GABBR1 monoallelic de novo variants linked to neurodevelopmental delay and epilepsy.

GABAB receptors are obligatory heterodimers responsible for prolonged neuronal inhibition in the central nervous system. The two receptor subunits are encoded by GABBR1 and GABBR2. Variants in GABBR2 have been associated with a Rett-like phenotype (MIM: 617903), epileptic encephalopathy (MIM: 617904), and milder forms of developmental delay with absence epilepsy. To date, however, no phenotypes associated with pathogenic variants of GABBR1 have been established. Through GeneMatcher, we have ascertained four individuals who each have a monoallelic GABBR1 de novo non-synonymous variant; these individuals exhibit motor and/or language delay, ranging from mild to severe, and in one case, epilepsy. Further phenotypic features include varying degrees of intellectual disability, learning difficulties, autism, ADHD, ODD, sleep disorders, and muscular hypotonia. We functionally characterized the four de novo GABBR1 variants, p.Glu368Asp, p.Ala397Val, p.Ala535Thr, and p.Gly673Asp, in transfected HEK293 cells. GABA fails to efficiently activate the variant receptors, most likely leading to an increase in the excitation/inhibition balance in the central nervous system. Variant p.Gly673Asp in transmembrane domain 3 (TMD3) renders the receptor completely inactive, consistent with failure of the receptor to reach the cell surface. p.Glu368Asp is located near the orthosteric binding site and reduces GABA potency and efficacy at the receptor. GABA exhibits normal potency but decreased efficacy at the p.Ala397Val and p.Ala535Thr variants. Functional characterization of GABBR1-related variants provides a rationale for understanding the severity of disease phenotypes and points to possible therapeutic strategies.

Clinical variants paired with phenotype: A rich resource for brain gene curation.

PURPOSE: Clinically ascertained variants are under-utilized in neurodevelopmental disorder research. We established the Brain Gene Registry (BGR) to coregister clinically identified variants in putative brain genes with participant phenotypes. Here, we report 179 genetic variants in the first 179 BGR registrants and analyze the proportion that were novel to ClinVar at the time of entry and those that were absent in other disease databases. METHODS: From 10 academically affiliated institutions, 179 individuals with 179 variants were enrolled into the BGR. Variants were cross-referenced for previous presence in ClinVar and for presence in 6 other genetic databases. RESULTS: Of 179 variants in 76 genes, 76 (42.5%) were novel to ClinVar, and 62 (34.6%) were absent from all databases analyzed. Of the 103 variants present in ClinVar, 37 (35.9%) were uncertain (ClinVar aggregate classification of variant of uncertain significance or conflicting classifications). For 5 variants, the aggregate ClinVar classification was inconsistent with the interpretation from the BGR site-provided classification. CONCLUSION: A significant proportion of clinical variants that are novel or uncertain are not shared, limiting the evidence base for new gene-disease relationships. Registration of paired clinical genetic test results with phenotype has the potential to advance knowledge of the relationships between genes and neurodevelopmental disorders.

Insufficient Evidence for "Autism-Specific" Genes.

Despite evidence that deleterious variants in the same genes are implicated across multiple neurodevelopmental and neuropsychiatric disorders, there has been considerable interest in identifying genes that, when mutated, confer risk that is largely specific for autism spectrum disorder (ASD). Here, we review the findings and limitations of recent efforts to identify relatively "autism-specific" genes, efforts which focus on rare variants of large effect size that are thought to account for the observed phenotypes. We present a divergent interpretation of published evidence; discuss practical and theoretical issues related to studying the relationships between rare, large-effect deleterious variants and neurodevelopmental phenotypes; and describe potential future directions of this research. We argue that there is currently insufficient evidence to establish meaningful ASD specificity of any genes based on large-effect rare-variant data.

Infant viewing of social scenes is under genetic control and is atypical in autism.

