CHAMP1 disorder is associated with a complex neurobehavioral phenotype including autism, ADHD, repetitive behaviors and sensory symptoms.

CHAMP1-related neurodevelopmental disorder, or CHAMP1 disorder, is a recently described genetic syndrome associated with developmental delay, intellectual disability, behavioral symptoms, medical comorbidities, and dysmorphic features. To date, literature has focused on medical review and dysmorphology but has yet to prospectively assess neurobehavioral core domains such as autism, or behavioral, language, cognitive, and sensory features. Here, we present deep phenotyping results for 11 individuals with CHAMP1 disorder, based on approximately 12 hours of remote clinician-administered assessments and standardized caregiver questionnaires. Diagnoses of autism spectrum disorder were given to 33% of participants; repetitive behaviors and sensory-seeking symptoms were prominent in this cohort. In addition, 60% of participants met the criteria for attention-deficit/hyperactivity disorder (ADHD). High rates of ADHD and relatively low rates of treatment suggest potential areas for intervention. This study represents the first prospective phenotyping analysis of individuals with CHAMP1 disorder. The utility of specific measures as clinical endpoints, as well as benefits and limitations of remote phenotyping, are described.

Strong evidence for genotype-phenotype correlations in Phelan-McDermid syndrome: results from the developmental synaptopathies consortium.

Individuals with Phelan-McDermid syndrome (PMS) present with a wide range of developmental, medical, cognitive and behavioral abnormalities. Previous literature has begun to elucidate genotype-phenotype associations that may contribute to the wide spectrum of features. Here, we report results of genotype-phenotype associations in a cohort of 170 individuals with PMS. Genotypes were defined as Class I deletions (including SHANK3 only or SHANK3 with ARSA and/or ACR and RABL2B), Class II deletions (all other deletions) or sequence variants. Phenotype data were derived prospectively from direct evaluation, caregiver interview and questionnaires, and medical history. Analyses revealed individuals with Class I deletions or sequence variants had fewer delayed developmental milestones and higher cognitive ability compared to those with Class II deletions but had more skill regressions. Individuals with Class II deletions were more likely to have a variety of medical features, including renal abnormalities, spine abnormalities, and ataxic gait. Those with Class I deletions or sequence variants were more likely to have psychiatric diagnoses including bipolar disorder, depression, and schizophrenia. Autism spectrum disorder diagnoses did not differ between groups. This study represents the largest and most rigorous genotype-phenotype analysis in PMS to date and provides important information for considering clinical functioning, trajectories and comorbidities as a function of specific genetic alteration.

Intranasal Oxytocin in Children and Adolescents with Autism Spectrum Disorder.

BACKGROUND: Experimental studies and small clinical trials have suggested that treatment with intranasal oxytocin may reduce social impairment in persons with autism spectrum disorder. Oxytocin has been administered in clinical practice to many children with autism spectrum disorder. METHODS: We conducted a 24-week, placebo-controlled phase 2 trial of intranasal oxytocin therapy in children and adolescents 3 to 17 years of age with autism spectrum disorder. Participants were randomly assigned in a 1:1 ratio, with stratification according to age and verbal fluency, to receive oxytocin or placebo, administered intranasally, with a total target dose of 48 international units daily. The primary outcome was the least-squares mean change from baseline on the Aberrant Behavior Checklist modified Social Withdrawal subscale (ABC-mSW), which includes 13 items (scores range from 0 to 39, with higher scores indicating less social interaction). Secondary outcomes included two additional measures of social function and an abbreviated measure of IQ. RESULTS: Of the 355 children and adolescents who underwent screening, 290 were enrolled. A total of 146 participants were assigned to the oxytocin group and 144 to the placebo group; 139 and 138 participants, respectively, completed both the baseline and at least one postbaseline ABC-mSW assessments and were included in the modified intention-to-treat analyses. The least-squares mean change from baseline in the ABC-mSW score (primary outcome) was -3.7 in the oxytocin group and -3.5 in the placebo group (least-squares mean difference, -0.2; 95% confidence interval, -1.5 to 1.0; P = 0.61). Secondary outcomes generally did not differ between the trial groups. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS: This placebo-controlled trial of intranasal oxytocin therapy in children and adolescents with autism spectrum disorder showed no significant between-group differences in the least-squares mean change from baseline on measures of social or cognitive functioning over a period of 24 weeks. (Funded by the National Institute of Child Health and Human Development; SOARS-B ClinicalTrials.gov number, NCT01944046.).

