The Phenotypic variability of 16p11.2 distal BP2-BP3 deletion in a transgenerational family and in neurodevelopmentally ascertained samples.

BACKGROUND: We present genomic and phenotypic findings of a transgenerational family consisting of three male offspring, each with a maternally inherited distal 220 kb deletion at locus 16p11.2 (BP2-BP3). Genomic analysis of all family members was prompted by a diagnosis of autism spectrum disorder (ASD) in the eldest child, who also presented with a low body mass index. METHODS: All male offspring underwent extensive neuropsychiatric evaluation. Both parents were also assessed for social functioning and cognition. The family underwent whole-genome sequencing. Further data curation was undertaken from samples ascertained for neurodevelopmental disorders and congenital abnormalities. RESULTS: On medical examination, both the second and third-born male offspring presented with obesity. The second-born male offspring met research diagnostic criteria for ASD at 8 years of age and presented with mild attention deficits. The third-born male offspring was only noted as having motor deficits and received a diagnosis of developmental coordination disorder. Other than the 16p11.2 distal deletion, no additional contributing variants of clinical significance were observed. The mother was clinically evaluated and noted as having a broader autism phenotype. CONCLUSION: In this family, the phenotypes observed are most likely caused by the 16p11.2 distal deletion. The lack of other overt pathogenic mutations identified by genomic sequencing reinforces the variable expressivity that should be heeded in a clinical setting. Importantly, distal 16p11.2 deletions can present with a highly variable phenotype even within a single family. Our additional data curation provides further evidence on the variable clinical presentation among those with pathogenetic 16p11.2 (BP2-BP3) mutations.

Cross-Diagnosis Structural Correlates of Autistic-Like Social Communication Differences.

Social communication differences are seen in autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD), but the brain mechanisms contributing to these differences remain largely unknown. To address this gap, we used a data-driven and diagnosis-agnostic approach to discover brain correlates of social communication differences in ASD, ADHD, and OCD, and subgroups of individuals who share similar patterns of brain-behavior associations. A machine learning pipeline (regression clustering) was used to discover the pattern of association between structural brain measures (volume, surface area, and cortical thickness) and social communication abilities. Participants (n = 416) included children with a diagnosis of ASD (n = 192, age = 12.0[5.6], 19% female), ADHD (n = 109, age = 11.1[4.1], 18% female), or OCD (n = 50, age = 12.3[4.2], 42% female), and typically developing controls (n = 65, age = 11.6[7.1], 48% female). The analyses revealed (1) associations with social communication abilities in distributed cortical and subcortical networks implicated in social behaviors, language, attention, memory, and executive functions, and (2) three data-driven, diagnosis-agnostic subgroups based on the patterns of association in the above networks. Our results suggest that different brain networks may contribute to social communication differences in subgroups that are not diagnosis-specific.

Mental health profiles of autistic children and youth during the COVID-19 pandemic.

Objectives: Canadian province-wide lockdowns have challenged children's mental health (MH) during the COVID-19 pandemic, with autistic children being at particular risk. The purpose of our study was to identify sub-groups of autistic children with distinct mental health change profiles, to understand the child-, parent-, and system-specific factors associated with such profiles in order to ultimately inform future interventions. Methods: Data were drawn from a large Canadian cohort (N=1,570) across Ontario, resulting in 265 autistic children (mean age=10.9 years, 76% male). K-means clustering analyses were employed to partition distinct MH profiles in six MH measures (mood, anxiety, OCD symptoms, irritability, inattention, hyperactivity) and group differences were examined with reference to the above factors. Additionally, we investigated the characteristics of children who accessed acute MH services. Results: The optimal number of clusters was two; one included those experiencing MH deterioration across all six MH measures (61.3%, 95% confidence interval [CI]=54.9 to 67.4), and a second included youth that did not experience MH changes (38.7%, 95%CI=32.6 to 45.1). Child-specific factors associated with MH deterioration included higher pre-existing internalizing symptoms, high levels of COVID stress. Parental MH challenges and system-specific factors, such as the loss of learning supports, access to physicians and material deprivation, were also associated with MH deterioration. Access to acute MH services were primarily associated with financial insecurity and loss of services. Conclusions: More than half of autistic children experienced MH deterioration, and person-specific (pre-existing MH, COVID related stress), parent-specific (Parent MH) and system-level (loss of services and material deprivation) characteristics were associated with such decline, providing clinical and policy opportunities for intervention at multiple levels.

