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Background: Autism spectrum disorder (ASD), a neurodevelopmental disorder defined by social communication deficits plus repetitive behaviors and restricted interests, currently affects 1/36 children in the general population. Recent advances in functional brain imaging show promise to provide useful biomarkers of ASD diagnostic likelihood, behavioral trait severity, and even response to therapeutic intervention. However, current gold-standard neuroimaging methods (e.g., functional magnetic resonance imaging, fMRI) are limited in naturalistic studies of brain function underlying ASD-associated behaviors due to the constrained imaging environment. Compared to fMRI, high-density diffuse optical tomography (HD-DOT), a non-invasive and minimally constraining optical neuroimaging modality, can overcome these limitations. Herein, we aimed to establish HD-DOT to evaluate brain function in autistic and non-autistic school-age children as they performed a biological motion perception task previously shown to yield results related to both ASD diagnosis and behavioral traits., Methods: We used HD-DOT to image brain function in 46 ASD school-age participants and 49 non-autistic individuals (NAI) as they viewed dynamic point-light displays of coherent biological and scrambled motion. We assessed group-level cortical brain function with statistical parametric mapping. Additionally, we tested for brain-behavior associations with dimensional metrics of autism traits, as measured with the Social Responsiveness Scale-2, with hierarchical regression models., Results: We found that NAI participants presented stronger brain activity contrast (coherent > scrambled) than ASD children in cortical regions related to visual, motor, and social processing. Additionally, regression models revealed multiple cortical regions in autistic participants where brain function is significantly associated with dimensional measures of ASD traits., Limitations: Optical imaging methods are limited in depth sensitivity and so cannot measure brain activity within deep subcortical regions. However, the field of view of this HD-DOT system includes multiple brain regions previously implicated in both task-based and task-free studies on autism., Conclusions: This study demonstrates that HD-DOT is sensitive to brain function that both differentiates between NAI and ASD groups and correlates with dimensional measures of ASD traits. These findings establish HD-DOT as an effective tool for investigating brain function in autistic and non-autistic children. Moreover, this study established neural correlates related to biological motion perception and its association with dimensional measures of ASD traits., (© 2024. The Author(s).)

Background: According to the most recent U.S. CDC surveillance data, the rise in prevalence of childhood autism spectrum disorder among minority children has begun to outpace that of non-Hispanic white children. Since prior research has identified possible differences in the extent of mate selection for autistic traits across families of different ethnicity, this study examined variation in autism related traits in contemporaneous, epidemiologically ascertained samples of spousal pairs representing Hispanic and non-Hispanic white populations. The purpose was to determine whether discrepancies by ethnicity could contribute to differential increases in prevalence in the current generation of young children., Methods: Birth records were used to identify all twin pairs born between 2011 and 2013 in California and Missouri. Families were selected at random from pools of English-speaking Hispanic families in California and Non-Hispanic White families in Missouri. Autistic trait data of parents was obtained using the Adult Report Form of the Social Responsiveness Scale (SRS-2)., Results: We did not identify a statistically significant difference in the degree of mate selection for autism related traits between Hispanic and non-Hispanic white spousal pairs. However, the degree of spousal correlation observed in this recent cohort was pronounced (on the order of ICC 0.45) and exceeded that typically reported in prior research (on the order of 0.30), surpassing also widely reported estimates for sibling correlation (also on the order of 0.30)., Limitations: The sample did not allow for a direct appraisal of change in the magnitude of spousal correlation over time and the ascertainments of trait burden were derived from spouse report., Conclusion: Across two epidemiologically ascertained samples of spousal pairs representing Hispanic and non-Hispanic white families across two U.S. states (respectively, California and Missouri), the extent of autism-related trait co-variation for parents of the current generation of young children is substantial and exceeds correlations typically observed for siblings. Given the heritability of these traits and their relation to autism risk, societal trends in the degree of mate selection for these traits should be considered as possible contributors to subtle increases in the incidence of autism over time and across generations., (© 2024. The Author(s).)