Development of webcam-collected and artificial-intelligence-derived social and cognitive performance measures for neurodevelopmental genetic syndromes.

This study focused on the development and initial psychometric evaluation of a set of online, webcam-collected, and artificial intelligence-derived patient performance measures for neurodevelopmental genetic syndromes (NDGS). Initial testing and qualitative input was used to develop four stimulus paradigms capturing social and cognitive processes, including social attention, receptive vocabulary, processing speed, and single-word reading. The paradigms were administered to a sample of 375 participants, including 163 with NDGS, 56 with idiopathic neurodevelopmental disability (NDD), and 156 neurotypical controls. Twelve measures were created from the four stimulus paradigms. Valid completion rates varied from 87 to 100% across measures, with lower but adequate completion rates in participants with intellectual disability. Adequate to excellent internal consistency reliability (α = 0.67 to 0.95) was observed across measures. Test-retest reproducibility at 1-month follow-up and stability at 4-month follow-up was fair to good (r = 0.40-0.73) for 8 of the 12 measures. All gaze-based measures showed evidence of convergent and discriminant validity with parent-report measures of other cognitive and behavioral constructs. Comparisons across NDGS groups revealed distinct patterns of social and cognitive functioning, including people with PTEN mutations showing a less impaired overall pattern and people with SYNGAP1 mutations showing more attentional, processing speed, and social processing difficulties relative to people with NFIX mutations. Webcam-collected performance measures appear to be a reliable and potentially useful method for objective characterization and monitoring of social and cognitive processes in NDGS and idiopathic NDD. Additional validation work, including more detailed convergent and discriminant validity analyses and examination of sensitivity to change, is needed to replicate and extend these observations.

Prospective phenotyping of CHAMP1 disorder indicates that coding mutations may not act through haploinsufficiency.

CHAMP1 disorder is a genetic neurodevelopmental condition caused by mutations in the CHAMP1 gene that result in premature termination codons. The disorder is associated with intellectual disability, medical comorbidities, and dysmorphic features. Deletions of the CHAMP1 gene, as part of 13q34 deletion syndrome, have been briefly described with the suggestion of a milder clinical phenotype. To date, no studies have directly assessed differences between individuals with mutations in CHAMP1 to those with deletions of the gene. We completed prospective clinical evaluations of 16 individuals with mutations and eight with deletions in CHAMP1. Analyses revealed significantly lower adaptive functioning across all domains assessed (i.e., communication, daily living skills, socialization, and motor skills) in the mutation group. Developmental milestones and medical features further showed difference between groups. The phenotypes associated with mutations, as compared to deletions, indicate likely difference in pathogenesis between groups, where deletions are acting through CHAMP1 haploinsufficiency and mutations are acting through dominant negative or gain of function mechanisms, leading to a more severe clinical phenotype. Understanding this pathogenesis is important to the future of novel therapies for CHAMP1 disorder and illustrates that mechanistic understanding of mutations must be carefully considered prior to treatment development.

Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype.

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.

Development of informant-report neurobehavioral survey scales for PTEN hamartoma tumor syndrome and related neurodevelopmental genetic syndromes.

