testing.
14. Other species / natural disease
No naturally occurring veterinary syndrome linked to ADNP was identified in the retrieved evidence.
15. Model organisms
15.1 Mouse models (key implementations)
- Adnp knockout: complete loss is embryonic lethal with severe brain formation defects (neural tube defects, ~E9.5 lethality reported in review). (d’incal2023chromatinremodeleractivitydependent pages 19-20, d’incal2023chromatinremodeleractivitydependent pages 4-6)
- Adnp haploinsufficiency (Adnp+/–) and related heterozygous models: recapitulate neurodevelopmental/behavioral phenotypes and synaptic pathology, including dendritic spine deficits responsive to NAP. (hacohenkleiman2018activitydependentneuroprotectiveprotein pages 1-2)
- Adnp-HT (exon 5 heterozygous deletion) synaptic plasticity model (2023): adult mice show excessive LTP and decreased LTD with CaMKIIα Thr286 hyperphosphorylation; moderate CaMKIIα inhibition (KN-62) normalized LTP in slices, implicating CaMKIIα hyperactivity as a mechanistic driver of cognitive inflexibility. (Molecular Psychiatry; published Jun 2023) (cho2023adnpmutantmicewith pages 9-10)
Suggested GO terms for model readouts: GO:0048167 regulation of synaptic plasticity; GO:0099536 synaptic signaling.
Key compiled evidence table
| Finding | Key details | Best recent source (year, DOI/URL) | Evidence type |
|---|---|---|---|
| Identifiers and synonyms | Preferred names: ADNP-related syndrome, ADNP syndrome, Helsmoortel–Van der Aa syndrome (HVDAS); MONDO: ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder (MONDO:0014379); OMIM: 615873; disorder is a rare monogenic neurodevelopmental syndrome caused by pathogenic ADNP variants at 20q13.13 (OpenTargets Search: ADNP-related syndrome,Helsmoortel-Van der Aa syndrome, ge2024clinicalimpactand pages 1-2, d’incal2023chromatinremodeleractivitydependent pages 1-2) | D’Incal et al., 2023, https://doi.org/10.1186/s13148-023-01450-8; Ge et al., 2024, https://doi.org/10.1186/s13229-024-00584-7 | Disease review + cohort + curated disease-target association |
| Core phenotype frequencies | D’Incal 2023 Table 1 summarizes high-frequency features: intellectual disability 100%, speech delay 99%, motor delay 96%, autism/autistic features 93%, feeding/GI problems 83%, behavioral problems 78%, visual problems 74%, sleep problems 65%, hand/foot abnormalities 62%, brain abnormalities/seizures 62%, musculoskeletal issues 55%, frequent infections 51%; image-confirmed from Table 1 (d’incal2023chromatinremodeleractivitydependent pages 6-8, d’incal2023chromatinremodeleractivitydependent media ebbb8a81) | D’Incal et al., 2023, https://doi.org/10.1186/s13148-023-01450-8 | Review synthesizing human cohorts; table/image evidence |
| Additional cohort frequencies (Van Dijck 2019) | In a 78-person cohort: GI/feeding problems 83%, visual problems 73.6% (including strabismus 49.2%, hypermetropia 40.3%, cortical visual impairment 41%), oral movement problems 45.6%, recurrent infections 51%, male cryptorchidism 34%, overweight 20.9%, obesity 7.5%, mild childhood hearing loss 11.7%; brain malformations and several comorbidities were also common (dijck2019clinicalpresentationof pages 13-18, dijck2019clinicalpresentationof pages 1-5) | Van Dijck et al., 2019, https://doi.org/10.1016/j.biopsych.2018.02.1173 | Large human clinical cohort |
| Genetics and variant spectrum | Pathogenic variants are predominantly heterozygous de novo loss-of-function changes, especially nonsense and frameshift variants; most cluster in exon 5 / last exon, often predicted to escape nonsense-mediated decay (NMD), supporting expression of truncated protein rather than simple haploinsufficiency alone; recurrent hotspots include p.Tyr719*, p.Arg730*, and p.Asn832Lysfs*81 / p.Leu831Ilefs*82; a single whole-gene deletion has been reported (d’incal2023chromatinremodeleractivitydependent pages 6-8, helsmoortel2014aswisnfrelated pages 2-4, dijck2019clinicalpresentationof pages 13-18) | D’Incal et al., 2023, https://doi.org/10.1186/s13148-023-01450-8; Helsmoortel et al., 2014, https://doi.org/10.1038/ng.2899 | Human genetics studies + review |
| Epidemiology / contribution to ASD | Original discovery screened 5,776 patients and identified 10 ADNP mutations; authors estimated ADNP is mutated in at least 0.17% of ASD cases, making it one of the more frequent single-gene ASD causes; truncating de novo variants were significantly enriched in cases (Fisher p=0.001852; OR 13.24668) (helsmoortel2014aswisnfrelated pages 2-4, helsmoortel2014aswisnfrelated pages 1-2) | Helsmoortel et al., 2014, https://doi.org/10.1038/ng.2899 | Human sequencing discovery cohort |
