Dataset Information

The Neuroanatomy of Autism Spectrum Disorder Symptomatology in 22q11.2 Deletion Syndrome.

ABSTRACT: 22q11.2 Deletion Syndrome (22q11.2DS) is a genetic condition associated with a high prevalence of neuropsychiatric conditions that include autism spectrum disorder (ASD). While evidence suggests that clinical phenotypes represent distinct neurodevelopmental outcomes, it remains unknown whether this translates to the level of neurobiology. To fractionate the 22q11.2DS phenotype on the level of neuroanatomy, we examined differences in vertex-wise estimates of cortical volume, surface area, and cortical thickness between 1) individuals with 22q11.2DS (n = 62) and neurotypical controls (n = 57) and 2) 22q11.2DS individuals with ASD symptomatology (n = 30) and those without (n = 25). We firstly observed significant differences in surface anatomy between 22q11.2DS individuals and controls for all 3 neuroanatomical features, predominantly in parietotemporal regions, cingulate and dorsolateral prefrontal cortices. We also established that 22q11.2DS individuals with ASD symptomatology were neuroanatomically distinct from 22q11.2DS individuals without ASD symptoms, particularly in brain regions that have previously been linked to ASD (e.g., dorsolateral prefrontal cortices and the entorhinal cortex). Our findings indicate that different clinical 22q11.2DS phenotypes, including those with ASD symptomatology, may represent different neurobiological subgroups. The spatially distributed patterns of neuroanatomical differences associated with ASD symptomatology in 22q11.2DS may thus provide useful information for patient stratification and the prediction of clinical outcomes.

SUBMITTER: Gudbrandsen M

PROVIDER: S-EPMC6644859 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The Neuroanatomy of Autism Spectrum Disorder Symptomatology in 22q11.2 Deletion Syndrome.

Gudbrandsen M M Daly E E Murphy C M CM Wichers R H RH Stoencheva V V Perry E E Andrews D D Blackmore C E CE Rogdaki M M Kushan L L Bearden C E CE Murphy D G M DGM Craig M C MC Ecker C C

Cerebral cortex (New York, N.Y. : 1991) 20190701 8

22q11.2 Deletion Syndrome (22q11.2DS) is a genetic condition associated with a high prevalence of neuropsychiatric conditions that include autism spectrum disorder (ASD). While evidence suggests that clinical phenotypes represent distinct neurodevelopmental outcomes, it remains unknown whether this translates to the level of neurobiology. To fractionate the 22q11.2DS phenotype on the level of neuroanatomy, we examined differences in vertex-wise estimates of cortical volume, surface area, and cor ...[more]

PMID: 30272146

Similar Datasets

Project description:Background and aimChildren with Developmental Language Disorder (DLD) are at an increased risk to develop behaviors associated with Autism Spectrum Disorder (ASD). The relationship between early language difficulties and the occurrence of ASD-related behaviors in DLD is poorly understood. One factor that may hinder progress in understanding this relationship is the etiological heterogeneity of DLD. We therefore study this relationship in an etiologically homogeneous group of children, who share phenotypic characteristics with children with DLD: children with the 22q11.2 Deletion Syndrome (22q11DS). We compare children with 22q11DS, to children with DLD and age-matched typically developing children (TD).Method44 children with 22q11DS, 65 children with DLD and 81 TD children, between 3.0-6.5 years old, participated in a longitudinal cohort study that included a baseline measure and a follow-up measure with a 1-year interval. A parental questionnaire (SRS-2) was used to measure the incidence of behaviors in two key behavioral domains associated with ASD: Social Communication and Interaction and Restricted Repetitive Behaviors and Interests. At baseline, we assessed children's expressive and receptive language abilities as well as their intellectual functioning with standardized tests. We compared the distribution of ASD-related behaviors between the three groups. We used regression analyses to investigate whether language abilities at baseline predict ASD-related behavior at follow-up, accounting for ASD-related behavior at baseline, demographic variables and intellectual functioning.ResultsBoth the children with 22q11DS and the children with DLD displayed significantly more ASD-related behaviors than the TD children. Over 30% of children in both clinical groups had scores exceeding the subclinical threshold for ASD in both behavioral domains. Both in 22q11DS and DLD, baseline receptive language scores were negatively correlated with ASD-related behaviors 1 year later, when controlling for baseline SRS-scores. However, this association was statistically significant only in children with 22q11DS, even when controlled for IQ-scores, and it was significantly stronger as than in the TD group. The strength of the association did not differ significantly between 22q11DS and DLD.ConclusionBoth children with 22q11DS and children with DLD present with elevated rates of ASD-related behaviors at a preschool-age. Only in children with 22q11DS we observed that weaker receptive language skills were related to increased behavioral problems in the domain of social communication and interaction one year later.ImplicationsOur findings indicate that relations between early language impairment and other behavioral phenotypes may be more feasible to detect in a subgroup of children with a homogeneous etiology, than in a group of children with a heterogeneous etiology (such as children with DLD). Our results in 22q11DS reveal that receptive language is especially important in predicting the occurrence of ASD-related behaviors. Future research is needed to determine to what extent receptive language predicts the occurrence of ASD-related behaviors in children with DLD, especially among those children with DLD with the weakest receptive language. Clinically, screening for ASD-related behaviors in children with developmental language difficulties is recommended from a young age, especially among children with receptive language difficulties.