There are few well-validated measures that are appropriate for assessing the full range of neurobehavioral presentations in PTEN hamartoma tumor syndrome (PHTS) and other neurodevelopmental genetic syndromes (NDGS). As potential therapeutics are developed, having reliable, valid, free, and easily accessible measures to track a range of neurobehavioral domains will be crucial for future clinical trials. This study focused on the development and initial psychometric evaluation of a set of freely available informant-report survey scales for PHTS-the Neurobehavioral Evaluation Tool (NET). Concept elicitation, quantitative ratings, and cognitive interviewing processes were conducted with stakeholders and clinician-scientist experts, used to identify the most important neurobehavioral domains for this population, and to ensure items were appropriate for the full range of individuals with PHTS. Results of this process identified a PHTS neurobehavioral impact model with 11 domains. The final NET scales assessing these domains were administered to a sample of 384 participants (median completion time = 20.6 min), including 32 people with PHTS, 141 with other NDGS, 47 with idiopathic neurodevelopmental disorder (NDD), and 164 neurotypical controls. Initial psychometric results for the total scores of each scale indicated very good model (ω = 0.83-0.99) and internal consistency reliability (α = 0.82-0.98) as well as excellent test-retest reproducibility at 1-month follow-up (r = 0.78-0.98) and stability at 4-month follow-up (r = 0.76-0.96). Conditional reliability estimates indicated very strong measurement precision in key score ranges for assessing PHTS and other people with NDGS and/or idiopathic NDD. Comparisons across domains between PHTS and the other groups revealed specific patterns of symptoms and functioning, including lower levels of challenging behavior and more developed daily living and executive functioning skills relative to other NDGS. The NET appears to be a reliable and potentially useful tool for clinical characterization and monitoring of neurobehavioral symptoms in PHTS and may also have utility in the assessment of other NDGS and idiopathic NDD. Additional validation work, including convergent and discriminant validity analyses, are needed to replicate and extend these observations.

Updated consensus guidelines on the management of Phelan-McDermid syndrome.

Phelan-McDermid syndrome (PMS) is a genetic condition caused by SHANK3 haploinsufficiency and characterized by a wide range of neurodevelopmental and systemic manifestations. The first practice parameters for assessment and monitoring in individuals with PMS were published in 2014; recently, knowledge about PMS has grown significantly based on data from longitudinal phenotyping studies and large-scale genotype-phenotype investigations. The objective of these updated clinical management guidelines was to: (1) reflect the latest in knowledge in PMS and (2) provide guidance for clinicians, researchers, and the general community. A taskforce was established with clinical experts in PMS and representatives from the parent community. Experts joined subgroups based on their areas of specialty, including genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry. Taskforce members convened regularly between 2021 and 2022 and produced specialty-specific guidelines based on iterative feedback and discussion. Taskforce leaders then established consensus within their respective specialty group and harmonized the guidelines. The knowledge gained over the past decade allows for improved guidelines to assess and monitor individuals with PMS. Since there is limited evidence specific to PMS, intervention mostly follows general guidelines for treating individuals with developmental disorders. Significant evidence has been amassed to guide the management of comorbid neuropsychiatric conditions in PMS, albeit mainly from caregiver report and the experience of clinical experts. These updated consensus guidelines on the management of PMS represent an advance for the field and will improve care in the community. Several areas for future research are also highlighted and will contribute to subsequent updates with more refined and specific recommendations as new knowledge accumulates.

Enhancing Child and Adolescent Psychiatry Recruitment Through a Medical Student Mentorship Network: A Qualitative Study.

OBJECTIVE: There is a shortage of psychiatrists necessary to meet the clinical needs of children and adolescents. Efforts over the past decade to enhance the workforce have had a limited impact. This study sought to identify the critical components of a medical student mentorship network designed to increase recruitment into the subspecialty. METHODS: The authors conducted interviews via synchronized videoconferencing of network site leaders and medical students at 14 schools throughout the USA. In addition, they analyzed verbatim transcripts using a thematic-phenomenological qualitative approach. RESULTS: The authors interviewed thirty-eight program participants during seven focus group sessions: nine program directors and 29 medical students or graduates, a median of five participants per session. They constructed a framework consisting of two overarching domains, comprised of three themes each: (1) life cycle of a subspecialty mentorship network (Origins, Initiation, and Continuity); and (2) next steps to improve the program (Refining goals, Increasing accessibility, and Defining a path forward). CONCLUSION: Preliminary data have already documented the positive impact of participation in this mentorship program on medical student match rates into psychiatry. The qualitative model of this study provides a blueprint to develop, maintain, and optimize this and similar efforts aimed at increasing the child and adolescent psychiatry workforce.

Cancer risk in individuals with intellectual disability in Sweden: A population-based cohort study.