Importance: Autism spectrum disorder (ASD) is a neurodevelopmental disorder more prevalent in males than in females. The cause of ASD is largely genetic, but the association of genetics with the skewed sex ratio is not yet understood. To our knowledge, no large population-based study has provided estimates of heritability by sex., Objective: To estimate the sex-specific heritability of ASD., Design, Setting, and Participants: This was a population-based, retrospective analysis using national health registers of nontwin siblings and cousins from Sweden born between January 1, 1985, and December 31, 1998, with follow-up to 19 years of age. Data analysis occurred from August 2022 to November 2023., Main Outcomes and Measures: Models were fitted to estimate the relative variance in risk for ASD occurrence owing to sex-specific additive genetics, shared environmental effects, and a common residual term. The residual term conceptually captured other factors that promote individual behavioral variation (eg, maternal effects, de novo variants, rare genetic variants not additively inherited, or gene-environment interactions). Estimates were adjusted for differences in prevalence due to birth year and maternal and paternal age by sex., Results: The sample included 1 047 649 individuals in 456 832 families (538 283 males [51.38%]; 509 366 females [48.62%]). Within the entire sample, 12 226 (1.17%) received a diagnosis of ASD, comprising 8128 (1.51%) males and 4098 (0.80%) females. ASD heritability was estimated at 87.0% (95% CI, 81.4%-92.6%) for males and 75.7% (95% CI, 68.4%-83.1%) for females with a difference in heritability estimated at 11.3% (95% CI, 1.0%-21.6%). There was no support for shared environmental contributions., Conclusions and Relevance: These findings suggest that the degree of phenotypic variation attributable to genetic differences (heritability) differs between males and females, indicating that some of the underlying causes of the condition may differ between the 2 sexes. The skewed sex ratio in ASD may be partly explained by differences in genetic variance between the sexes.

Monogenic disorders account for a large proportion of population-attributable risk for neurodevelopmental disabilities. However, the data necessary to infer a causal relationship between a given genetic variant and a particular neurodevelopmental disorder is often lacking. Recognizing this scientific roadblock, 13 Intellectual and Developmental Disabilities Research Centers (IDDRCs) formed a consortium to create the Brain Gene Registry (BGR), a repository pairing clinical genetic data with phenotypic data from participants with variants in putative brain genes. Phenotypic profiles are assembled from the electronic health record (EHR) and a battery of remotely administered standardized assessments collectively referred to as the Rapid Neurobehavioral Assessment Protocol (RNAP), which include cognitive, neurologic, and neuropsychiatric assessments, as well as assessments for attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Co-enrollment of BGR participants in the Clinical Genome Resource's (ClinGen's) GenomeConnect enables display of variant information in ClinVar. The BGR currently contains data on 479 participants who are 55% male, 6% Asian, 6% Black or African American, 76% white, and 12% Hispanic/Latine. Over 200 genes are represented in the BGR, with 12 or more participants harboring variants in each of these genes: CACNA1A, DNMT3A, SLC6A1, SETD5, and MYT1L. More than 30% of variants are de novo and 43% are classified as variants of uncertain significance (VUSs). Mean standard scores on cognitive or developmental screens are below average for the BGR cohort. EHR data reveal developmental delay as the earliest and most common diagnosis in this sample, followed by speech and language disorders, ASD, and ADHD. BGR data has already been used to accelerate gene-disease validity curation of 36 genes evaluated by ClinGen's BGR Intellectual Disability (ID)-Autism (ASD) Gene Curation Expert Panel. In summary, the BGR is a resource for use by stakeholders interested in advancing translational research for brain genes and continues to recruit participants with clinically reported variants to establish a rich and well-characterized national resource to promote research on neurodevelopmental disorders., (© 2024. The Author(s).)

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., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