Predictors of health-related quality of life for children with neurodevelopmental conditions.

Neurodevelopmental conditions can be associated with decreased health-related quality of life; however, the predictors of these outcomes remain largely unknown. We characterized the predictors of health-related quality of life (HRQoL) in a sample of neurodiverse children and youth. We used a cross-sectional subsample from the Province of Ontario Neurodevelopmental Disorders Network (POND) consisting of those children and young people in the POND dataset with complete study data (total n = 615; 31% female; age: 11.28 years ± 2.84 years). Using a structural equation model, we investigated the effects of demographics (age, sex, socioeconomic status), core features (Social Communication Questionnaire, Toronto Obsessive Compulsive Scale, Strengths and Weaknesses of attention deficit/hyperactivity disorder (ADHD)-symptoms and Normal Behavior), co-occurring symptoms (Child Behaviour Checklist), and adaptive functioning (Adaptive Behaviour Assessment System) on HRQoL (KINDL). A total of 615 participants had complete data for this study (autism = 135, ADHD = 273, subthreshold ADHD = 7, obsessive-compulsive disorder (OCD) = 38, sub-threshold OCD = 1, neurotypical = 161). Of these participants, 190 (31%) identified as female, and 425 (69%) identified as male. The mean age was 11.28 years ± 2.84 years. Health-related quality of life was negatively associated with co-occurring symptoms (B = - 0.6, SE = 0.20, CI (- 0.95, - 0.19), p = 0.004)) and age (B = - 0.1, SE = 0.04, CI (- 0.19, - 0.01), p = 0.037). Fewer co-occurring symptoms were associated with higher socioeconomic status (B = - 0.5, SE = - 0.05, CI (- 0.58, - 0.37), p < 0.001). This study used a cross-sectional design. Given that one's experiences, needs, supports, and environment and thus HrQoL may change significantly over the lifespan and a longitudinal analysis of predictors is needed to capture these changes. Future studies with more diverse participant groups are needed. These results demonstrate the importance of behavioural and sociodemographic characteristics on health-related quality of life across neurodevelopmental conditions.

Behaviour-correlated profiles of cerebellar-cerebral functional connectivity observed in independent neurodevelopmental disorder cohorts.

The cerebellum, through its connectivity with the cerebral cortex, plays an integral role in regulating cognitive and affective processes, and its dysregulation can result in neurodevelopmental disorder (NDD)-related behavioural deficits. Identifying cerebellar-cerebral functional connectivity (FC) profiles in children with NDDs can provide insight into common connectivity profiles and their correlation to NDD-related behaviours. 479 participants from the Province of Ontario Neurodevelopmental Disorders (POND) network (typically developing = 93, Autism Spectrum Disorder = 172, Attention Deficit/Hyperactivity Disorder = 161, Obsessive-Compulsive Disorder = 53, mean age = 12.2) underwent resting-state functional magnetic resonance imaging and behaviour testing (Social Communication Questionnaire, Toronto Obsessive-Compulsive Scale, and Child Behaviour Checklist - Attentional Problems Subscale). FC components maximally correlated to behaviour were identified using canonical correlation analysis. Results were then validated by repeating the investigation in 556 participants from an independent NDD cohort provided from a separate consortium (Healthy Brain Network (HBN)). Replication of canonical components was quantified by correlating the feature vectors between the two cohorts. The two cerebellar-cerebral FC components that replicated to the greatest extent were correlated to, respectively, obsessive-compulsive behaviour (behaviour feature vectors, rPOND-HBN = -0.97; FC feature vectors, rPOND-HBN = -0.68) and social communication deficit contrasted against attention deficit behaviour (behaviour feature vectors, rPOND-HBN = -0.99; FC feature vectors, rPOND-HBN = -0.78). The statistically stable (|z| > 1.96) features of the FC feature vectors, measured via bootstrap re-sampling, predominantly comprised of correlations between cerebellar attentional and control network regions and cerebral attentional, default mode, and control network regions. In both cohorts, spectral clustering on FC loading values resulted in subject clusters mixed across diagnostic categories, but no cluster was significantly enriched for any given diagnosis as measured via chi-squared test (p > 0.05). Overall, two behaviour-correlated components of cerebellar-cerebral functional connectivity were observed in two independent cohorts. This suggests the existence of generalizable cerebellar network differences that span across NDD diagnostic boundaries.