BACKGROUND: A knowledge gap exists about the risk of cancer in individuals with intellectual disability (ID). The primary aim of this study was to estimate the cancer risk among individuals with ID compared to individuals without ID. METHODS AND FINDINGS: We conducted a population-based cohort study of all children live-born in Sweden between 1974 and 2013 and whose mothers were born in a Nordic country. All individuals were followed from birth until cancer diagnosis, emigration, death, or 31 December 2016 (up to age 43 years), whichever came first. Incident cancers were identified from the Swedish Cancer Register. We fitted Cox regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) as measures of cancer risk in relation to ID after adjusting for several potential confounders. We analyzed ID by severity, as well as idiopathic ID and syndromic ID separately. We performed a sibling comparison to investigate familial confounding. The study cohort included a total of 3,531,305 individuals, including 27,956 (0.8%) individuals diagnosed with ID. Compared with the reference group (individuals without ID and without a full sibling with ID), individuals with ID were in general more likely to be male. The median follow-up time was 8.9 and 23.0 years for individuals with ID and individuals without ID, respectively. A total of 188 cancer cases were identified among individuals with ID (incidence rate [IR], 62 per 1,000 person-years), and 24,960 among individuals in the reference group (IR, 31 per 1,000 person-years). A statistically significantly increased risk was observed for any cancer (HR 1.57, 95% CI 1.35-1.82; P < 0.001), as well as for several cancer types, including cancers of the esophagus (HR 28.4, 95% CI 6.2-130.6; P < 0.001), stomach (HR 6.1, 95% CI 1.5-24.9; P = 0.013), small intestine (HR 12.0, 95% CI 2.9-50.1; P < 0.001), colon (HR 2.0, 95% CI 1.0-4.1; P = 0.045), pancreas (HR 6.0, 95% CI 1.5-24.8; P = 0.013), uterus (HR 11.7, 95% CI 1.5-90.7; P = 0.019), kidney (HR 4.4, 95% CI 2.0-9.8; P < 0.001), central nervous system (HR 2.7, 95% CI 2.0-3.7; P < 0.001), and other or unspecified sites (HR 4.8, 95% CI 1.8-12.9; P = 0.002), as well as acute lymphoid leukemia (HR 2.4, 95% CI 1.3-4.4; P = 0.003) and acute myeloid leukemia (HR 3.0, 95% CI 1.4-6.4; P = 0.004). Cancer risk was not modified by ID severity or sex but was higher for syndromic ID. The sibling comparison showed little support for familial confounding. The main study limitations were the limited statistical power for the analyses of specific cancer types, and the potential for underestimation of the studied associations (e.g., due to potential underdetection or delayed diagnosis of cancer among individuals with ID). CONCLUSIONS: In this study, we found that individuals with ID showed an increased risk of any cancer, as well as of several specific cancer types. These findings suggest that extended surveillance and early intervention for cancer among individuals with ID are warranted.

Synaptic, transcriptional and chromatin genes disrupted in autism.

The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.

Heightened brain response to pain anticipation in high-functioning adults with autism spectrum disorder.

Autism spectrum disorder (ASD) is marked by both socio-communicative difficulties and abnormalities in sensory processing. Much of the work on sensory deficits in ASD has focused on tactile sensations and the perceptual aspects of somatosensation, such as encoding of stimulus intensity and location. Although aberrant pain processing has often been noted in clinical observations of patients with ASD, it remains largely uninvestigated. Importantly, the neural mechanism underlying higher order cognitive aspects of pain processing such as pain anticipation also remains unknown. Here we examined both pain perception and anticipation in high-functioning adults with ASD and matched healthy controls (HC) using an anticipatory pain paradigm in combination with functional magnetic resonance imaging (fMRI) and concurrent skin conductance response (SCR) recording. Participants were asked to choose a level of electrical stimulation that would feel moderately painful to them. Compared to HC group, ASD group chose a lower level of stimulation prior to fMRI. However, ASD participants showed greater activation in both rostral and dorsal anterior cingulate cortex during the anticipation of stimulation, but not during stimulation delivery. There was no significant group difference in insular activation during either pain anticipation or perception. However, activity in the left anterior insula correlated with SCR during pain anticipation. Taken together, these results suggest that ASD is marked with aberrantly higher level of sensitivity to upcoming aversive stimuli, which may reflect abnormal attentional orientation to nociceptive signals and a failure in interoceptive inference.

