RARE DISEASE
ADNP syndrome
ADNP syndrome
ADNP syndrome
Synonyms: ADNP-related syndromic intellectual disability-autism spectrum disorder, HVDAS, Helsmoortel-Van Der Aa Syndrome
Synonyms: ADNP-related syndromic intellectual disability-autism spectrum disorder, HVDAS, Helsmoortel-Van Der Aa Syndrome
Synonyms: ADNP-related syndromic intellectual disability-autism spectrum disorder, HVDAS, Helsmoortel-Van Der Aa Syndrome
Drug discovery
2
drugs
With orphan designations
Overview
ADNP syndrome (Helsmoortel-VanDerAa syndrome) is a rare neurodevelopmental disorder caused by de novo mutations in the ADNP gene, affecting chromatin remodeling and neurodevelopment. Core features include global developmental delay, intellectual disability (ranging from mild to profound), autism spectrum disorder (67% of cases), and speech apraxia. Multisystem involvement often includes hypotonia (75%), seizures (16-40%), congenital heart defects (38%), gastrointestinal dysfunction, vision abnormalities (74%), and early tooth eruption. Prevalence is estimated at 1-2/100,000, representing ~0.17% of ASD cases [1][7][11][17].
Burden
Clinical: 65% require lifelong care for severe ID; 40% have life-threatening comorbidities (sepsis, liver failure, cardiomyopathy) [2][4][6]
Functional: 52% never achieve independent speech; median walking age 3.5 years [1][14]
Economic: High healthcare utilization (83% require frequent specialist visits); 20% mortality <10 years from organ failure [2][4][6]
Therapies
Symptomatic care: Multidisciplinary therapy (speech/OT/PT), behavioral interventions (ABA), PROMPT method for apraxia [3][14]
Investigational: Low-dose ketamine (improves social/behavioral symptoms in trials) [8][12], CP201 peptide therapy (targets tauopathy) [2], CRISPR/gene therapy research [6]
Management: Seizure control, cardiac surveillance, nutritional support [7][9]
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases
Research Papers
55 drug discovery papers about ADNP syndrome, with 1 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
55 drug discovery papers about ADNP syndrome, with 1 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-08-11 | Dramatic sex differences leading to different brain disease presentation: The requirement for sex-specific medications with ADNP/davunetide as a case study.
Focusing on the brain-essential gene revealed in our laboratory, activity-dependent neuroprotective protein (ADNP) and its neuroprotective site, the investigational drug davunetide (NAP), we discuss ADNP regulating steroid hormone biosynthesis and sex chromosome genes coupled with sex-dependent shuttling between the nuclei and cytoplasm. Further coupled with sex-dependent transcriptional control, ADNP/davunetide cytoplasmic microtubule/Tau targeting is translated into differential sex regulation of key cellular processes including neurogenesis, synaptic function, and axonal transport, then decoded into sexual dichotomy in multicellular processes directing sex-dependent behavioral outcomes. ADNP regulation of these sex-specific processes serves as a target for davunetide intervention, toward sex-directed precision medicine, revealing sexually dichotomized neuroprotection against tauopathy risk and progression spanning from coronary artery bypass grafting (CABG) to prodromal Alzheimer's disease, progressive supranuclear palsy (PSP), and schizophrenia, as well as the pediatric ADNP syndrome. Sex-specific intranasal bioavailability of davunetide, regulated by the estrous cycle, provides a mechanistic foundation for these differential outcomes.
2026-07-07 | ADNP Functions During Early Brain Development and Their Relevance to ASD and ADNP Syndrome
The Activity-Dependent Neuroprotective Protein (ADNP) is an important regulator of early brain development, especially during cortical neurogenesis and neurite formation. De novo point mutations or haploinsufficiency of the ADNP gene result in ADNP syndrome, which is also known as Helsmoortel-Van der Aa syndrome, a complex neurodevelopmental disorder recognized as a leading single-gene cause of syndromic autism spectrum disorder (ASD) and intellectual disability. ADNP works as both a transcription factor and a microtubule (MT) regulator. As a transcription factor, ADNP is a key component of chromatin remodeling complexes such as ChAHP (CHD4 (Chromodomain Helicase DNA-binding Protein 4)-ADNP-HP1 (Heterochromatin Protein 1)) and SWI/SNF (Switch/Sucrose Non-Fermentable), and it tightly regulates the expression of numerous essential developmental genes. ADNP also modulates the Wnt/β-catenin signaling pathway. During neural differentiation, ADNP is redistributed from the nucleus to the cytoplasm, and this redistribution is regulated by binding to 14-3-3 proteins, which are phosphorylated by protein Kinase C (PKC). After relocating to the cytoplasm, ADNP functions as an MT regulator by binding to microtubule end-binding proteins (EB1 and EB3) and Tau to control neurite formation. Previous studies have focused on NAP (also known as Davunetide, a peptide derived from ADNP) in MT regulation and its therapeutic potential for autism spectrum disorder (ASD) and neurodegenerative diseases, such as Alzheimer’s disease. This review highlights the functions of full-length ADNP and NAP in early brain development, particularly in neurogenesis and neurite formation during cortical development. We will also discuss the potential of NAP as a therapeutic medication for neurodevelopmental disorders, especially ASD and ADNP syndrome.
2026-01-28 | A Systematic Review Illustrates the Expanding Clinical and Molecular Landscape of Helsmoortel-Van der Aa Syndrome.
Background: Helsmoortel-Van der Aa syndrome (HVDAS) is a rare multisystemic neurodevelopmental disorder caused by pathogenic variants in the Activity-Dependent Neuroprotective Homeobox Protein (ADNP) gene. Since the extensive clinical description of a cohort of 78 affected individuals in 2019, numerous reports described additional cases affected by the condition. However, no systematic synthesis of the clinical and molecular spectrum of these additional individuals has been conducted to date. Methods: In accordance with the PRISMA 2020 guidelines, we performed a systematic review of all publications describing individuals with genetically confirmed HVDAS. Clinical characteristics, comorbidities, and developmental milestones were systematically extracted to illustrate novel or underrecognized manifestations. Results: A total of 105 individuals reported across 34 publications were included. Of these, 66 were clinically and genetically evaluated, and 39 were analyzed only at the genetic level. Our analysis refines the phenotypic spectrum of HVDAS, including developmental delay, visual anomalies, and congenital heart defects. The additional literature also allows us to characterize in more detail the ophthalmological abnormalities, gait disturbances, and the cognitive profile of HVDAS. Advances in ADNP methylation profiling further enhance diagnostic precision and variant interpretation in this evolving neurodevelopmental syndrome. Conclusions: This systematic review provides a comprehensive synthesis of the clinical, genetic, and epigenetic landscape of HVDAS. It underscores the multisystemic nature of the disorder and the need for multidisciplinary management. The expanding phenotypic heterogeneity likely reflects both improved clinical recognition of the more subtle features and the tendency to prioritize publication of more complex or severely affected cases.
2025-09-22 | The De Novo p.(Ser802Phe) Variant Causes Helsmoortel-Van der Aa/ADNP Syndrome in a 24-Year-Old Woman and Is Predicted to Perturb ADNP-DNA Affinity.
The ADNP syndrome, also known as Helsmoortel-Van der Aa syndrome (HVDAS), is an autosomal dominant neurodevelopmental disorder caused by heterozygous truncating variants abolishing the homeobox and/or HP1 domains of ADNP. Rare missense changes in the ADNP gene are usually variants of uncertain significance or reclassified as (likely) benign because they are inherited from an unaffected parent, and a causative role was documented for only three of them. We report a 24-year-old Italian woman presenting with intellectual disability, visual and severe speech impairment, microcephaly, truncal obesity, and hirsutism. Behavioral disturbance was significant and included fragmented sleep, self- and hetero-aggression, outbursts of anger, and verbal and physical violence crises. Additional unusual findings were hyperandrogenism and secondary amenorrhea. Next-generation sequencing showed the novel de novo missense variant c.2405C>T, p.(Ser802Phe) affecting the DNA-binding homeodomain of ADNP. In silico analysis revealed this variant is located in a genomic region highly intolerant to missense changes, and several tools predicted a deleterious effect on protein function. Counterintuitively to the known molecular pathogenesis for ADNP syndrome, calculation of the binding free energy and dissociation constant of the p.(Ser802Phe) missense substitution suggested a stronger ADNP-DNA interaction, thus opening the path to the hypothesis of a gain-of-function effect. This clinical report expands genotype-phenotype variability and correlations in ADNP syndrome.
2024-11-14 | Protective inherited mutations in activity-dependent neuroprotective protein (ADNP): the good, the bad, and the ugly
Activity-dependent neuroprotective protein (ADNP), essential for brain formation/function, reveals multiple cytoplasmic and chromatin interacting sites. Computational modeling, alongside the Vineland Adaptive Behavior Scales, a leading instrument supporting the diagnosis of intellectual/developmental disabilities, now revealed a protective frame shift/stop mutation in ADNP. Thus, a woman with inherited mutation, ADNP_Glu931Glyfs * 12 (VB), showed above average Vineland performance. Bioinformatics/ in silico protein modeling indicated that while ADNP contains four 14-3-3 protein interaction sites (instrumental for ADNP nuclear/cytoplasmic shuttling), ADNP_Glu931Glyfs * 12 contains an additional fifth 14-3-3 interaction site, implicating stronger associations. Furthermore, the endogenous neuroprotective (investigational drug, davunetide) NAPVSIPQ (NAP) site was involved in the ADNP and ADNP_Glu931Glyfs * 12-14-3-3 interactions. In this respect, the mutation also enhanced ADNP-SH3 associations (another NAPVISP interaction site 354-361 aa on ADNP, critical for cytoskeletal/cellular signaling). HB, the 8-year-old VB's son, while inheriting the mother's ADNP mutation, further presented a heterozygous pathogenic de novo mutation ADNP, p.Arg730Thrfs * 5. However, in comparison to carriers of a similar p.Arg730 * mutation (part of the autistic/intellectual disability ADNP syndrome), HB exhibited overall better Vineland 3 standard score of 70–80 for all measures, compared to the nominal score of 20 in a 27-year-old ADNP, p.Arg730 * subject and the 100 ± 15 norm, corroborating ADNP_Glu931Glyfs * 12 protection.
small molecules
2026-06-27 | Aging ADNP syndrome mice exhibit mutation/sex-dependent disruption of motor behavior and circadian rhythmicity.
