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Background: Neurodevelopmental conditions such as intellectual disability (ID) and autism spectrum disorder (ASD) can stem from a broad array of inherited and de novo genetic differences, with marked physiological and behavioral impacts. We currently know little about the psychiatric phenotypes of rare genetic variants associated with ASD, despite heightened risk of psychiatric concerns in ASD more broadly. Understanding behavioral features of these variants can identify shared versus specific phenotypes across gene groups, facilitate mechanistic models, and provide prognostic insights to inform clinical practice. In this paper, we evaluate behavioral features within three gene groups associated with ID and ASD - ADNP, CHD8, and DYRK1A - with two aims: (1) characterize phenotypes across behavioral domains of anxiety, depression, ADHD, and challenging behavior; and (2) understand whether age and early developmental milestones are associated with later mental health outcomes., Methods: Phenotypic data were obtained for youth with disruptive variants in ADNP, CHD8, or DYRK1A (N = 65, mean age = 8.7 years, 40% female) within a long-running, genetics-first study. Standardized caregiver-report measures of mental health features (anxiety, depression, attention-deficit/hyperactivity, oppositional behavior) and developmental history were extracted and analyzed for effects of gene group, age, and early developmental milestones on mental health features., Results: Patterns of mental health features varied by group, with anxiety most prominent for CHD8, oppositional features overrepresented among ADNP, and attentional and depressive features most prominent for DYRK1A. For the full sample, age was positively associated with anxiety features, such that elevations in anxiety relative to same-age and same-sex peers may worsen with increasing age. Predictive utility of early developmental milestones was limited, with evidence of early language delays predicting greater difficulties across behavioral domains only for the CHD8 group., Conclusions: Despite shared associations with autism and intellectual disability, disruptive variants in ADNP, CHD8, and DYRK1A may yield variable psychiatric phenotypes among children and adolescents. With replication in larger samples over time, efforts such as these may contribute to improved clinical care for affected children and adolescents, allow for earlier identification of emerging mental health difficulties, and promote early intervention to alleviate concerns and improve quality of life., (© 2024. The Author(s).)