Autonomic and brain responses associated with empathy deficits in autism spectrum disorder.

Accumulating evidence suggests that autonomic signals and their cortical representations are closely linked to emotional processes, and that related abnormalities could lead to social deficits. Although socio-emotional impairments are a defining feature of autism spectrum disorder (ASD), empirical evidence directly supporting the link between autonomic, cortical, and socio-emotional abnormalities in ASD is still lacking. In this study, we examined autonomic arousal indexed by skin conductance responses (SCR), concurrent cortical responses measured by functional magnetic resonance imaging, and effective brain connectivity estimated by dynamic causal modeling in seventeen unmedicated high-functioning adults with ASD and seventeen matched controls while they performed an empathy-for-pain task. Compared to controls, adults with ASD showed enhanced SCR related to empathetic pain, along with increased neural activity in the anterior insular cortex, although their behavioral empathetic pain discriminability was reduced and overall SCR was decreased. ASD individuals also showed enhanced correlation between SCR and neural activities in the anterior insular cortex. Importantly, significant group differences in effective brain connectivity were limited to greater reduction in the negative intrinsic connectivity of the anterior insular cortex in the ASD group, indicating a failure in attenuating anterior insular responses to empathetic pain. These results suggest that aberrant interoceptive precision, as indexed by abnormalities in autonomic activity and its central representations, may underlie empathy deficits in ASD.

Differential Effects of Oxytocin on Agency and Communion for Anxiously and Avoidantly Attached Individuals.

Oxytocin promotes prosocial behavior, especially in those individuals who are low in affiliation (e.g., avoidantly attached individuals), but can exacerbate interpersonal insecurities in those preoccupied with closeness (e.g., anxiously attached individuals). One explanation for these opposing observations is that oxytocin induces a communal, other-orientation. Becoming more other oriented should help those people who focus on the self to the exclusion of others, but could be detrimental to those who are other focused but have little sense of an agentic self. Using a within-subjects design, we administered intranasal oxytocin and placebo to 40 males and measured their agency (self-orientation) and communion (other-orientation). Oxytocin produced a slight increase in communion for the average participant; however, as predicted, avoidantly attached individuals were especially likely to perceive themselves as more communal ("kind," "warm," "gentle," etc.) after receiving oxytocin than after receiving the placebo. There was no main effect of oxytocin on agency for the average participant; however, anxiously attached individuals showed a selective decrease in agency ("independent," "self-confident," etc.) following administration of oxytocin. These data help explain the complex social effects of oxytocin.

Abnormal autonomic and associated brain activities during rest in autism spectrum disorder.

Autism spectrum disorders are associated with social and emotional deficits, the aetiology of which are not well understood. A growing consensus is that the autonomic nervous system serves a key role in emotional processes, by providing physiological signals essential to subjective states. We hypothesized that altered autonomic processing is related to the socio-emotional deficits in autism spectrum disorders. Here, we investigated the relationship between non-specific skin conductance response, an objective index of sympathetic neural activity, and brain fluctuations during rest in high-functioning adults with autism spectrum disorder relative to neurotypical controls. Compared with control participants, individuals with autism spectrum disorder showed less skin conductance responses overall. They also showed weaker correlations between skin conductance responses and frontal brain regions, including the anterior cingulate and anterior insular cortices. Additionally, skin conductance responses were found to have less contribution to default mode network connectivity in individuals with autism spectrum disorders relative to controls. These results suggest that autonomic processing is altered in autism spectrum disorders, which may be related to the abnormal socio-emotional behaviours that characterize this condition.

Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.

Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with approximately 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 x 10(-3)). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 x 10(-3)). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 x 10(-6)). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.

Individual common variants exert weak effects on the risk for autism spectrum disorders.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

De novo SCN2A splice site mutation in a boy with Autism spectrum disorder.

BACKGROUND: SCN2A is a gene that codes for the alpha subunit of voltage-gated, type II sodium channels, and is highly expressed in the brain. Sodium channel disruptions, such as mutations in SCN2A, may play an important role in psychiatric disorders. Recently, de novo SCN2A mutations in autism spectrum disorder (ASD) have been identified. The current study characterizes a de novo splice site mutation in SCN2A that alters mRNA and protein products. CASE PRESENTATION: We describe results from clinical and genetic characterizations of a seven-year-old boy with ASD. Psychiatric interview and gold standard autism diagnostic instruments (ADOS and ADI-R) were used to confirm ASD diagnosis, in addition to performing standardized cognitive and adaptive functioning assessments (Leiter-R and Vineland Adaptive Behavior Scale), and sensory reactivity assessments (Sensory Profile and Sensory Processing Scales). Genetic testing by whole exome sequencing revealed four de novo events, including a splice site mutation c.476 + 1G > A in SCN2A, a missense mutation (c.2263G > A) causing a p.V755I change in the TLE1 gene, and two synonymous mutations (c.2943A > G in the BUB1 gene, and c.1254 T > A in C10orf68 gene). The de novo SCN2A splice site mutation produced a stop codon 10 amino acids downstream, possibly resulting in a truncated protein and/or a nonsense-mediated mRNA decay. The participant met new DSM-5 criteria for ASD, presenting with social and communication impairment, repetitive behaviors, and sensory reactivity issues. The participant's adaptive and cognitive skills fell in the low range of functioning. CONCLUSION: This report indicates that a splice site mutation in SCN2A might be contributing to the risk of ASD. Describing the specific phenotype associated with SCN2A mutations might help to reduce heterogeneity seen in ASD.

Caregiver perspectives on patient-focused drug development for Phelan-McDermid syndrome.

BACKGROUND: Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by SHANK3 haploinsufficiency with clinical manifestations that can be devastating and profoundly affect quality of life. RESULTS: The Externally Led Patient-Focused Drug Development (EL-PFDD) meeting was an opportunity for families affected by PMS to share with the Food and Drug Administration (FDA) how symptoms impact their lives and how treatments could be most meaningful. The Voice of the Patient report serves as a summary of this meeting to influence upcoming drug development and clinical trials. The purpose of this report is to provide a clinical perspective on the results of the EL-PFDD meeting to amplify the voice of these caregivers to the scientific community. CONCLUSIONS: Caregivers prioritize an improved quality of life for their loved ones characterized by improved cognitive function, improved communication, increased independence, and reduced risk of regression. With these caregiver priorities in mind, this report provides the FDA and the scientific community with a clear understanding of which aspects of PMS should influence the development of future therapeutics.

Racial Differences in the Prevalence of Autism Spectrum Disorder: A Systematic Review.

PURPOSE: Racial differences in prevalence rates of autism spectrum disorder (ASD) have shifted in the United States (US) since the 1990s. This review addresses the nature and context of this shift and discusses potential contributing factors and areas for future research. METHODS: Seventeen population-based epidemiological birth cohort studies on ASD prevalence in the US that included race as a variable are included in the review. Studies were identified via a keyword search on PubMed. To be included, studies were required to include race or ethnicity as a variable in the prevalence estimates, include at least 1000 cases with autism, and be published in English by June 3rd, 2023. RESULTS: Results suggest that in nearly all birth cohorts prior to 2010, ASD prevalence rates were highest among White children. ASD prevalence rates among Black, Hispanic, and Asian/Pacific Islander (API) children (22.3, 22.5, and 22.2 per 1000, respectively) surpassed prevalence rates among White children (21.2 per 1000) in the 2010 birth cohort and continued to increase in the 2012 birth cohorts. CONCLUSIONS: There are persistent racial differences in ASD prevalence in the US, and these differences were inverted after 2010, when ASD prevalence among Black, Hispanic, & API children surpassed ASD prevalence among White children. Possible drivers of this racial repatterning of ASD prevalence include changes in ASD screening and diagnosis, changes to health insurance policy, changes to immigration policy, and increased education attainment by minority groups.