Circadian disruption is an early and clinically relevant feature of Alzheimer's disease and related neurodegenerative conditions, yet the molecular determinants underlying its emergence remain incompletely understood. Activity-dependent neuroprotective protein (ADNP) is a key regulator of neurodevelopment and neuroprotection, with de novo mutations driving the neurodevelopmental ADNP syndrome tauopathy and with somatic mutations implicated in tauopathy and neurodegeneration in Alzheimer's disease, but its role in circadian system function has not been systematically explored. Here, with Alzheimer's disease being twice as prevalent in women, we performed a comprehensive characterization of circadian locomotor activity, explicitly considering sex as a biological variable in aged mouse models of ADNP disruption, representing two key phenotypes of the syndrome. Using recordings of voluntary wheel-running activity combined with cosinor-based rhythmometry, we quantified parameters of circadian organization, including activity levels, timing, and rhythm integrity. We demonstrate that ADNP haploinsufficiency with late tau deposition was associated with impaired circadian organization in a strongly sex-dependent manner. In Adnp+/- mice, circadian alterations diverged between sexes: males exhibited a pronounced reduction in overall activity levels and rhythmic output, whereas females showed alterations in circadian timing (phase shift), and increased waveform complexity, indicative of fragmented activity patterns. Notably, reduced rhythm robustness was observed in both sexes, pointing to impaired stability of circadian output. In contrast to Adnp+/- mice, mice carrying a heterozygous Adnp p.Tyr718* mutation (with early tauopathy) exhibited marked vulnerability only under a circadian challenge paradigm. This was characterized by a high incidence of arrhythmicity based on cosinor-based zero-amplitude testing, with a particularly severe phenotype in a small exploratory cohort of males, in which all examined Tyr718* mice failed to exhibit detectable circadian rhythmicity. Importantly, the study was conducted in aged mice, a context relevant to age-associated neurodegenerative vulnerability. These findings position ADNP as a contributor to circadian system stability and highlight its associated signaling pathways as candidate targets for future mechanistic and therapeutic investigation.
2026-04-07 | ADNP missense variant p.C687R disrupts chromatin regulation and GABAergic differentiation in Helsmoortel-Van der Aa syndrome.
BACKGROUND: Activity-dependent neuroprotective protein (ADNP) is a critical regulator of neurodevelopment, and most pathogenic variants reported in Helsmoortel–Van der Aa syndrome (HVDAS) are truncating variants. In contrast, the functional consequences of ADNP missense variants remain largely unclear. We integrated an ADNP variant cohort in China with variants recorded in the NCBI ClinVar database, revealing a major gap in the interpretation of ADNP missense variants. METHODS: We investigated a rare de novo ADNP missense variant, p.C687R, predicted to disrupt the ninth zinc finger domain. In vitro, p.C687R was overexpressed in HEK293T cells to assess subnuclear localization by immunofluorescence and chromatin binding patterns using CUT&Tag, with chromatin interactions inferred from published Hi-C datasets. CRISPR/Cas9-mediated ADNP knockout was performed for comparison. In vivo, wild-type ADNP or p.C687R was introduced into the embryonic mouse cortex at E14.5 via in utero electroporation (IUE) and neuronal development was evaluated at E18.5 and P14. Patient-derived induced pluripotent stem cells (iPSCs) from a de novo p.C687R carrier were differentiated into neural progenitor cells (NPCs) and analyzed by multi-omic profiling (RNA-seq, ChIP-seq, ATAC-seq), with lineage-specific markers examined by immunofluorescence. RESULTS: p.C687R displays altered subnuclear localization and redistributes wild-type ADNP when overexpressed in HEK293T. IUE in the mouse cortical plate revealed impaired neuronal migration and abnormal cortical arborization. Genome-wide profiling in HEK293T demonstrated a p.C687R-specific chromatin occupancy pattern, preferentially targeting histone modification-related genes. Knockout of ADNP led to upregulation of neuronal genes, including GABAergic lineage-associated genes. In patient-derived iPSCs, a distinct set of neurodevelopmental genes, including key regulators of GABAergic differentiation, showed increased bivalent histone marks (H3K4me3/H3K27me3). Although their promoters remained in an open chromatin state, these genes were transcriptionally silent in pluripotent cells but became more activated upon GABAergic differentiation. LIMITATIONS: 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. Replication in additional patient-derived or engineered lines is required to determine the generalizability. CONCLUSIONS: 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.
2025-11-11 | A frameshift variant in activity-dependent neuroprotective protein (ADNP) causes nucleocytoskeletal alterations in a dizygotic male twin: a case study.
The Helsmoortel-Van der Aa syndrome is an autosomal-dominant neurodevelopment disorder caused by heterozygous de novo variants in the Activity-Dependent Neuroprotective Protein (ADNP) gene, characterized by autism, intellectual disability, dysmorphic facial features, and deficits in multiple organ systems. ADNP is a zinc finger DNA-binding protein that primarily interacts with chromatin remodelers regulating embryonic development, while also associating with components of the cytoskeleton, thereby regulating autophagy and microtubule dynamics during development. In this study, we investigated these nucleocytoskeletal alterations explaining neurodevelopmental delay in a child with Helsmoortel-Van der Aa syndrome who had an unaffected dizygotic twin brother. We performed a genome-wide methylation array on PBMCs from dizygotic twins, showing a predominant CpG hypomethylation episignature. Enrichment analysis of methylated genes revealed significant pathway changes in actin filament organization, Wnt signaling, embryonic development, heart development, and the immune system. In addition, transcriptome sequencing substantiated the affected pathways regulating nuclear and cytoskeletal filamentous alterations associated with autism and neurodevelopmental delay. Brain magnetic resonance imaging showed a mild generalized prominence of the subarachnoid space overlying both hemispheres, revealing intricate patterns of neurodevelopmental delay. We report the first molecular study performed on dizygotic twins of which one was diagnosed with Helsmoortel-Van der Aa syndrome, revealing Wnt signaling and filamentous cytoskeletal alterations as a potential drug targets for therapy. Indications for neurodegeneration, following these cytoskeletal perturbations, have been observed in cellular and murine models for the Helsmoortel-Van der Aa syndrome. However, clinical evidence remains unclear due to the young age of patients, limiting long-term studies on the aging brain. Further longitudinal imaging studies combined with histopathological autopsy sections are required to study the impact of an ADNP variant in the brain as patients come to age.
2025-11-11 | Missense Mutation ADNP p.C687R Disrupts Chromatin Regulation and GABAergic Differentiation in HVDAS
Abstract Activity-dependent neuroprotective protein (ADNP) is a key regulator of neurodevelopment and a high-risk gene for autism spectrum disorder (ASD). Most pathogenic variants cause loss-of-function in Helsmoortel–Van der Aa syndrome (HVDAS), yet the impact of missense mutations remains unclear. Here, we characterized a ADNP missense mutation (p.C687R) identified from a HVDAS patient, predicted to disrupt its ninth zinc finger domain. Overexpression of p.C687R altered subnuclear localization and affected wild-type ADNP distribution. In utero electroporation revealed impaired neuronal migration and cortical branching. CUT&Tag profiling showed mutant- specific chromatin binding, preferentially targeting histone modification genes through both direct and distal interactions. Patient-derived iPSCs carrying p.C687R exhibited upregulated bivalent histone marks (H3K4me3 and H3K27me3) on neurodevelopmental genes, including regulators of GABAergic differentiation, which became transcriptionally activated in neural progenitors. These findings reveal a gain-of-function mechanism by which ADNP p.C687R perturbs chromatin regulation and disrupts GABAergic lineage specification, expanding the molecular framework of ADNP pathogenesis. The Paper Explained Problem Mutations in the gene ADNP cause Helsmoortel–Van der Aa syndrome (HVDAS), a severe neurodevelopmental disorder, and also increase the risk for autism spectrum disorder (ASD). While most known ADNP mutations lead to loss of protein function, many missense mutations that alter a single amino acid remain poorly understood regarding their effects on brain development and disease contribution. Results We characterized a specific missense mutation, ADNP p.C687R, from a patient diagnosed with HVDAS, and found that it does not simply inactivate the protein but instead confers a disruptive new function. Across multiple models, from cells to mice, the p.C687R mutant exhibits abnormal chromatin binding, altered subnuclear localization, and impaired neuronal migration and differentiation. Importantly, in patient-derived iPSCs, it marks distinct neurodevelopmental genes with bivalent histone modifications, which become aberrantly activated during differentiation into GABAergic neural progenitor cells. Impact These findings confirm the pathogenicity of the missense mutation ADNP p.C687R in HVDAS, reveal a gain-of-function mechanism whereby the mutant disrupts chromatin regulation and GABAergic lineage specification, and advance our understanding of ADNP-related neurodevelopmental disorders.
2025-10-08 | The ADNP-Mediated Transcriptome Response to Ketamine Impairs the Cytoskeletal Protein Axis.
De novo variants in the Activity-Dependent Neuroprotective Protein (ADNP) gene cause the autistic Helsmoortel-Van der Aa syndrome with patients showing mild to disastrous phenotypes impacting brain functioning, behavior, and organ functions. In this respect, two treatment strategies have been proposed to alleviate symptoms in patients with this syndrome: (1) the ADNP-derived octapeptide investigational drug NAP (davunetide), which enhances ADNP's ability to target cytoskeletal deficits, and (2) subnarcotic levels of ketamine, which are suggested to increase endogenous ADNP mRNA levels. Here, we focus on the perspective of ketamine and investigated the transcriptomic response of low-dose and high-dose ketamine applications at different time points, experimentally controlled by the non-toxic drug NAP, in lymphoblastoid cell lines obtained from individuals with Helsmoortel-Van der Aa syndrome. Transcriptome profiling was performed at baseline conditions, followed by dose (low or high) and time (40 min or 4 h)-dependent ketamine application in patient and control lymphoblastoid cell lines. We showed that ketamine affected ADNP expression levels in a dose- and time-dependent manner with only toxic ketamine concentrations increasing ADNP protein levels. Ketamine application also triggered a transcriptomic response with profound gene expression alterations centered around processes such as immune response-regulating signaling pathways and cell fate commitment at low-dose ketamine, together with organelle assembly and cytoskeletal dysregulation at high doses. A parallel control experiment with NAP under the same experimental conditions did not induce detectable gene expression differences in patient-derived cell lines. The ketamine-induced cytoskeletal alterations were functionally studied using immunoblotting, showing a disturbed expression of α-tubulin, β-actin, and to a minor extent microtubule-associated protein EB3 in patient-derived lymphoblastoid cells. Ketamine upregulates wild-type ADNP transcript and protein levels in a dose- and time-dependent manner in patient-derived lymphoblastoid cell lines from individuals with Helsmoortel-Van der Aa syndrome, while inducing a transcriptomic response that affects key processes including immune system signaling and cytoskeletal organization.