Long before infants reach, crawl or walk, they explore the world by looking: they look to learn and to engage, giving preferential attention to social stimuli, including faces, face-like stimuli and biological motion. This capacity-social visual engagement-shapes typical infant development from birth and is pathognomonically impaired in children affected by autism. Here we show that variation in viewing of social scenes, including levels of preferential attention and the timing, direction and targeting of individual eye movements, is strongly influenced by genetic factors, with effects directly traceable to the active seeking of social information. In a series of eye-tracking experiments conducted with 338 toddlers, including 166 epidemiologically ascertained twins (enrolled by representative sampling from the general population), 88 non-twins with autism and 84 singleton controls, we find high monozygotic twin-twin concordance (0.91) and relatively low dizygotic concordance (0.35). Moreover, the characteristics that are the most highly heritable, preferential attention to eye and mouth regions of the face, are also those that are differentially decreased in children with autism (χ2 = 64.03, P < 0.0001). These results implicate social visual engagement as a neurodevelopmental endophenotype not only for autism, but also for population-wide variation in social-information seeking. In addition, these results reveal a means of human biological niche construction, with phenotypic differences emerging from the interaction of individual genotypes with early life experience.

Early brain development in infants at high risk for autism spectrum disorder.

Brain enlargement has been observed in children with autism spectrum disorder (ASD), but the timing of this phenomenon, and the relationship between ASD and the appearance of behavioural symptoms, are unknown. Retrospective head circumference and longitudinal brain volume studies of two-year olds followed up at four years of age have provided evidence that increased brain volume may emerge early in development. Studies of infants at high familial risk of autism can provide insight into the early development of autism and have shown that characteristic social deficits in ASD emerge during the latter part of the first and in the second year of life. These observations suggest that prospective brain-imaging studies of infants at high familial risk of ASD might identify early postnatal changes in brain volume that occur before an ASD diagnosis. In this prospective neuroimaging study of 106 infants at high familial risk of ASD and 42 low-risk infants, we show that hyperexpansion of the cortical surface area between 6 and 12 months of age precedes brain volume overgrowth observed between 12 and 24 months in 15 high-risk infants who were diagnosed with autism at 24 months. Brain volume overgrowth was linked to the emergence and severity of autistic social deficits. A deep-learning algorithm that primarily uses surface area information from magnetic resonance imaging of the brain of 6-12-month-old individuals predicted the diagnosis of autism in individual high-risk children at 24 months (with a positive predictive value of 81% and a sensitivity of 88%). These findings demonstrate that early brain changes occur during the period in which autistic behaviours are first emerging.

Modifying the social responsiveness scale for adaptive administration.

PURPOSE: The social responsiveness scale (SRS) is frequently used to quantify the autism-related phenotype and is gaining use in health outcomes research. However, it has a high respondent burden (65 items) for large-scale studies. Further, most evaluations of it have focused on the school-age form, not the preschool form. More validity evidence of shortened forms is necessary in the general population to support the broader health outcomes context of use. METHODS: We evaluated the psychometrics of the SRS in 7030 individuals from multiple predominantly neurotypical samples in order to shorten it based on non-autistic sample metrics. Analyses included item factor analysis, differential item functioning (DIF), and multiple-group item response theory (IRT) to place the SRS items on a comparable scale, which was then simulated via computer adaptive testing (CAT) administration. RESULTS: The SRS was broadly unidimensional with few methodological residual dependencies. On average, males had more autistic characteristics than females, and preschoolers had fewer characteristics than school-age children. The final IRT calibration included 45 items equated across forms, and each form had 11 with significant wording discrepancies and 9 items with near-identical wording that exhibited form-related DIF. The CAT simulation suggested a median of 14 items was sufficient to reach a reliable score, demonstrating its feasibility across the range of impairments. CONCLUSION: IRT allows practitioners the ability to get highly reliable scores with fewer items than the full-length SRS. This supports the future application of the SRS in a computer adaptive testing mode in both neurotypical and ASD samples.

Neonatal CSF vasopressin concentration predicts later medical record diagnoses of autism spectrum disorder.