Harmonizing data on correlates of sleep in children within and across neurodevelopmental disorders: lessons learned from an Ontario Brain Institute cross-program collaboration.

There is an increasing desire to study neurodevelopmental disorders (NDDs) together to understand commonalities to develop generic health promotion strategies and improve clinical treatment. Common data elements (CDEs) collected across studies involving children with NDDs afford an opportunity to answer clinically meaningful questions. We undertook a retrospective, secondary analysis of data pertaining to sleep in children with different NDDs collected through various research studies. The objective of this paper is to share lessons learned for data management, collation, and harmonization from a sleep study in children within and across NDDs from large, collaborative research networks in the Ontario Brain Institute (OBI). Three collaborative research networks contributed demographic data and data pertaining to sleep, internalizing symptoms, health-related quality of life, and severity of disorder for children with six different NDDs: autism spectrum disorder; attention deficit/hyperactivity disorder; obsessive compulsive disorder; intellectual disability; cerebral palsy; and epilepsy. Procedures for data harmonization, derivations, and merging were shared and examples pertaining to severity of disorder and sleep disturbances were described in detail. Important lessons emerged from data harmonizing procedures: prioritizing the collection of CDEs to ensure data completeness; ensuring unprocessed data are uploaded for harmonization in order to facilitate timely analytic procedures; the value of maintaining variable naming that is consistent with data dictionaries at time of project validation; and the value of regular meetings with the research networks to discuss and overcome challenges with data harmonization. Buy-in from all research networks involved at study inception and oversight from a centralized infrastructure (OBI) identified the importance of collaboration to collect CDEs and facilitate data harmonization to improve outcomes for children with NDDs.

Linkage of whole genome sequencing and administrative health data in autism: A proof of concept study.

Whether genetic testing in autism can help understand longitudinal health outcomes and health service needs is unclear. The objective of this study was to determine whether carrying an autism-associated rare genetic variant is associated with differences in health system utilization by autistic children and youth. This retrospective cohort study examined 415 autistic children/youth who underwent genome sequencing and data collection through a translational neuroscience program (Province of Ontario Neurodevelopmental Disorders Network). Participant data were linked to provincial health administrative databases to identify historical health service utilization, health care costs, and complex chronic medical conditions during a 3-year period. Health administrative data were compared between participants with and without a rare genetic variant in at least 1 of 74 genes associated with autism. Participants with a rare variant impacting an autism-associated gene (n = 83, 20%) were less likely to have received psychiatric care (at least one psychiatrist visit: 19.3% vs. 34.3%, p = 0.01; outpatient mental health visit: 66% vs. 77%, p = 0.04). Health care costs were similar between groups (median: $5589 vs. $4938, p = 0.4) and genetic status was not associated with odds of being a high-cost participant (top 20%) in this cohort. There were no differences in the proportion with complex chronic medical conditions between those with and without an autism-associated genetic variant. Our study highlights the feasibility and potential value of genomic and health system data linkage to understand health service needs, disparities, and health trajectories in individuals with neurodevelopmental conditions.