proteins
2026-08-11 | Dramatic sex differences leading to different brain disease presentation: The requirement for sex-specific medications with ADNP/davunetide as a case study.
Focusing on the brain-essential gene revealed in our laboratory, activity-dependent neuroprotective protein (ADNP) and its neuroprotective site, the investigational drug davunetide (NAP), we discuss ADNP regulating steroid hormone biosynthesis and sex chromosome genes coupled with sex-dependent shuttling between the nuclei and cytoplasm. Further coupled with sex-dependent transcriptional control, ADNP/davunetide cytoplasmic microtubule/Tau targeting is translated into differential sex regulation of key cellular processes including neurogenesis, synaptic function, and axonal transport, then decoded into sexual dichotomy in multicellular processes directing sex-dependent behavioral outcomes. ADNP regulation of these sex-specific processes serves as a target for davunetide intervention, toward sex-directed precision medicine, revealing sexually dichotomized neuroprotection against tauopathy risk and progression spanning from coronary artery bypass grafting (CABG) to prodromal Alzheimer's disease, progressive supranuclear palsy (PSP), and schizophrenia, as well as the pediatric ADNP syndrome. Sex-specific intranasal bioavailability of davunetide, regulated by the estrous cycle, provides a mechanistic foundation for these differential outcomes.
2026-07-07 | ADNP Functions During Early Brain Development and Their Relevance to ASD and ADNP Syndrome
The Activity-Dependent Neuroprotective Protein (ADNP) is an important regulator of early brain development, especially during cortical neurogenesis and neurite formation. De novo point mutations or haploinsufficiency of the ADNP gene result in ADNP syndrome, which is also known as Helsmoortel-Van der Aa syndrome, a complex neurodevelopmental disorder recognized as a leading single-gene cause of syndromic autism spectrum disorder (ASD) and intellectual disability. ADNP works as both a transcription factor and a microtubule (MT) regulator. As a transcription factor, ADNP is a key component of chromatin remodeling complexes such as ChAHP (CHD4 (Chromodomain Helicase DNA-binding Protein 4)-ADNP-HP1 (Heterochromatin Protein 1)) and SWI/SNF (Switch/Sucrose Non-Fermentable), and it tightly regulates the expression of numerous essential developmental genes. ADNP also modulates the Wnt/β-catenin signaling pathway. During neural differentiation, ADNP is redistributed from the nucleus to the cytoplasm, and this redistribution is regulated by binding to 14-3-3 proteins, which are phosphorylated by protein Kinase C (PKC). After relocating to the cytoplasm, ADNP functions as an MT regulator by binding to microtubule end-binding proteins (EB1 and EB3) and Tau to control neurite formation. Previous studies have focused on NAP (also known as Davunetide, a peptide derived from ADNP) in MT regulation and its therapeutic potential for autism spectrum disorder (ASD) and neurodegenerative diseases, such as Alzheimer’s disease. This review highlights the functions of full-length ADNP and NAP in early brain development, particularly in neurogenesis and neurite formation during cortical development. We will also discuss the potential of NAP as a therapeutic medication for neurodevelopmental disorders, especially ASD and ADNP syndrome.
2026-01-28 | A Systematic Review Illustrates the Expanding Clinical and Molecular Landscape of Helsmoortel-Van der Aa Syndrome.
Background: Helsmoortel-Van der Aa syndrome (HVDAS) is a rare multisystemic neurodevelopmental disorder caused by pathogenic variants in the Activity-Dependent Neuroprotective Homeobox Protein (ADNP) gene. Since the extensive clinical description of a cohort of 78 affected individuals in 2019, numerous reports described additional cases affected by the condition. However, no systematic synthesis of the clinical and molecular spectrum of these additional individuals has been conducted to date. Methods: In accordance with the PRISMA 2020 guidelines, we performed a systematic review of all publications describing individuals with genetically confirmed HVDAS. Clinical characteristics, comorbidities, and developmental milestones were systematically extracted to illustrate novel or underrecognized manifestations. Results: A total of 105 individuals reported across 34 publications were included. Of these, 66 were clinically and genetically evaluated, and 39 were analyzed only at the genetic level. Our analysis refines the phenotypic spectrum of HVDAS, including developmental delay, visual anomalies, and congenital heart defects. The additional literature also allows us to characterize in more detail the ophthalmological abnormalities, gait disturbances, and the cognitive profile of HVDAS. Advances in ADNP methylation profiling further enhance diagnostic precision and variant interpretation in this evolving neurodevelopmental syndrome. Conclusions: This systematic review provides a comprehensive synthesis of the clinical, genetic, and epigenetic landscape of HVDAS. It underscores the multisystemic nature of the disorder and the need for multidisciplinary management. The expanding phenotypic heterogeneity likely reflects both improved clinical recognition of the more subtle features and the tendency to prioritize publication of more complex or severely affected cases.