| Epigenetic / episignature diagnostics | Blood DNA methylation studies identified two mutation-location-dependent episignatures: class I (outside ~c.2000–2340) and class II (within that region, including p.Tyr719*). In independent replication, 24 affected individuals split evenly by class; class I showed 6,448 differentially methylated autosomal CpGs and class II 2,582. Utility appears strongest for variant interpretation/diagnosis, while phenotype correlation is modest and should not be overinterpreted clinically (breen2020episignaturesstratifyinghelsmoortelvan pages 1-2, breen2020episignaturesstratifyinghelsmoortelvan pages 2-4, breen2020episignaturesstratifyinghelsmoortelvan pages 4-5, breen2020episignaturesstratifyingadnp pages 4-6) | Breen et al., 2020, https://doi.org/10.1016/j.ajhg.2020.07.003 | Human methylation biomarker study |
| Ketamine clinical development (2022 trial) | Open-label, single-dose IV ketamine 0.5 mg/kg over 40 min in 10 children with molecularly confirmed ADNP syndrome; generally well tolerated with no serious adverse events. Common AEs included elation/silliness 50%, fatigue 40%, increased aggression 40%; caregiver/clinician measures showed nominal short-term improvements in irritability, social withdrawal, stereotypies, sensory symptoms, and attention-related measures; trial registered as NCT04388774, completed, results posted 2023-07-07 (kolevzon2022anopenlabelstudy pages 1-2, kolevzon2022anopenlabelstudy pages 5-6, kolevzon2022anopenlabelstudy pages 3-5, NCT04388774 chunk 1) | Kolevzon et al., 2022, https://doi.org/10.1016/j.xhgg.2022.100138; ClinicalTrials.gov NCT04388774 | Human open-label interventional trial |
| Ketamine molecular follow-up (2024) | Transcriptomic follow-up after the same single 0.5 mg/kg ketamine infusion in 10 individuals found immediate and profound but transient blood RNA changes, enriched for monocyte-related signals, with upregulation of immune/inflammatory processes and downregulation of RNA processing/metabolism; changes returned toward baseline by 24 h to 1 week (grice2024transientperipheralblood pages 1-2, grice2024transientperipheralblood pages 2-3) | Grice et al., 2024, https://doi.org/10.1038/s41398-024-03005-8 | Human longitudinal transcriptomics |
| NAP / davunetide / CP201 | NAP (NAPVSIPQ; davunetide; CP201) is an ADNP-derived peptide that binds EB1/EB3 via an SxIP/SIP motif and supports microtubule- and tau-related functions. In Adnp+/− and mutant models it partially rescued dendritic spine deficits, developmental delay, vocalization, gait/motor phenotypes, social/object memory, autophagy-related abnormalities, and some microbiome changes; delivery reported as systemic/nasal in mice, including intranasal use in some studies. Clinical status remains preclinical/early translational for ADNP syndrome; review and case literature note prior non-ADNP human exposure with favorable safety, and one report notes FDA orphan drug designation for ADNP syndrome (hacohenkleiman2018activitydependentneuroprotectiveprotein pages 9-10, levine2019developmentalphenotypeof pages 8-9, kapitansky2020microbiotachangesassociated pages 1-2, hacohenkleiman2018activitydependentneuroprotectiveprotein pages 1-2, d’incal2023chromatinremodeleractivitydependent pages 13-14, d’incal2023chromatinremodeleractivitydependent pages 14-15) | D’Incal et al., 2023, https://doi.org/10.1186/s13148-023-01450-8; Hacohen-Kleiman et al., 2018, https://doi.org/10.1172/jci98199 | Preclinical mouse/cellular studies + translational review |
| Ongoing natural history / characterization study | Observational study NCT03718936 (Mount Sinai Seaver Autism Center) is recruiting and aims to characterize ADNP-related neurodevelopmental disorders using standardized autism, developmental, neurological, EEG, eyetracking, and biospecimen measures; planned enrollment 30; useful as current real-world natural history infrastructure (NCT03718936 chunk 1, NCT03718936 chunk 2) | ClinicalTrials.gov NCT03718936, https://clinicaltrials.gov/study/NCT03718936 | Observational natural history study |
Table: This table compacts the most actionable disease-characteristics evidence for ADNP-related syndrome, including identifiers, phenotype frequencies, variant architecture, and the current therapeutic landscape. It is designed to support rapid knowledge-base population with recent, source-linked findings.