Importance: Autism spectrum disorder is a common and early-emerging neurodevelopmental condition. While 80% of parents report having had concerns for their child's development before age 2 years, many children are not diagnosed until ages 4 to 5 years or later., Objective: To develop an objective performance-based tool to aid in early diagnosis and assessment of autism in children younger than 3 years., Design, Setting, and Participants: In 2 prospective, consecutively enrolled, broad-spectrum, double-blind studies, we developed an objective eye-tracking-based index test for children aged 16 to 30 months, compared its performance with best-practice reference standard diagnosis of autism (discovery study), and then replicated findings in an independent sample (replication study). Discovery and replication studies were conducted in specialty centers for autism diagnosis and treatment. Reference standard diagnoses were made using best-practice standardized protocols by specialists blind to eye-tracking results. Eye-tracking tests were administered by staff blind to clinical results. Children were enrolled from April 27, 2013, until September 26, 2017. Data were analyzed from March 28, 2018, to January 3, 2019., Main Outcomes and Measures: Prespecified primary end points were the sensitivity and specificity of the eye-tracking-based index test compared with the reference standard. Prespecified secondary end points measured convergent validity between eye-tracking-based indices and reference standard assessments of social disability, verbal ability, and nonverbal ability., Results: Data were collected from 1089 children: 719 children (mean [SD] age, 22.4 [3.6] months) in the discovery study, and 370 children (mean [SD] age, 25.4 [6.0] months) in the replication study. In discovery, 224 (31.2%) were female and 495 (68.8%) male; in replication, 120 (32.4%) were female and 250 (67.6%) male. Based on reference standard expert clinical diagnosis, there were 386 participants (53.7%) with nonautism diagnoses and 333 (46.3%) with autism diagnoses in discovery, and 184 participants (49.7%) with nonautism diagnoses and 186 (50.3%) with autism diagnoses in replication. In the discovery study, the area under the receiver operating characteristic curve was 0.90 (95% CI, 0.88-0.92), sensitivity was 81.9% (95% CI, 77.3%-85.7%), and specificity was 89.9% (95% CI, 86.4%-92.5%). In the replication study, the area under the receiver operating characteristic curve was 0.89 (95% CI, 0.86-0.93), sensitivity was 80.6% (95% CI, 74.1%-85.7%), and specificity was 82.3% (95% CI, 76.1%-87.2%). Eye-tracking test results correlated with expert clinical assessments of children's individual levels of ability, explaining 68.6% (95% CI, 58.3%-78.6%), 63.4% (95% CI, 47.9%-79.2%), and 49.0% (95% CI, 33.8%-65.4%) of variance in reference standard assessments of social disability, verbal ability, and nonverbal cognitive ability, respectively., Conclusions and Relevance: In two diagnostic studies of children younger than 3 years, objective eye-tracking-based measurements of social visual engagement quantified diagnostic status as well as individual levels of social disability, verbal ability, and nonverbal ability in autism. These findings suggest that objective measurements of social visual engagement can be used to aid in autism diagnosis and assessment.

Background and Objectives: Child maltreatment (CM) is a recurrent adverse life event known to cause enduring psychiatric impairment throughout life. For young children in protective custody for a first episode of CM, specialized court-coordinated intervention to optimize reunification has shown promise for preventing CM recidivism, with case series documenting short-term successes., Methods: We tracked 10-year (Nov 2011-March 2022) court re-entry outcomes in a cohort of 272 young children, birth to six years, reunited with their families following placement in protective custody and court referral to the SYNCHRONY Project, a voluntary clinical service providing Incredible YearsTM parenting education, parental psychiatric care, and serial dyadic clinical evaluation to inform medical recommendations on safety for visitation and reunification. Re-entry was operationalized as rereferral to any Missouri Court and proportions compared with contemporaneous State and national data., Results: SYNCHRONY-enrolled/reunified children experienced frequencies of guardianship (22%) and reunification (46%), in keeping with Missouri averages. In these categories, 3.4% and 7.1% respectively were re-referred to the Court over the 10-year follow-up. In care as usual nationally for this age group, the re-referral proportions are 18% (OR 7.5, P < .0001) and 35% (OR 6.1, P < .0001) respectively. In care as usual in Missouri across all ages, the re-referral proportion is 16% (odds ratio [OR] 3.09, P < .0001)., Conclusions: Judicious implementation of evidence-based parenting education, 2-generation psychiatric care, and clinical consultation were associated with marked reduction in court re-entry versus care-as-usual and warrant consideration in intervention standards for young children in foster care., (Copyright © 2023 by the American Academy of Pediatrics.)