Atypical oscillatory dynamics during emotional face processing in paediatric obsessive-compulsive disorder with MEG.

Children and youth with obsessive-compulsive disorder (OCD) demonstrate difficulties with social, emotional and cognitive functions in addition to the core diagnosis of obsessions and compulsions. This is the first magnetoencephalography (MEG) study to examine whole-brain neurophysiological functional connectivity of emotional face processing networks in paediatric OCD. Seventy-two participants (OCD: n = 36; age 8-17 yrs; typically developing controls: n = 36, age 8-17 yrs) completed an implicit emotional face processing task in the MEG. Functional connectivity networks in canonical frequency bands were compared between groups, and within OCD and control groups between emotions (angry vs. happy). Between groups, participants with OCD showed increased functional connectivity in the gamma band to angry faces, suggesting atypical perception of angry faces in OCD. Within groups, the OCD group showed greater engagement of the beta band, suggesting the over-use of top-down processing when perceiving happy versus angry emotions, while controls engaged in bottom-up gamma processing, also greater to happy faces. Over-activation of top-down processing has been linked to difficulties modifying one's cognitive set. Findings establish altered patterns of neurophysiological connectivity in children with OCD, and are striking in their oscillatory specificity. Our results contribute to a greater understanding of the neurobiology of the disorder, and are foundational for the possibility of alternative targets for intervention.

Identifying Replicable Subgroups in Neurodevelopmental Conditions Using Resting-State Functional Magnetic Resonance Imaging Data.

Importance: Neurodevelopmental conditions, such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD), have highly heterogeneous and overlapping phenotypes and neurobiology. Data-driven approaches are beginning to identify homogeneous transdiagnostic subgroups of children; however, findings have yet to be replicated in independently collected data sets, a necessity for translation into clinical settings. Objective: To identify subgroups of children with and without neurodevelopmental conditions with shared functional brain characteristics using data from 2 large, independent data sets. Design, Setting, and Participants: This case-control study used data from the Province of Ontario Neurodevelopmental (POND) network (study recruitment began June 2012 and is ongoing; data were extracted April 2021) and the Healthy Brain Network (HBN; study recruitment began May 2015 and is ongoing; data were extracted November 2020). POND and HBN data are collected from institutions across Ontario and New York, respectively. Participants who had diagnoses of ASD, ADHD, and OCD or were typically developing (TD); were aged between 5 and 19 years; and successfully completed the resting-state and anatomical neuroimaging protocol were included in the current study. Main Outcomes and Measures: The analyses consisted of a data-driven clustering procedure on measures derived from each participant's resting-state functional connectome, performed independently on each data set. Differences between each pair of leaves in the resulting clustering decision trees in the demographic and clinical characteristics were tested. Results: Overall, 551 children and adolescents were included from each data set. POND included 164 participants with ADHD; 217 with ASD; 60 with OCD; and 110 with TD (median [IQR] age, 11.87 [9.51-14.76] years; 393 [71.2%] male participants; 20 [3.6%] Black, 28 [5.1%] Latino, and 299 [54.2%] White participants) and HBN included 374 participants with ADHD; 66 with ASD; 11 with OCD; and 100 with TD (median [IQR] age, 11.50 [9.22-14.20] years; 390 [70.8%] male participants; 82 [14.9%] Black, 57 [10.3%] Hispanic, and 257 [46.6%] White participants). In both data sets, subgroups with similar biology that differed significantly in intelligence as well as hyperactivity and impulsivity problems were identified, yet these groups showed no consistent alignment with current diagnostic categories. For example, there was a significant difference in Strengths and Weaknesses ADHD Symptoms and Normal Behavior Hyperactivity/Impulsivity subscale (SWAN-HI) between 2 subgroups in the POND data (C and D), with subgroup D having increased hyperactivity and impulsivity traits compared with subgroup C (median [IQR], 2.50 [0.00-7.00] vs 1.00 [0.00-5.00]; U = 1.19 × 104; P = .01; η2 = 0.02). A significant difference in SWAN-HI scores between subgroups g and d in the HBN data was also observed (median [IQR], 1.00 [0.00-4.00] vs 0.00 [0.00-2.00]; corrected P = .02). There were no differences in the proportion of each diagnosis between the subgroups in either data set. Conclusions and Relevance: The findings of this study suggest that homogeneity in the neurobiology of neurodevelopmental conditions transcends diagnostic boundaries and is instead associated with behavioral characteristics. This work takes an important step toward translating neurobiological subgroups into clinical settings by being the first to replicate our findings in independently collected data sets.