2025-09-22 | The De Novo p.(Ser802Phe) Variant Causes Helsmoortel-Van der Aa/ADNP Syndrome in a 24-Year-Old Woman and Is Predicted to Perturb ADNP-DNA Affinity.
The ADNP syndrome, also known as Helsmoortel-Van der Aa syndrome (HVDAS), is an autosomal dominant neurodevelopmental disorder caused by heterozygous truncating variants abolishing the homeobox and/or HP1 domains of ADNP. Rare missense changes in the ADNP gene are usually variants of uncertain significance or reclassified as (likely) benign because they are inherited from an unaffected parent, and a causative role was documented for only three of them. We report a 24-year-old Italian woman presenting with intellectual disability, visual and severe speech impairment, microcephaly, truncal obesity, and hirsutism. Behavioral disturbance was significant and included fragmented sleep, self- and hetero-aggression, outbursts of anger, and verbal and physical violence crises. Additional unusual findings were hyperandrogenism and secondary amenorrhea. Next-generation sequencing showed the novel de novo missense variant c.2405C>T, p.(Ser802Phe) affecting the DNA-binding homeodomain of ADNP. In silico analysis revealed this variant is located in a genomic region highly intolerant to missense changes, and several tools predicted a deleterious effect on protein function. Counterintuitively to the known molecular pathogenesis for ADNP syndrome, calculation of the binding free energy and dissociation constant of the p.(Ser802Phe) missense substitution suggested a stronger ADNP-DNA interaction, thus opening the path to the hypothesis of a gain-of-function effect. This clinical report expands genotype-phenotype variability and correlations in ADNP syndrome.
2024-11-14 | Protective inherited mutations in activity-dependent neuroprotective protein (ADNP): the good, the bad, and the ugly
Activity-dependent neuroprotective protein (ADNP), essential for brain formation/function, reveals multiple cytoplasmic and chromatin interacting sites. Computational modeling, alongside the Vineland Adaptive Behavior Scales, a leading instrument supporting the diagnosis of intellectual/developmental disabilities, now revealed a protective frame shift/stop mutation in ADNP. Thus, a woman with inherited mutation, ADNP_Glu931Glyfs * 12 (VB), showed above average Vineland performance. Bioinformatics/ in silico protein modeling indicated that while ADNP contains four 14-3-3 protein interaction sites (instrumental for ADNP nuclear/cytoplasmic shuttling), ADNP_Glu931Glyfs * 12 contains an additional fifth 14-3-3 interaction site, implicating stronger associations. Furthermore, the endogenous neuroprotective (investigational drug, davunetide) NAPVSIPQ (NAP) site was involved in the ADNP and ADNP_Glu931Glyfs * 12-14-3-3 interactions. In this respect, the mutation also enhanced ADNP-SH3 associations (another NAPVISP interaction site 354-361 aa on ADNP, critical for cytoskeletal/cellular signaling). HB, the 8-year-old VB's son, while inheriting the mother's ADNP mutation, further presented a heterozygous pathogenic de novo mutation ADNP, p.Arg730Thrfs * 5. However, in comparison to carriers of a similar p.Arg730 * mutation (part of the autistic/intellectual disability ADNP syndrome), HB exhibited overall better Vineland 3 standard score of 70–80 for all measures, compared to the nominal score of 20 in a 27-year-old ADNP, p.Arg730 * subject and the 100 ± 15 norm, corroborating ADNP_Glu931Glyfs * 12 protection.
small molecules
2026-06-27 | Aging ADNP syndrome mice exhibit mutation/sex-dependent disruption of motor behavior and circadian rhythmicity.