Visual evidence (phenotype frequency table)
A cropped Table 1 image summarizing hallmark phenotype frequencies (ID 100%, speech delay 99%, ASD ~93%, etc.) is available from the 2023 Clinical Epigenetics review. (d’incal2023chromatinremodeleractivitydependent media ebbb8a81)
Recent developments prioritized (2023–2024)
1) 2023 integrated mechanistic review: consolidates ADNP’s chromatin remodeling roles (SWI/SNF, ChAHP, HP1/POGZ), cytoskeletal EB interactions, and highlights phenotype frequencies across cohorts. (Published Mar 2023; https://doi.org/10.1186/s13148-023-01450-8) (d’incal2023chromatinremodeleractivitydependent pages 6-8) 2) 2024 cohort + in vitro functional work: first Chinese pediatric cohort with systematic clinical phenotypes and variant expression/localization effects (notably p.Y719 impacting nuclear localization). (Published Jan 2024; https://doi.org/10.1186/s13229-024-00584-7) (ge2024clinicalimpactand pages 1-2, ge2024clinicalimpactand pages 4-5) 3) 2024 ketamine molecular profiling*: longitudinal blood RNA-seq after ketamine infusion shows transient monocyte/inflammatory program engagement, contributing a molecular “response signature” layer. (Published Jul 2024; https://doi.org/10.1038/s41398-024-03005-8) (grice2024transientperipheralblood pages 1-2)
Appendix: authoritative-source viewpoints (expert interpretation grounded in texts)
- Evidence across cohorts shows ADNP syndrome is consistently associated with severe developmental outcomes and broad comorbidity; however, prognosis and longitudinal staging remain uncertain (“little is known with certainty about the prognosis”). (ge2024clinicalimpactand pages 1-2)
- Epigenetic episignatures are reproducible and diagnostically useful but should be interpreted cautiously for behavioral severity stratification (“limited phenotypic differences…”; “no profound alterations in the blood transcriptome”). (breen2020episignaturesstratifyinghelsmoortelvan pages 1-2)
URLs and publication dates (selected key sources)
- D’Incal et al., Clinical Epigenetics, Mar 2023. https://doi.org/10.1186/s13148-023-01450-8 (d’incal2023chromatinremodeleractivitydependent pages 6-8)
- Cho et al., Molecular Psychiatry, Jun 2023. https://doi.org/10.1038/s41380-023-02129-5 (cho2023adnpmutantmicewith pages 9-10)
- Ge et al., Molecular Autism, Jan 2024. https://doi.org/10.1186/s13229-024-00584-7 (ge2024clinicalimpactand pages 1-2)
- Grice et al., Translational Psychiatry, Jul 2024. https://doi.org/10.1038/s41398-024-03005-8 (grice2024transientperipheralblood pages 1-2)
- Kolevzon et al., Human Genetics and Genomics Advances, Oct 2022. https://doi.org/10.1016/j.xhgg.2022.100138 (kolevzon2022anopenlabelstudy pages 3-5)
- ClinicalTrials.gov NCT04388774 (results posted 2023-07-07). (NCT04388774 chunk 1)
- Helsmoortel et al., Nature Genetics, Feb 2014. https://doi.org/10.1038/ng.2899 (helsmoortel2014aswisnfrelated pages 1-2)
References
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(dijck2019clinicalpresentationof pages 13-18): Anke Van Dijck, Anneke T. Vulto-van Silfhout, Elisa Cappuyns, Ilse M. van der Werf, Grazia M. Mancini, Andreas Tzschach, Raphael Bernier, Illana Gozes, Evan E. Eichler, Corrado Romano, Anna Lindstrand, Ann Nordgren, Madhura Bakshi, Meredith Wilson, Yemina Berman, Rebecca Dickson, Erik Fransen, Céline Helsmoortel, Jenneke Van den Ende, Nathalie Van der Aa, Marina J. van de Wijdeven, Jessica Rosenblum, Fabíola Monteiro, Fernando Kok, Nada Quercia, Sarah Bowdin, David Dyment, David Chitayat, Ebba Alkhunaizi, Susanne E. Boonen, Boris Keren, Aurelia Jacquette, Laurence Faivre, Stephane Bezieau, Bertrand Isidor, Angelika Rieß, Ute Moog, Sally Ann Lynch, Terri McVeigh, Orly Elpeleg, Marie Falkenberg Smeland, Madeleine Fannemel, Arie van Haeringen, Saskia M. Maas, H.E. Veenstra-Knol, Meyke Schouten, Marjolein H. Willemsen, Carlo L. Marcelis, Charlotte Ockeloen, Ineke van der Burgt, Ilse