Shared and Distinct Patterns of Functional Connectivity to Emotional Faces in Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder Children.

Impairments in emotional face processing are demonstrated by individuals with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), which is associated with altered emotion processing networks. Despite accumulating evidence of high rates of diagnostic overlap and shared symptoms between ASD and ADHD, functional connectivity underpinning emotion processing across these two neurodevelopmental disorders, compared to typical developing peers, has rarely been examined. The current study used magnetoencephalography to investigate whole-brain functional connectivity during the presentation of happy and angry faces in 258 children (5-19 years), including ASD, ADHD and typically developing (TD) groups to determine possible differences in emotion processing. Data-driven clustering was also applied to determine whether the patterns of connectivity differed among diagnostic groups. We found reduced functional connectivity in the beta band in ASD compared to TD, and a further reduction in the ADHD group compared to the ASD and the TD groups, across emotions. A group-by-emotion interaction in the gamma frequency band was also observed. Greater connectivity to happy compared to angry faces was found in the ADHD and TD groups, while the opposite pattern was seen in ASD. Data-driven subgrouping identified two distinct subgroups: NDD-dominant and TD-dominant; these subgroups demonstrated emotion- and frequency-specific differences in connectivity. Atypicalities in specific brain networks were strongly correlated with the severity of diagnosis-specific symptoms. Functional connectivity strength in the beta network was negatively correlated with difficulties in attention; in the gamma network, functional connectivity strength to happy faces was positively correlated with adaptive behavioural functioning, but in contrast, negatively correlated to angry faces. Our findings establish atypical frequency- and emotion-specific patterns of functional connectivity between NDD and TD children. Data-driven clustering further highlights a high degree of comorbidity and symptom overlap between the ASD and ADHD children.

Atypical Functional Connectivity During Unfamiliar Music Listening in Children With Autism.

Background: Atypical processing of unfamiliar, but less so familiar, stimuli has been described in Autism Spectrum Disorder (ASD), in particular in relation to face processing. We examined the construct of familiarity in ASD using familiar and unfamiliar songs, to investigate the link between familiarity and autism symptoms, such as repetitive behavior. Methods: Forty-eight children, 24 with ASD (21 males, mean age = 9.96 years ± 1.54) and 24 typically developing (TD) controls (21 males, mean age = 10.17 ± 1.90) completed a music familiarity task using individually identified familiar compared to unfamiliar songs, while magnetoencephalography (MEG) was recorded. Each song was presented for 30 s. We used both amplitude envelope correlation (AEC) and the weighted phase lag index (wPLI) to assess functional connectivity between specific regions of interest (ROI) and non-ROI parcels, as well as at the whole brain level, to understand what is preserved and what is impaired in familiar music listening in this population. Results: Increased wPLI synchronization for familiar vs. unfamiliar music was found for typically developing children in the gamma frequency. There were no significant differences within the ASD group for this comparison. During the processing of unfamiliar music, we demonstrated left lateralized increased theta and beta band connectivity in children with ASD compared to controls. An interaction effect found greater alpha band connectivity in the TD group compared to ASD to unfamiliar music only, anchored in the left insula. Conclusion: Our results revealed atypical processing of unfamiliar songs in children with ASD, consistent with previous studies in other modalities reporting that processing novelty is a challenge for ASD. Relatively typical processing of familiar stimuli may represent a strength and may be of interest to strength-based intervention planning.

A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is genetically complex with ~100 copy number variants and genes involved. To try to establish more definitive genotype and phenotype correlations in ASD, we searched genome sequence data, and the literature, for recurrent predicted damaging sequence-level variants affecting single genes. We identified 18 individuals from 16 unrelated families carrying a heterozygous guanine duplication (c.3679dup; p.Ala1227Glyfs*69) occurring within a string of 8 guanines (genomic location [hg38]g.50,721,512dup) affecting SHANK3, a prototypical ASD gene (0.08% of ASD-affected individuals carried the predicted p.Ala1227Glyfs*69 frameshift variant). Most probands carried de novo mutations, but five individuals in three families inherited it through somatic mosaicism. We scrutinized the phenotype of p.Ala1227Glyfs*69 carriers, and while everyone (17/17) formally tested for ASD carried a diagnosis, there was the variable expression of core ASD features both within and between families. Defining such recurrent mutational mechanisms underlying an ASD outcome is important for genetic counseling and early intervention.

Exploring the Neural Structures Underlying the Procedural Memory Network as Predictors of Language Ability in Children and Adolescents With Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder.

Introduction: There is significant overlap in the type of structural language impairments exhibited by children with autism spectrum disorder (ASD) and children with attention deficit hyperactivity disorder (ADHD). This similarity suggests that the cognitive impairment(s) contributing to the structural language deficits in ASD and ADHD may be shared. Previous studies have speculated that procedural memory deficits may be the shared cognitive impairment. The procedural deficit hypothesis (PDH) argues that language deficits can be explained by differences in the neural structures underlying the procedural memory network. This hypothesis is based on the premise that the neural structures comprising the procedural network support language learning. In this study, we aimed to test the PDH in children with ASD, ADHD, and typical development (TD). Methods: One hundred and sixty-three participants (ages 10-21): 91 with ASD, 26 with ADHD, and 46 with TD, completed standardized measures of cognitive and language ability as well as structural magnetic resonance imaging. We compared the structural language abilities, the neural structures underlying the procedural memory network, and the relationship between structural language and neural structure across diagnostic groups. Results: Our analyses revealed that while the structural language abilities differed across ASD, ADHD, and TD groups, the thickness, area, and volume of the structures supporting the procedural memory network were not significantly different between diagnostic groups. Also, several neural structures were associated with structural language abilities across diagnostic groups. Only two of these structures, the inferior frontal gyrus, and the left superior parietal gyrus, are known to be linked to the procedural memory network. Conclusions: The inferior frontal gyrus and the left superior parietal gyrus, have well-established roles in language learning independent of their role as part of the procedural memory system. Other structures such as the caudate and cerebellum, with critical roles in the procedural memory network, were not associated with structural language abilities across diagnostic groups. It is unclear whether the procedural memory network plays a fundamental role in language learning in ASD, ADHD, and TD.

Meta-Analysis of Sex Differences in Social and Communication Function in Children With Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder.

Background: Sex differences in the prevalence of neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are well documented, but studies examining sex differences in social and communication function remain limited and inconclusive. Objectives: The objective of this study is to conduct a meta-analysis of sex differences in social-communication function in children with ASD or ADHD and typically developing controls. Methods: Using PRISMA, a search was performed on Medline and PSYCHINFO on English-language journals (2000-2017) examining sex differences in social and communication function in ASD and ADHD compared to controls. Inclusion criteria: 1) peer reviewed journal articles, 2) diagnosis of ASD or ADHD and controls, 3) age 6-18 years, 4) measures of social-communication function, and 5) means, standard deviations, and sample sizes reported in order to calculate standardized mean differences (SMD). Results: Eleven original/empirical studies met inclusion criteria for ASD and six for ADHD. No significant sex differences were found between ASD and controls in social (SMD = -0.43; p = 0.5; CI: -1.58-0.72), or communication function (SMD = 0.86; p = 0.5 CI; -1.57--3.30) and between ADHD and controls in social function (SMD = -0.68: p = 0.7, CI: -4.17-2.81). No studies evaluated sex differences in communication in ADHD. Significant heterogeneity was noted in all analyses. Type of measure may have partially accounted for some variability between studies. Conclusions: The meta-analysis did not detect sex differences in social and communication function in children with ASD and ADHD; however, significant heterogeneity was noted. Future larger studies, controlling for measure and with adequate numbers of female participants are required to further understand sex differences in these domains.