Purpose: This study aims to characterize the eye-related quality of life of children with neurodevelopmental and ocular disorders at baseline and after refractive surgery., Design: Prospective interventional case series., Methods: We enrolled children and adolescents 5 to 18 of age with neurodevelopmental disorders undergoing refractive surgery (6 for pre-/postsurgical assessment and 14 for baseline analysis). Eye-related quality of life was measured using the Pediatric Eye Questionnaire (PedEyeQ). Baseline levels of adaptive functioning and social behaviors were measured using the Adaptive Behavioral Assessment System (ABAS-3) and Social Responsiveness Scale (SRS-2). We assessed the correlation between baseline PedEyeQ scores, number of ocular comorbidities, magnitude of refractive error, and ABAS-3 and SRS-2 scores., Results: At baseline, 14 patients demonstrated decreased median eye-related quality of life (<60/100) in 5 of 9 PedEyeQ domains, moderate deficiencies in social behaviors (SRS-2 median 71, range 49-90), and low adaptive functioning (ABAS-3 median percentile for age of 0.100). Baseline PedEyeQ scores did not correlate with magnitude of refractive error or adaptive functioning scores but did correlate with number of ocular comorbidities and social behavior scores. Six patients have undergone refractive surgery without complication. Postoperatively, 11 of 11 eyes were within ±1.5 diopters spherical equivalent. Four of 6 patients exhibited clinically significant improvements in PedEyeQ scores after surgery., Conclusions: Even in the presence of significant social and adaptive impairments, quality of life in children with neurodevelopmental disorders is decreased by ocular disorders. Refractive surgery is associated with clinically significant improvements in eye-related quality of life., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: A central challenge in preclinical research investigating the biology of autism spectrum disorder (ASD) is the translation of ASD-related social phenotypes across humans and animal models. Social orienting, an observable, evolutionarily conserved behavior, represents a promising cross-species ASD phenotype given that disrupted social orienting is an early-emerging ASD feature with evidence for predicting familial recurrence. Here, we adapt a competing-stimulus social orienting task from domesticated dogs to naturalistic play behavior in human toddlers and test whether this approach indexes decreased social orienting in ASD., Methods: Play behavior was coded from the Autism Diagnostic Observation Schedule (ADOS) in two samples of toddlers, each with and without ASD. Sample 1 (n = 16) consisted of community-ascertained research participants, while Sample 2 involved a prospective study of infants at a high or low familial liability for ASD (n = 67). Coding quantified the child's looks towards the experimenter and caregiver, a social stimulus, while playing with high-interest toys, a non-social stimulus. A competing-stimulus measure of "Social Attention During Object Engagement" (SADOE) was calculated by dividing the number of social looks by total time spent playing with toys. SADOE was compared based on ASD diagnosis and differing familial liability for ASD., Results: In both samples, toddlers with ASD exhibited significantly lower SADOE compared to toddlers without ASD, with large effect sizes (Hedges' g ≥ 0.92) driven by a lower frequency of child-initiated spontaneous looks. Among toddlers at high familial likelihood of ASD, toddlers with ASD showed lower SADOE than toddlers without ASD, while SADOE did not differ based on presence or absence of familial ASD risk alone. SADOE correlated negatively with ADOS social affect calibrated severity scores and positively with the Communication and Symbolic Behavior Scales social subscale. In a binary logistic regression model, SADOE alone correctly classified 74.1% of cases, which rose to 85.2% when combined with cognitive development., Conclusions: This work suggests that a brief behavioral measure pitting a high-interest nonsocial stimulus against the innate draw of social partners can serve as a feasible cross-species measure of social orienting, with implications for genetically informative behavioral phenotyping of social deficits in ASD and other neurodevelopmental disorders., (© 2022. The Author(s).)

Male sex is a strong risk factor for autism spectrum disorder (ASD). The leading theory for a "female protective effect" (FPE) envisions males and females have "differing thresholds" under a "liability threshold model" (DT-LTM). Specifically, this model posits that females require either a greater number or larger magnitude of risk factors (i.e., greater liability) to manifest ASD, which is supported by the finding that a greater proportion of females with ASD have highly penetrant genetic mutations. Herein, we derive testable hypotheses from the DT-LTM for ASD, investigating heritability, familial recurrence, correlation between ASD penetrance and sex ratio, population traits, clinical features, the stability of the sex ratio across diagnostic changes, and highlight other key prerequisites. Our findings reveal that several key predictions of the DT-LTM are not supported by current data, requiring us to establish a different conceptual framework for evaluating alternate models that explain sex differences in ASD., Competing Interests: Declaration of interests J.N.C. receives royalties from Western Psychological Services for the commercial distribution of the social responsiveness scale, a quantitative measure of autistic traits implemented in some of the studies cited in this article., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