ADNP and POGZ are two top-ranking risk factors for autism spectrum disorder and intellectual disability, but how they are linked to these neurodevelopmental disorders is largely unknown. Both ADNP and POGZ are chromatin regulators, which could profoundly affect gene transcription and cellular function in the brain. Using post-mortem tissue from patients with autism spectrum disorder, we found diminished expression of ADNP and POGZ in the prefrontal cortex, a region highly implicated in neurodevelopmental disorders. To understand the functional role of these neurodevelopmental disorder risk factors, we used viral-based gene transfer to investigate how Adnp or Pogz deficiency in mouse prefrontal cortex affects behavioural, transcriptomic and synaptic function. Mice with prefrontal cortex deficiency of Adnp or Pogz exhibited specific impairment of cognitive task performance. RNA-sequencing revealed that Adnp or Pogz deficiency induced prominent upregulation of overlapping genes enriched in neuroinflammation, similar to the elevation of pro-inflammatory genes in humans with neurodevelopmental disorders. Concomitantly, Adnp or Pogz deficiency led to the significant increase of pro-phagocytic microglial activation in prefrontal cortex, as well as the significant decrease of glutamatergic transmission and postsynaptic protein expression. These findings have uncovered the convergent functions of two top risk factors for autism spectrum disorder and intellectual disability in prefrontal cortex, providing a mechanism linking chromatin, transcriptional and synaptic dysregulation to cognitive deficits associated with neurodevelopmental disorders., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Helsmoortel-Van der Aa syndrome (HVDAS) is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. HVDAS is caused by mutations in activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with HVDAS, adding to the group of neurodevelopmental disorders with an epigenetic signature. This methylation signature segregated those with HVDAS into two groups based on the location of the mutations. Here, we conducted an independent study on 24 individuals with HVDAS and replicated the existence of the two mutation-dependent episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of HVDAS. 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. Moreover, in spite of the methylation changes, we observed no profound alterations in the blood transcriptome of individuals with HVDAS. Our data warrant caution in harnessing methylation signatures in HVDAS as a tool for clinical stratification, at least with regard to behavioral phenotypes., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Autism spectrum disorder (ASD) affects approximately one in 59 children. Variants in the activity-dependent neuroprotector homeobox ADNP (OMIM #611386) gene may be one of the most common single-gene causes of syndromic ASD. Most patients diagnosed with ADNP syndrome have ASD as a comorbidity, and all patients have mild-to-severe intellectual disability., Methods/case Report: We present a case report of a patient diagnosed with ADNP syndrome at 2.5 years of age. The patient has many of the key features of the syndrome, including ASD, global developmental delay, behavioral problems, congenital heart defect, early tooth eruption, and vision problems. The patient's initial presentation included congenital diaphragmatic hernia (CDH), which has not been previously reported in this condition., Results: The patient exhibited frequent behavioral outbursts and was initiated on antipsychotic medication with near-complete resolution of symptoms allowing her to engage more fully in early intervention therapies leading to progress in language acquisition., Conclusion: This short report provides guidance for antipsychotic medication dosing to improve early intervention outcomes. This is the first report of CDH in this syndrome., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Pathogenic disruptions to the activity-dependent neuroprotector homeobox (ADNP) gene are among the most common heterozygous genetic mutations associated with autism spectrum disorders (ASDs). Individuals with ADNP disruptions share a constellation of medical and psychiatric features, including ASD, intellectual disability (ID), dysmorphic features, and hypotonia. However, the profile of ASD symptoms associated with ADNP may differ from that of individuals with another ASD-associated single gene disruption or with ASD without a known genetic cause. The current study examined the ASD phenotype in a sample of representative youth with ADNP disruptions. Participants (N = 116, ages 4-22 years) included a cohort with ADNP mutations (n = 11) and three comparison groups with either a mutation to CHD8 (n = 11), a mutation to another ASD-associated gene (other mutation; n = 53), or ASD with no known genetic etiology (idiopathic ASD; n = 41). As expected, individuals with ADNP disruptions had higher rates of ID but less severe social affect symptoms compared to the CHD8 and Idiopathic ASD groups. In addition, verbal intelligence explained more variance in social impairment in the ADNP group compared to CHD8, other mutation, and idiopathic ASD comparison groups. Restricted and repetitive behaviors in the ADNP group were characterized by high levels of stereotyped motor behaviors, whereas the idiopathic ASD group showed high levels of restricted interests. Taken together, these results underscore the role of ADNP in cognitive functioning and suggest that social impairments in ADNP syndrome are consistent with severity of verbal deficits. Autism Res 2018, 11: 1300-1310. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Disruptions to the ADNP gene (i.e., ADNP syndrome) have been associated with autism spectrum disorder (ASD). This article describes intellectual disability, mild social difficulties, and severe repetitive motor movements in a group of 11 youth with ADNP Syndrome. We found lower rates of ASD than previously reported. Verbal skills explained individual variability in social impairment. This pattern suggests that the ADNP gene is primarily associated with learning and memory, and level of social difficulties is consistent with level of verbal impairment., (© 2018 International Society for Autism Research, Wiley Periodicals, Inc.)

Truncating de novo mutations in ADNP have been identified in patients with the Helsmoortel-Van der Aa syndrome. However correlations between the distinct mutations and their impact on the protein have not been studied before. Here we report the effect of mutations in ADNP by examining the expression and subcellular localization of GFP-tagged mutant transcripts in transfected HEK293T cells. ADNP encloses a bipartite nuclear localization signal and we found mutations therein to stall the mutant protein within the cytoplasm. Using immunocytochemistry, we could demonstrate colocalization of wild-type ADNP with heterochromatin. We found mutations presenting a pattern based on the genetic position. For certain mutant proteins enrichment at pericentromeric heterochromatin seems partially lost. Finally, N-terminal truncated ADNP mutants are routed towards cytosolic proteasomal degradation and rescued with the proteasome inhibitor MG132. Our results suggest a correlation between the position of the mutations across the protein, its stability and subcellular localization.

BackgroundHelsmoortel–van der Aa syndrome, also known as ADNP syndrome, is a condition that causes developmental delay, language impairment, autism spectrum, and variable extraneurologic features. It is caused by heterozygous mutations in the ADNP gene on chromosome 20q13. Most of the genetic causes of Helsmoortel–van der Aa syndrome have been reported are as de novo nonsense or frameshift stop mutations in exon 5 of ADNP gene, while fewer truncating variants were discovered in exons 4 and the 5′ end of exon 5.MethodsIn our study, a 4-year-old female Chinese patient was reported with delayed psychomotor development, language impairment, ataxia, anxiety, aggressive behavior, and congenital heart defect. Trio whole exome sequencing and copy number variation sequencing were performed.ResultsA novel de novo heterozygous pathogenic mutation c.568C > T (p.Gln190Ter) was identified in the ADNP gene of the proband. His unaffected parents did not have the variant. According to the American College of Medical Genetics (ACMG) guidelines, c.568C > T was classified as “pathogenic”.ConclusionOur report indicated that c.568C > T (p.Gln190Ter) in ADNP gene is the cause of abnormal development of the nervous system, congenital heart disease and strabismus, broadening the spectrum of ADNP gene mutations associated with Helsmoortel–van der Aa syndrome.

Summary: Activity-dependent neuroprotective protein (ADNP) syndrome is a rare genetic condition associated with intellectual disability and autism spectrum disorder. Preclinical evidence suggests that low-dose ketamine may induce expression of ADNP and that neuroprotective effects of ketamine may be mediated by ADNP. The goal of the proposed research was to evaluate the safety, tolerability, and behavioral outcomes of low-dose ketamine in children with ADNP syndrome. We also sought to explore the feasibility of using electrophysiological markers of auditory steady-state response and computerized eye tracking to assess biomarker sensitivity to treatment. 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. Ketamine was generally well tolerated, and there were no serious adverse events. The most common adverse events were elation/silliness (50%), fatigue (40%), and increased aggression (40%). Using parent-report instruments to assess treatment effects, ketamine was associated with nominally significant improvement in a wide array of domains, including social behavior, attention deficit and hyperactivity, restricted and repetitive behaviors, and sensory sensitivities, a week after administration. Results derived from clinician-rated assessments aligned with findings from the parent reports. Overall, nominal improvement was evident based on the Clinical Global Impressions - Improvement scale, in addition to clinician-based scales reflecting key domains of social communication, attention deficit and hyperactivity, restricted and repetitive behaviors, speech, thinking, and learning, activities of daily living, and sensory sensitivities. Results also highlight the potential utility of electrophysiological measurement of auditory steady-state response and eye-tracking to index change with ketamine treatment. Findings are intended to be hypothesis generating and provide preliminary support for the safety and efficacy of ketamine in ADNP syndrome in addition to identifying useful endpoints for a ketamine clinical development program. However, results must be interpreted with caution given limitations of this study, most importantly the small sample size and absence of a placebo-control group.

Abstract Background Autism spectrum disorder (ASD) affects approximately one in 59 children. Variants in the activity‐dependent neuroprotector homeobox ADNP (OMIM #611386) gene may be one of the most common single‐gene causes of syndromic ASD. Most patients diagnosed with ADNP syndrome have ASD as a comorbidity, and all patients have mild‐to‐severe intellectual disability. Methods/Case Report We present a case report of a patient diagnosed with ADNP syndrome at 2.5 years of age. The patient has many of the key features of the syndrome, including ASD, global developmental delay, behavioral problems, congenital heart defect, early tooth eruption, and vision problems. The patient's initial presentation included congenital diaphragmatic hernia (CDH), which has not been previously reported in this condition. Results The patient exhibited frequent behavioral outbursts and was initiated on antipsychotic medication with near‐complete resolution of symptoms allowing her to engage more fully in early intervention therapies leading to progress in language acquisition. Conclusion This short report provides guidance for antipsychotic medication dosing to improve early intervention outcomes. This is the first report of CDH in this syndrome.

Le syndrome ADNP, pour protéine neuroprotectrice dépendante de l'activité, décrit en 2014, est une cause de déficience intellectuelle et d'autisme syndromiques. Nous rapportons l'état actuel des connaissances, 5 ans après sa découverte. Cette revue de la littérature reprend la description clinique, les outils diagnostiques et la prise en charge de ce syndrome. Nous avons réalisé une revue de la littérature sur le syndrome ADNP, d'avril 2014 à juillet 2019, sur la base des données bibliographiques Medline, via le serveur PubMed, et avons complété notre recherche par une recherche manuelle. Dix-huit articles restituaient des descriptions cliniques de patients porteurs d'un syndrome ADNP, 6 articles décrivant une série de cas ou une étude de cohorte descriptive, 12 articles rapportant des cas cliniques isolés. L'analyse de la littérature souligne l'importance du séquençage de l'exome complet, afin d'établir un diagnostic précoce du syndrome ADNP, dans les cas de syndrome polymalformatif associé à une déficience intellectuelle et/ou un autisme. Une éruption prématurée des dents de lait, un colobome et/ou un blépharophimosis sont évocateurs, sachant que de très nombreux organes peuvent être concernés (malformations cérébro-cranio-faciales, gastroentérologiques, cardiaques, urogénitales, musculosquelettiques notamment). La prise en charge requiert une collaboration étroite entre somaticiens et psychiatres. Des améliorations sont décrites lorsque des soins multidimensionnels, intégratifs et intensifs sont prodigués. Notons que des recherches cliniques sont en cours afin d'offrir aux jeunes avec ADNP une stratégie thérapeutique ciblée, en utilisant de nouveaux peptides de l'ADNP biologiquement actifs. Le syndrome ADNP doit être reconnu précocement pour améliorer la prise en charge multidisciplinaire et la qualité de vie des patients atteints et de leurs familles. En cas de trouble du spectre autistique avec déficience intellectuelle et anomalies congénitales multiples, une analyse génétique avec séquençage de l'exome complet s'avère indispensable. Recently described in 2014, the activity-dependent neuroprotective protein (ADNP) syndrome combines a neurodevelopmental delay (intellectual disability and/or autism) with multiple body organ involvements. ADNP syndrome is a prevalent syndromic autism spectrum disorder caused by a single de novo mutation, leading to an increasing interest in the ADNP gene as well in clinical and behavioral manifestations of the syndrome. However, the full extent of ADNP syndrome is unknown and a comprehensive clinical overview is needed. We report the current state of knowledge about ADNP syndrome, five years after its discovery. This literature review offers a clinical description and specifies the diagnostic tools and the management of this rare syndrome. We conducted a literature review on the ADNP syndrome from April 2014 to July 2019, based on Medline bibliographic data, via the PubMed server. We completed our search with a manual search. Eighteen articles provide clinical descriptions of patients with ADNP syndrome. Six articles describe a series of cases or a descriptive cohort study. Twelve articles report isolated clinical cases. The literature review emphasizes the importance of whole-exome sequencing, in order to establish an early diagnosis of the ADNP syndrome, in cases of polymalformative syndrome associated with intellectual disability and/or autism spectrum disorder. An early primary tooth eruption (almost fully erupted dentition by 1 year of age), a coloboma and/or a blepharophimosis are suggestive features, knowing that many organs may be involved (cerebro-cranio-facial malformations, gastrointestinal, cardiac, urogenital, musculoskeletal in particular). Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected. Management requires close collaboration between somaticians and psychiatrists. Improvements may be achieved over time when intensive multidimensional and integrative care is provided. It is worth noting that clinical research is underway to offer ADNP children a target-specific therapeutic strategy, using novel biologically active ADNP peptides. Extensive knowledge concerning the ADNP syndrome is very recent. Early recognition of ADNP syndrome is required to improve the multidisciplinary management and quality of life of affected patients and their families. Genetic testing with next generation sequencing strategies such as whole exome sequencing is compulsory for patients with autism spectrum disorder, intellectual disability and multiple congenital anomalies. [ABSTRACT FROM AUTHOR]

Pathogenic disruptions to the activity‐dependent neuroprotector homeobox (ADNP) gene are among the most common heterozygous genetic mutations associated with autism spectrum disorders (ASDs). Individuals with ADNP disruptions share a constellation of medical and psychiatric features, including ASD, intellectual disability (ID), dysmorphic features, and hypotonia. However, the profile of ASD symptoms associated with ADNP may differ from that of individuals with another ASD‐associated single gene disruption or with ASD without a known genetic cause. The current study examined the ASD phenotype in a sample of representative youth with ADNP disruptions. Participants (N = 116, ages 4–22 years) included a cohort with ADNP mutations (n = 11) and three comparison groups with either a mutation to CHD8 (n = 11), a mutation to another ASD‐associated gene (other mutation; n = 53), or ASD with no known genetic etiology (idiopathic ASD; n = 41). As expected, individuals with ADNP disruptions had higher rates of ID but less severe social affect symptoms compared to the CHD8 and Idiopathic ASD groups. In addition, verbal intelligence explained more variance in social impairment in the ADNP group compared to CHD8, other mutation, and idiopathic ASD comparison groups. Restricted and repetitive behaviors in the ADNP group were characterized by high levels of stereotyped motor behaviors, whereas the idiopathic ASD group showed high levels of restricted interests. Taken together, these results underscore the role of ADNP in cognitive functioning and suggest that social impairments in ADNP syndrome are consistent with severity of verbal deficits. Autism Res2018, 11: 1300–1310. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary: Disruptions to the ADNP gene (i.e., ADNP syndrome) have been associated with autism spectrum disorder (ASD). This article describes intellectual disability, mild social difficulties, and severe repetitive motor movements in a group of 11 youth with ADNP Syndrome. We found lower rates of ASD than previously reported. Verbal skills explained individual variability in social impairment. This pattern suggests that the ADNP gene is primarily associated with learning and memory, and level of social difficulties is consistent with level of verbal impairment. [ABSTRACT FROM AUTHOR]