Feenstra, Jasper van der Smagt, Aleksandra Jezela-Stanek, Malgorzata Krajewska-Walasek, Domingo González-Lamuño, Britt-Marie Anderlid, Helena Malmgren, Magnus Nordenskjöld, Emma Clement, Jane Hurst, Kay Metcalfe, Sahar Mansour, Katherine Lachlan, Jill Clayton-Smith, Laura G. Hendon, Omar A. Abdulrahman, Eric Morrow, Clare McMillan, Jennifer Gerdts, Joseph Peeden, Samantha A. Schrier Vergano, Caitlin Valentino, Wendy K. Chung, Jillian R. Ozmore, Sandra Bedrosian-Sermone, Anna Dennis, Kayla Treat, Susan Starling Hughes, Nicole Safina, Jean-Baptiste Le Pichon, Marianne McGuire, Elena Infante, Suneeta Madan-Khetarpal, Sonal Desai, Paul Benke, Alyson Krokosky, Ingrid Cristian, Laura Baker, Karen Gripp, Holly A. Stessman, Jacob Eichenberger, Parul Jayakar, Amy Pizzino, Melanie Ann Manning, Leah Slattery, Malin Kvarnung, Tjitske Kleefstra, Bert B.A. de Vries, Sébastien Küry, Jill A. Rosenfeld, Marije E. Meuwissen, Geert Vandeweyer, and R. Frank Kooy. Clinical presentation of a complex neurodevelopmental disorder caused by mutations in adnp. Biological Psychiatry, 85(4):287-297, Feb 2019. URL: https://doi.org/10.1016/j.biopsych.2018.02.1173, doi:10.1016/j.biopsych.2018.02.1173. This article has 181 citations and is from a highest quality peer-reviewed journal.
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(helsmoortel2014aswisnfrelated pages 2-4): Céline Helsmoortel, Anneke T Vulto-van Silfhout, Bradley P Coe, Geert Vandeweyer, Liesbeth Rooms, Jenneke van den Ende, Janneke H M Schuurs-Hoeijmakers, Carlo L Marcelis, Marjolein H Willemsen, Lisenka E L M Vissers, Helger G Yntema, Madhura Bakshi, Meredith Wilson, Kali T Witherspoon, Helena Malmgren, Ann Nordgren, Göran Annerén, Marco Fichera, Paolo Bosco, Corrado Romano, Bert B A de Vries, Tjitske Kleefstra, R Frank Kooy, Evan E Eichler, and Nathalie Van der Aa. A swi/snf related autism syndrome caused by de novo mutations in adnp. Nature genetics, 46:380-384, Feb 2014. URL: https://doi.org/10.1038/ng.2899, doi:10.1038/ng.2899. This article has 441 citations and is from a highest quality peer-reviewed journal.
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(d’incal2023chromatinremodeleractivitydependent media ebbb8a81): Claudio Peter D’Incal, Kirsten Esther Van Rossem, Kevin De Man, Anthony Konings, Anke Van Dijck, Ludovico Rizzuti, Alessandro Vitriolo, Giuseppe Testa, Illana Gozes, Wim Vanden Berghe, and R. Frank Kooy. Chromatin remodeler activity-dependent neuroprotective protein (adnp) contributes to syndromic autism. Clinical Epigenetics, Mar 2023. URL: https://doi.org/10.1186/s13148-023-01450-8, doi:10.1186/s13148-023-01450-8. This article has 43 citations and is from a peer-reviewed journal.
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(ge2024clinicalimpactand pages 4-5): Chuanhui Ge, Yuxin Tian, Chunchun Hu, Lianni Mei, Dongyun Li, Ping Dong, Ying Zhang, Huiping Li, Daijing Sun, Wenzhu Peng, Xiu Xu, Yan Jiang, and Qiong Xu. Clinical impact and in vitro characterization of adnp variants in pediatric patients. Molecular Autism, Jan 2024. URL: https://doi.org/10.1186/s13229-024-00584-7, doi:10.1186/s13229-024-00584-7. This article has 10 citations and is from a peer-reviewed journal.
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(kolevzon2022anopenlabelstudy pages 1-2): Alexander Kolevzon, Tess Levy, Sarah Barkley, Sandra Bedrosian-Sermone, Matthew Davis, Jennifer Foss-Feig, Danielle Halpern, Katherine Keller, Ana Kostic, Christina Layton, Rebecca Lee, Bonnie Lerman, Matthew Might, Sven Sandin, Paige M. Siper, Laura G. Sloofman, Hannah Walker, Jessica Zweifach, and Joseph D. Buxbaum. An open-label study evaluating the safety, behavioral, and electrophysiological outcomes of low-dose ketamine in children with adnp syndrome. Oct 2022. URL: https://doi.org/10.1016/j.xhgg.2022.100138, doi:10.1016/j.xhgg.2022.100138. This article has 23 citations and is from a peer-reviewed journal.