GABA B 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., Competing Interests: Declaration of interests S.E.A. is a cofounder and CEO of Medigenome, Swiss Institute of Genomic Medicine; he is also a member of the Scientific Advisory Board of the “Imagine Institute”, Paris. E.R. is also a cofounder and medical director of Medigenome, Swiss Institute of Genomic Medicine. M.L.C. is an intern in the federally recognized clinical training program for Genetic Medicine of Medigenome. L.N. was supported by the grant NV19-07-00136 from the Ministry of Health of the Czech Republi, and The National Center for Medical Genomics (LM2018132) for support with the WES analyses., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: The Social Responsiveness Scale (SRS) is a 65-item measure yielding a continuous score capturing autism-related traits. Scores based on SRS item subsets have been analytically examined but administration of shortened versions has not been evaluated prospectively., Objective: The goal of this study was to compare psychometric properties of two shortened versions of the SRS to the full 65-item SRS, in young children from both a clinical and general population setting., Methods: Study participants (aged 3-5 years) were drawn from the AJ Drexel Autism Institute clinic ( n  = 154) and Kaiser Permanente Northern California ( n  = 201) and block randomized to receive either the 16-item short SRS, a newly developed computer adaptive testing-SRS, or the published full-length SRS. Total scores across the three SRS administration methods were scaled to facilitate comparisons. Scores were plotted to assess distributional properties, while Receiver Operating Characteristic analysis was used to estimate Area Under the Curve (AUC) and address predictive ability., Results: Overall, distributional properties of the three administration methods were highly comparable, with shortened measures demonstrating similar ability to capture the range of the distribution and case non-case separation as the full SRS. In addition, AUC values were high (0.91-0.97) and comparable across the administration methods, though there was evidence of difference in predictive ability across measures for females (AUC for full SRS = 0.99 vs. 0.84 for short). Within individual comparisons of short versus full scores (available only for participants at the general population site) suggested underestimation of actual full SRS scores with the CAT-SRS., Conclusions: Our findings broadly support the construct validity and performance of shortened SRS versions examined here, though the full measure may be needed to more accurately assess traits consistent with ASD diagnosis in females. This work suggests opportunities for collection of ASD-related phenotype in settings where participant burden or feasibility considerations may have otherwise prohibited such measurement., Competing Interests: John N. Constantino receives royalties from Western Psychological Services for the commercial distribution of the Social Responsiveness Scale‐2. The remaining authors have declared that they have no competing or potential conflicts of interest., (© 2022 The Authors. JCPP Advances published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Objective: Autism spectrum disorder (ASD) is heritable, and younger siblings of ASD probands are at higher likelihood of developing ASD themselves. Prospective MRI studies of siblings report that atypical brain development precedes ASD diagnosis, although the link between brain maturation and genetic factors is unclear. Given that familial recurrence of ASD is predicted by higher levels of ASD traits in the proband, the authors investigated associations between proband ASD traits and brain development among younger siblings., Methods: In a sample of 384 proband-sibling pairs (89 pairs concordant for ASD), the authors examined associations between proband ASD traits and sibling brain development at 6, 12, and 24 months in key MRI phenotypes: total cerebral volume, cortical surface area, extra-axial cerebrospinal fluid, occipital cortical surface area, and splenium white matter microstructure. Results from primary analyses led the authors to implement a data-driven approach using functional connectivity MRI at 6 months., Results: Greater levels of proband ASD traits were associated with larger total cerebral volume and surface area and larger surface area and reduced white matter integrity in components of the visual system in siblings who developed ASD. This aligned with weaker functional connectivity between several networks and the visual system among all siblings during infancy., Conclusions: The findings provide evidence that specific early brain MRI phenotypes of ASD reflect quantitative variation in familial ASD traits. Multimodal anatomical and functional convergence on cortical regions, fiber pathways, and functional networks involved in visual processing suggest that inherited liability has a role in shaping the prodromal development of visual circuitry in ASD.

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., (© 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Background: Canonical babbling-producing syllables with a mature consonant, full vowel, and smooth transition-is an important developmental milestone that typically occurs in the first year of life. Some studies indicate delayed or reduced canonical babbling in infants at high familial likelihood for autism spectrum disorder (ASD) or who later receive an ASD diagnosis, but evidence is mixed. More refined characterization of babbling in the first year of life in infants with high likelihood for ASD is needed., Methods: Vocalizations produced at 6 and 12 months by infants (n = 267) taking part in a longitudinal study were coded for canonical and non-canonical syllables. Infants were categorized as low familial likelihood (LL), high familial likelihood diagnosed with ASD at 24 months (HL-ASD) or not diagnosed (HL-Neg). Language delay was assessed based on 24-month expressive and receptive language scores. Canonical babble ratio (CBR) was calculated by dividing the number of canonical syllables by the number of total syllables. Generalized linear (mixed) models were used to assess the relationship between group membership and CBR, controlling for site, sex, and maternal education. Logistic regression was used to assess whether canonical babbling ratios at 6 and 12 months predict 24-month diagnostic outcome., Results: No diagnostic group differences in CBR were detected at 6 months, but HL-ASD infants produced significantly lower CBR than both the HL-Neg and LL groups at 12 months. HL-Neg infants with language delay also showed reduced CBR at 12 months. Neither 6- nor 12-month CBR was significant predictors of 24-month diagnostic outcome (ASD versus no ASD) in logistic regression., Limitations: Small numbers of vocalizations produced by infants at 6 months may limit the reliability of CBR estimates. It is not known if results generalize to infants who are not at high familial likelihood, or infants from more diverse racial and socioeconomic backgrounds., Conclusions: Lower canonical babbling ratios are apparent by the end of the first year of life in ASD regardless of later language delay, but are also observed for infants with later language delay without ASD. Canonical babbling may lack specificity as an early marker when used on its own., (© 2022. The Author(s).)

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., (© 2022. The Author(s).)

Evidence continues to mount that the brains of children living in poverty show tangible alterations. Our authors, all part of a team that studies the issue at Washington University School of Medicine, explain the challenges and the necessary steps needed to build a healthier and more productive society., (Copyright 2022 The Dana Foundation All Rights Reserved.)

Rare genomic disorders (RGDs) confer elevated risk for neurodevelopmental psychiatric disorders. In this era of intense genomics discoveries, the landscape of RGDs is rapidly evolving. However, there has not been comparable progress to date in scalable, harmonized phenotyping methods. As a result, beyond associations with categorical diagnoses, the effects on dimensional traits remain unclear for many RGDs. The nature and specificity of RGD effects on cognitive and behavioral traits is an area of intense investigation: RGDs are frequently associated with more than one psychiatric condition, and those studied to date affect, to varying degrees, a broad range of developmental and cognitive functions. Although many RGDs have large effects, phenotypic expression is typically influenced by additional genomic and environmental factors. There is emerging evidence that using polygenic risk scores in individuals with RGDs offers opportunities to refine prediction, thus allowing for the identification of those at greatest risk of psychiatric illness. However, translation into the clinic is hindered by roadblocks, which include limited genetic testing in clinical psychiatry, and the lack of guidelines for following individuals with RGDs, who are at high risk of developing psychiatric symptoms. The Genes to Mental Health Network (G2MH) is a newly funded National Institute of Mental Health initiative that will collect, share, and analyze large-scale data sets combining genomics and dimensional measures of psychopathology spanning diverse populations and geography. The authors present here the most recent understanding of the effects of RGDs on dimensional behavioral traits and risk for psychiatric conditions and discuss strategies that will be pursued within the G2MH network, as well as how expected results can be translated into clinical practice to improve patient outcomes.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder diagnosed based on social impairment, restricted interests, and repetitive behaviors. Contemporary theories posit that cerebellar pathology contributes causally to ASD by disrupting error-based learning (EBL) during infancy. The present study represents the first test of this theory in a prospective infant sample, with potential implications for ASD detection., Methods: Data from the Infant Brain Imaging Study ( n = 94, 68 male) were used to examine 6-month cerebellar functional connectivity magnetic resonance imaging in relation to later (12/24-month) ASD-associated behaviors and outcomes. Hypothesis-driven univariate analyses and machine learning-based predictive tests examined cerebellar-frontoparietal network (FPN; subserves error signaling in support of EBL) and cerebellar-default mode network (DMN; broadly implicated in ASD) connections. Cerebellar-FPN functional connectivity was used as a proxy for EBL, and cerebellar-DMN functional connectivity provided a comparative foil. Data-driven functional connectivity magnetic resonance imaging enrichment examined brain-wide behavioral associations, with post hoc tests of cerebellar connections., Results: Cerebellar-FPN and cerebellar-DMN connections did not demonstrate associations with ASD. Functional connectivity magnetic resonance imaging enrichment identified 6-month correlates of later ASD-associated behaviors in networks of a priori interest (FPN, DMN), as well as in cingulo-opercular (also implicated in error signaling) and medial visual networks. Post hoc tests did not suggest a role for cerebellar connections., Conclusions: We failed to identify cerebellar functional connectivity-based contributions to ASD. However, we observed prospective correlates of ASD-associated behaviors in networks that support EBL. Future studies may replicate and extend network-level positive results, and tests of the cerebellum may investigate brain-behavior associations at different developmental stages and/or using different neuroimaging modalities., (© 2021 The Authors.)