Examining overlap and homogeneity in ASD, ADHD, and OCD: a data-driven, diagnosis-agnostic approach.

The validity of diagnostic labels of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and obsessive compulsive disorder (OCD) is an open question given the mounting evidence that these categories may not correspond to conditions with distinct etiologies, biologies, or phenotypes. The objective of this study was to determine the agreement between existing diagnostic labels and groups discovered based on a data-driven, diagnosis-agnostic approach integrating cortical neuroanatomy and core-domain phenotype features. A machine learning pipeline, called bagged-multiview clustering, was designed to discover homogeneous subgroups by integrating cortical thickness data and measures of core-domain phenotypic features of ASD, ADHD, and OCD. This study was conducted using data from the Province of Ontario Neurodevelopmental Disorders (POND) Network, a multi-center study in Ontario, Canada. Participants (n = 226) included children between the ages of 6 and 18 with a diagnosis of ASD (n = 112, median [IQR] age = 11.7[4.8], 21% female), ADHD (n = 58, median [IQR] age = 10.2[3.3], 14% female), or OCD (n = 34, median [IQR] age = 12.1[4.2], 38% female), as well as typically developing controls (n = 22, median [IQR] age = 11.0[3.8], 55% female). The diagnosis-agnostic groups were significantly different than each other in phenotypic characteristics (SCQ: χ2(9) = 111.21, p < 0.0001; SWAN: χ2(9) = 142.44, p < 0.0001) as well as cortical thickness in 75 regions of the brain. The analyses revealed disagreement between existing diagnostic labels and the diagnosis-agnostic homogeneous groups (normalized mutual information < 0.20). Our results did not support the validity of existing diagnostic labels of ASD, ADHD, and OCD as distinct entities with respect to phenotype and cortical morphology.

Haploinsufficiency in the ANKS1B gene encoding AIDA-1 leads to a neurodevelopmental syndrome.

Neurodevelopmental disorders, including autism spectrum disorder, have complex polygenic etiologies. Single-gene mutations in patients can help define genetic factors and molecular mechanisms underlying neurodevelopmental disorders. Here we describe individuals with monogenic heterozygous microdeletions in ANKS1B, a predicted risk gene for autism and neuropsychiatric diseases. Affected individuals present with a spectrum of neurodevelopmental phenotypes, including autism, attention-deficit hyperactivity disorder, and speech and motor deficits. Neurons generated from patient-derived induced pluripotent stem cells demonstrate loss of the ANKS1B-encoded protein AIDA-1, a brain-specific protein highly enriched at neuronal synapses. A transgenic mouse model of Anks1b haploinsufficiency recapitulates a range of patient phenotypes, including social deficits, hyperactivity, and sensorimotor dysfunction. Identification of the AIDA-1 interactome using quantitative proteomics reveals protein networks involved in synaptic function and the etiology of neurodevelopmental disorders. Our findings formalize a link between the synaptic protein AIDA-1 and a rare, previously undefined genetic disease we term ANKS1B haploinsufficiency syndrome.

Structural neuroimaging correlates of social deficits are similar in autism spectrum disorder and attention-deficit/hyperactivity disorder: analysis from the POND Network.

Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD) have been associated with difficulties recognizing and responding to social cues. Neuroimaging studies have begun to map the social brain; however, the specific neural substrates contributing to social deficits in neurodevelopmental disorders remain unclear. Three hundred and twelve children underwent structural magnetic resonance imaging of the brain (controls = 32, OCD = 44, ADHD = 77, ASD = 159; mean age = 11). Their social deficits were quantified on the Social Communication Questionnaire (SCQ) and the Reading the Mind in the Eyes Test (RMET). Multivariable regression models were used to examine the structural neuroimaging correlates of social deficits, with both a region of interest and a whole-brain vertex-wise approach. For the region of interest analysis, social brain regions were grouped into three networks: (1) lateral mentalization (e.g., temporal-parietal junction), (2) frontal cognitive (e.g., orbitofrontal cortex), and (3) subcortical affective (e.g., limbic system) regions. Overall, social communication deficits on the SCQ were associated with thinner cortices in the left lateral regions and the right insula, and decreased volume in the ventral striatum, across diagnostic groups (p = 0.006 to <0.0001). Smaller subcortical volumes were associated with more severe social deficits on the SCQ in ASD and ADHD, and less severe deficits in OCD. On the RMET, larger amygdala/hippocampal volumes were associated with fewer deficits across groups. Overall, patterns of associations were similar in ASD and ADHD, supporting a common underlying biology and the blurring of the diagnostic boundaries between these disorders.

Oxytocin Receptor Polymorphisms are Differentially Associated with Social Abilities across Neurodevelopmental Disorders.

Oxytocin is a pituitary neuropeptide that affects social behaviour. Single nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR) have been shown to explain some variability in social abilities in control populations. Whether these variants similarly contribute to the severity of social deficits experienced by children with neurodevelopmental disorders is unclear. Social abilities were assessed in a group of children with autism spectrum disorder (ASD, n = 341) or attention deficit hyperactivity disorder (ADHD, n = 276) using two established social measures. Scores were compared by OXTR genotype (rs53576, rs237887, rs13316193, rs2254298). Unexpectedly, the two most frequently studied OXTR SNPs in the general population (rs53576 and rs2254298) were associated with an increased severity of social deficits in ASD (p < 0.0001 and p = 0.0005), yet fewer social deficits in ADHD (p = 0.007 and p < 0.0001). We conclude that these genetic modifier alleles are not inherently risk-conferring with respect to their impact on social abilities; molecular investigations are greatly needed.

A randomized, placebo controlled trial of omega-3 fatty acids in the treatment of young children with autism.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting more than 1% of children. It is characterized by social communication deficits and repetitive behaviors/restricted interests. In the absence of any medications known to improve core symptom domains, parents often use complementary alternative treatments, including omega-3 fatty acid supplements. METHODS: We conducted a 6-month, randomized, placebo controlled trial of omega-3 fatty acid supplements (1.5 g) vs placebo in children 2 to 5 years of age with ASD. Primary outcome measures included the autism composite score of the Pervasive Developmental Disorders Behavioral Inventory (PDDBI) and the externalizing problems score of the Behavior Assessment System for Children (BASC-2). Secondary outcome measures included clinical global improvement (Clinical Global Impression-Improvement (CGI-I)), adaptive function (Vineland Adaptive Behavior Scale (VABS-II)), and language gains (Preschool Language Scale (PLS-4)), as well as safety. Exploratory analysis investigated potential correlations between changes in cytokine profiles and treatment response. RESULTS: Thirty-eight participants were randomized in a 1:1 fashion. There was no significant difference between groups on the 0- to 24-week change in PDDBI autism composite scores (p = 0.5). There was a significant group by week interaction on the BASC-2 externalizing problem score, with participants randomized to the treatment group demonstrating worsening scores (p = 0.02). There was no statistically significant week by group effect on either adaptive function (p = 0.09) or language (p = 0.6). Omega-3s were relatively well tolerated. Changes in cytokines during the study did not significantly correlate with treatment response. CONCLUSIONS: This study does not support high dose supplementation of omega-3 fatty acids in young children with ASD. TRIAL REGISTRATION: Clinicaltrials.gov NCT01248728. Registered 22 November 2010.