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(helsmoortel2014aswisnfrelated pages 1-2): Céline Helsmoortel, Anneke T Vulto-van Silfhout, Bradley P Coe, Geert Vandeweyer, Liesbeth Rooms, Jenneke van den Ende, Janneke H M Schuurs-Hoeijmakers, Carlo L Marcelis, Marjolein H Willemsen, Lisenka E L M Vissers, Helger G Yntema, Madhura Bakshi, Meredith Wilson, Kali T Witherspoon, Helena Malmgren, Ann Nordgren, Göran Annerén, Marco Fichera, Paolo Bosco, Corrado Romano, Bert B A de Vries, Tjitske Kleefstra, R Frank Kooy, Evan E Eichler, and Nathalie Van der Aa. A swi/snf related autism syndrome caused by de novo mutations in adnp. Nature genetics, 46:380-384, Feb 2014. URL: https://doi.org/10.1038/ng.2899, doi:10.1038/ng.2899. This article has 441 citations and is from a highest quality peer-reviewed journal.
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(breen2020episignaturesstratifyingadnp pages 4-6): Michael S. Breen, Paras Garg, Lara Tang, Danielle Mendonca, Tess Levy, Mafalda Barbosa, Anne B Arnett, Evangeline Kurtz-Nelson, Emanuele Agolini, Agatino Battaglia, Andreas G Chiocchetti, Christine M Freitag, Alicia Garcia-Alcon, Paola Grammatico, Irva Hertz-Picciotto, Yunin Ludena-Rodriguez, Carmen Moreno, Antonio Novelli, Mara Parellada, Giulia Pascolini, Flora Tassone, Dorothy E Grice, Raphael A Bernier, Alexander Kolevzon, Andrew Sharp, Joseph D Buxbaum, Paige M Siper, and Silvia De Rubeis. Episignatures stratifying adnp syndrome show modest correlation with phenotype. BioRxiv, Apr 2020. URL: https://doi.org/10.1101/2020.04.01.014902, doi:10.1101/2020.04.01.014902. This article has 5 citations.
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(breen2020episignaturesstratifyinghelsmoortelvan pages 2-4): Michael S. Breen, Paras Garg, Lara Tang, Danielle Mendonca, Tess Levy, Mafalda Barbosa, Anne B. Arnett, Evangeline Kurtz-Nelson, Emanuele Agolini, Agatino Battaglia, Andreas G. Chiocchetti, Christine M. Freitag, Alicia Garcia-Alcon, Paola Grammatico, Irva Hertz-Picciotto, Yunin Ludena-Rodriguez, Carmen Moreno, Antonio Novelli, Mara Parellada, Giulia Pascolini, Flora Tassone, Dorothy E. Grice, Daniele Di Marino, Raphael A. Bernier, Alexander Kolevzon, Andrew J. Sharp, Joseph D. Buxbaum, Paige M. Siper, and Silvia De Rubeis. Episignatures stratifying helsmoortel-van der aa syndrome show modest correlation with phenotype. Sep 2020. URL: https://doi.org/10.1016/j.ajhg.2020.07.003, doi:10.1016/j.ajhg.2020.07.003. This article has 59 citations.
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(breen2020episignaturesstratifyinghelsmoortelvan pages 4-5): Michael S. Breen, Paras Garg, Lara Tang, Danielle Mendonca, Tess Levy, Mafalda Barbosa, Anne B. Arnett, Evangeline Kurtz-Nelson, Emanuele Agolini, Agatino Battaglia, Andreas G. Chiocchetti, Christine M. Freitag, Alicia Garcia-Alcon, Paola Grammatico, Irva Hertz-Picciotto, Yunin Ludena-Rodriguez, Carmen Moreno, Antonio Novelli, Mara Parellada, Giulia Pascolini, Flora Tassone, Dorothy E. Grice, Daniele Di Marino, Raphael A. Bernier, Alexander Kolevzon, Andrew J. Sharp, Joseph D. Buxbaum, Paige M. Siper, and Silvia De Rubeis. Episignatures stratifying helsmoortel-van der aa syndrome show modest correlation with phenotype. Sep 2020. URL: https://doi.org/10.1016/j.ajhg.2020.07.003, doi:10.1016/j.ajhg.2020.07.003. This article has 59 citations.
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(d’incal2023chromatinremodeleractivitydependent pages 1-2): Claudio Peter D’Incal, Kirsten Esther Van Rossem, Kevin De Man, Anthony Konings, Anke Van Dijck, Ludovico Rizzuti, Alessandro Vitriolo, Giuseppe Testa, Illana Gozes, Wim Vanden Berghe, and R. Frank Kooy. Chromatin remodeler activity-dependent neuroprotective protein (adnp) contributes to syndromic autism. Clinical Epigenetics, Mar 2023. URL: https://doi.org/10.1186/s13148-023-01450-8, doi:10.1186/s13148-023-01450-8. This article has 43 citations and is from a peer-reviewed journal.