Autism spectrum disorder (ASD) is a brain disorder characterized by social impairments. ASD is currently diagnosed on the basis of behavioral criteria because no robust biomarkers have been identified. However, we recently found that cerebrospinal fluid (CSF) concentration of the "social" neuropeptide arginine vasopressin (AVP) is significantly lower in pediatric ASD cases vs. controls. As an initial step in establishing the direction of causation for this association, we capitalized upon a rare biomaterials collection of newborn CSF samples to conduct a quasi-prospective test of whether this association held before the developmental period when ASD first manifests. CSF samples had been collected in the course of medical care of 0- to 3-mo-old febrile infants (n = 913) and subsequently archived at -70 °C. We identified a subset of CSF samples from individuals later diagnosed with ASD, matched them 1:2 with appropriate controls (n = 33 total), and quantified their AVP and oxytocin (OXT) concentrations. Neonatal CSF AVP concentrations were significantly lower among ASD cases than controls and individually predicted case status, with highest precision when cases with comorbid attention-deficit/hyperactivity disorder were removed from the analysis. The associations were specific to AVP, as ASD cases and controls did not differ in neonatal CSF concentrations of the structurally related neuropeptide, OXT. These preliminary findings suggest that a neurochemical marker of ASD may be present very early in life, and if replicated in a larger, prospective study, this approach could transform how ASD is detected, both in behaviorally symptomatic children, and in infants at risk for developing it.

Tibial Component Subsidence in a Total Ankle System Comparing Standard Technique Versus a Hybrid Technique.

Total ankle arthroplasty (TAA) is a viable treatment option for end-stage ankle arthritis. However, implant survivorship remains an important consideration. Concerns regarding early component loosening with the low-profile tibial tray utilized by fourth-generation TAA systems have been raised in the literature. We have previously described our preliminary outcomes of a hybrid technique combining a stemmed intramedullary tibial component with a chamfer-cut talar component for TAA. A retrospective study comparing short-term outcomes of the tibial component between a standard fourth-generation TAA system versus our hybrid technique was performed. 46 patients with a minimum of 1-year follow up were included in the analyses. There were 25 subjects in the standard implant cohort utilizing a low-profile tibial tray, and 21 subjects in the hybrid group utilizing a stemmed intramedullary tibial component. No statistically significant difference between the demographics of each group was found. The rate of tibial component subsidence was 8% (n = 2) in the standard implant group, and 0% (n = 0) in the hybrid group, though this did not meet statistical significance (p = .49). Mean time to subsidence was 6 months, and revision rate due to tibial component subsidence was 2.1% (n = 1). Periprosthetic lucency was present on most recent follow-up radiographs in 32% and 9.5% of ankles in the standard and hybrid groups, respectively (p = .08). Despite prior concerns for tibial component subsidence with the standard fourth-generation system, we demonstrated low rates in both implant groups. Additional studies are needed to further explore factors that may predispose patients to early tibial component subsidence and resulting implant failure.

Germline mosaicism of a missense variant in KCNC2 in a multiplex family with autism and epilepsy characterized by long-read sequencing.

Currently, protein-coding de novo variants and large copy number variants have been identified as important for ~30% of individuals with autism. One approach to identify relevant variation in individuals who lack these types of events is by utilizing newer genomic technologies. In this study, highly accurate PacBio HiFi long-read sequencing was applied to a family with autism, epileptic encephalopathy, cognitive impairment, and mild dysmorphic features (two affected female siblings, unaffected parents, and one unaffected male sibling) with no known clinical variant. From our long-read sequencing data, a de novo missense variant in the KCNC2 gene (encodes Kv3.2) was identified in both affected children. This variant was phased to the paternal chromosome of origin and is likely a germline mosaic. In silico assessment revealed the variant was not in controls, highly conserved, and predicted damaging. This specific missense variant (Val473Ala) has been shown in both an ortholog and paralog of Kv3.2 to accelerate current decay, shift the voltage dependence of activation, and prevent the channel from entering a long-lasting open state. Seven additional missense variants have been identified in other individuals with neurodevelopmental disorders (p = 1.03 × 10-5 ). KCNC2 is most highly expressed in the brain; in particular, in the thalamus and is enriched in GABAergic neurons. Long-read sequencing was useful in discovering the relevant variant in this family with autism that had remained a mystery for several years and will potentially have great benefits in the clinic once it is widely available.