Circadian disruption is an early and clinically relevant feature of Alzheimer's disease and related neurodegenerative conditions, yet the molecular determinants underlying its emergence remain incompletely understood. Activity-dependent neuroprotective protein (ADNP) is a key regulator of neurodevelopment and neuroprotection, with de novo mutations driving the neurodevelopmental ADNP syndrome tauopathy and with somatic mutations implicated in tauopathy and neurodegeneration in Alzheimer's disease, but its role in circadian system function has not been systematically explored. Here, with Alzheimer's disease being twice as prevalent in women, we performed a comprehensive characterization of circadian locomotor activity, explicitly considering sex as a biological variable in aged mouse models of ADNP disruption, representing two key phenotypes of the syndrome. Using recordings of voluntary wheel-running activity combined with cosinor-based rhythmometry, we quantified parameters of circadian organization, including activity levels, timing, and rhythm integrity. We demonstrate that ADNP haploinsufficiency with late tau deposition was associated with impaired circadian organization in a strongly sex-dependent manner. In Adnp+/- mice, circadian alterations diverged between sexes: males exhibited a pronounced reduction in overall activity levels and rhythmic output, whereas females showed alterations in circadian timing (phase shift), and increased waveform complexity, indicative of fragmented activity patterns. Notably, reduced rhythm robustness was observed in both sexes, pointing to impaired stability of circadian output. In contrast to Adnp+/- mice, mice carrying a heterozygous Adnp p.Tyr718* mutation (with early tauopathy) exhibited marked vulnerability only under a circadian challenge paradigm. This was characterized by a high incidence of arrhythmicity based on cosinor-based zero-amplitude testing, with a particularly severe phenotype in a small exploratory cohort of males, in which all examined Tyr718* mice failed to exhibit detectable circadian rhythmicity. Importantly, the study was conducted in aged mice, a context relevant to age-associated neurodegenerative vulnerability. These findings position ADNP as a contributor to circadian system stability and highlight its associated signaling pathways as candidate targets for future mechanistic and therapeutic investigation.
2026-04-07 | ADNP missense variant p.C687R disrupts chromatin regulation and GABAergic differentiation in Helsmoortel-Van der Aa syndrome.
BACKGROUND: Activity-dependent neuroprotective protein (ADNP) is a critical regulator of neurodevelopment, and most pathogenic variants reported in Helsmoortel–Van der Aa syndrome (HVDAS) are truncating variants. In contrast, the functional consequences of ADNP missense variants remain largely unclear. We integrated an ADNP variant cohort in China with variants recorded in the NCBI ClinVar database, revealing a major gap in the interpretation of ADNP missense variants. METHODS: We investigated a rare de novo ADNP missense variant, p.C687R, predicted to disrupt the ninth zinc finger domain. In vitro, p.C687R was overexpressed in HEK293T cells to assess subnuclear localization by immunofluorescence and chromatin binding patterns using CUT&Tag, with chromatin interactions inferred from published Hi-C datasets. CRISPR/Cas9-mediated ADNP knockout was performed for comparison. In vivo, wild-type ADNP or p.C687R was introduced into the embryonic mouse cortex at E14.5 via in utero electroporation (IUE) and neuronal development was evaluated at E18.5 and P14. Patient-derived induced pluripotent stem cells (iPSCs) from a de novo p.C687R carrier were differentiated into neural progenitor cells (NPCs) and analyzed by multi-omic profiling (RNA-seq, ChIP-seq, ATAC-seq), with lineage-specific markers examined by immunofluorescence. RESULTS: p.C687R displays altered subnuclear localization and redistributes wild-type ADNP when overexpressed in HEK293T. IUE in the mouse cortical plate revealed impaired neuronal migration and abnormal cortical arborization. Genome-wide profiling in HEK293T demonstrated a p.C687R-specific chromatin occupancy pattern, preferentially targeting histone modification-related genes. Knockout of ADNP led to upregulation of neuronal genes, including GABAergic lineage-associated genes. In patient-derived iPSCs, a distinct set of neurodevelopmental genes, including key regulators of GABAergic differentiation, showed increased bivalent histone marks (H3K4me3/H3K27me3). Although their promoters remained in an open chromatin state, these genes were transcriptionally silent in pluripotent cells but became more activated upon GABAergic differentiation. LIMITATIONS: 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. Replication in additional patient-derived or engineered lines is required to determine the generalizability. CONCLUSIONS: 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.
2025-11-11 | A frameshift variant in activity-dependent neuroprotective protein (ADNP) causes nucleocytoskeletal alterations in a dizygotic male twin: a case study.
The Helsmoortel-Van der Aa syndrome is an autosomal-dominant neurodevelopment disorder caused by heterozygous de novo variants in the Activity-Dependent Neuroprotective Protein (ADNP) gene, characterized by autism, intellectual disability, dysmorphic facial features, and deficits in multiple organ systems. ADNP is a zinc finger DNA-binding protein that primarily interacts with chromatin remodelers regulating embryonic development, while also associating with components of the cytoskeleton, thereby regulating autophagy and microtubule dynamics during development. In this study, we investigated these nucleocytoskeletal alterations explaining neurodevelopmental delay in a child with Helsmoortel-Van der Aa syndrome who had an unaffected dizygotic twin brother. We performed a genome-wide methylation array on PBMCs from dizygotic twins, showing a predominant CpG hypomethylation episignature. Enrichment analysis of methylated genes revealed significant pathway changes in actin filament organization, Wnt signaling, embryonic development, heart development, and the immune system. In addition, transcriptome sequencing substantiated the affected pathways regulating nuclear and cytoskeletal filamentous alterations associated with autism and neurodevelopmental delay. Brain magnetic resonance imaging showed a mild generalized prominence of the subarachnoid space overlying both hemispheres, revealing intricate patterns of neurodevelopmental delay. We report the first molecular study performed on dizygotic twins of which one was diagnosed with Helsmoortel-Van der Aa syndrome, revealing Wnt signaling and filamentous cytoskeletal alterations as a potential drug targets for therapy. Indications for neurodegeneration, following these cytoskeletal perturbations, have been observed in cellular and murine models for the Helsmoortel-Van der Aa syndrome. However, clinical evidence remains unclear due to the young age of patients, limiting long-term studies on the aging brain. Further longitudinal imaging studies combined with histopathological autopsy sections are required to study the impact of an ADNP variant in the brain as patients come to age.