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(d’incal2023chromatinremodeleractivitydependent pages 19-20): Claudio Peter D’Incal, Kirsten Esther Van Rossem, Kevin De Man, Anthony Konings, Anke Van Dijck, Ludovico Rizzuti, Alessandro Vitriolo, Giuseppe Testa, Illana Gozes, Wim Vanden Berghe, and R. Frank Kooy. Chromatin remodeler activity-dependent neuroprotective protein (adnp) contributes to syndromic autism. Clinical Epigenetics, Mar 2023. URL: https://doi.org/10.1186/s13148-023-01450-8, doi:10.1186/s13148-023-01450-8. This article has 43 citations and is from a peer-reviewed journal.
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(d’incal2023chromatinremodeleractivitydependent pages 11-13): Claudio Peter D’Incal, Kirsten Esther Van Rossem, Kevin De Man, Anthony Konings, Anke Van Dijck, Ludovico Rizzuti, Alessandro Vitriolo, Giuseppe Testa, Illana Gozes, Wim Vanden Berghe, and R. Frank Kooy. Chromatin remodeler activity-dependent neuroprotective protein (adnp) contributes to syndromic autism. Clinical Epigenetics, Mar 2023. URL: https://doi.org/10.1186/s13148-023-01450-8, doi:10.1186/s13148-023-01450-8. This article has 43 citations and is from a peer-reviewed journal.
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(d’incal2023chromatinremodeleractivitydependent pages 4-6): Claudio Peter D’Incal, Kirsten Esther Van Rossem, Kevin De Man, Anthony Konings, Anke Van Dijck, Ludovico Rizzuti, Alessandro Vitriolo, Giuseppe Testa, Illana Gozes, Wim Vanden Berghe, and R. Frank Kooy. Chromatin remodeler activity-dependent neuroprotective protein (adnp) contributes to syndromic autism. Clinical Epigenetics, Mar 2023. URL: https://doi.org/10.1186/s13148-023-01450-8, doi:10.1186/s13148-023-01450-8. This article has 43 citations and is from a peer-reviewed journal.
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(hacohenkleiman2018activitydependentneuroprotectiveprotein pages 1-2): Gal Hacohen-Kleiman, Shlomo Sragovich, Gidon Karmon, Andy Y. L. Gao, Iris Grigg, Metsada Pasmanik-Chor, Albert Le, Vlasta Korenková, R. Anne McKinney, and Illana Gozes. Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome. Journal of Clinical Investigation, 128:4956–4969, Sep 2018. URL: https://doi.org/10.1172/jci98199, doi:10.1172/jci98199. This article has 108 citations and is from a highest quality peer-reviewed journal.
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(d’incal2023chromatinremodeleractivitydependent pages 13-14): Claudio Peter D’Incal, Kirsten Esther Van Rossem, Kevin De Man, Anthony Konings, Anke Van Dijck, Ludovico Rizzuti, Alessandro Vitriolo, Giuseppe Testa, Illana Gozes, Wim Vanden Berghe, and R. Frank Kooy. Chromatin remodeler activity-dependent neuroprotective protein (adnp) contributes to syndromic autism. Clinical Epigenetics, Mar 2023. URL: https://doi.org/10.1186/s13148-023-01450-8, doi:10.1186/s13148-023-01450-8. This article has 43 citations and is from a peer-reviewed journal.
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(cho2023adnpmutantmicewith pages 9-10): Heejin Cho, Taesun Yoo, Heera Moon, Hyojin Kang, Yeji Yang, MinSoung Kang, Esther Yang, Dowoon Lee, Daehee Hwang, Hyun Kim, Doyoun Kim, Jin Young Kim, and Eunjoon Kim. Adnp-mutant mice with cognitive inflexibility, camkiiα hyperactivity, and synaptic plasticity deficits. Molecular Psychiatry, 28:3548-3562, Jun 2023. URL: https://doi.org/10.1038/s41380-023-02129-5, doi:10.1038/s41380-023-02129-5. This article has 27 citations and is from a highest quality peer-reviewed journal.