Project description:22q11.2 Deletion Syndrome (22q11DS) represents one of the most common known genetic risk factors for the development of psychotic illness, and is also associated with high rates of autistic spectrum disorders (ASD) in childhood. We performed integrated genomic analyses of 22q11DS to identify genes and pathways related to specific phenotypes. Eighty percent of 22q11DS individuals (n=37) carried the typical 3 Mb deletion, with significant variability in the deletion characteristics in the remainder of the sample (n=9). Both analysis of differential expression and weighted gene coexpression network analysis (WGCNA) identified peripheral changes in gene expression related to psychotic symptom expression in patients, including a module of co-expressed genes which was associated with psychosis in 22q11DS and involved in pathways associated with transcriptional regulation. Remarkably, this 22q11DS psychosis module was significantly enriched for brain-expressed genes, was not related to antipsychotic medication use, and showed significant overlap with transcriptional changes occurring in idiopathic schizophrenia in an independent dataset. In those with 22q11DS-ASD, both differential expression and WGCNA analyses pointed towards dysregulation of immune response pathways. The ASD-associated module showed overlap with a neuronal module enriched for known autism susceptibility genes identified in brain transcriptome data from individuals with idiopathic autism. These findings further support the use of peripheral tissue in the study of major mutational models of diseases affecting the brain, and point towards specific pathways dysregulated in 22q11DS carriers with psychosis and ASD, warranting their further investigation in idiopathic illness. Participants. Forty-six patients with a molecularly confirmed diagnosis of a 22q11.2 deletion and 66 controls (24 unrelated controls and 42 first-degree relatives of 22q11DS patients) were recruited from an ongoing longitudinal study. Comparative Genomic Hybridization Arrays. To characterize the boundaries of the 22q11.2 deletion, we designed a custom NimbleGen 12*135 HX12 array. Microarray-based gene expression analysis. Whole-genome transcriptional profiling was performed using Illumina Human HT-12 microarrays.Gene ontology annotation was performed using DAVID (http://david.abcc.ncifcrf.gov/) and pathway analysis was performed by using the Functional Analysis Annotation tool in the Ingenuity Pathways Analysis (IPA) software (Ingenuity Systems, www.ingenuity.com). Because the healthy control group included parents of 22q11DS patients, there were significant age differences between groups (Table 1, p<.001); thus, we corrected for age in all analyses.Weighted Gene Co-expression Network Analysis (WGCNA). We conducted WGCNA, a systems biology approach used to identify networks of co-expressed genes in relation to phenotypic data, using the R package. Phenotypic traits examined within the 22q11DS group included: categorical and dimensional indicators of psychosis (i.e. psychosis diagnosis and SIPS psychotic symptom severity score), ASD, and gender. For modules that showed a statistically significant relationship with any phenotypic trait (p<.05), GO analyses and IPA were conducted. Validation with published datasets. In order to validate our gene expression and WGCNA results, we overlapped gene lists obtained from microarray differential expression analysis for 22q11DS vs. Controls,