2025-11-11 | Missense Mutation ADNP p.C687R Disrupts Chromatin Regulation and GABAergic Differentiation in HVDAS
Abstract Activity-dependent neuroprotective protein (ADNP) is a key regulator of neurodevelopment and a high-risk gene for autism spectrum disorder (ASD). Most pathogenic variants cause loss-of-function in Helsmoortel–Van der Aa syndrome (HVDAS), yet the impact of missense mutations remains unclear. Here, we characterized a ADNP missense mutation (p.C687R) identified from a HVDAS patient, predicted to disrupt its ninth zinc finger domain. Overexpression of p.C687R altered subnuclear localization and affected wild-type ADNP distribution. In utero electroporation revealed impaired neuronal migration and cortical branching. CUT&Tag profiling showed mutant- specific chromatin binding, preferentially targeting histone modification genes through both direct and distal interactions. Patient-derived iPSCs carrying p.C687R exhibited upregulated bivalent histone marks (H3K4me3 and H3K27me3) on neurodevelopmental genes, including regulators of GABAergic differentiation, which became transcriptionally activated in neural progenitors. These findings reveal a gain-of-function mechanism by which ADNP p.C687R perturbs chromatin regulation and disrupts GABAergic lineage specification, expanding the molecular framework of ADNP pathogenesis. The Paper Explained Problem Mutations in the gene ADNP cause Helsmoortel–Van der Aa syndrome (HVDAS), a severe neurodevelopmental disorder, and also increase the risk for autism spectrum disorder (ASD). While most known ADNP mutations lead to loss of protein function, many missense mutations that alter a single amino acid remain poorly understood regarding their effects on brain development and disease contribution. Results We characterized a specific missense mutation, ADNP p.C687R, from a patient diagnosed with HVDAS, and found that it does not simply inactivate the protein but instead confers a disruptive new function. Across multiple models, from cells to mice, the p.C687R mutant exhibits abnormal chromatin binding, altered subnuclear localization, and impaired neuronal migration and differentiation. Importantly, in patient-derived iPSCs, it marks distinct neurodevelopmental genes with bivalent histone modifications, which become aberrantly activated during differentiation into GABAergic neural progenitor cells. Impact These findings confirm the pathogenicity of the missense mutation ADNP p.C687R in HVDAS, reveal a gain-of-function mechanism whereby the mutant disrupts chromatin regulation and GABAergic lineage specification, and advance our understanding of ADNP-related neurodevelopmental disorders.
2025-10-08 | The ADNP-Mediated Transcriptome Response to Ketamine Impairs the Cytoskeletal Protein Axis.
De novo variants in the Activity-Dependent Neuroprotective Protein (ADNP) gene cause the autistic Helsmoortel-Van der Aa syndrome with patients showing mild to disastrous phenotypes impacting brain functioning, behavior, and organ functions. In this respect, two treatment strategies have been proposed to alleviate symptoms in patients with this syndrome: (1) the ADNP-derived octapeptide investigational drug NAP (davunetide), which enhances ADNP's ability to target cytoskeletal deficits, and (2) subnarcotic levels of ketamine, which are suggested to increase endogenous ADNP mRNA levels. Here, we focus on the perspective of ketamine and investigated the transcriptomic response of low-dose and high-dose ketamine applications at different time points, experimentally controlled by the non-toxic drug NAP, in lymphoblastoid cell lines obtained from individuals with Helsmoortel-Van der Aa syndrome. Transcriptome profiling was performed at baseline conditions, followed by dose (low or high) and time (40 min or 4 h)-dependent ketamine application in patient and control lymphoblastoid cell lines. We showed that ketamine affected ADNP expression levels in a dose- and time-dependent manner with only toxic ketamine concentrations increasing ADNP protein levels. Ketamine application also triggered a transcriptomic response with profound gene expression alterations centered around processes such as immune response-regulating signaling pathways and cell fate commitment at low-dose ketamine, together with organelle assembly and cytoskeletal dysregulation at high doses. A parallel control experiment with NAP under the same experimental conditions did not induce detectable gene expression differences in patient-derived cell lines. The ketamine-induced cytoskeletal alterations were functionally studied using immunoblotting, showing a disturbed expression of α-tubulin, β-actin, and to a minor extent microtubule-associated protein EB3 in patient-derived lymphoblastoid cells. Ketamine upregulates wild-type ADNP transcript and protein levels in a dose- and time-dependent manner in patient-derived lymphoblastoid cell lines from individuals with Helsmoortel-Van der Aa syndrome, while inducing a transcriptomic response that affects key processes including immune system signaling and cytoskeletal organization.
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Drug Discovery Landscape
2 orphan drug designations for ADNP syndrome.
2 orphan drug designations for ADNP syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Davunetide | peptides | EMA | 2024-12-13 | — | AdRes EU B.V. |
davunetide | peptides | FDA | 2018-02-22 | — | Exonavis Therapeutics Ltd. |
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