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(dijck2019clinicalpresentationof pages 1-5): Anke Van Dijck, Anneke T. Vulto-van Silfhout, Elisa Cappuyns, Ilse M. van der Werf, Grazia M. Mancini, Andreas Tzschach, Raphael Bernier, Illana Gozes, Evan E. Eichler, Corrado Romano, Anna Lindstrand, Ann Nordgren, Madhura Bakshi, Meredith Wilson, Yemina Berman, Rebecca Dickson, Erik Fransen, Céline Helsmoortel, Jenneke Van den Ende, Nathalie Van der Aa, Marina J. van de Wijdeven, Jessica Rosenblum, Fabíola Monteiro, Fernando Kok, Nada Quercia, Sarah Bowdin, David Dyment, David Chitayat, Ebba Alkhunaizi, Susanne E. Boonen, Boris Keren, Aurelia Jacquette, Laurence Faivre, Stephane Bezieau, Bertrand Isidor, Angelika Rieß, Ute Moog, Sally Ann Lynch, Terri McVeigh, Orly Elpeleg, Marie Falkenberg Smeland, Madeleine Fannemel, Arie van Haeringen, Saskia M. Maas, H.E. Veenstra-Knol, Meyke Schouten, Marjolein H. Willemsen, Carlo L. Marcelis, Charlotte Ockeloen, Ineke van der Burgt, Ilse Feenstra, Jasper van der Smagt, Aleksandra Jezela-Stanek, Malgorzata Krajewska-Walasek, Domingo González-Lamuño, Britt-Marie Anderlid, Helena Malmgren, Magnus Nordenskjöld, Emma Clement, Jane Hurst, Kay Metcalfe, Sahar Mansour, Katherine Lachlan, Jill Clayton-Smith, Laura G. Hendon, Omar A. Abdulrahman, Eric Morrow, Clare McMillan, Jennifer Gerdts, Joseph Peeden, Samantha A. Schrier Vergano, Caitlin Valentino, Wendy K. Chung, Jillian R. Ozmore, Sandra Bedrosian-Sermone, Anna Dennis, Kayla Treat, Susan Starling Hughes, Nicole Safina, Jean-Baptiste Le Pichon, Marianne McGuire, Elena Infante, Suneeta Madan-Khetarpal, Sonal Desai, Paul Benke, Alyson Krokosky, Ingrid Cristian, Laura Baker, Karen Gripp, Holly A. Stessman, Jacob Eichenberger, Parul Jayakar, Amy Pizzino, Melanie Ann Manning, Leah Slattery, Malin Kvarnung, Tjitske Kleefstra, Bert B.A. de Vries, Sébastien Küry, Jill A. Rosenfeld, Marije E. Meuwissen, Geert Vandeweyer, and R. Frank Kooy. Clinical presentation of a complex neurodevelopmental disorder caused by mutations in adnp. Biological Psychiatry, 85(4):287-297, Feb 2019. URL: https://doi.org/10.1016/j.biopsych.2018.02.1173, doi:10.1016/j.biopsych.2018.02.1173. This article has 181 citations and is from a highest quality peer-reviewed journal.
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(breen2020episignaturesstratifyinghelsmoortelvan pages 1-2): Michael S. Breen, Paras Garg, Lara Tang, Danielle Mendonca, Tess Levy, Mafalda Barbosa, Anne B. Arnett, Evangeline Kurtz-Nelson, Emanuele Agolini, Agatino Battaglia, Andreas G. Chiocchetti, Christine M. Freitag, Alicia Garcia-Alcon, Paola Grammatico, Irva Hertz-Picciotto, Yunin Ludena-Rodriguez, Carmen Moreno, Antonio Novelli, Mara Parellada, Giulia Pascolini, Flora Tassone, Dorothy E. Grice, Daniele Di Marino, Raphael A. Bernier, Alexander Kolevzon, Andrew J. Sharp, Joseph D. Buxbaum, Paige M. Siper, and Silvia De Rubeis. Episignatures stratifying helsmoortel-van der aa syndrome show modest correlation with phenotype. Sep 2020. URL: https://doi.org/10.1016/j.ajhg.2020.07.003, doi:10.1016/j.ajhg.2020.07.003. This article has 59 citations.
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(kolevzon2022anopenlabelstudy pages 3-5): Alexander Kolevzon, Tess Levy, Sarah Barkley, Sandra Bedrosian-Sermone, Matthew Davis, Jennifer Foss-Feig, Danielle Halpern, Katherine Keller, Ana Kostic, Christina Layton, Rebecca Lee, Bonnie Lerman, Matthew Might, Sven Sandin, Paige M. Siper, Laura G. Sloofman, Hannah Walker, Jessica Zweifach, and Joseph D. Buxbaum. An open-label study evaluating the safety, behavioral, and electrophysiological outcomes of low-dose ketamine in children with adnp syndrome. Oct 2022. URL: https://doi.org/10.1016/j.xhgg.2022.100138, doi:10.1016/j.xhgg.2022.100138. This article has 23 citations and is from a peer-reviewed journal.