Problem/condition: Autism spectrum disorder (ASD)., Period Covered: 2018., Description of System: The Autism and Developmental Disabilities Monitoring Network is an active surveillance program that estimates ASD prevalence and monitors timing of ASD identification among children aged 4 and 8 years. This report focuses on children aged 4 years in 2018, who were born in 2014 and had a parent or guardian who lived in the surveillance area in one of 11 sites (Arizona, Arkansas, California, Georgia, Maryland, Minnesota, Missouri, New Jersey, Tennessee, Utah, and Wisconsin) at any time during 2018. Children were classified as having ASD if they ever received 1) an ASD diagnostic statement (diagnosis) in an evaluation, 2) a special education classification of ASD (eligibility), or 3) an ASD International Classification of Diseases (ICD) code. Suspected ASD also was tracked among children aged 4 years. Children who did not meet the case definition for ASD were classified as having suspected ASD if their records contained a qualified professional's statement indicating a suspicion of ASD., Results: For 2018, the overall ASD prevalence was 17.0 per 1,000 (one in 59) children aged 4 years. Prevalence varied from 9.1 per 1,000 in Utah to 41.6 per 1,000 in California. At every site, prevalence was higher among boys than girls, with an overall male-to-female prevalence ratio of 3.4. Prevalence of ASD among children aged 4 years was lower among non-Hispanic White (White) children (12.9 per 1,000) than among non-Hispanic Black (Black) children (16.6 per 1,000), Hispanic children (21.1 per 1,000), and Asian/Pacific Islander (A/PI) children (22.7 per 1,000). Among children aged 4 years with ASD and information on intellectual ability, 52% met the surveillance case definition of co-occurring intellectual disability (intelligence quotient ≤70 or an examiner's statement of intellectual disability documented in an evaluation). Of children aged 4 years with ASD, 72% had a first evaluation at age ≤36 months. Stratified by census-tract-level median household income (MHI) tertile, a lower percentage of children with ASD and intellectual disability was evaluated by age 36 months in the low MHI tertile (72%) than in the high MHI tertile (84%). Cumulative incidence of ASD diagnosis or eligibility received by age 48 months was 1.5 times as high among children aged 4 years (13.6 per 1,000 children born in 2014) as among those aged 8 years (8.9 per 1,000 children born in 2010). Across MHI tertiles, higher cumulative incidence of ASD diagnosis or eligibility received by age 48 months was associated with lower MHI. Suspected ASD prevalence was 2.6 per 1,000 children aged 4 years, meaning for every six children with ASD, one child had suspected ASD. The combined prevalence of ASD and suspected ASD (19.7 per 1,000 children aged 4 years) was lower than ASD prevalence among children aged 8 years (23.0 per 1,000 children aged 8 years)., Interpretation: Groups with historically lower prevalence of ASD (non-White and lower MHI) had higher prevalence and cumulative incidence of ASD among children aged 4 years in 2018, suggesting progress in identification among these groups. However, a lower percentage of children with ASD and intellectual disability in the low MHI tertile were evaluated by age 36 months than in the high MHI group, indicating disparity in timely evaluation. Children aged 4 years had a higher cumulative incidence of diagnosis or eligibility by age 48 months compared with children aged 8 years, indicating improvement in early identification of ASD. The overall prevalence for children aged 4 years was less than children aged 8 years, even when prevalence of children suspected of having ASD by age 4 years is included. This finding suggests that many children identified after age 4 years do not have suspected ASD documented by age 48 months., Public Health Action: Children born in 2014 were more likely to be identified with ASD by age 48 months than children born in 2010, indicating increased early identification. However, ASD identification among children aged 4 years varied by site, suggesting opportunities to examine developmental screening and diagnostic practices that promote earlier identification. Children aged 4 years also were more likely to have co-occurring intellectual disability than children aged 8 years, suggesting that improvement in the early identification and evaluation of developmental concerns outside of cognitive impairments is still needed. Improving early identification of ASD could lead to earlier receipt of evidence-based interventions and potentially improve developmental outcomes., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Problem/condition: Autism spectrum disorder (ASD)., Period Covered: 2018., Description of System: The Autism and Developmental Disabilities Monitoring (ADDM) Network conducts active surveillance of ASD. This report focuses on the prevalence and characteristics of ASD among children aged 8 years in 2018 whose parents or guardians lived in 11 ADDM Network sites in the United States (Arizona, Arkansas, California, Georgia, Maryland, Minnesota, Missouri, New Jersey, Tennessee, Utah, and Wisconsin). To ascertain ASD among children aged 8 years, ADDM Network staff review and abstract developmental evaluations and records from community medical and educational service providers. In 2018, children met the case definition if their records documented 1) an ASD diagnostic statement in an evaluation (diagnosis), 2) a special education classification of ASD (eligibility), or 3) an ASD International Classification of Diseases (ICD) code., Results: For 2018, across all 11 ADDM sites, ASD prevalence per 1,000 children aged 8 years ranged from 16.5 in Missouri to 38.9 in California. The overall ASD prevalence was 23.0 per 1,000 (one in 44) children aged 8 years, and ASD was 4.2 times as prevalent among boys as among girls. Overall ASD prevalence was similar across racial and ethnic groups, except American Indian/Alaska Native children had higher ASD prevalence than non-Hispanic White (White) children (29.0 versus 21.2 per 1,000 children aged 8 years). At multiple sites, Hispanic children had lower ASD prevalence than White children (Arizona, Arkansas, Georgia, and Utah), and non-Hispanic Black (Black) children (Georgia and Minnesota). The associations between ASD prevalence and neighborhood-level median household income varied by site. Among the 5,058 children who met the ASD case definition, 75.8% had a diagnostic statement of ASD in an evaluation, 18.8% had an ASD special education classification or eligibility and no ASD diagnostic statement, and 5.4% had an ASD ICD code only. ASD prevalence per 1,000 children aged 8 years that was based exclusively on documented ASD diagnostic statements was 17.4 overall (range: 11.2 in Maryland to 29.9 in California). The median age of earliest known ASD diagnosis ranged from 36 months in California to 63 months in Minnesota. Among the 3,007 children with ASD and data on cognitive ability, 35.2% were classified as having an intelligence quotient (IQ) score ≤70. The percentages of children with ASD with IQ scores ≤70 were 49.8%, 33.1%, and 29.7% among Black, Hispanic, and White children, respectively. Overall, children with ASD and IQ scores ≤70 had earlier median ages of ASD diagnosis than children with ASD and IQ scores >70 (44 versus 53 months)., Interpretation: In 2018, one in 44 children aged 8 years was estimated to have ASD, and prevalence and median age of identification varied widely across sites. Whereas overall ASD prevalence was similar by race and ethnicity, at certain sites Hispanic children were less likely to be identified as having ASD than White or Black children. The higher proportion of Black children compared with White and Hispanic children classified as having intellectual disability was consistent with previous findings., Public Health Action: The variability in ASD prevalence and community ASD identification practices among children with different racial, ethnic, and geographical characteristics highlights the importance of research into the causes of that variability and strategies to provide equitable access to developmental evaluations and services. These findings also underscore the need for enhanced infrastructure for diagnostic, treatment, and support services to meet the needs of all children., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Neurodevelopmental neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia, have strong genetic risk components, but the underlying mechanisms have proven difficult to decipher. Rare, high-risk variants may offer an opportunity to delineate the biological mechanisms responsible more clearly for more common idiopathic diseases. Indeed, different rare variants can cause the same behavioral phenotype, demonstrating genetic heterogeneity, while the same rare variant can cause different behavioral phenotypes, demonstrating variable expressivity. These observations suggest convergent underlying biological and neurological mechanisms; identification of these mechanisms may ultimately reveal new therapeutic targets. At the 2021 Keystone eSymposium "Neuropsychiatric and Neurodevelopmental Disorders: Harnessing Rare Variants" a panel of experts in the field described significant progress in genomic discovery and human phenotyping and raised several consistent issues, including the need for detailed natural history studies of rare disorders, the challenges in cohort recruitment, and the importance of viewing phenotypes as quantitative traits that are impacted by rare variants., (© 2021 New York Academy of Sciences.)

Human genetics have defined a new neurodevelopmental syndrome caused by loss-of-function mutations in MYT1L, a transcription factor known for enabling fibroblast-to-neuron conversions. However, how MYT1L mutation causes intellectual disability, autism, ADHD, obesity, and brain anomalies is unknown. Here, we developed a Myt1l haploinsufficient mouse model that develops obesity, white-matter thinning, and microcephaly, mimicking common clinical phenotypes. During brain development we discovered disrupted gene expression, mediated in part by loss of Myt1l gene-target activation, and identified precocious neuronal differentiation as the mechanism for microcephaly. In contrast, in adults we discovered that mutation results in failure of transcriptional and chromatin maturation, echoed in disruptions in baseline physiological properties of neurons. Myt1l haploinsufficiency also results in behavioral anomalies, including hyperactivity, muscle weakness, and social alterations, with more severe phenotypes in males. Overall, our findings provide insight into the mechanistic underpinnings of this disorder and enable future preclinical studies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)