Project description:Recently, increasing numbers of rare pathogenic genetic variants have been identified that are associated with variably elevated risks of a range of neurodevelopmental outcomes, notably including Autism Spectrum Disorders (ASD), Schizophrenia Spectrum Disorders (SSD), and Intellectual Disability (ID). This review is organized along three main questions: First, how can we unify the exclusively descriptive basis of our current psychiatric diagnostic classification system with the recognition of an identifiable, highly penetrant genetic risk factor in an increasing proportion of patients with ASD or SSD? Second, what can be learned from studies of individuals with ASD or SSD who share a common genetic basis? And third, what accounts for the observed variable penetrance and pleiotropy of neuropsychiatric phenotypes in individuals with the same pathogenic variant? In this review, we focus on findings of clinical and preclinical studies of the 22q11.2 deletion syndrome (22q11DS). This particular variant is not only one of the most common among the increasing list of known rare pathogenic variants, but also one that benefits from a relatively long research history. Consequently, 22q11DS is an appealing model as it allows us to: (1) elucidate specific genotype-phenotype associations, (2) prospectively study behaviorally defined classifications, such as ASD or SSD, in the context of a known, well-characterized genetic basis, and (3) elucidate mechanisms underpinning variable penetrance and pleiotropy, phenomena with far-reaching ramifications for research and clinical practice. We discuss how findings from animal and in vitro studies relate to observations in human studies and can help elucidate factors, including genetic, environmental, and stochastic, that impact the expression of neuropsychiatric phenotypes in 22q11DS, and how this may inform mechanisms underlying neurodevelopmental expression in the general population. We conclude with research priorities for the field, which may pave the way for novel therapeutics.

Project description:BackgroundThe 1.6 Mb 3q29 deletion is associated with neurodevelopmental and neuropsychiatric phenotypes, including a 19-fold increased risk for autism spectrum disorder (ASD). Previous work by our team identified elevated social disability in this population via parent-report questionnaires. However, clinical features of ASD in this population have not been explored in detail.MethodsThirty-one individuals with 3q29 deletion syndrome (3q29del, 61.3% male) were evaluated using two gold-standard clinical ASD evaluations: the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), and the Autism Diagnostic Interview, Revised (ADI-R). Four matched comparators for each subject were ascertained from the National Database for Autism Research. Item-level scores on the ADOS-2 and ADI-R were compared between subjects with 3q29del and matched comparators.ResultsSubjects with 3q29del and no ASD (3q29del-ASD) had greater evidence of social disability compared to typically developing (TD) comparison subjects across the ADOS-2. Subjects with 3q29del and ASD (3q29del + ASD) were largely indistinguishable from non-syndromic ASD (nsASD) subjects on the ADOS-2. 3q29del + ASD performed significantly better on social communication on the ADI-R than nsASD (3q29 + ASD mean = 11.36; nsASD mean = 15.70; p = 0.01), and this was driven by reduced deficits in nonverbal communication (3q29 + ASD mean = 1.73; nsASD mean = 3.63; p = 0.03). 3q29del + ASD reported significantly later age at the first two-word phrase compared to nsASD (3q29del + ASD mean = 43.89 months; nsASD mean = 37.86 months; p = 0.01). However, speech delay was not related to improved nonverbal communication in 3q29del + ASD.LimitationsThere were not enough TD comparators with ADI-R data in NDAR to include in the present analysis. Additionally, our relatively small sample size made it difficult to assess race and ethnicity effects.Conclusions3q29del is associated with significant social disability, irrespective of ASD diagnosis. 3q29del + ASD have similar levels of social disability to nsASD, while 3q29del-ASD have significantly increased social disability compared to TD individuals. However, social communication is reasonably well preserved in 3q29del + ASD relative to nsASD. It is critical that verbal ability and social disability be examined separately in this population to ensure equal access to ASD and social skills evaluations and services.

Dataset Information

The Neuroanatomy of Autism Spectrum Disorder Symptomatology in 22q11.2 Deletion Syndrome.

Publications

The Neuroanatomy of Autism Spectrum Disorder Symptomatology in 22q11.2 Deletion Syndrome.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets