Shared and divergent mental health characteristics of ADNP-, CHD8- and DYRK1A-related neurodevelopmental conditions
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ABSTRACT:
SUBMITTER: Neuhaus E
PROVIDER: S-EPMC11017562 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundAutism 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 reportWe 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.ResultsThe 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.ConclusionThis short report provides guidance for antipsychotic medication dosing to improve early intervention outcomes. This is the first report of CDH in this syndrome.
| S-EPMC7284036 | biostudies-literature
Project description:We have cloned the cDNAs of the zebrafish (Danio rerio) members of the matrilin family of extracellular adaptor proteins. In contrast to mammals, no orthologue of matrilin-2 was found in zebrafish, either by RT (reverse-transcriptase) PCR using degenerated primers or by screening the databases (Ensembl and NCBI); however, two forms of matrilin-3, matrilin-3a and -3b, were present. The identity with the mammalian matrilins is from more than 70% for the VWA (von Willebrand factor A)-like domains to only 28% for the coiled-coil domains of matrilin-3a and -3b. In all zebrafish matrilins we found a greater variety of splice variants than in mammals, with splicing mainly affecting the number of EGF (epidermal growth factor)-like repeats. The exon-intron organization is nearly identical with that of mammals, and also the characteristic AT-AC intron interrupting the exons coding for the coiled-coil domain is conserved. In the matrilin-3b gene a unique exon codes for a proline- and serine/threonine-rich domain, possibly having mucin-like properties. The matrilin-1 and -3a genes were mapped to chromosome 19 and 20 respectively by the radiation hybrid method. The temporal and spatial expression of zebrafish matrilins is similar to that seen in the mouse. Zebrafish matrilin-4 is highly expressed as early as 24 hpf (h post fertilization), whereas the other matrilins show peak expression at 72 hpf. By immunostaining of whole mounts and sections, we found that matrilin-1 and -3a show predominantly skeletal staining, whereas matrilin-4 is more widespread, with the protein also being present in loose connective tissues and epithelia.
| S-EPMC1134802 | biostudies-literature
Project description: Not available
| S-EPMC9650912 | biostudies-literature
Project description:BackgroundIn genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking.MethodsWe identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires.ResultsWe report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected.ConclusionsThis overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype.
| S-EPMC6139063 | biostudies-literature
Project description: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.
| S-EPMC10233273 | biostudies-literature
Project description:Truncating mutations of chromodomain helicase DNA-binding protein 8 (CHD8), and of many other genes with diverse functions, are strong-effect risk factors for autism spectrum disorder (ASD), suggesting multiple mechanisms of pathogenesis. We explored the transcriptional networks that CHD8 regulates in neural progenitor cells (NPCs) by reducing its expression and then integrating transcriptome sequencing (RNA sequencing) with genome-wide CHD8 binding (ChIP sequencing). Suppressing CHD8 to levels comparable with the loss of a single allele caused altered expression of 1,756 genes, 64.9% of which were up-regulated. CHD8 showed widespread binding to chromatin, with 7,324 replicated sites that marked 5,658 genes. Integration of these data suggests that a limited array of direct regulatory effects of CHD8 produced a much larger network of secondary expression changes. Genes indirectly down-regulated (i.e., without CHD8-binding sites) reflect pathways involved in brain development, including synapse formation, neuron differentiation, cell adhesion, and axon guidance, whereas CHD8-bound genes are strongly associated with chromatin modification and transcriptional regulation. Genes associated with ASD were strongly enriched among indirectly down-regulated loci (P < 10(-8)) and CHD8-bound genes (P = 0.0043), which align with previously identified coexpression modules during fetal development. We also find an intriguing enrichment of cancer-related gene sets among CHD8-bound genes (P < 10(-10)). In vivo suppression of chd8 in zebrafish produced macrocephaly comparable to that of humans with inactivating mutations. These data indicate that heterozygous disruption of CHD8 precipitates a network of gene-expression changes involved in neurodevelopmental pathways in which many ASD-associated genes may converge on shared mechanisms of pathogenesis.
| S-EPMC4210312 | biostudies-literature
Project description:Mutations in the gene encoding the chromodomain helicase DNA-binding protein 8 (CHD8) are strongly associated with autism spectrum disorder (ASD). Although duplications of the locus spanning CHD8 are also found in individuals with neurodevelopmental disorders, the role of CHD8 duplication in clinical phenotypes and the underlying mechanisms have remained unknown. Here we show that mice with Chd8 overexpression modeling human CHD8 duplication manifest growth retardation, microcephaly, and behavioral abnormalities including hyperactivity and reduced anxiety-like behavior. Chd8 overexpression results in alterations of transcription and chromatin accessibility of genes involved in neurogenesis that are associated with aberrant binding of CHD8 to enhancer regions and impairs differentiation of deep-layer neurons. Furthermore, genetic and pharmacological interventions rescue hyperactive behavior of Chd8 overexpression mice. Our results thus indicate that Chd8 overexpression mice recapitulate key features of CHD8 duplication syndrome, and they provide insight into cellular and molecular pathogenesis underlying neurodevelopmental disorders.
2025-04-05 | GSE263334 | GEO
Project description:Iron deficiency (ID) and restlessness are associated with sleep/wake-disorders (e.g., restless legs syndrome (RLS)) and neurodevelopmental disorders (attention deficit/hyperactivity and autism spectrum disorders (ADHD; ASD)). However, a standardized approach to assessing ID and restlessness is missing. We reviewed iron status and family sleep/ID history data collected at a sleep/wake behavior clinic under a quality improvement/quality assurance project. Restlessness was explored through patient and parental narratives and a 'suggested clinical immobilization test'. Of 199 patients, 94% had ID, with 43% having a family history of ID. ADHD (46%) and ASD (45%) were common conditions, along with chronic insomnia (61%), sleep-disordered breathing (50%), and parasomnias (22%). In unadjusted analysis, a family history of ID increased the odds (95% CI) of familial RLS (OR: 5.98, p = 0.0002, [2.35-15.2]), insomnia/DIMS (OR: 3.44, p = 0.0084, [1.37-8.64]), and RLS (OR: 7.00, p = 0.01, [1.49-32.93]) in patients with ADHD, and of insomnia/DIMS (OR: 4.77, p = 0.0014, [1.82-12.5]), RLS/PLMS (OR: 5.83, p = 0.009, [1.54-22.1]), RLS (OR: 4.05, p = 0.01, [1.33-12.3]), and familial RLS (OR: 2.82, p = 0.02, [1.17-6.81]) in patients with ASD. ID and restlessness were characteristics of ADHD and ASD, and a family history of ID increased the risk of sleep/wake-disorders. These findings highlight the need to integrate comprehensive blood work and family history to capture ID in children and adolescents with restless behaviors.
| S-EPMC11435348 | biostudies-literature
Project description:BackgroundParents of individuals with rare neurodevelopmental conditions and intellectual disabilities (ID) are vulnerable to mental health difficulties, which vary between parents and within parents over time. The underlying cause of a child's condition can influence parents' mental health, via uncertain pathways and within unknown time-windows.ResultsWe analysed baseline data from the IMAGINE-ID cohort, comprising 2655 parents of children and young people with ID of known genetic origin. First, we conducted a factor analysis of the SDQ Impact scale to isolate specific pathways from genetic aetiology to parents' mental health. This suggested a two-factor structure for the SDQ Impact scale, with a "home & distress" dimension and a "participation" dimension. Second, we tested via structural equation modelling (SEM) whether genetic diagnosis affects Impact and mental health directly, or indirectly via children's characteristics. This analysis identified an indirect pathway linking genetic aetiology to parents' mental health, serially through child characteristics (physical disabilities, emotional and behavioural difficulties) and Impact: home & distress. Third, we conducted moderation analysis to explore the influence of time elapsed since genetic diagnosis. This showed that the serial mediation model was moderated by time since diagnosis, with strongest mediating effects among recently diagnosed cases.ConclusionsThere are multiple steps on the pathway from ID-associated genetic diagnoses to parents' mental health. Pathway links are strongest within 5 years of receiving a genetic diagnosis, highlighting opportunities for better post-diagnostic support. Recognition and enhanced support for children's physical and behavioural needs might reduce impact on family life, ameliorating parents' vulnerabilities to mental health difficulties.
| S-EPMC10870533 | biostudies-literature
Project description:Mutations in the gene encoding the chromodomain helicase DNA-binding protein 8 (CHD8) are strongly associated with autism spectrum disorder (ASD). Although duplications of the locus spanning CHD8 are also found in individuals with neurodevelopmental disorders, the role of CHD8 duplication in clinical phenotypes and the underlying mechanisms have remained unknown. Here we show that mice with Chd8 overexpression modeling human CHD8 duplication manifest growth retardation, microcephaly, and behavioral abnormalities including hyperactivity and reduced anxiety-like behavior. Chd8 overexpression results in alterations of transcription and chromatin accessibility of genes involved in neurogenesis that are associated with aberrant binding of CHD8 to enhancer regions and impairs differentiation of deep-layer neurons. Furthermore, genetic and pharmacological interventions rescue hyperactive behavior of Chd8 overexpression mice. Our results thus indicate that Chd8 overexpression mice recapitulate key features of CHD8 duplication syndrome, and they provide insight into cellular and molecular pathogenesis underlying neurodevelopmental disorders.
2025-04-05 | GSE288732 | GEO