Social motivation in infancy is associated with familial recurrence of ASD.

Pre-diagnostic deficits in social motivation are hypothesized to contribute to autism spectrum disorder (ASD), a heritable neurodevelopmental condition. We evaluated psychometric properties of a social motivation index (SMI) using parent-report item-level data from 597 participants in a prospective cohort of infant siblings at high and low familial risk for ASD. We tested whether lower SMI scores at 6, 12, and 24 months were associated with a 24-month ASD diagnosis and whether social motivation's course differed relative to familial ASD liability. The SMI displayed good internal consistency and temporal stability. Children diagnosed with ASD displayed lower mean SMI T-scores at all ages and a decrease in mean T-scores across age. Lower group-level 6-month scores corresponded with higher familial ASD liability. Among high-risk infants, strong decline in SMI T-scores was associated with 10-fold odds of diagnosis. Infant social motivation is quantifiable by parental report, differentiates children with versus without later ASD by age 6 months, and tracks with familial ASD liability, consistent with a diagnostic and susceptibility marker of ASD. Early decrements and decline in social motivation indicate increased likelihood of ASD, highlighting social motivation's importance to risk assessment and clarification of the ontogeny of ASD.

Parameterizing Toxic Stress in Early Childhood: Maternal Depression, Maltreatment, and HPA-Axis Variation in a Pilot Intervention Study.

Adverse experiences superseding a child's capacity to sustain regulation of emotion and adaptive function are theorized to constitute "toxic stressors" when they induce a deleterious biological response within an individual. We ascertained presumptive parameters of toxic stress among 164 low-income infants and toddlers (ages 4-48 months) from 132 families enrolled in Early Head Start (EHS). We randomized a subset of these families into a pilot intervention arm of parenting education (the Incredible Years, TIY), which supplemented the EHS curriculum. Official report child abuse and neglect (CAN) and child behavior were serially ascertained over the course of the study. We observed relatively low associations among maternal depression, CAN, caregiver-child relationship quality, hair cortisol, and adverse child behavioral outcomes. Moreover, despite poverty and the high prevalence (51%) of CAN in this sample, the frequency of clinical-level internalizing and externalizing behavior among the children did not exceed that of the general population, by their parents' report. The pilot supplementation of EHS with TIY improved attendance in group meetings but did not significantly reduce adverse behavioral outcomes or CAN. This study revealed marked independence of standard indices of toxic stress (child maltreatment, maternal depression, caregiver emotional unavailability) which have been presumed to be risk factors for the development of psychopathology. That they were weakly inter-correlated, and only modestly predictive of child behavioral outcomes in this EHS sample, caution against presumptions about the toxicity of individual stressors, highlight the importance of ascertaining risk (and compensatory influences) comprehensively, suggest buffering effects of programs like EHS, and demonstrate the need for greater understanding of what parameterizes resilience in early childhood.

Altered neuronal physiology, development, and function associated with a common chromosome 15 duplication involving CHRNA7.

BACKGROUND: Copy number variants (CNVs) linked to genes involved in nervous system development or function are often associated with neuropsychiatric disease. While CNVs involving deletions generally cause severe and highly penetrant patient phenotypes, CNVs leading to duplications tend instead to exhibit widely variable and less penetrant phenotypic expressivity among affected individuals. CNVs located on chromosome 15q13.3 affecting the alpha-7 nicotinic acetylcholine receptor subunit (CHRNA7) gene contribute to multiple neuropsychiatric disorders with highly variable penetrance. However, the basis of such differential penetrance remains uncharacterized. Here, we generated induced pluripotent stem cell (iPSC) models from first-degree relatives with a 15q13.3 duplication and analyzed their cellular phenotypes to uncover a basis for the dissimilar phenotypic expressivity. RESULTS: The first-degree relatives studied included a boy with autism and emotional dysregulation (the affected proband-AP) and his clinically unaffected mother (UM), with comparison to unrelated control models lacking this duplication. Potential contributors to neuropsychiatric impairment were modeled in iPSC-derived cortical excitatory and inhibitory neurons. The AP-derived model uniquely exhibited disruptions of cellular physiology and neurodevelopment not observed in either the UM or unrelated controls. These included enhanced neural progenitor proliferation but impaired neuronal differentiation, maturation, and migration, and increased endoplasmic reticulum (ER) stress. Both the neuronal migration deficit and elevated ER stress could be selectively rescued by different pharmacologic agents. Neuronal gene expression was also dysregulated in the AP, including reduced expression of genes related to behavior, psychological disorders, neuritogenesis, neuronal migration, and Wnt, axonal guidance, and GABA receptor signaling. The UM model instead exhibited upregulated expression of genes in many of these same pathways, suggesting that molecular compensation could have contributed to the lack of neurodevelopmental phenotypes in this model. However, both AP- and UM-derived neurons exhibited shared alterations of neuronal function, including increased action potential firing and elevated cholinergic activity, consistent with increased homomeric CHRNA7 channel activity. CONCLUSIONS: These data define both diagnosis-associated cellular phenotypes and shared functional anomalies related to CHRNA7 duplication that may contribute to variable phenotypic penetrance in individuals with 15q13.3 duplication. The capacity for pharmacological agents to rescue some neurodevelopmental anomalies associated with diagnosis suggests avenues for intervention for carriers of this duplication and other CNVs that cause related disorders.

Clinical and Translational Implications of an Emerging Developmental Substructure for Autism.

A vast share of the population-attributable risk for autism relates to inherited polygenic risk. A growing number of studies in the past five years have indicated that inherited susceptibility may operate through a finite number of early developmental liabilities that, in various permutations and combinations, jointly predict familial recurrence of the convergent syndrome of social communication disability that defines the condition. Here, we synthesize this body of research to derive evidence for a novel developmental substructure for autism, which has profound implications for ongoing discovery efforts to elucidate its neurobiological causes, and to inform future clinical and biomarker studies, early interventions, and personalized approaches to therapy.

Intellectual and developmental disabilities research centers: Fifty years of scientific accomplishments.

Progress in addressing the origins of intellectual and developmental disabilities accelerated with the establishment 50 years ago of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health and associated Intellectual and Developmental Disabilities Research Centers. Investigators at these Centers have made seminal contributions to understanding human brain and behavioral development and defining mechanisms and treatments of disorders of the developing brain. ANN NEUROL 2019;86:332-343.

On the Nature of Monozygotic Twin Concordance and Discordance for Autistic Trait Severity: A Quantitative Analysis.

The characterizing features of autism spectrum disorder (ASD) are continuously distributed in nature; however, prior twin studies have not systematically incorporated this knowledge into estimations of concordance and discordance. We conducted a quantitative analysis of twin-twin similarity for autistic trait severity in three existing data sets involving 366 pairs of uniformly-phenotyped monozygotic (MZ) twins with and without ASD. Probandwise concordance for ASD was 96%; however, MZ trait correlations differed markedly for pairs with ASD trait burden below versus above the threshold for clinical diagnosis, with R2s on the order of 0.6 versus 0.1, respectively. Categorical MZ twin discordance for ASD diagnosis is rare and more appropriately operationalized by standardized quantification of twin-twin differences. Here we provide new evidence that although ASD itself is highly heritable, variation-in-severity of symptomatology above the diagnostic threshold is substantially influenced, in contrast, by non-shared environmental factors which may identify novel targets of early ASD amelioration.

Research Review: Outcomes of 24- to 36-month-old children with autism spectrum disorder vary by ascertainment strategy: a systematic review and meta-analysis.

BACKGROUND: Despite widespread recommendations for early surveillance of risk for autism spectrum disorder (ASD), no research to date has shown that early surveillance leads to better clinical outcomes. Preliminary research has suggested that children with ASD ascertained via prospective follow-up have better outcomes than those ascertained via community referral. Because prospective studies include early surveillance, by comparing outcomes of children with ASD across ascertainment strategies, we may gain insight into the effects of early surveillance relative to its absence. METHODS: A systematic review was conducted to identify studies reporting outcomes of 24- to 36-month-olds with ASD ascertained via prospective follow-up, community referral, or universal screening. A meta-analysis using a random effects model was used to calculate overall effect size estimates for developmental level and symptom severity across ascertainment cohorts. RESULTS: Eleven prospective, ten community referral, and eight universal screening studies were identified, reporting on 1,658 toddlers with ASD. We found no differences in outcomes between community referral and universal screening studies. Relative to both, prospective studies reported significantly higher developmental levels and lower symptom severities. CONCLUSIONS: Outcomes of young children with ASD ascertained via prospective follow-up are better than those of children with ASD recruited via community referral or universal screening. Although we discuss why sampling bias is not likely the driving force behind these findings, we cannot rule out the possibility that sampling bias contributes to the observed differences; future studies should probe the effects of sociodemographic variables on clinical outcomes as a function of ascertainment strategy. This limitation notwithstanding, our results raise the possibility that prospective follow-up may confer a 'surveillance effect' that contributes to improved developmental and diagnostic outcomes in children with ASD. Future research should test this hypothesis and determine the specific mechanism by which surveillance may improve outcomes.

A video-based measure to identify autism risk in infancy.

BACKGROUND: Signs of autism are present in the first 2 years of life, but the average age of diagnosis lags far behind. Instruments that improve detection of autism risk in infancy are needed. This study developed and tested the psychometric properties of a novel video-based approach to detecting ASD in infancy. METHODS: A prospective longitudinal study of children at elevated or lower risk for autism spectrum disorder was conducted. Participants were 76 infants with an older sibling with ASD and 37 infants with no known family history of autism. The Video-referenced Infant Rating System for Autism (VIRSA) is a web-based application that presents pairs of videos of parents and infants playing together and requires forced-choice judgments of which video is most similar to the child being rated. Parents rated participants on the VIRSA at 6, 9, 12, and 18 months of age. We examined split-half and test-retest reliability; convergent and discriminant validity; and sensitivity, specificity, and negative and positive predictive value for concurrent and 36-month ASD diagnoses. RESULTS: The VIRSA demonstrated satisfactory reliability and convergent and discriminant validity. VIRSA ratings were significantly lower for children ultimately diagnosed with ASD than children with typical development by 12 months of age. VIRSA scores at 18 months identified all children diagnosed with ASD at that age, as well as 78% of children diagnosed at 36 months. CONCLUSIONS: This study represents an initial step in the development of a novel video-based approach to detection of ASD in infancy. The VIRSA's psychometric properties were promising when used by parents with an older affected child, but still must be tested in community samples with no family history of ASD. If results are replicated, then the VIRSA's low-burden, web-based format has the potential to reduce disparities in communities with limited access to screening.

Toward Actionable Practice Parameters for "Dual Diagnosis": Principles of Assessment and Management for Co-Occurring Psychiatric and Intellectual/Developmental Disability.

PURPOSE OF REVIEW: Although treatment algorithms and parameters for best practice are readily available for all major syndromes of psychiatric impairment, the occurrence of psychiatric syndromes in individuals with intellectual and developmental disability (IDD) invokes serious contextual challenges for interpretation of symptoms, diagnosis, and optimization of treatment, both for clinicians and for the service sectors in which care and support of individuals with IDD are delivered. Recognizing that there exist very few definitive resources for best practice under the circumstance of this form of "dual diagnosis," the Missouri Department of Mental Health convened an expert panel to conduct a focused review and synthesis of the relevant scientific literature from which to develop guidance in the form of decision support to clinicians. This article summarizes the findings for three of the most common and impairing clusters of psychiatric symptoms that co-occur with IDD-aggression, depression, and addictions. RECENT FINDINGS: Individuals with IDD are at high risk for the development of psychiatric symptoms (PS), which often manifest uniquely in IDD and for which evidence for effective intervention is steadily accruing. Interventions that are commonly implemented in the IDD service sector (e.g., functional communication training and positive behavioral support planning) are capable of mitigating severe behavioral impairment, yet rarely invoked when dual diagnosis patients are seen in the psychiatric service sector. Conversely, state-of-the-art interventions for traumatic stress, pharmacotherapy, and psychotherapy have proven capable of improving behavioral impairments in IDD but are typically restricted to the psychiatric service sector, where there exist significant barriers to access for patients with IDD, including limitations imposed by diagnostic eligibility and practitioner experience. Bridging these gaps in knowledge and clinical capacity across the respective IDD and PS service sectors should be of very high priority in strategizing the care and support of IDD patients with serious co-occurring psychiatric conditions.

Expediting clinician assessment in the diagnosis of autism spectrum disorder.

AIM: To investigate a novel observational rating protocol designed to expedite clinical diagnosis of autism spectrum disorder (ASD). METHOD: Two hundred and forty patients referred to a tertiary autism center (median age 8y 9mo, range 2y 6mo-34y 8mo; 188 males, 52 females) were rated using an adaptation of the Childhood Autism Rating Scale, Second Edition (CARS-2) based exclusively on patient observation (CARS-2obs ). Scores were compared to expert diagnosis of ASD, parent-reported Social Responsiveness Scale, Second Edition (SRS-2) and, in a selected subset of patients, the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2). RESULTS: CARS-2obs distinguished patients with a clinical diagnosis of ASD from those with non-ASD neuropsychiatric disorders (mean score=18 vs 11.7, p<0.001). Severity ratings on the CARS-2obs correlated with the ADOS-2 (r=0.68, ρ=0.64) and SRS-2 (r=0.31, ρ=0.32). A CARS-2obs cutoff point equal to or greater than 16 demonstrated 95.8% specificity and 62.3% sensitivity in discriminating individuals with ASD from individuals without ASD in a specialty referral setting. INTERPRETATION: The CARS-2obs allows the rapid acquisition of quantitative ratings of autistic severity by direct observation. Coupled with parent/teacher-reported symptoms and developmental history, the measure may contribute to a low-cost diagnostic paradigm in clinical and public health settings, where positive results might help reduce delays in diagnosis, and negative results could prompt further specialty assessment. WHAT THIS PAPER ADDS: The Childhood Autism Rating Scale, Second Edition based on patient observation distinguished individuals with versus without autism spectrum disorder (ASD). A score equal to or greater than 16 on this assessment showed high specificity for a diagnosis of ASD.

Affording autism an early brain development re-definition.

The national priority to advance early detection and intervention for children with autism spectrum disorder (ASD) has not reduced the late age of ASD diagnosis in the US over several consecutive Centers for Disease Control and Prevention (CDC) surveillance cohorts, with traditionally under-served populations accessing diagnosis later still. In this review, we explore a potential perceptual barrier to this enterprise which views ASD in terms that are contradicted by current science, and which may have its origins in the current definition of the condition and in its historical associations. To address this perceptual barrier, we propose a re-definition of ASD in early brain development terms, with a view to revisit the world of opportunities afforded by current science to optimize children's outcomes despite the risks that they are born with. This view is presented here to counter outdated notions that potentially devastating disability is determined the moment a child is born, and that these burdens are inevitable, with opportunities for improvement being constrained to only alleviation of symptoms or limited improvements in adaptive skills. The impetus for this piece is the concern that such views of complex neurodevelopmental conditions, such as ASD, can become self-fulfilling science and policy, in ways that are diametrically opposed to what we currently know, and are learning every day, of how genetic risk becomes, or not, instantiated as lifetime disabilities.