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(kolevzon2022anopenlabelstudy pages 5-6): Alexander Kolevzon, Tess Levy, Sarah Barkley, Sandra Bedrosian-Sermone, Matthew Davis, Jennifer Foss-Feig, Danielle Halpern, Katherine Keller, Ana Kostic, Christina Layton, Rebecca Lee, Bonnie Lerman, Matthew Might, Sven Sandin, Paige M. Siper, Laura G. Sloofman, Hannah Walker, Jessica Zweifach, and Joseph D. Buxbaum. An open-label study evaluating the safety, behavioral, and electrophysiological outcomes of low-dose ketamine in children with adnp syndrome. Oct 2022. URL: https://doi.org/10.1016/j.xhgg.2022.100138, doi:10.1016/j.xhgg.2022.100138. This article has 23 citations and is from a peer-reviewed journal.
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(NCT04388774 chunk 1): Alexander Kolevzon. Low-Dose Ketamine in Children With ADNP Syndrome. Alexander Kolevzon. 2020. ClinicalTrials.gov Identifier: NCT04388774
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(kapitansky2020microbiotachangesassociated pages 1-2): Oxana Kapitansky, Eliezer Giladi, Iman Jaljuli, Stefan Bereswill, Markus M. Heimesaat, and Illana Gozes. Microbiota changes associated with adnp deficiencies: rapid indicators for nap (cp201) treatment of the adnp syndrome and beyond. Journal of Neural Transmission, 127:251-263, Feb 2020. URL: https://doi.org/10.1007/s00702-020-02155-5, doi:10.1007/s00702-020-02155-5. This article has 16 citations and is from a peer-reviewed journal.
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(levine2019developmentalphenotypeof pages 8-9): Joseph Levine, David Cohen, Carole Herman, Alain Verloes, Vincent Guinchat, Lautaro Diaz, Cora Cravero, Anne Mandel, and Illana Gozes. Developmental phenotype of the rare case of dj caused by a unique adnp gene de novo mutation. Journal of Molecular Neuroscience, 68:321-330, May 2019. URL: https://doi.org/10.1007/s12031-019-01333-9, doi:10.1007/s12031-019-01333-9. This article has 28 citations and is from a peer-reviewed journal.
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(grice2024transientperipheralblood pages 2-3): Ariela S. Buxbaum Grice, Laura Sloofman, Tess Levy, Hannah Walker, Gauri Ganesh, Miguel Rodriguez de los Santos, Pardis Amini, Joseph D. Buxbaum, Alexander Kolevzon, Ana Kostic, and Michael S. Breen. Transient peripheral blood transcriptomic response to ketamine treatment in children with adnp syndrome. Translational Psychiatry, Jul 2024. URL: https://doi.org/10.1038/s41398-024-03005-8, doi:10.1038/s41398-024-03005-8. This article has 5 citations and is from a peer-reviewed journal.
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(hacohenkleiman2018activitydependentneuroprotectiveprotein pages 9-10): Gal Hacohen-Kleiman, Shlomo Sragovich, Gidon Karmon, Andy Y. L. Gao, Iris Grigg, Metsada Pasmanik-Chor, Albert Le, Vlasta Korenková, R. Anne McKinney, and Illana Gozes. Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome. Journal of Clinical Investigation, 128:4956–4969, Sep 2018. URL: https://doi.org/10.1172/jci98199, doi:10.1172/jci98199. This article has 108 citations and is from a highest quality peer-reviewed journal.
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(d’incal2023chromatinremodeleractivitydependent pages 14-15): Claudio Peter D’Incal, Kirsten Esther Van Rossem, Kevin De Man, Anthony Konings, Anke Van Dijck, Ludovico Rizzuti, Alessandro Vitriolo, Giuseppe Testa, Illana Gozes, Wim Vanden Berghe, and R. Frank Kooy. Chromatin remodeler activity-dependent neuroprotective protein (adnp) contributes to syndromic autism. Clinical Epigenetics, Mar 2023. URL: https://doi.org/10.1186/s13148-023-01450-8, doi:10.1186/s13148-023-01450-8. This article has 43 citations and is from a peer-reviewed journal.
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(NCT03718936 chunk 1): Alexander Kolevzon. ADNP Syndrome: The Seaver Autism Center for Research and Treatment is Characterizing ADNP-related Neurodevelopmental Disorders Using Genetic, Medical, and Neuropsychological Measures.. Icahn School of Medicine at Mount Sinai. 2017. ClinicalTrials.gov Identifier: NCT03718936
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(NCT03718936 chunk 2): Alexander Kolevzon. ADNP Syndrome: The Seaver Autism Center for Research and Treatment is Characterizing ADNP-related Neurodevelopmental Disorders Using Genetic, Medical, and Neuropsychological Measures.. Icahn School of Medicine at Mount Sinai. 2017. ClinicalTrials.gov Identifier: NCT03718936
